Health and Fitness

Waldenström's macroglobulinemia

2009-01-08T07:53:00.000-08:00

Waldenström's macroglobulinemia (WM, also known as lymphoplasmacytic lymphoma) is cancer involving a subtype of white blood cells called lymphocytes. The main attributing antibody is IgM. It is a type of lymphoproliferative disease, and shares clinical characteristics with the indolent non-Hodgkin lymphomas.

It is named after the Swedish physician Jan G. Waldenström, who first identified the condition.

History and classification

WM was first described by Jan G. Waldenström (1906–1996) in 1944 in two patients with bleeding from the nose and mouth, anemia, decreased levels of fibrinogen in the blood (hypofibrinogenemia), swollen lymph nodes, neoplastic plasma cells in bone marrow, and increased viscosity of the blood due to increased levels of a class of heavy proteins called macroglobulins.

For a period of time, WM was considered to be related to multiple myeloma due to the presence of monoclonal gammopathy and infiltration of the bone marrow and other organs by plasmacytoid lymphocytes. The new World Health Organization (WHO) classification, however, places WM under the category of lymphoplasmacytic lymphomas, itself a subcategory of the indolent (low-grade) non-Hodgkin lymphomas.

Causes

The underlying cause is not yet known but a number of risk factors have been identified. There has been an association demonstrated with the locus 6p21.3 on chromosome 6. There is a 2- to 3-fold risk increase of developing WM in people with a personal history of autoimmune diseases with autoantibodies and particularly elevated risks associated with hepatitis, human immunodeficiency virus, and rickettsiosis.

There are genetic factors, with first-degree relatives shown to have a highly increased risk of also contracting Waldenstrom's.

Epidemiology

Of all cancers involving the same class of blood cell, 1% of cases are WM.

WM is a rare disorder, with fewer than 1,500 cases occurring in the United States annually. The median age of onset of WM is between 60 and 65 years, with some cases occurring in late teens.

Symptoms

Symptoms of WM include weakness, fatigue, weight loss and chronic oozing of blood from the nose and gums. Peripheral neuropathy can occur in 10% of patients. Lymphadenopathy, splenomegaly, and/or hepatomegaly are present in 30-40% of cases. Some symptoms are due to the effects of the IgM paraprotein, which may cause autoimmune phenomenon or cryoglobulinemia. Other symptoms of WM are due to the hyperviscosity syndrome, which is present in 6-20% of patients. This is attributed to the IgM monoclonal protein increasing the viscosity of the blood. Symptoms of this are mainly neurologic and can include blurring or loss of vision, headache, and (rarely) stroke or coma.

Diagnosis

A distinguishing feature of WM is the presence of an IgM monoclonal protein (or paraprotein) that is produced by the cancer cells.

Lab Studies:

The laboratory diagnosis of Waldenström macroglobulinemia is contingent on demonstrating a significant monoclonal IgM spike and identifying malignant cells consistent with Waldenström macroglobulinemia (usually found in bone marrow biopsy samples and aspirates). General studies include a full blood count, red cell indices, platelet count, and a peripheral smear. Normocytic normochromic anemia, leukopenia, and thrombocytopenia may be observed. Anemia is the most common finding, present in 80% of patients with symptomatic Waldenström macroglobulinemia.

The peripheral smear may reveal plasmacytoid lymphocytes, normocytic normochromic red cells, and rouleaux formation.

Neutropenia can be found in some patients.

Thrombocytopenia is found in approximately 50% of patients with bleeding diathesis. Chemistry tests include lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate (ESR), renal and hepatic function, total protein levels, and an albumin-to-globulin ratio. The ESR and uric acid level may be elevated. Creatinine is occasionally elevated and electrolytes are occasionally abnormal. Hypercalcemia is noted in approximately 4% of patients. The LDH level is frequently elevated, indicating the extent of Waldenström macroglobulinemia–related tissue involvement. Rheumatoid factor, cryoglobulins, direct antiglobulin test and cold agglutinin titre results can be positive. Beta-2-microglobulin and C-reactive protein test results are not specific for Waldenström macroglobulinemia. Beta-2-microglobulin is elevated in proportion to tumor mass. Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional. Serum protein electrophoresis results indicate evidence of a monoclonal spike but cannot establish the spike as IgM. An M component with beta-to-gamma mobility is highly suggestive of Waldenström macroglobulinemia. Immunoelectrophoresis and immunofixation studies help identify the type of immunoglobulin, the clonality of the light chain, and the monoclonality and quantitation of the paraprotein. High-resolution electrophoresis and serum and urine immunofixation are recommended to help identify and characterize the monoclonal IgM paraprotein.

The light chain of the monoclonal protein is usually the kappa light chain. At times, patients with Waldenström macroglobulinemia may exhibit more than one M protein. Plasma viscosity must be measured. Results from characterization studies of urinary immunoglobulins indicate that light chains (Bence Jones protein), usually of the kappa type, are found in the urine. Urine collections should be concentrated.

Bence Jones proteinuria is observed in approximately 40% of patients and exceeds 1 g/d in approximately 3% of patients. Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin associated glycoprotein serology.

Prognosis

Current medical treatments result in survival some longer than 10 years. In part this is because better diagnostic testing means early diagnosis and treatments. Older diagnosis and treatments resulted in published reports of median survival of approximately 5 years from time of diagnosis. New treatments have made longer term survival a reality for many with this condition. In rare instances, WM progresses to multiple myeloma.

The International Prognostic Scoring System for Waldenström’s Macroglobulinemia (IPSSWM) is a predictive model to characterise long-term outcome. According to the model, factors predicting survival are:

age >65 years;
hemoglobin ≥11.5 g/dL;
platelet count ≤100×10⁹/L;
B2-microglobulin >3 mg/L;
serum monoclonal protein concentration >70 g/L.

Low risk is defined by the presence of ≤1 adverse variable except age;
high risk by the presence of >2 adverse characteristics and intermediate risk by the presence of 2 adverse characteristics or age >65 years; 5-year survival rates are 87%, 68% and 36% respectively.

The IPSSWM has been shown applicable to patients on a Rituximab-based treatment regimen. An additional predictive factor is elevated serum lactate dehydrogenase (LDH).

Treatment

There is no single accepted treatment for WM. Indeed, in 1991, Waldenström himself raised the question of the need for effective therapy. In the absence of symptoms, many clinicians will recommend simply monitoring the patient. Should treatment be started it should address both the paraprotein level and the lymphocytic B-cells.

In 2002, a panel at the International Workshop on Waldenstrom Macroglobulinemia agreed on criteria for the initiation of therapy. They recommended starting therapy in patients with constitutional symptoms such as recurrent fever, night sweats, fatigue due to anemia, weight loss, progressive symptomatic lymphadenopathy or splenomegaly, and anemia due to marrow infiltration. Complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia were also suggested as indications for therapy.

Treatment includes the monoclonal antibody rituximab, sometimes in combination with chemotherapeutic drugs such as chlorambucil, cyclophosphamide, or vincristine or with thalidomide. Corticosteroids may also be used in combination. Plasmapheresis can be used to treat the hyperviscosity syndrome by removing the paraprotein from the blood, although it does not address the underlying disease.

Recently, autologous bone marrow transplantation has been added to the available treatment options.

Drug pipeline

A database of clinical trials investigating Waldenstrom's macroglobulinemia is maintained by the National Institutes of Health in the US.

Phase IV

none

Phase III

Comparison between Chlorambucil and Fludarabine

Phase II

There are over 100 active trials studying different interventions. Interventions include either individually or combinations of Fludarabine, Perifosine, Bortezomib, Rituximab, Sildenafil citrate, CC-5013, Thalidomide, Simvastatin, Campath-1H, Dexamethasone, Antineoplaston, Beta Alethine, Dolastatin 10, Cyclophosphamide, Yttrium Y 90 Ibritumomab, ABT-263, and Denileukin diftitox.

Vulvar cancer

2009-01-08T07:50:00.000-08:00

Vulvar cancer, a malignant invasive growth in the vulva, accounts for about 4 % of all gynecological cancers and typically affects women in later life. It is estimated that in the United States in 2006 about 3,740 new cases will be diagnosed and about 880 women will die as a result of vulvar cancer. Vulvar carcinoma is separated from vulvar intraepithelial neoplasia (VIN), a non-invasive lesion of the epithelium that can progress via carcinoma-in-situ to squamous cell cancer, and from Paget disease of the vulva.

Types

Squamous cell carcinoma

The vast majority of vulvar cancer is caused by squamous cell carcinoma originating from the epidermis of the vulva tissue. Carcinoma-in-situ is a precursor stage of squamous cell cancer prior to invading through the basement membrane. Most lesions originate in the labia, primarily the labia majora. Other areas affected are the clitoris, and fourchette, and the local glands. While the lesion is more common with advancing age, younger women who have risk factors (v.i.) may also be affected. In the elderly treatment may be complicated by the interference of other medical conditions.

Squamous lesions tend to be unifocal, growing with local extension, and spreading via the local lymph system. The lymphatic drainage of the labia proceeds to the upper vulva and mons, then to the inguinal and femoral nodes with both superficial and deep lymph nodes. The last deep femoral node is called the Cloquet’s node; spread beyond this node affects the lymph nodes of the pelvis. The tumor may also invade adjacent organs such as the vagina, urethra, and rectum and spread via their lymphatics.

A verrucous carcinoma of the vulva is a subtype of the squamous cell cancer and tend to appear as a slowly growing wart.

Melanoma

About 5% of vulvar malignancy is caused by melanoma of the vulva. Such melanoma behaves like melanoma in other locations and may affect a much younger population. Contrary to squamous carcinoma, melanoma has a high risk of metastasis.

Basal cell carcinoma

Basal cell carcinoma affects about 1-2% of vulvar cancer is a slowly growing lesion and affects the elderly. Its behavior is similar to basal cell carcinoma in other locations that is it tends to grow locally with a low potential of deep invasion or metastasis.

Other lesions

Vulvar cancer can be caused by other lesions such as adenocarcinoma or sarcoma.

Signs and Symptoms

Typically a lesion is present in form of a lump or ulceration, often associated with itching, irritation, sometimes local bleeding and discharge. Also dysuria, dyspareunia and pain may be noted. Because of modesty or embarrassment, symptoms may not be heeded in a timely fashion. Melanomas tend to display the typical dark discoloration. Adenocarcinoma can arise from the Bartholin gland and results in a lump that may be quite painful.

Diagnosis

Examination of the vulva is part of the gynecologic evaluation and may reveal ulceration, a lump, or a mass. A suspicious lesion needs to undergo a biopsy that generally can be performed in an office setting under local anesthesia. Small lesion can be excised under local anesthesia. Examination of the vulva should include a thorough inspection of the perineal area, including areas around the clitoris and urethra. Palpation of the Bartholin's glands should be performed as well. Supplemental evaluation may include a chest X-ray, an IVP, cystoscopy and proctoscopy, as well as blood counts and metabolic assessment.

Differential diagnosis

Other neoplastic lesions that need to be considered in the differential diagnosis are Paget disease of the vulva and VIN. Non-neoplastic vulvar disease includes lichen sclerosus, squamous cell hyperplasia, and vulvar vestibulitis. Infectious disease lesions can be caused by a number of diseases including herpes genitalis, human papillomavirus, syphilis, chancroid, granuloma inguinale, and lymphogranuloma venereum.

Etiology

The etiology of the cancer is unclear; however, some condition such as condyloma or squamous dysplasias may have preceded the cancer. Human papillomavirus (HPV) is suspected to be a possible risk factor in the etiology of vulvar cancer. Patients infected with HIV tend to be more susceptible to vulvar malignancy. Also, smokers tend to be at higher risk.

Staging

Preclinical staging has been supplemented by surgical staging since 1988. FIGO’s revised staging TNM classification system uses criteria of tumor size (T), involvement of lymph nodes (N), and metastasis (M). Stage I describes the early stage of the cancer that still appears to be confined to the site of origin, stage II and III define less or more extensive extensions to neighboring tissue and lymph nodes, while stage IV indicates metastatic disease.

Treatment

Staging and treatment are generally handled by an oncologist familiar with gynecologic cancer. The extent of the surgery is dictated by the surgical staging. Surgery is a mainstay of therapy and usually accomplished by use of a radical vulvectomy, removal of vulvar tissue as well as the removal of lymph nodes from the inguinal and femoral areas. Complications of such surgery include wound infection, sexual dysfunction, edema and thrombosis. Surgery is significantly more extensive when vulvar cancer has spread to adjacent organs such as urethra, vagina, and rectum. In cases of early vulvar carcinoma the surgery may be less radical and disfiguring and consist of wide excision or a simple vulvectomy.

Radiation therapy and chemotherapy are usually not a primary choice of therapy but may be used in selected cases of advanced vulvar cancer.

Prognosis

The prognosis of vulvar cancer shows overall about a 75% five year survival rate, but, of course, individually affected by many factors, notably stage and type of the lesion and age and general medical health. Five-year survival is down to about 20% when pelvic lymph nodes are involved but better than 90% for patients with stage I lesions. Thus early diagnosis is imperative.

Vaginal cancer

2009-01-08T07:44:00.000-08:00

Vaginal cancer is any type of cancer that forms in the tissues of the vagina. Vaginal cancer is not common. It occurs primarily in women over age 50, but can occur at any age, even in infancy. When found and treated in early stages, it often can be cured.

Types of vaginal cancer

Types of vaginal cancer, in order of prevalence, include:

Vaginal squamous cell carcinoma arises from the thin, flat squamous cells that line the vagina. This is the most common type of vaginal cancer. It is found most often in women aged 60 or older.

Vaginal adenocarcinoma arises from the glandular (secretory) cells in the lining of the vagina that produce some vaginal fluids. Adenocarcinoma is more likely than squamous cell cancer to spread to the lungs and lymph nodes. It is found most often in women aged 30 or younger, and has been found in a small percent of women whose mothers in the 1950s used diethylstilbestrol to prevent threatened abortions.

Vaginal germ cell tumors (primarily teratoma and endodermal sinus tumor) are rare. They are found most often in infants and children.

Sarcoma botryoides, a rhabdomyosarcoma also is found most often in infants and children.

Signs and Symptoms

The most common sign is abnormal vaginal bleeding, which may be postcoital, intermenstrual, prepubertal, or postmenopausal. Other, less specific signs include difficult or painful urination, pain during intercourse, and pain in the pelvic area.

Diagnosis

Several tests are used to diagnose vaginal cancer, including:

Physical exam and history
Biopsy

Uterine sarcoma

2009-01-08T07:23:00.000-08:00

A uterine sarcoma is a malignant tumor that arises from the smooth muscle or connective tissue of the uterus. If the lesion originates from the stroma of the uterine lining it is an endometrial stromal sarcoma, and if the uterine muscle cell is the originator the tumor is a uterine leiomyosarcoma. A lesion that also contains malignant tumor cells of epithelial origin is termed uterine carcinosarcoma (formerly called malignant mixed mesodermal/mullerian tumor).

Prevalence

The vast majority of malignancies of the uterine body are endometrial carcinomas - only about 4% will be uterine sarcomas. Generally, the cause of the lesion is not known, however patients with a history of pelvic radiation are at higher risk. Most tumors occur after menopause. Women who take long-term tamoxifen are at higher risk.

Signs and Symptoms

Unusual or postmenopausal bleeding may be a sign of a malignancy including uterine sarcoma and needs to be investigated. Other signs include pelvic pain, pressure, and unusual discharge. A nonpregnant uterus that enlarges quickly is suspicious. However, none of the signs are specific. Specific screening test have not been developed; a Pap smear is a screening test for cervical cancer and not designed to detect uterine sarcoma.

Diagnosis

Investigations by the physician include imaging (ultrasound, CAT scan, MRI) and, if possible, obtaining a tissue diagnosis by biopsy, hysteroscopy, or D&C. Ultimately the diagnosis is established by the histologic examination of the specimen. Typically malignant lesions have >10 mitosis per high power field. In contrast a uterine leiomyoma as a benign lesion would have <>

Staging

Uterine sarcoma is staged like endometrial carcinoma at time of surgery using the FIGO cancer staging system.

Stage IA: tumor is limited to the endometrium
Stage IB: invasion of less than half the myometrium
Stage IC: invasion of more than half the myometrium
Stage IIA: endocervical glandular involvement only
Stage IIB: cervical stromal invasion
Stage IIIA: tumor invades serosa or adnexa, or malignant peritoneal cytology
Stage IIIB: vaginal metastasis
Stage IIIC: metastasis to pelvic or para-aortic lymph nodes
Stage IVA: invasion of the bladder or bowel
Stage IVB: distant metastasis, including intraabdominal or inguinal lymph nodes

Therapy

Therapy is based on staging and patient condition and utilizes one or more of the following approaches. Surgery is the mainstay of therapy if feasible involving total abdominal hysterectomy with bilateral salpingo-oophorectomy. Other approaches include radiation therapy, chemotherapy, and hormonal therapy.

Urethral cancer

2009-01-08T07:21:00.000-08:00

Urethral cancer is a rare type of cancer originating from the urethra. It is more common in women than in men.

It is a rare cancer that forms in tissues of the urethra. Types of urethral cancer include transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma.

Symptoms

These are the symptoms that may be caused by urethral cancer:

Bleeding from the urethra or blood in the urine.
Weak or interrupted flow of urine.
Urination occurs often.
A lump or thickness in the perineum or penis.
Discharge from the urethra.
Enlarged lymph nodes in the groin area.

Risk factors

Having a history of bladder cancer.
Having conditions that cause chronic, swollen, reddened part in the urethra.
Being 60 or older.
Being a white female.

Diagnosis

In male urethral cancer, diagnosis is established by transurethral biopsy. In women the diagnosis is established in much the same way. Pathologically most tumors are squamous cell carcinomas although transitional cell carcinomas, adenocarcinomas and melanomas may also be seen.

Treatment

Surgery is the most common treatment for cancer of the urethra. One of the following types of surgery may be done:

Open excision surgery.
Electro-resection with flash surgery.
Laser surgery.
Cystourethrectomy surgery.
Cystoprostatectomy surgery.
Anterior body cavity surgery.
Incomplete or basic penectomy surgery.

Gestational trophoblastic disease

2009-01-08T07:15:00.000-08:00

Gestational trophoblastic disease is any type of abnormal proliferation of trophoblasts during pregnancy.

Types include:

abnormal placenta, mostly due to abnormal fertilization
- hydatidiform mole (HM)
frank malignant tumors of trophoblast
- invasive mole, choriocarcinoma (CCA)
- placental site trophoblastic tumor (PSTT)
- epithelioid trophoblastic tumor (ETT)
not true neoplasms, representing abnormally formed placentas
- exaggerated placenta site (EPS)
- placental site nodule (PSN)

What Is Gestational Trophoblastic Disease?

Gestational trophoblastic disease (GTD) is a group of rare tumors that involve abnormal growth of cells inside a woman's uterus. GTD does not develop from cells of the uterus like cervical cancer or endometrial (uterine lining) cancer do. Instead, these tumors start in the cells that would normally develop into the placenta during pregnancy. (The term "gestational" refers to pregnancy.)

GTD begins in the layer of cells called the trophoblast that normally surrounds an embryo. (Tropho- means "nutrition," and -blast means "bud" or "early developmental cell.") Early in normal development, the cells of this layer form tiny, finger-like projections known as villi. These villi grow into the lining of the uterus. In time, the trophoblast layer develops into the placenta, the organ that protects and nourishes a growing fetus.

Most GTDs are benign (non cancerous) and they don't invade deeply into body tissues or spread to other parts of the body. But some are cancerous. Because not all of these tumors are cancerous, this group of tumors may be referred to as gestational trophoblastic disease, gestational trophoblastic tumors, or gestational trophoblastic neoplasia. (The word neoplasia simply means "new growth.")

All forms of GTD can be treated. And in most cases the treatment produces a complete cure.

Types of gestational trophoblastic disease

The main types of gestational trophoblastic diseases are:

   * hydatidiform mole (complete or partial)
  * invasive mole
  * choriocarcinoma
  * placental site trophoblastic tumor

Hydatidiform mole

The most common form of GTD is called a hydatidiform mole, also known as a molar pregnancy. The moles are actually villi that have become swollen with fluid. The swollen villi grow in clusters that look like bunches of grapes. Although this is called a molar "pregnancy," it is not possible for a normal baby to form. Hydatidiform moles are not cancerous, but they may develop into cancerous GTDs.

There are 2 types of hydatidiform moles: complete and partial.

A complete hydatidiform mole most often develops when either 1 or 2 sperm cells fertilize an "empty" egg cell (a cell that contains no nucleus or DNA). All the genetic material comes from the father's sperm cell. Therefore, there is no fetal tissue.

Surgery can totally remove most complete moles, but in as many as 1 in 5 women there will be some persistent molar tissue (see "Persistent gestational trophoblastic disease" below). Most often this is an invasive mole, but in rare cases it is a choriocarcinoma, a malignant (cancerous) form of GTD. In either case it will require further treatment.

A partial hydatidiform mole develops when 2 sperm fertilize a normal egg. These tumors contain some fetal tissue, but this is often mixed in with the trophoblastic tissue. It is important to know that a viable (able to live) fetus is not being formed.

Partial moles are usually completely removed by surgery. Only a small number of women with partial moles need further treatment after initial surgery. Partial moles rarely develop into malignant GTD.

Persistent gestational trophoblastic disease

This is not a separate type of GTD, but a term used to describe GTD that is not cured by initial surgery. Persistent GTD occurs when the tumor has grown into the muscle layer of the uterus (myometrium). Surgery to scrape the inside of the uterus (called suction dilation and curettage, or D&C) removes only the inner layer of the uterus. It does not remove the tumor deep in the muscular wall of the uterus.

Most cases of persistent GTD are invasive moles, although in rare cases they are choriocarcinomas or placental site trophoblastic tumors (see below).

Invasive mole

An invasive mole (formerly known as chorioadenoma destruens) is a hydatidiform mole that grows into the myometrium. Invasive moles can be either complete or partial, but complete moles become invasive much more often than partial moles. Invasive moles develop in a little less than 1 out of 5 women who have had a complete mole removed. The risk of developing an invasive mole in these women increases if:

   * There is a long time (more than 4 months) between the last menstrual period and treatment.
  * The uterus has become very large.
  * The woman is older than 40 years.
  * The woman has had GTD in the past.

Because these moles have grown into the uterine muscle layer, they aren't completely removed by surgery. Invasive moles sometimes go away on their own, but most require treatment with chemotherapy.

A tumor or mole that grows completely through the myometrium may result in bleeding, which can be life threatening.

In about 15% of cases, the tumor spreads (metastasizes) to other parts of the body, most often the lungs.

Choriocarcinoma

Choriocarcinoma is a malignant form of GTD. It is much more likely than other types of GTD to grow quickly and spread to organs away from the uterus.

Although choriocarcinoma most often develops from a complete hydatidiform mole, it can also occur after a partial mole, a normal pregnancy, or a pregnancy in which the fetus is lost early.

Rarely, choriocarcinomas can develop in other parts of the body in both men and women. These are not related to pregnancy. They may develop in the ovaries, testicles, chest, or abdomen. In these cases, choriocarcinoma is usually mixed with other types of cancer, forming a mixed germ cell tumor. Choriocarcinomas starting in these locations are not considered to be gestational and are not discussed in this document. Non-gestational choriocarcinoma tends to be less responsive to chemotherapy and has a less favorable prognosis (outlook) than gestational choriocarcinoma. For more information, see the American Cancer Society documents, Ovarian Cancer and Testicular Cancer.

Placental site trophoblastic tumor

Placental site trophoblastic tumor (PSTT) is a very rare form of GTD that develops where the placenta attaches to the uterus. This tumor most often develops after a normal pregnancy or abortion, but it may also develop after a complete or partial mole is removed.

Most PSTTs do not spread to other sites in the body. But these tumors have a tendency to invade the muscle layer of the uterus.

Although most forms of GTD are very sensitive to chemotherapy drugs, PSTTs are not. Instead, they are treated with surgery, aimed at completely removing disease.

Thyroid cancer

2009-01-08T07:11:00.000-08:00


Thyroid cancer
Micrograph (high power view) of papillary thyroid carcinoma demonstrating diagnostic features (nuclearH&E stain. clearing and overlapping nuclei).

Thyroid cancer refers to any of four kinds of malignant tumors of the thyroid gland: papillary, follicular, medullary or anaplastic. Papillary and follicular tumors are the most common. They grow slowly and may recur, but are generally not fatal in patients under 45 years of age. Medullary tumors have a good prognosis if restricted to the thyroid gland and a poorer prognosis if metastasis occurs. Anaplastic tumors are fast-growing and respond poorly to therapy.

Thyroid nodules are diagnosed by ultrasound guided fine needle aspiration (USG/FNA) or frequently by thyroidectomy (surgical removal and subsequent histological examination). As thyroid cancer can take up iodine, radioactive iodine is commonly used to treat thyroid carcinomas, followed by TSH suppression by thyroxine therapy.

Symptoms

Most often the first symptom of thyroid cancer is a nodule in the thyroid region of the neck. However, many adults have small nodules in their thyroids. But typically under 5% of these nodules are found to be malignant. Sometimes the first sign is an enlarged lymph node. Later symptoms that can be present are pain in the anterior region of the neck and changes in voice.

Thyroid cancer is usually found in a euthyroid patient, but hyperthyroidism may be a symptom of a large or metastatic well-differentiated tumor.

Nodules should be of particular concern when they are found in children or those under the age of 20. The presentation of benign nodules at this age is less likely, and thus the potential for malignancy is far greater.

Diagnosis

After a nodule is found during a physical examination, a referral to an endocrinologist, or a thyroidologist is the best approach. Most commonly an ultrasound is performed to confirm the presence of a nodule, and assess the status of the whole gland. Measurement of thyroid stimulating hormone and anti-thyroid antibodies will help decide if there is a functional thyroid disease such as Hashimoto's thyroiditis present, a known cause of a benign nodular goiter.

Fine needle biopsy

One approach used to determine whether the nodule is malignant is the fine needle biopsy (FNB), which some have described as the most cost-effective, sensitive and accurate test. FNB or ultrasound-guided FNA usually yields sufficient thyroid cells to assess the risk of malignancy, although in some cases, the suspected nodule may need to be removed surgically for pathological examination.

Rarely, a biopsy is done using a large cutting needle, so that a piece of nodule capsule can be obtained.

Blood tests

Blood or imaging tests may be done prior to or in lieu of a biopsy. The possibility of a nodule which secretes thyroid hormone (which is less likely to be cancer) or hypothyroidism is investigated by measuring thyroid stimulating hormone (TSH), and the thyroid hormones thyroxine (T4) and triiodothyronine (T3).

Tests for serum thyroid autoantibodies are sometimes done as these may indicate autoimmune thyroid disease (which can mimic nodular disease).

Imaging

The blood assays may be accompanied by ultrasound imaging of the nodule to determine the position, size and texture, and to assess whether the nodule may be cystic (fluid filled). Also suspicious findings in a nodule are hypoechoic, irregular borders, microcalcifications, or very high levels of blood flow within the nodule. Less suspicious findings in benign nodules include, hyperechoic, comet tail artifacts from colloid, no blood flow in the nodule and a halo, or smooth border.

Some clinicians will also request technetium (Tc) or radioactive iodine (I) imaging of the thyroid. An 123I scan showing a hot nodule, accompanied by a lower than normal TSH, is strong evidence that the nodule is not cancerous.

Classification

Thyroid cancers can be classified according to their pathological characteristics. The following variants can be distinguished (distribution over various subtypes may show regional variation):

Papillary thyroid cancer Up to 75%
Follicular thyroid cancer Up to 15%
Medullary thyroid cancer (Up to 8%)
Anaplastic thyroid cancer Less than 5%
Others
- Squamous cell carcinoma, sarcoma

The follicular and papillary types together can be classified as "differentiated thyroid cancer". These types have a more favorable prognosis than the medullary and undifferentiated types.

Thymoma

2009-01-08T06:29:00.000-08:00


Thymoma
An encapsulated thymoma (mixed lymphocytic and epithelial type).

In medicine (oncology), thymoma is a tumor originating from the thymus. It consists of any type of thymic epithelial cell as well as lymphocytes that are usually abundant and probably not neoplastic. Thymoma usually is benign, and frequently encapsulated; when occasionally malignant, then it is invasive: metastasis is extremely rare. Malignant lymphomas that involve the thymus, e.g., lymphosarcoma, Hodgkin's disease (termed "granulomatous thymoma" in the past), should not be regarded as thymoma. Thymoma is a rare disease, best known for its enigmatic association with the neuromuscular disorder myasthenia gravis.

Signs and symptoms

A third of all people with a thymoma have symptoms due to compression of the surrounding organs by an expansive mass. This may take the form of superior vena cava syndrome (compression of the upper caval vein), dysphagia (difficulty swallowing), cough or chest pain.

A third have a thymoma detected because they have an associated autoimmune disorder. The most common condition in this group is myasthenia gravis (of which 10-15% are associated with a thymoma and 30-45% of patients with thymomas have MG); patients with myasthenia are routinely screened for thymoma. Other associated autoimmune conditions are pure red cell aplasia and Good's syndrome (thymoma with combined immunodeficiency and hypogammaglobulinemia). Rare associations that have been reported are: acute pericarditis, Addison's disease, agranulocytosis, alopecia areata, ulcerative colitis, Cushing's disease, hemolytic anemia, limbic encephalopathy, myocarditis, nephrotic syndrome, panhypopituitarism, pernicious anemia, polymyositis, rheumatoid arthritis, sarcoidosis, scleroderma, sensorimotor radiculopathy, stiff person syndrome, systemic lupus erythematosus and thyroiditis.

A third to half of all people with a thymoma have no symptoms at all, and the mass is identified on a chest X-ray performed for an unrelated problem.

Diagnosis

CT scan of the chest revealing a large necrotic mass in the left anterior mediastinum (indicated by the red line). Histology later proved the diagnosis of a thymoma.

Another axial slice of a CT scan of the chest showing a small thymoma just in front of the heart (marked with the red line).

When a thymic mass is identified, the diagnosis is confrmed with a histology (obtaining a tissue sample of the mass) study. When a thymoma is suspected, a CT/CAT scan is generally performed to estimate the size of the tumor, and can be biopsied with a CT-guided needle. There is a small risk of pneumomediastinum, mediastinitis and the risk of damaging the heart or large blood vessels. The final diagnosis is made by removing the thymus. Pathological investigation of the specimen will reveal if the tumor was benign or malignant, although the initial biopsy is usually indicative.

The tumor is generally located inside the thymus, and can be calcified. Increased vascular enhancement can be indicative of malignancy, as can be pleural deposits.

If the suspicion is high, some blood tests are often performed to look for associated problems or possible spread. These include: full blood count, protein electrophoresis, antibodies to the acetylcholine receptor (indicative of myasthenia), electrolytes, liver enzymes and renal function.

Pathophysiology

Thymoma originates from the epithelial cell population in the thymus. Many subtypes are recognized, some of which have a better- or worse-than-general prognosis. There are two major types of thymoma. Type A if the epithelial cells have an oval shape or Type B if they have an epithelioid shape. If the cells have a combination of both types, they are designated type AB. Type B has three subtypes B1, B2 and B3.

Staging

The Masaoka Staging System is used widely and based on anatomic extent of disease at the time of surgery:

I: Completely encapsulated
II-1: Macroscopic invasion into surrounding fatty tissue
II-2: Microscopic invasion into capsule
III: Macroscopic invasion into adjacent organs
IVA: Pleural or pericardial implants
IVB: Lymphatogenous or hematogenous metastasis

Treatment

Surgery is the mainstay of treatment. If the tumor is malignant and very large, chemotherapy may be required to shrink the tumor before surgery is attempted. If the tumor was benign and was removed completely, no further therapy is necessary. Removal of the thymus in adults does not appear to induce a severe immune deficiency. In children, however, added care and scrupulous vaccination are necessary to protect from infections. Malignant tumors may need additional treatment with radiotherapy, and for recurrence with chemotherapy (cyclophosphamide, doxorubicin and cisplatin) if a lifetime dose of radiation was delivered to the tumor area.

Prognosis

Thymomas associated with autoimmune disorders usually are benign. Malignant thymomas can metastasize, generally to pleura, kidney, bone, liver or brain.

Epidemiology

Men and women are equally affected. The typical age at diagnosis is 30-40, although cases have been described in every age group.

Additional images

An encapsulated cystic thymoma.	A locally invasive circumscribed thymoma (mixed lymphocytic and epithelial, mixed polygonal and spindle).	Histopathological image of thymoma type B1. Anterior mediastinal mass surgically resected. Hematoxylin & eosin stain.	Histopathological image of thymoma type B1. Anterior mediastinal mass surgically resected. Cytokeratin CAM5.2 immunostain.
Histopathological image representing a noninvasive thymoma type B1, surgically resected. Hematoxylin & eosin.

Throat cancer

2009-01-08T06:27:00.000-08:00

Throat cancer may refer to:

Head and neck cancer, a group of pooy similar cancers originating from the upper aerodigestive tract, including the lip, oral cavity (mouth), nasal cavity, paranasal sinuses, pharynx, and larynx
Esophageal cancer, malignancy of the esophagus

Testicular Cancer

2009-01-08T06:17:00.000-08:00


Testicular Cancer
7.4 x 5.5-cm seminoma in a radical orchiectomy specimen.

Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system.

In the United States, between 7,500 and 8,000 diagnoses of testicular cancer are made each year. Over his lifetime, a man's risk of testicular cancer is roughly 1 in 250 (four tenths of one percent, or 0.4 percent). It is most common among males aged 15-35 years, particularly those in their mid-twenties. Testicular cancer has one of the highest cure rates of all cancers: in excess of 90 percent; essentially 100 percent if it has not metastasized. Even for the relatively few cases in which malignant cancer has spread widely, chemotherapy offers a cure rate of at least 85 percent today. Not all lumps on the testicles are tumors, and not all tumors are malignant; there are many other conditions such as epididymal cysts, appendix testis (hydatid of Morgagni), and so on which may be painful but are non-cancerous.

Prevalence and distribution

Testicular cancer is most common among whites and rare among men of African descent. Testicular cancer is uncommon in Asia and Africa. Worldwide incidence has doubled since the 1960s, with the highest rates of prevalence in Scandinavia, Germany, and New Zealand.

Incidence among African Americans doubled from 1988 to 2001 with a bias towards seminoma. The lack of significant increase in the incidence of early-stage testicular cancer during this timeframe suggests that the overall increase was not due to heightened awareness of the disease.

Although testicular cancer is most common among men aged 15-40 years, it has three peaks: infancy, ages 25-40 years, and age 60 years.

Germ cell tumors of the testis are the most common cancer in young men between the ages of 15 and 35 years.

A major risk factor for the development of testis cancer is cryptorchidism (undescended testicles). Other risk factors include inguinal hernia, mumps orchitis. Physical activity is associated with decreased risk and sedentary lifestyle is associated with increased risk. Early onset of male characteristics is associated with increased risk. These may reflect endogenous or environmental hormones.

Signs and symptoms

Because testicular cancer is curable (stage I can have a success rate of >90%) when detected early, experts recommend regular monthly testicular self-examination after a hot shower or bath, when the scrotum is looser. Men should examine each testicle, feeling for pea-shaped lumps. The testicle should normally feel smooth to the touch. Ridges may be felt because of enlarged blood vessels or tumor growth. Additionally the entire testicle may feel hard and bumpy to the touch.

Symptoms may include one or more of the following:

a lump in one testis or a hardening of one of the testicles
abnormal sensitivity (either numbness or pain)
loss of sexual activity
sexual withdrawal
build-up of fluid in the scrotum
a dull ache in the lower abdomen or groin
lumbago
An increase, or significant decrease, in the size of one testis. The testicle with a tumor may be severely enlarged, as much as 3 times the original size. Simultaneously the other testicle may be shrunken in size, due to the tumor taking up the majority of the blood supply to the scrotum.
blood in semen
general weak and tired feeling

The nature of any palpated lump in the scrotum is evaluated by scrotal ultrasound, which can determine exact location, size, and some characteristics of the lump, such as cystic vs solid, uniform vs heterogeneous, sharply circumscribed or poorly defined. The extent of the disease is evaluated by CT scans, which are used to locate metastases. Blood tests are also used to identify and measure tumor markers that are specific to testicular cancer. AFP alpha1 feto protein, Beta-HCG, and LDH are the typical markers used to identify testicular cancer. The diagnosis is made by performing an orchiectomy, surgical excision of the entire testis along with attached structures epididymis and spermatic cord; the resected specimen is evaluated by a pathologist. A biopsy should not be performed, as it raises the risk of migrating cancer cells into the scrotum. The reason why inguinal orchiectomy is the preferred method is that the lymphatic system of the scrotum links to the lower extremities and that of the testicle links to the retroperitoneum. A transscrotal biopsy or orchiectomy will potentially leave cancer cells in the scrotum and create two vectors for cancer spread, while in an inguinal orchiectomy only the retroperitoneal route exists.

Diagnosis

The cardinal diagnostic finding in the patient with testis cancer is a mass in the substance of the testis. Unilateral enlargement of the testis with or without pain in the adolescent or young adult male should raise concern for testis cancer.

An incorrect diagnosis is made at the initial examination in up to 25% of patients with testicular tumors and may result in delay in treatment or a suboptimal approach (scrotal incision) for exploration.

Epididymitis or epididymoorchitis

The differential diagnosis of testicular cancer requires examining the histology of tissue obtained from an orchiectomy specimen. Orchiectomy, rather than transcrotal biopsy, is preferred to reduce the risk of spill and thus the risk of metastasis, in the event that the tumor is malignant. For orchiectomy, an inguinal surgical approach is preferred.

Management

Before 1970, the young man with recurrent testicular cancer was destined to have rapid progression and death from disseminated disease. Currently, although 7000 to 8000 new cases of testicular cancer occur in the United States yearly, only 400 men are expected to die of the disease. Much of this improvement is due to advances in adjuvant therapy.

Due to the risk of subsequent metastasis, post-surgical adjuvant therapy may be offered to the patient following orchiectomy. The type of adjuvant therapy depends largely on the histology of the tumor and the stage of progression at the time of surgery. These two factors contribute to the risk of recurrence, including metastasis. Adjuvant treatments may involve chemotherapy, radiotherapy or careful surveillance by frequent CT scans and blood tests by oncologists.

Classification

Although testicular cancer can be derived from any cell type found in the testicles, more than 95% of testicular cancers are germ cell tumors. Most of the remaining 5% derive from Leydig cells or Sertoli cells. Thus, the focus of diagnosis is on determining which germ cell tumor is present. Correct diagnosis is necessary to ensure the most effective and least harmful treatment. To some extent, this can be done via blood tests for tumor markers, but differential diagnosis requires examination of the histology of a specimen by a pathologist.

Staging

After removal, a testicular tumor is staged by a pathologist according to the TNM Classification of Malignant Tumors as published in the AJCC Cancer Staging Manual. Testicular cancer is categorized as being in one of three stages (which have subclassifications). The size of the tumor in the testis is irrelevant to staging. In broad terms, testicular cancer is staged as follows:

Stage I: the cancer remains localized to the testis.
Stage II: the cancer involves the testis and metastasis to retroperitoneal and/or Paraaortic lymph nodes (lymph nodes below the urogenital diaphragm).
Stage III: the cancer involves the testis and metastasis beyond the retroperitoneal and Paraaortic lymph nodes. Stage III is further subdivided into nonbulky stage III and bulky stage III.
Stage IV: if there is liver and/or lung secondaries

Histology

After removal, a testicular tumor is classified by a pathologist according to its histology.

Germ cell tumors of the testis, by frequency

It contained the following materials

40% mixed (usually teratoma plus another)
35% seminoma (germinoma of the testis)
20% embryonal carcinoma
5% teratoma (pure)
<1% href="http://en.wikipedia.org/wiki/Choriocarcinoma" title="Choriocarcinoma">

Also: Intratubular germ cell neoplasms (the in-situ stage of germ cell tumors)

Non-germ cell tumors of the testis

Sertoli-Leydig cell tumor (usually benign)

Secondary tumors of the testis

Leukemic infiltration of the testis
Metastatic tumors

Treatment

The three basic types of treatment are surgery, radiation therapy, and chemotherapy.

Surgery is performed by urologists; radiation therapy is administered by radiation oncologists; and chemotherapy is the work of medical oncologists.

In most patients with testicular cancer, the disease is cured readily with minimal long-term morbidity.

Surgery

Orchiectomy

While it may be possible, in some cases, to remove testicular cancer tumors from a testis while leaving the testis functional, this is almost never done, as more than 95% of testicular tumors are malignant. Since only one testis is typically required to maintain fertility, hormone production, and other male functions, the afflicted testis is almost always removed completely in a procedure called inguinal orchiectomy. (The testicle is almost never removed through the scrotum; an incision is made beneath the belt line in the inguinal area.) Most notably, since removing the tumor alone does not eliminate the precancerous cells that exist in the testis, it is usually better in the long run to remove the entire testis to prevent another tumor. A plausible exception could be in the case of the second testis later developing cancer as well.

Retroperitoneal Lymph Node Dissection (RPLND)

In the case of nonseminomas that appear to be stage I, surgery may be done on the retroperitoneal/Paraaortic lymph nodes (in a separate operation) to accurately determine whether the cancer is in stage I or stage II and to reduce the risk that malignant testicular cancer cells that may have metastasized to lymph nodes in the lower abdomen. This surgery is called Retroperitoneal Lymph Node Dissection (RPLND). However, this approach, while standard in many places, especially the United States, is out of favor due to costs and the high level of expertise required to perform the surgery. The urologist may take extra care in the case of males who have not fathered children, to preserve the nerves involved in ejaculation.

Many patients are instead choosing surveillance, where no further surgery is performed unless tests indicate that the cancer has returned. This approach maintains a high cure rate because of the growing accuracy of surveillance techniques.

Lymph node surgery may also be performed after chemotherapy to remove masses left behind, particularly in the cases of advanced initial cancer or large nonseminomas.

Radiation therapy

Radiation may be used to treat stage II seminoma cancers, or as adjuvant (preventative) therapy in the case of stage I seminomas, to minimize the likelihood that tiny, non-detectable tumors exist and will spread (in the inguinal and para-aortic lymph nodes). Radiation is never used as a primary therapy for nonseminoma.

Chemotherapy

As an adjuvant treatment, use of chemotherapy as an alternative to radiation therapy is increasing, because radiation therapy appears to have more significant long-term side effects (for example, internal scarring, increased risks of secondary malignancies, etc.). Two doses, or occasionally a single dose of carboplatin, typically delivered three weeks apart, is proving to be a successful adjuvant treatment, with recurrence rates in the same ranges as those of radiotherapy.

Chemotherapy is the standard treatment for non-seminoma (teratoma) when the cancer has spread to other parts of the body (that is, stage II or III). The standard chemotherapy protocol is three, or sometimes four, rounds of Bleomycin-Etoposide-Cisplatin (BEP). This treatment was developed by Dr. Lawrence Einhorn at Indiana University. An alternative, equally effective treatment involves the use of four cycles of Etoposide-Cisplatin (EP).

While treatment success depends on the stage, the average survival rate after five years is around 95%, and stage I cancers cases (if monitored properly) have essentially a 100% survival rate (which is why prompt action, when testicular cancer is a possibility, is extremely important).

Actions after treatment

Surveillance

For stage I cancers that have not had any adjuvant (preventative) therapy, close monitoring for at least a year is important, and should include blood tests (in cases of nonseminomas) and CT-scans (in all cases), to ascertain whether the cancer has metastasized (spread to other parts of the body). For other stages, and for those cases in which radiation therapy or chemotherapy was administered, the extent of monitoring (tests) will vary on the basis of the circumstances, but normally should be done for five years (with decreasing intensity). For the first year blood tests for tumor markers should be done monthly, and decreasing to once every three months in the years after. CT scans should be performed once every three months in the first year and decreasing to once every six months thereafter. The high cost of CT scans and the relative danger of the radiation involved both being factors in the relative infrequence with which tests are performed. CT-scans are performed on the abdomen (and sometimes the pelvis) whereas chest x-rays are preferred for the lungs as they give sufficient detail combined with a lower false-positive rate and significantly smaller radiation dose.

Fertility

A man with one remaining testis can lead a normal life, because the remaining testis takes up the burden of testosterone production and will generally have adequate fertility. However, it is worth the (minor) expense of measuring hormone levels before removal of a testicle, and sperm banking may be appropriate for younger men who still plan to have children, since fertility may be lessened by removal of one testicle, and can be severely affected if extensive chemotherapy and/or radiotherapy is done.

Less than five percent of those who have testicular cancer will have it again in the remaining testis. A man who loses both testicles will normally have to take hormone supplements (in particular, testosterone, which is created in the testicles), and will be infertile, but can lead an otherwise normal life.

Sézary's disease

2008-12-30T10:03:00.000-08:00

Sézary's disease (often named Sézary syndrome) is a type of cutaneous lymphoma which was first described by Albert Sézary. The affected cells are T-cells that have pathological quantities of mucopolysaccharides. Sézary's disease is sometimes considered a late stage of mycosis fungoides. There are currently no known causes of Sézary's disease.

Signs and symptoms

Sézary syndrome and mycosis fungoides are T-cell lymphomas whose primary manifestation is in the skin. The disease's origin is a peripheral CD4+ T-lymphocyte, although rarer CD8+/CD4- cases have been observed. Epidermotropism by neoplastic CD4+ lymphocytes with the formation of Pautrier's microabscesses is the hallmark sign of the disease. The dominant symptoms of the disease are:

Generalized erythroderma
Atypical T-cells ("Sézary cells") in the peripheral blood

Diagnosis

Patients who have Sézary's disease often present with skin lesions that do not heal with normal medication. A blood test generally reveals any change in the levels of lymphocytes in the blood which is often associated with a cutaneous T-cell lymphoma. Finally, a biopsy of a skin lesion can be performed to rule out any other causes.

Treatment

Vorinostat (Zolinza) is a second-line drug for cutaneous T-cell lymphoma. Treatments are often used in combination with phototherapy and chemotherapy.

Epidemiology

Mycosis fungoides is the most common form of cutaneous T-cell lymphoma. In the western population there are around 0.3 cases of Sezary syndrome per 100,000 people. Sézary disease is more common in males with a ratio of 2:1, and the mean age of diagnosis is between 55 and 60 years of age. Patients with Sézary disease have a median survival of 5 years.

Kaposi's sarcoma

2008-12-24T05:37:00.000-08:00


Kaposi's sarcoma
Papular cutaneous Kaposi's Sarcoma

Kaposi's sarcoma (KS) is a tumor caused by Human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV). It was originally described by Moritz Kaposi, a Hungarian dermatologist practicing at the University of Vienna in 1872. It became more widely known as one of the AIDS defining illnesses in the 1980s. The viral cause for this cancer was discovered in 1994. Although KS is now well-established to be caused by a virus infection, there is widespread lack of awareness of this even among persons at risk for KSHV/HHV-8 infection.

Epidemiological varieties

HHV-8 is responsible for all varieties of KS.

Classic KS as originally described was a relatively indolent disease affecting elderly men from the Mediterranean region, or of Eastern European descent. Countries bordering the Mediterranean basin have higher rates of KSHV/HHV-8 infection than the remainder of Europe.

Endemic KS was described later in young African people, mainly from sub-Saharan Africa, as a more aggressive disease which infiltrated the skin extensively, especially on the lower limbs. This, it should be noted, is unrelated to HIV infection. The high rate of KS in sub-Saharan countries is due to the high rates of HHV 8 infection in their general populations, frequently greater than 50%.

Transplant Related KS had been described, but only rarely until the advent of calcineurin inhibitors (such as ciclosporin, which are inhibitors of T-cell function) for transplant patients in the 1980s, when its incidence grew rapidly. The tumor arises either when an HHV 8-infected organ is transplanted into someone who has not been exposed to the virus or when the transplant recipient already harbors pre-existing HHV 8 infection.

Epidemic KS was described during the 1980s as an aggressive disease in AIDS patients (HIV also causes a defect in T-cell immunity). It is over 300 times more common in AIDS patients than in renal transplant recipients. In this case, HHV 8 is sexually transmitted among gay and bisexual men who are also at risk for sexually transmitted HIV infection.

Clinical features

KS lesions are nodules or blotches that may be red, purple, brown, or black, and are usually papular (i.e. palpable or raised).

They are typically found on the skin, but spread elsewhere is common, especially the mouth, gastrointestinal tract and respiratory tract. Growth can range from very slow to explosively fast, and is associated with significant mortality and morbidity.

Skin

Commonly affected areas include the lower limbs, face, mouth and genitalia. The lesions are usually as described above, but may occasionally be plaque-like (often on the soles of the feet) or even involved in skin breakdown with resulting fungating lesions. Associated swelling may be from either local inflammation or lymphoedema (obstruction of local lymphatic vessels by the lesion). Skin lesions may be quite disfiguring for the sufferer, and a cause of much psychosocial pathology.

Mouth

Intraoral Kaposi’s sarcoma lesion with an overlying candidiasis infection

Is involved in about 30%, and is the initial site in 15% of AIDS related KS. In the mouth, the hard palate is most frequently affected, followed by the gums. Lesions in the mouth may be easily damaged by chewing and bleed or suffer secondary infection, and even interfere with eating or speaking.

Gastrointestinal tract

Involvement can be common in those with transplant related or AIDS related KS, and it may occur in the absence of skin involvement. The gastrointestinal lesions may be silent or cause weight loss, pain, nausea/vomiting, diarrhea, bleeding (either vomiting blood or passing it with bowel motions), malabsorption, or intestinal obstruction.

Respiratory tract

Involvement of the airway can present with shortness of breath, fever, cough, hemoptysis (coughing up blood), or chest pain, or as an incidental finding on chest x-ray. The diagnosis is usually confirmed by bronchoscopy when the lesions are directly seen, and often biopsied.

Pathophysiology and diagnosis

Despite its name, it is generally not considered a true sarcoma, which is a tumor arising from mesenchymal tissue. KS actually arises as a cancer of lymphatic endothelium and forms vascular channels that fill with blood cells, giving the tumor its characteristic bruise-like appearance. KSHV proteins are uniformly detected in KS cancer cells.

KS lesions contain tumor cells with a characteristic abnormal elongated shape, called spindle cells. The tumor is highly vascular, containing abnormally dense and irregular blood vessels, which leak red blood cells into the surrounding tissue and give the tumor its dark color. Inflammation around the tumor may produce swelling and pain.

Although KS may be suspected from the appearance of lesions and the patient's risk factors, a definite diagnosis can only be made by biopsy and microscopic examination, which will show the presence of spindle cells. Detection of the KSHV protein LANA in tumor cells confirms the diagnosis.

Treatment and prevention

Blood tests to detect antibodies against KSHV have been developed and can be used to determine if a patient is at risk for transmitting infection to his or her sexual partner, or if an organ is infected prior to transplantation. Unfortunately, these tests are not available except as research tools and thus there is little screening for persons at risk for becoming infected with KSHV, such as transplant patients.

Kaposi's sarcoma is not curable, in the usual sense of the word, but it can often be effectively palliated for many years and this is the aim of treatment. In KS associated with immunodeficiency or immunosuppression, treating the cause of the immune system dysfunction can slow or stop the progression of KS. In 40% or more of patients with AIDS-associated Kaposi's sarcoma, the Kaposi lesions will shrink upon first starting highly active antiretroviral therapy (HAART). However, in a certain percentage of such patients, Kaposi's sarcoma may again grow after a number of years on HAART, especially if HIV is not completely suppressed. Patients with a few local lesions can often be treated with local measures such as radiation therapy or cryosurgery. Surgery is generally not recommended as Kaposi's sarcoma can appear in wound edges. More widespread disease, or disease affecting internal organs, is generally treated with systemic therapy with interferon alpha, liposomal anthracyclines (such as Doxil) or paclitaxel.

With the decrease in the death rate among AIDS patients receiving new treatments in the 1990s, the incidence and severity of epidemic KS also decreased. However, the number of patients living with AIDS is increasing substantially in the United States, and it is possible that the number of patients with AIDS-associated Kaposi's sarcoma will again rise as these patients live longer with HIV infection.

History and theories

Discovery

The disease is named after Moritz Kaposi (1837–1902), a Hungarian dermatologist who first described the symptoms in 1872. Research over the next century suggested that KS, like some other forms of cancer, might be caused by a virus or genetic factors, but no definite cause was found.

Relationship to AIDS

With the rise of the AIDS epidemic, KS, as initially one of the most common AIDS symptoms, was researched more intensively in hopes that it might reveal the cause of AIDS.

San Francisco doctors reported a Kaposi's sarcoma cluster among gay men. All 15 patients undergoing treatment are long-term HIV patients whose HIV infections are firmly controlled with antiviral drugs. None appears to be in any danger. The new cases are not aggressive, invasive or lethal as was typical with uncontrolled HIV during the 1980s. The lesions are unsightly, difficult to treat and raise questions about the immune response aging of HIV patients.

Viral cause isolated

In 1994, Yuan Chang, Patrick S. Moore, and Ethel Cesarman at Columbia University in New York isolated genetic pieces of a virus from a KS lesion. They used representational difference analysis (a method to subtract out all of the human DNA from a sample) to isolate the viral genes. They then used these small DNA fragments as starting points to sequence the rest of the viral genome in 1996. This, the eighth human herpesvirus (HHV-8)—now known as Kaposi's sarcoma-associated herpesvirus (KSHV)—has since been found in all KS lesions tested, and is considered the cause of the disease. KSHV is a unique human tumor virus that has incorporated cellular genes that cause tumors into its genome ("molecular piracy"); the stolen cellular genes may help the virus escape from the immune system, but in doing so it also causes cells to proliferate. It is related to Epstein-Barr virus, a very common herpesvirus that can also cause human cancers. KSHV is readily found in all forms of KS. The virus is sexually transmitted among men having sex with men and can be transmitted through organ donation. In Africa, high rates of KSHV infection has led to KS becoming the most common cancer in sub-Saharan Africa. KSHV infection is thought to be life-long so that persons infected with KSHV may develop KS years later if they develop AIDS or other immunosuppression.

Unknown factors

Like other tumor viruses, KSHV infection only leads to cancer in a minority of infected persons. Other factors are required, such as pre-existing immune system damage, for disease to erupt. In Africa has shown that even in the absence of HIV/AIDS, KS is more common in men than women although KSHV infection is equal between both sexes. This suggests that sex hormones may either protect from or predispose to KS in persons infected with the virus. Although older theories suggested that HIV might directly initiate KS, aside from its effects on the immune system, HIV and KSHV infect different cells and HIV is not found in KS tumors making this theory obsolete.

Awareness

Only 6% of men having sex with men are aware that KS is caused by a virus different from HIV. Thus, there is little community effort to prevent KSHV infection. Similarly, no systematic screening of organ donations is in place.

In AIDS patients, Kaposi's sarcoma is considered an opportunistic infection, a disease that is able to gain a foothold in the body because the immune system has been weakened. With the rise of HIV/AIDS in Africa, where KSHV is widespread, KS has become the most frequently reported cancer in some countries, such as Zimbabwe.

Nigerian bandleader Fela Kuti succumbed to the disease in 1997.

Because of their highly visible nature, external lesions are sometimes the presenting symptom of AIDS. Kaposi's sarcoma entered the awareness of the general public with the release of the film Philadelphia, in which the main character was fired after his employers found out he was HIV-positive due to visible lesions. Unfortunately, by the time KS lesions appear, it is likely that the immune system has already been severely weakened.

Ewing's sarcoma

2008-12-24T05:33:00.000-08:00


Ewing sarcoma
X-Ray of a child with Ewing sarcoma of the tibia

Ewing sarcoma is a malignant round-cell tumor. It is a rare disease in which cancer cells are found in the bone or in soft tissue. The most common areas in which it occurs are the pelvis, the femur, the humerus, and the ribs.

Because a common genetic locus is responsible for a large percentage of Ewing sarcoma and primitive neuroectodermal tumors, these are sometimes grouped together in a category known as the Ewing family of tumors. The diseases are, however, considered to be different: peripheral primitive neuroectodermal tumors are generally not associated with bones, while Ewing sarcomas are most commonly related to bone.

Ewing sarcoma occurs most frequently in male teenagers, with a male/female ratio of 1.6:1.

Although usually classified as a bone tumor, Ewing sarcoma can have characteristics of both mesodermal and ectodermal origin, making it difficult to classify.

Eponym

James Ewing (1866-1943) first described the tumor, establishing that the disease was separate from lymphoma and other types of cancer known at that time.

Causes

Ewing sarcoma is the result of a translocation between chromosomes 11 and 22, which fuses the EWS gene of chromosome 22 to the FLI1 gene of chromosome 11.

EWS/FLI functions as the master regulator.

Clinical findings

Ewing sarcoma is more common in males and usually presents in childhood or early adulthood, with a peak between 10 and 20 years of age. It can occur anywhere in the body, but most commonly in the pelvis and proximal long tubular bones. The diaphyses of the femur are the most common sites, followed by the tibia and the humerus. Thirty percent are overtly metastatic at presentation.

It is positive for CD99 and negative for CD45.

Imaging findings

Genetic exchange between chromosomes can cause cells to become cancerous, like these cells from metastasized Ewing sarcoma

On conventional radiographs, the most common osseous presentation is a permeative lytic lesion with periosteal reaction. The classic description of lamellated or "onion skin" type periosteal reaction is often associated with this lesion. Plain films add valuable information in the initial evaluation or screening. The wide zone of transition (e.g. permeative) is the most useful plain film characteristic in differentiation of benign versus aggressive or malignant lytic lesions.

MRI should be routinely used in the work-up of malignant tumors. MRI will show the full bony and soft tissue extent and relate the tumor to other nearby anatomic structures (e.g. vessels). Gadolinium contrast is not necessary as it does not give additional information over noncontrast studies, though some current researchers argue that dynamic, contrast enhanced MRI may help determine the amount of necrosis within the tumor, thus help in determining response to treatment prior to surgery.

CT can also be used to define the extraosseous extent of the tumor, especially in the skull, spine, ribs and pelvis. Both CT and MRI can be used to follow response to radiation and/or chemotherapy.

Bone scintigraphy can also be used to follow tumor response to therapy.

Differential diagnosis

Other entities that may have a similar clinical presentation include osteomyelitis, osteosarcoma (especially telangiectatic osteosarcoma) and eosinophilic granuloma. Soft tissue neoplasms such as malignant fibrous histiocytoma that erode into adjacent bone may also have a similar appearance.

Epidemiology

The frequency in the United States depends on the patient's age, with a rate of 0.3 case per 1,000,000 children in those younger than 3 years of age to as high as 4.6 cases per 1,000,000 in adolescents aged 15-19 years. Internationally the annual incidence rate averages less than 2 cases per 1,000,000 children. In the United Kingdom an average of six children per year are diagnosed, mainly males in early stages of puberty. Due to the prevalence of diagnosis during teenage years, there may possibly be a link between the onset of puberty and the early stages of this disease, although no research is currently being conducted to confirm this theory.

Treatment

Because almost all patients with apparently localized disease at diagnosis have occult metastatic disease, multidrug chemotherapy (often including ifosfamide and etoposide) as well as local disease control with surgery and/or radiation is indicated in the treatment of all patients.

Treatment often consists of neo-adjuvant chemotherapy generally followed by wide or radical excision, and may also include radiotherapy. Complete excision at the time of biopsy may be performed if malignancy is confirmed at that time. Treatment lengths vary depending on location and stage of the disease at diagnosis. Radical chemotherapy may be as short as 6 treatments at 3 week cycles, however most patients will undergo chemotherapy for 6-12 months and radiation therapy for 5-8 weeks.

Antisense oligodeoxynucleotides have been proposed as possible treatment by down-regulating the expression of the oncogenic fusion protein associated with the development of Ewing sarcoma resulting from the EWS-ETS gene translocation. In addition, the synthetic retinoid derivative fenretinide (4-hydroxy(phenyl)retinamide) has been reported to induce high levels of cell death in Ewing sarcoma cell lines in vitro and to delay growth of Ewing sarcoma xenografts in vivo mouse models.

Prognosis

Staging attempts to distinguish patients with localized from those with metastatic disease. Most commonly, metastases occur in the chest, bone and/or bone marrow. Less common sites include the central nervous system and lymph nodes.

Survival for localized disease is 70% to 80% when treated with chemotherapy. Long term survival for metastatic disease can be less than 10% but some sources state it is 25-30%.

Rhabdomyosarcoma

2008-12-24T05:29:00.000-08:00

A rhabdomyosarcoma is a type of cancer, specifically a sarcoma (cancer of connective tissues), in which the cancer cells are thought to arise from skeletal muscle progenitors. It can also be found attached to muscle tissue, wrapped around intestines, or anywhere, to exclude the neck area.

Presentation

Its two most common forms are embryonal rhabdomyosarcoma and alveolar rhabdomyosarcoma. In the former, which is more common in younger children, the cancer cells resemble those of a typical 6-to-8-week embryo. In the latter, which is more common in older children and teenagers, they resemble those of a typical 10-to-12-week embryo.

Epidemiology

Rhabdomyosarcoma is a relatively rare form of cancer.

It is most common in children ages one to five, and is also found in teens aged 15 to 19, although this is more rare. This cancer is also an adult cancer but it is rare.

St. Jude Children's Research Hospital reports that rhabdomyosarcoma is the most common soft tissue sarcoma in children. Soft tissue sarcomas make up 7 - 8% of childhood cancers.

Diagnosis

When rhabdomyosarcoma is suspected, tests will be run for blood, muscle, and marrow.

Diagnosis of rhabdomyosarcoma depends on recognition of differentiation toward skeletal muscle cells. The protein myo D1 is a protein normally found in developing skeletal muscle cells which disappears after the muscle matures and becomes innervated by a nerve. Thus, myo D1 is not found in normal skeletal muscle and serves as a useful immunohistochemical marker of rhabdomyosarcoma. Early manifestation can be misdiagnosed as a pseudotumor that is non responsive to steroid treatment.

Treatment

Treatment for rhabdomyosarcoma consists of chemotherapy, radiation therapy and sometimes surgery. Surgery to remove the tumor is often difficult or impossible because the tumor is usually embedded deep within the tissue, leaving it difficult to reach. If a tumor presents itself in the extremities, amputation is often necessary to improve chances of survival.

If there is no evidence of metastasis, surgery combined with chemotherapy and radiation offer the best prognosis. Patients whose tumors have metastasized usually have a poor chance for long-term survival. In patients who began treatment before metastasis, the prognosis is better, although the disease is generally incurable because the tumors that cannot be surgically removed tend to spread.

St Jude's Children's Research Hospital reports that more than 70% of children diagnosed with localized rhabdomyosarcoma have long-term survival.

Tungsten Alloy and RMS

A study has shown a link between RMS and Tungsten alloy embedded in muscle (e.g. shrapnel).

Retinoblastoma

2008-12-24T04:44:00.000-08:00


Retinoblastoma
Rb tumours taken with a retinoscan before and during chemotherapy

Retinoblastoma (Rb) is a rapidly developing cancer which develops in the cells of the retina, the light sensitive cells of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers (95-98%), with more than nine out of every ten sufferers surviving into adulthood. Retinoblastoma is a very treatable cancer.

There are two forms of the disease; a genetic heritable form and a non-genetic non-inheritable form. Approximately 55% of children with Rb have the non-genetic form. If there is no history of the disease within the family, the disease is labelled "sporadic", but this does not necessarily indicate that it is the non-genetic form. In about two thirds of cases, only one eye is affected (unilateral retinoblastoma); in the other third, tumours develop in both eyes (bilateral retinoblastoma). The number and size of tumours on each eye may vary. The position, size and quantity of tumours are considered when choosing the type of treatment for the disease.

Symptoms

The most common and obvious symptom is an abnormal appearance of the pupil. In a healthy eye, the pupil may appear red when captured on a photograph where a flash has been used (Red Eye), whereas on an affected eye, the pupil may appear white or yellow (leukocoria). The yellowy appearance may also be visible in low artificial light and will resemble a cat’s eye.

Other less common symptoms are: deterioration of vision, a red and irritated eye, faltering growth or delayed development. Some children with retinoblastoma can develop a squint (strabismus).

Should you notice any of these symptoms or have cause for concern, you should visit your GP or paediatrician. If a white eye reflection has been spotted on a photograph, take the photograph with you when you see your GP/Paediatrician. Depending on the position of the tumours, they may be visible using an ophthalmoscope to look through the pupil. A positive diagnosis is usually made only with an examination under anaesthetic (EUA).

Note: A white eye reflection is not always a positive indication of Rb and can be caused by light being reflected badly or by other conditions such as Coats's Disease.

Frequency of retinoblastoma

Retinoblastoma is rare and affects approximately 1 in 20,000 births worldwide. In the UK around 40 to 50 new cases are diagnosed each year. Most children are diagnosed before the age of five years old. In the UK bilateral cases usually present within the first year with the average age at diagnosis being 9 months. Diagnosis of unilateral cases peaks between 24 and 30 months.

Cause of retinoblastoma

In children with the heritable genetic form of retinoblastoma there is something wrong with part of the genetic material on chromosome 13, called the RB1 gene. The genetic codes found in chromosomes control the way in which cells grow and develop within the body. If a portion of the code is missing or altered (mutation) a cancer may develop. The defective RB1 gene can be inherited from either parent, however in some children, the mutation occurs in the early stages of foetal development. It is not known what causes the gene abnormality; it is most likely to be a random mistake during the copy process which occurs when a cell divides.

Treatment

Treatment of retinoblastoma varies from country to country. The first priority is to preserve the life of the child, then to preserve the vision and thirdly to minimize any complications or side effects of the treatment. The exact course of treatment will depend on the individual case and will be decided by the Ophthalmologist in discussion with the Paediatric Oncologist. Options for treatment include: chemotherapy, cryotherapy, radioactive plaques, laser therapy, external beam radiotherapy and surgery. Any combinations of these treatments may be adopted.

Support

Help for survivors of retinoblastoma and the families of children with the disease is available in many countries. The following is a list of some charities and organizations that are there to help:

Retinoblastoma International (RBI)

Country	Organization	Description
United Kingdom	The Childhood Eye Cancer Trust (CHECT)	A charity for families and individuals affected by retinoblastoma. They offer support and information, fund research and raise awareness of this rare cancer.
Global – focus on developing countries	Daisy’s Eye Cancer Fund	'A global response to childhood retinoblastoma' Daisy's Eye Cancer Fund is a registered charity in England, and a special fund within SickKids Foundation (the Charitable Foundation of Toronto's Hospital for Sick Children), Canada. Daisy’s Eye Cancer Fund is the world's only retinoblastoma charity taking a global approach to the needs of children affected by this cancer. With a particular focus on developing countries, they are committed to improving care for all children diagnosed with retinoblastoma. Their goal is to encourage the development of sustainable, locally managed diagnosis and treatment programs in under-served regions of the world so that, one day soon, no child will face death from an entirely treatable cancer due to lack of awareness or resources. Daisy’s Fund is named in honour of a brave school girl from Devon, England and driven by the memory of another Valliant little girl from Africa.
France	Retinostop	Retinostop is a charity which supports families, facilitate parents meetings, support research and help equip treatment centres. They promote early diagnosis amongst health professionals and government administrations. They have produced a booklet for children about a girl called Mirabelle and her cat Tino who both need artificial eyes made for them.
United States	Eye Cancer Network	Ocular oncology; diseases, treatment and research. 'An educational website about the diagnosis and treatment of eye tumours. Find eye tumour doctors, eye tumour information and support (for eye tumour patients and their families)' An American website, supported by The Eye Care Foundation, that is concerned with all forms of eye cancer but has a link to Retinoblastoma on the home page. The information is simple but informative; it is interesting to look at Retinoblastoma alongside other forms of eye cancer.
Retinoblastoma International (RBI)	'Fighting children's eye cancer' RBI is a non profit organisation founded in LA in 1998 since then RBI has been committed to supporting education, clinical care, research, early diagnosis and awareness. In the year 2000, RBI helped pass California Assembly Bill 2185, AB2185 which promotes early and regular eye examinations for infants, to detect the presence of tumours and numerous other eye problems.
United States	Retinoblastoma.com	Written by Dr David H. Abramsom now Chief of Ophthalmic Oncology at memorial Sloan-Kettering Cancer Center (MSKCC) in New York City. He runs the largest programme for children with Retinoblastoma in the US. Several years ago Dr Abramsom put together this website describing Retinoblastoma, his programme and some of the educational resources available to individuals with Retinoblastoma.
Canada	The Canadian Retinoblastoma Society (CRBS)	CRBS is a charitable organisation which supports Canadians affected by retinoblastoma. It also works to raise awareness through education and also provides an advocacy service.

Additional images

Retinoblastoma rosette

Retina scan before and during chemotherapy treatment

Prostate cancer

2008-12-23T08:47:00.000-08:00


Prostate cancer

Prostate cancer is a disease in which cancer develops in the prostate, a gland in the male reproductive system. It occurs when cells of the prostate mutate and begin to multiply out of control. These cells may spread (metastasize) from the prostate to other parts of the body, especially the bones and lymph nodes. Prostate cancer may cause pain, difficulty in urinating, problems during sexual intercourse, erectile dysfunction and other symptoms.

Rates of prostate cancer vary widely across the world. Although the rates vary widely between countries, it is least common in South and East Asia, more common in Europe, and most common in the United States. Prostate cancer develops most frequently in men over fifty. This cancer can occur only in men, as the prostate is exclusively of the male reproductive tract. It is one of the most common types of cancer in men. However, many men who develop prostate cancer never have symptoms, undergo no therapy, and eventually die of other causes. That is because malignant neoplasms of the prostate are, in most cases, slow-growing, and because most of those affected are over 60. Hence they often die of causes unrelated to the prostate cancer, such as heart/circulatory disease, pneumonia, other unconnected cancers or old age. Many factors, including genetics and diet, have been implicated in the development of prostate cancer.

Prostate cancer is most often discovered by PSA (prostate specific antigen) screening and less commonly by physical examination or by symptoms. There is some current concern about the accuracy of the PSA test and its usefulness. Suspected prostate cancer is typically confirmed by taking a biopsy of the prostate and examining it under a microscope. Further tests, such as CT scans and bone scans, may be performed to determine whether prostate cancer has spread.

Treatment options for prostate cancer with intent to cure are primarily surgery and radiation therapy. Other treatments such as hormonal therapy, chemotherapy, proton therapy, cryosurgery, high intensity focused ultrasound (HIFU) also exist depending on the clinical scenario and desired outcome. Abiraterone Acetate is showing promise in reducing Tumor Size and PSA levels in Aggressive end-stage prostate cancers. The age and underlying health of the man as well as the extent of spread, appearance under the microscope and response of the cancer to initial treatment are important in determining the outcome of the disease. The decision whether or not to treat localized prostate cancer (a tumor that is contained within the prostate) with curative intent is a patient trade-off between the expected beneficial and harmful effects in terms of patient survival and quality of life.

Prostate

The prostate is a part of the male reproductive organ which helps make and store seminal fluid. In adult men a typical prostate is about three centimeters long and weighs about twenty grams. It is located in the pelvis, under the urinary bladder and in front of the rectum. The prostate surrounds part of the urethra, the tube that carries urine from the bladder during urination and semen during ejaculation. Because of its location, prostate diseases often affect urination, ejaculation, and rarely defecation. The prostate contains many small glands which make about twenty percent of the fluid constituting semen. In prostate cancer the cells of these prostate glands mutate into cancer cells. The prostate glands require male hormones, known as androgens, to work properly. Androgens include testosterone, which is made in the testes; dehydroepiandrosterone, made in the adrenal glands; and dihydrotestosterone, which is converted from testosterone within the prostate itself. Androgens are also responsible for secondary sex characteristics such as facial hair and increased muscle mass.

Symptoms

Early prostate cancer usually causes no symptoms. Often it is diagnosed during the workup for an elevated PSA noticed during a routine checkup. Sometimes, however, prostate cancer does cause symptoms, often similar to those of diseases such as benign prostatic hypertrophy. These include frequent urination, increased urination at night, difficulty starting and maintaining a steady stream of urine, blood in the urine, and painful urination. Prostate cancer is associated with urinary dysfunction as the prostate gland surrounds the prostatic urethra. Changes within the gland therefore directly affect urinary function. Because the vas deferens deposits seminal fluid into the prostatic urethra, and secretions from the prostate gland itself are included in semen content, prostate cancer may also cause problems with sexual function and performance, such as difficulty achieving erection or painful ejaculation.

Advanced prostate cancer can spread to other parts of the body and this may cause additional symptoms. The most common symptom is bone pain, often in the vertebrae (bones of the spine), pelvis or ribs. Spread of cancer into other bones such as the femur is usually to the proximal part of the bone. Prostate cancer in the spine can also compress the spinal cord, causing leg weakness and urinary and fecal incontinence.

Pathophysiology

When normal cells are damaged beyond repair, they are eliminated by apoptosis. Cancer cells avoid apoptosis and continue to multiply in an unregulated manner.

Prostate cancer is classified as an adenocarcinoma, or glandular cancer, that begins when normal semen-secreting prostate gland cells mutate into cancer cells. The region of prostate gland where the adenocarcinoma is most common is the peripheral zone. Initially, small clumps of cancer cells remain confined to otherwise normal prostate glands, a condition known as carcinoma in situ or prostatic intraepithelial neoplasia (PIN). Although there is no proof that PIN is a cancer precursor, it is closely associated with cancer. Over time these cancer cells begin to multiply and spread to the surrounding prostate tissue (the stroma) forming a tumor. Eventually, the tumor may grow large enough to invade nearby organs such as the seminal vesicles or the rectum, or the tumor cells may develop the ability to travel in the bloodstream and lymphatic system. Prostate cancer is considered a malignant tumor because it is a mass of cells which can invade other parts of the body. This invasion of other organs is called metastasis. Prostate cancer most commonly metastasizes to the bones, lymph nodes, rectum, and bladder.

Etiology

The specific causes of prostate cancer remain unknown. A man's risk of developing prostate cancer is related to his age, genetics, race, diet, lifestyle, medications, and other factors. The primary risk factor is age. Prostate cancer is uncommon in men less than 45, but becomes more common with advancing age. The average age at the time of diagnosis is 70. However, many men never know they have prostate cancer. Autopsy studies of Chinese, German, Israeli, Jamaican, Swedish, and Ugandan men who died of other causes have found prostate cancer in thirty percent of men in their 50s, and in eighty percent of men in their 70s. In the year 2005 in the United States, there were an estimated 230,000 new cases of prostate cancer and 30,000 deaths due to prostate cancer.

A man's genetic background contributes to his risk of developing prostate cancer. This is suggested by an increased incidence of prostate cancer found in certain racial groups, in identical twins of men with prostate cancer, and in men with certain genes. In the United States, prostate cancer more commonly affects black men than white or Hispanic men, and is also more deadly in black men. Men who have a brother or father with prostate cancer have twice the usual risk of developing prostate cancer. Studies of twins in Scandinavia suggest that forty percent of prostate cancer risk can be explained by inherited factors. However, no single gene is responsible for prostate cancer; many different genes have been implicated. Two genes (BRCA1 and BRCA2) that are important risk factors for ovarian cancer and breast cancer in women have also been implicated in prostate cancer.

Dietary amounts of certain foods, vitamins, and minerals can contribute to prostate cancer risk. Men with higher serum levels of the short-chain ω-6 fatty acid linoleic acid have higher rates of prostate cancer. However, the same series of studies showed that men with elevated levels of long-chain ω-3 (EPA and DHA) had lowered incidence. A long-term study reports that "blood levels of trans fatty acids, in particular trans fats resulting from the hydrogenation of vegetable oils, are associated with an increased prostate cancer risk." Other dietary factors that may increase prostate cancer risk include low intake of vitamin E (Vitamin E is found in green, leafy vegetables), omega-3 fatty acids (found in fatty fishes like salmon), and the mineral selenium. A study in 2007 cast doubt on the effectiveness of lycopene (found in tomatoes) in reducing the risk of prostate cancer. Lower blood levels of vitamin D also may increase the risk of developing prostate cancer. This may be linked to lower exposure to ultraviolet (UV) light, since UV light exposure can increase vitamin D in the body.

There are also some links between prostate cancer and medications, medical procedures, and medical conditions. Daily use of anti-inflammatory medicines such as aspirin, ibuprofen, or naproxen may decrease prostate cancer risk. Use of the cholesterol-lowering drugs known as the statins may also decrease prostate cancer risk. More frequent ejaculation also may decrease a man's risk of prostate cancer. One study showed that men who ejaculated five times a week in their 20s had a decreased rate of prostate cancer, though others have shown no benefit. Infection or inflammation of the prostate (prostatitis) may increase the chance for prostate cancer. In particular, infection with the sexually transmitted infections chlamydia, gonorrhea, or syphilis seems to increase risk. Finally, obesity and elevated blood levels of testosterone may increase the risk for prostate cancer.

Research released in May 2007, found that US war veterans who had been exposed to Agent Orange had a 48% increased risk of prostate cancer recurrence following surgery.

Prostate cancer risk can be decreased by modifying known risk factors for prostate cancer, such as decreasing intake of animal fat.

One research study, by the Cancer Council Victoria, has shown that men who report that they regularly ("more than five times per week") masturbate have up to one third fewer occurrences of prostate cancer. The researchers hypothesize that this could be because regular ejaculation reduces the buildup of carcinogenic deposits such as 3-methylcholanthrene, produced from the breakdown of cholesterol, which could damage the cells lining the prostate. The researchers also speculated that frequent ejaculation may cause the prostate to mature fully, making it less susceptible to carcinogens. It is also possible that there is another factor (such as hormone levels) that is a common cause of both a reduced susceptibility to prostate cancer and a tendency toward frequent masturbation. There is also some evidence that frequent sexual intercourse is associated with reduced risk of prostate cancer, although contrarily the risks associated with STDs have been shown to increase the risk of prostate cancer. Once the lining of the prostate is affected with cancer, the only known treatments are surgery and radiation therapy. Both may limit the ability to have erections afterward.

Prevention

Vitamins and medication

Evidence from epidemiological studies supports protective roles in reducing prostate cancer for dietary selenium, vitamin E, lycopene, and soy foods. High plasma levels of Vitamin D may also have a protective effect. Estrogens from fermented soybeans and other plant sources (called phytoestrogens) may also help prevent prostate cancer. The selective estrogen receptor modulator drug toremifene has shown promise in early trials. Two medications which block the conversion of testosterone to dihydrotestosterone, finasteride and dutasteride, have also shown some promise. The use of these medications for primary prevention is still in the testing phase, and they are not widely used for this purpose. The initial problem with these medications is that they may preferentially block the development of lower-grade prostate tumors, leading to a relatively greater chance of higher grade cancers, and negating any overall survival improvement. More recent research found that finasteride did not increase the percentage of higher grade cancers. A 2008 study update found that finasteride reduces the incidence of prostate cancer by 30%. In the original study it turns that that the smaller prostate caused by finasteride means that a doctor is more likely to hit upon cancer nests and more likely to find aggressive-looking cells. Most of the men in the study who had cancer — aggressive or not — chose to be treated and many had their prostates removed. A pathologist then carefully examined every one of those 500 prostates and compared the kinds of cancers found at surgery to those initially diagnosed at biopsy. Finasteride did not increase the risk of High-Grade prostate cancer.

Green tea may be protective (due to its polyphenol content), although the most comprehensive clinical study indicates that it has no protective effect. A 2006 study of green tea derivatives demonstrated promising prostate cancer prevention in patients at high risk for the disease. Recent research published in the Journal of the National Cancer Institute suggests that taking multivitamins more than seven times a week can increase the risks of contracting the disease. This research was unable to highlight the exact vitamins responsible for this increase (almost double), although they suggest that vitamin A, vitamin E and beta-carotene may lie at its heart. It is advised that those taking multivitamins never exceed the stated daily dose on the label. Scientists recommend a healthy, well balanced diet rich in fiber, and to reduce intake of meat. A 2007 study published in the Journal of the National Cancer Institute found that men eating cauliflower, broccoli, or one of the other cruciferous vegetables, more than once a week were 40% less likely to develop prostate cancer than men who rarely ate those vegetables. The phytochemicals indole-3-carbinol and diindolylmethane, found in cruciferous vegetables, has antiandrogenic and immune modulating properties.

Ejaculation frequency

In 2003, an Australian research team led by Graham Giles of The Cancer Council Australia concluded that frequent masturbation by males appears to help prevent the development of prostate cancer. Australian research concluded that the more men ejaculate between the ages of 20 and 50, the less likely they are to develop prostate cancer. The protective effect is greatest while men are in their twenties: those who had ejaculated more than five times per week in their twenties, for instance, were one-third less likely to develop aggressive prostate cancer later in life. The results contradict those of previous studies, which have suggested that having had many sexual partners, or a high frequency of sexual activity, increases the risk of prostate cancer by up to 40 percent. The key difference is that these earlier studies defined sexual activity as sexual intercourse, whereas this study focused on the number of ejaculations, whether or not intercourse was involved. Another study completed in 2004 reported that "Most categories of ejaculation frequency were unrelated to risk of prostate cancer. However, high ejaculation frequency was related to decreased risk of total prostate cancer." The report abstract concluded, "Our results suggest that ejaculation frequency is not related to increased risk of prostate cancer."

More fish oil, less vegetable oil

A high consumption of omega-6 polyunsaturated fatty acids (PUFAs), which are found in most types of vegetable oil (e.g. corn oil - the most consumed oil in USA, soybean oil, sunflower oil, etc.), increased prostate tumor growth, speeded up histopathological progression, and decreased survival, while the omega-3 fatty acids (e.g. in fish oil) had the opposite, beneficial effect.

Myristic and palmitic saturated fatty acids

Some researches have indicated that some specific saturated fatty acids (myristic acidand palmitic acid are associated with increased risk of prostate cancer in a dose-dependent manner. Another study further investigated these and other saturated fatty acids. However it's still uncertain if this association is a cause or consequence of the disease.

Screening

Prostate cancer screening is an attempt to find unsuspected cancers. Screening tests may lead to more specific follow-up tests such as a biopsy, where small cores of the prostate are removed for closer study. Prostate cancer screening options include the digital rectal exam and the prostate specific antigen (PSA) blood test. Screening for prostate cancer is controversial because it is not clear if the benefits of screening outweigh the risks of follow-up diagnostic tests and cancer treatments.

Prostate cancer is usually a slow-growing cancer, very common among older men. In fact, most prostate cancers never grow to the point where they cause symptoms, and most men with prostate cancer die of other causes before prostate cancer has an impact on their lives. The PSA screening test may detect these small cancers that would never become life threatening. Doing the PSA test in these men may lead to overdiagnosis, including additional testing and treatment. Follow-up tests, such as prostate biopsy, may cause pain, bleeding and infection. Prostate cancer treatments may cause urinary incontinence and erectile dysfunction. Therefore, it is essential that the risks and benefits of diagnostic procedures and treatment be carefully considered before PSA screening.

Several medical societies have not found sufficient evidence to support routine screening for prostate cancer - but the American Urological Association supports annual screening and digital examination for men over 50 years old - and starting earlier for 'men at high risk (those with a family history of prostate cancer or African American men)'.

In 2002, the U.S. Preventive Services Task Force (USPSTF) concluded that the evidence was insufficient to recommend for or against routine screening for prostate cancer using PSA testing or digital rectal examination (DRE). The previous 1995 USPSTF recommendation was against routine screening.
In 1997, American Cancer Society (ACS) guidelines began recommending that beginning at age 50 (age 45 for African-American men and men with a family history of prostate cancer, and since 2001, age 40 for men with a very strong family history of prostate cancer), PSA testing and DRE be offered annually to men who have a life-expectancy of 10 or more years (average life expectancy is 10 years or more for U.S. men under age 76) along with information on the risks and benefits of screening. The previous ACS recommendations since 1980 had been for routine screening for prostate cancer with DRE annually beginning at age 40, and since 1992 had been for routine screening with DRE and PSA testing annually beginning at age 50.
The 2007 National Comprehensive Cancer Network (NCCN) guideline recommends offering a baseline PSA test and DRE at ages 40 and 45 and annual PSA testing and DRE beginning at age 50 (with annual PSA testing and DRE beginning at age 40 for African-American men, men with a family history of prostate cancer, and men with a PSA ≥ 0.6 ng/mL at age 40 or PSA > 0.6 ng/mL at age 45) through age 80, along with information on the risks and benefits of screening. Biopsy is recommended if DRE is positive or PSA ≥ 4 ng/mL, and biopsy considered if PSA > 2.5 ng/mL or PSA velocity ≥ 0.35 ng/mL/year when PSA ≤ 2.5 ng/mL.
Some U.S. radiation oncologists and medical oncologists who specialize in treating prostate cancer recommend obtaining a baseline PSA in all men at age 35 or beginning annual PSA testing in high risk men at age 35.
The American Urological Association Patient Guide to Prostate Cancer.

Since there is no general agreement that the benefits of PSA screening outweigh the harms, the consensus is that clinicians use a process of shared decision-making that includes discussing with patients the risks of prostate cancer, the potential benefits and harms of screening, and involving the patients in the decision.

However, because PSA screening is widespread in the United States, following the recommendations of major scientific and medical organizations to use shared decision-making is legally perilous in some U.S. states. In 2003, a Virginia jury found a family practice residency program guilty of malpractice and liable for $1 million for following national guidelines and using shared decision-making, thereby allowing a patient (subsequently found to have a high PSA and incurable advanced prostate cancer) to decline a screening PSA test, instead of routinely ordering without discussion PSA tests in all men ≥ 50 years of age as four local physicians testified was their practice, and was accepted by the jury as the local standard of care.

An estimated 20 million PSA tests are done per year in North America and possibly 20 million more outside of North America.

In 2000, 34.1% of all U.S. men age ≥ 50 had a screening PSA test within the past year and 56.8% reported ever having a PSA test.
In 2000, 33.6% of all U.S. men age 50–64 and 51.3% of men age ≥ 65 had a PSA test within the past year.
In 2005, 33.5% of all U.S. men age 50–64 had a PSA test in the past year.
- 37.5% of men with private health insurance, 20.8% of men with Medicaid insurance, 14.0% of currently uninsured men, and 11.5% of men uninsured for > 12 months.
In 2000–2001, 34.1% of all Canadian men age ≥ 50 had a screening PSA test within the past year and 47.5% reported ever having a screening PSA test.
Canadian men in Ontario were most likely to have had a PSA test within the past year and men in Alberta were least likely to have had a PSA test with the past year or ever.

Digital rectal examination

Digital rectal examination (DRE) is a procedure where the examiner inserts a gloved, lubricated finger into the rectum to check the size, shape, and texture of the prostate. Areas which are irregular, hard or lumpy need further evaluation, since they may contain cancer. Although the DRE only evaluates the back of the prostate, 85% of prostate cancers arise in this part of the prostate. Prostate cancer which can be felt on DRE is generally more advanced. The use of DRE has never been shown to prevent prostate cancer deaths when used as the only screening test.

Prostate specific antigen

The PSA test measures the blood level of prostate-specific antigen, an enzyme produced by the prostate. Specifically, PSA is a serine protease similar to kallikrein. Its normal function is to liquify gelatinous semen after ejaculation, allowing spermatozoa to more easily navigate through the uterine cervix.

The risk of prostate cancer increases with increasing PSA levels. 4 ng/mL was chosen arbitrarily as a decision level for biopsies in the clinical trial upon which the FDA in 1994 based adding prostate cancer detection in men age 50 and over as an approved indication for the first commercially available PSA test. 4 ng/mL was used as the biopsy decision level in the PLCO trial, 3 ng/mL was used in the ERSPC and ProtecT trials, and 2.5 ng/mL is used in the 2007 NCCN guideline.

PSA levels can change for many reasons other than cancer. Two common causes of high PSA levels are enlargement of the prostate (benign prostatic hypertrophy (BPH)) and infection in the prostate (prostatitis). It can also be raised for 24 hours after ejaculation and several days after catheterization. PSA levels are lowered in men who use medications used to treat BPH or baldness. These medications, finasteride (marketed as Proscar or Propecia) and dutasteride (marketed as Avodart), may decrease the PSA levels by 50% or more.

Several other ways of evaluating the PSA have been developed to avoid the shortcomings of simple PSA screening. The use of age-specific reference ranges improves the sensitivity and specificity of the test. The rate of rise of the PSA over time, called the PSA velocity, has been used to evaluate men with PSA levels between 4 and 10 ng/ml, but it has not proven to be an effective screening test. Comparing the PSA level with the size of the prostate, as measured by ultrasound or magnetic resonance imaging, has also been studied. This comparison, called PSA density, is both costly and has not proven to be an effective screening test. PSA in the blood may either be free or bound to other proteins. Measuring the amount of PSA which is free or bound may provide additional screening information, but questions regarding the usefulness of these measurements limit their widespread use.

Diagnosis

Normal prostate (A) and prostate cancer (B). In prostate cancer, the regular glands of the normal prostate are replaced by irregular glands and clumps of cells, as seen in these pictures taken through a microscope.

When a man has symptoms of prostate cancer, or a screening test indicates an increased risk for cancer, more invasive evaluation is offered.

The only test which can fully confirm the diagnosis of prostate cancer is a biopsy, the removal of small pieces of the prostate for microscopic examination. However, prior to a biopsy, several other tools may be used to gather more information about the prostate and the urinary tract. Cystoscopy shows the urinary tract from inside the bladder, using a thin, flexible camera tube inserted down the urethra. Transrectal ultrasonography creates a picture of the prostate using sound waves from a probe in the rectum.

Biopsy

If cancer is suspected, a biopsy is offered. During a biopsy a urologist or radiologist obtains tissue samples from the prostate via the rectum. A biopsy gun inserts and removes special hollow-core needles (usually three to six on each side of the prostate) in less than a second. Prostate biopsies are routinely done on an outpatient basis and rarely require hospitalization. Fifty-five percent of men report discomfort during prostate biopsy.

Gleason score

The tissue samples are then examined under a microscope to determine whether cancer cells are present, and to evaluate the microscopic features (or Gleason score) of any cancer found.

Tumor markers

Tissue samples can be stained for the presence of PSA and other tumor markers in order to determine the origin of maligant cells that have metastasized.

New tests being investigated

Currently, an active area of research involves non-invasive methods of prostate tumor detection. Adenoviruses modified to transfect tumor cells with harmless yet distinct genes (such as luciferase) have proven capable of early detection. So far, though, this area of research has only been tested in animal and LNCaP models.

PCA3

Another potential non-invasive method of early prostate tumor detection is through a molecular test that detects the presence of cell-associated PCA3 mRNA in urine. PCA3 mRNA is expressed almost exclusively by prostate cells and has been shown to be highly over-expressed in prostate cancer cells. PCA3 is not a replacement for PSA but an additional tool to help decide if, in men suspected of having prostate cancer, a biopsy is really needed. The higher the expression of PCA3 in urine, the greater the likelihood of a positive biopsy, i.e. the presence of cancer cells in the prostate. Company Diagnocure has an exclusive worldwide license for all diagnostic and therapeutic applications related to PCA3

Early prostate cancer

It was reported in April 2007 that a new blood test for early prostate cancer antigen-2 (EPCA-2) is being researched that may alert men if they have prostate cancer and how aggressive it will be.

Prostasomes

Epithelial cells of the prostate secrete prostasomes as well as PSA. Prostasomes are membrane –surrounded, prostate-derived organelles that appear extracellularly and one of their physiological functions is to protect the sperm from attacks by the female immune system. Cancerous prostate cells continue to synthesize and secrete prostasomes and may be shielded against immunological attacks by these prostasomes. Research of several aspects of prostasomal involvement in prostate cancer has been performed.

Prostate mapping

Prostate Mapping is a new diagnostic process developed by urology and radiology consultants in the UK. This is a method of diagnosis which may be accurate in determining the precise location and aggressiveness of cancer. It uses a combination of multi-sequence MRI imaging techniques and a template guided biopsy system and involves taking multiple biopsies through the skin that lies in front of the back passage rather than through the back passage. The procedure is carried out under general anaesthetic.

Staging

An important part of evaluating prostate cancer is determining the stage, or how far the cancer has spread. Knowing the stage helps define prognosis and is useful when selecting therapies. The most common system is the four-stage TNM system (abbreviated from Tumor/Nodes/Metastases). Its components include the size of the tumor, the number of involved lymph nodes, and the presence of any other metastases.

The most important distinction made by any staging system is whether or not the cancer is still confined to the prostate. In the TNM system, clinical T1 and T2 cancers are found only in the prostate, while T3 and T4 cancers have spread elsewhere. Several tests can be used to look for evidence of spread. These include computed tomography to evaluate spread within the pelvis, bone scans to look for spread to the bones, and endorectal coil magnetic resonance imaging to closely evaluate the prostatic capsule and the seminal vesicles. Bone scans should reveal osteoblastic appearance due to increased bone density in the areas of bone metastasis - opposite to what is found in many other cancers that metastasize.

Computed tomography (CT) and magnetic resonance imaging (MRI) currently do not add any significant information in the assessment of possible lymph node metastases in patients with prostate cancer according to a meta-analysis. The sensitivity of CT was 42% and specificity of CT was 82%. The sensitivity of MRI was 39% and the specificity of MRI was 82%. For patients at similar risk to those in this study (17% had positive pelvic lymph nodes in the CT studies and 30% had positive pelvic lymph nodes in the MRI studies), this leads to a positive predictive value (PPV) of 32.3% with CT, 48.1% with MRI, and negative predictive value (NPV) of 87.3% with CT, 75.8% with MRI.

After a prostate biopsy, a pathologist looks at the samples under a microscope. If cancer is present, the pathologist reports the grade of the tumor. The grade tells how much the tumor tissue differs from normal prostate tissue and suggests how fast the tumor is likely to grow. The Gleason system is used to grade prostate tumors from 2 to 10, where a Gleason score of 10 indicates the most abnormalities. The pathologist assigns a number from 1 to 5 for the most common pattern observed under the microscope, then does the same for the second most common pattern. The sum of these two numbers is the Gleason score. The Whitmore-Jewett stage is another method sometimes used. Proper grading of the tumor is critical, since the grade of the tumor is one of the major factors used to determine the treatment recommendation.

Risk assessment

Many prostate cancers are not destined to be lethal, and most men will ultimately die from causes other than of the disease. Decisions about treatment type and timing may therefore be informed by an estimation of the risk that the tumor will ultimately recur after treatment and/or progress to metastases and mortality. Several tools are available to help predict outcomes such as pathologic stage and recurrence after surgery or radiation therapy. Most combine stage, grade, and PSA level, and some also add the number or percent of biopsy cores positive, age, and/or other information.

The D’Amico classification stratifies men to low, intermediate, or high risk based on stage, grade, and PSA. It is used widely in clinical practice and research settings. The major downside to the 3-level system is that it does not account for multiple adverse parameters (e.g., high Gleason score and high PSA) in stratifying patients.

The Partin tables predict pathologic outcomes (margin status, extraprostatic extension, and seminal vesicle invasion) based on the same 3 variables, and are published as lookup tables.

The Kattan nomograms predict recurrence after surgery and/or radiation therapy, based on data available either at time of diagnosis or after surgery. The nomograms can be calculated using paper graphs, or using software available on a website or for handheld computers. The Kattan score represents the likelihood of remaining free of disease at a given time interval following treatment.

The UCSF Cancer of the Prostate Risk Assessment (CAPRA) score predicts both pathologic status and recurrence after surgery. It offers comparable accuracy as the Kattan preoperative nomogram, and can be calculated without paper tables or a calculator. Points are assigned based on PSA, Grade, stage, age, and percent of cores positive; the sum yields a 0–10 score, with every 2 points representing roughly a doubling of risk of recurrence. The CAPRA score was derived from community-based data in the CaPSURE database. It has been validated among over 10,000 prostatectomy patients, including patients from CaPSURE; the SEARCH registry, representing data from several Veterans Administration and active military medical centers; a multi-institutional cohort in Germany; and the prostatectomy cohort at Johns Hopkins University.

Treatment

Treatment for prostate cancer may involve watchful waiting, surgery, radiation therapy including brachytherapy (prostate brachytherapy) and external beam radiation, High Intensity Focused Ultrasound (HIFU), chemotherapy, cryosurgery, hormonal therapy, or some combination. Which option is best depends on the stage of the disease, the Gleason score, and the PSA level. Other important factors are the man's age, his general health, and his feelings about potential treatments and their possible side effects. Because all treatments can have significant side effects, such as erectile dysfunction and urinary incontinence, treatment discussions often focus on balancing the goals of therapy with the risks of lifestyle alterations.

The selection of treatment options may be a complex decision involving many factors. For example, radical prostatectomy after primary radiation failure is a very technically challenging surgery and may not be an option. This may enter into the treatment decision.

If the cancer has spread beyond the prostate, treatment options significantly change, so most doctors who treat prostate cancer use a variety of nomograms to predict the probability of spread. Treatment by watchful waiting, HIFU, radiation therapy, cryosurgery, and surgery are generally offered to men whose cancer remains within the prostate. Hormonal therapy and chemotherapy are often reserved for disease which has spread beyond the prostate. However, there are exceptions: radiation therapy may be used for some advanced tumors, and hormonal therapy is used for some early stage tumors. Cryotherapy, hormonal therapy, and chemotherapy may also be offered if initial treatment fails and the cancer progresses.

Active Surveillance

Active Surveillance refers to observation and regular monitoring without invasive treatment. Active surveillance is often used when an early stage, slow-growing prostate cancer is found in an older man. Conversely watchful waiting may also be suggested when the risks of surgery, radiation therapy, or hormonal therapy outweigh the possible benefits. Other treatments can be started if symptoms develop, or if there are signs that the cancer growth is accelerating (e.g., rapidly rising PSA, increase in Gleason score on repeat biopsy, etc.). Most men who choose active surveillance for early stage tumors eventually have signs of tumor progression, and they may need to begin treatment within three years. Although men who choose active surveillance avoid the risks of surgery and radiation, the risk of metastasis (spread of the cancer) may be increased.

For younger men, a trial of active surveillance may not mean avoiding treatment altogether, but may reasonably allow a delay of a few years or more, during which time the quality of life impact of active treatment can be avoided. Published data to date suggest that carefully selected men will not miss a window for cure with this approach. Additional health problems that develop with advancing age during the observation period can also make it harder to undergo surgery and radiation therapy.

Natural Therapy

As an alternative to active surveillance or invasive treatments, which does nothing to change the course of disease, a growing number of clinicians and researchers are looking at non-invasive ways to help men with apparently localized prostate cancer. Perhaps most convincing among this group are Dean Ornish, MD and colleagues, previously made famous for showing that aggressive lifestyle changes can reverse atherosclerosis, and now showing that PSA can be lowered in men with apparent localized prostate cancer using a vegan diet (fish allowed), regular exercise, and stress reduction. These results have so far proven durable after two-years' treatment.

Many other single agents have been shown to reduce PSA, slow PSA doubling times, or have similar effects on secondary markers in men with localized cancer in short term trials, such as the Wonderful variety of pomegranate juice 8 oz daily or genistein, an isoflavone found in various legumes, 60 mg per day. The potential of using multiple such agents in concert, let alone combining them with lifestyle changes, has not yet been studied but the potential is great. This is particularly true because most of these natural approaches have very low adverse effect rates, and in fact tend to help other risk factors and disease conditions such as atherosclerosis, diabetes, and risk for other cancers at the same time they are helping slow down prostate cancer. A more thorough review of natural approaches to prostate cancer has been published.

Surgery

Surgical removal of the prostate, or prostatectomy, is a common treatment either for early stage prostate cancer, or for cancer which has failed to respond to radiation therapy. The most common type is radical retropubic prostatectomy, when the surgeon removes the prostate through an abdominal incision. Another type is radical perineal prostatectomy, when the surgeon removes the prostate through an incision in the perineum, the skin between the scrotum and anus. Radical prostatectomy can also be performed laparoscopically, through a series of small (1cm) incisions in the abdomen, with or without the assistance of a surgical robot.

Radical prostatectomy is effective for tumors which have not spread beyond the prostate; cure rates depend on risk factors such as PSA level and Gleason grade. However, it may cause nerve damage that significantly alters the quality of life of the prostate cancer survivor.

Radical prostatectomy has traditionally been used alone when the cancer is small. In the event of positive margins or locally advanced disease found on pathology, adjuvant radiation therapy may offer improved survival. Surgery may also be offered when a cancer is not responding to radiation therapy. However, because radiation therapy causes tissue changes, prostatectomy after radiation has a higher risk of complications.

Laparoscopic radical prostatectomy, LRP, is a new way to approach the prostate surgically with intent to cure. Contrasted with the open surgical form of prostate cancer surgery, laparoscopic radical prostatectomy does not require a large incision. Relying on modern technology, such as miniaturization, fiber optics, and the like, laparoscopic radical prostatectomy is a minimally invasive prostate cancer treatment.

In the hands of an experienced surgeon, robotic assisted laparoscopic prostatectomy (RALP) may reduce positive surgical margins when compared to radical retropubic prostatectomy (RRP) among patients with prostate cancer according to a retrospective study. The relative risk reduction was 57.7%. For patients at similar risk to those in this study (35.5% of patients had positive surgical margins following RRP), this leads to an absolute risk reduction of 20.5%. 4.9 patients must be treated for one to benefit (number needed to treat = 4.9). The relative merits of RALP and benefits over open radical prostatectomy are an area of intense research currently in urology and no definitive data, that has been widely accepted by the broader urological community, exists to say it is superior to a open radical retropubic prostatectomy.

Transurethral resection of the prostate, commonly called a "TURP," is a surgical procedure performed when the tube from the bladder to the penis (urethra) is blocked by prostate enlargement. TURP is generally for benign disease and is not meant as definitive treatment for prostate cancer. During a TURP, a small instrument (cystoscope) is placed into the penis and the blocking prostate is cut away.

In metastatic disease, where cancer has spread beyond the prostate, removal of the testicles (called orchiectomy) may be done to decrease testosterone levels and control cancer growth. (See hormonal therapy, below).

The most common serious complications of surgery are loss of urinary control and impotence. Reported rates of both complications vary widely depending on how they are assessed, by whom, and how long after surgery, as well as the setting (e.g., academic series vs. community-based or population-based data). Although penile sensation and the ability to achieve orgasm usually remain intact, erection and ejaculation are often impaired. Medications such as sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra) may restore some degree of potency. For most men with organ-confined disease, a more limited "nerve-sparing" technique may help reduce urinary incontinence and impotence.

Radiation therapy

Brachytherapy for prostate cancer is administered using "seeds," small radioactive rods implanted directly into the tumor.

Radiation therapy, also known as radiotherapy, is often used to treat all stages of prostate cancer, or when surgery fails. Radiotherapy uses ionizing radiation to kill prostate cancer cells. When absorbed in tissue, Ionizing radiation such as Gamma and x-rays damage the DNA in cells, which increases the probability of apoptosis (cell death). Two different kinds of radiation therapy are used in prostate cancer treatment: external beam radiation therapy and brachytherapy (specifically prostate brachytherapy).

External beam radiation therapy uses a linear accelerator to produce high-energy x-rays which are directed in a beam towards the prostate. A technique called Intensity Modulated Radiation Therapy (IMRT) may be used to adjust the radiation beam to conform with the shape of the tumor, allowing higher doses to be given to the prostate and seminal vesicles with less damage to the bladder and rectum. External beam radiation therapy is generally given over several weeks, with daily visits to a radiation therapy center. New types of radiation therapy may have fewer side effects than traditional treatment. One of these is Tomotherapy.

External beam radiation therapy for prostate cancer is delivered by a linear accelerator, such as this one.

Permanent implant brachytherapy is a popular treatment choice for patients with low to intermediate risk features, can be performed on an outpatient basis, and is associated with good 10-year outcomes with relatively low morbidity It involves the placement of about 100 small "seeds" containing radioactive material (such as iodine-125 or palladium-103) with a needle through the skin of the perineum directly into the tumor while under spinal or general anesthetic. These seeds emit lower-energy X-rays which are only able to travel a short distance. Although the seeds eventually become inert, they remain in the prostate permanently. The risk of exposure to others from men with implanted seeds is generally accepted to be insignificant.

Radiation therapy is commonly used in prostate cancer treatment. It may be used instead of surgery or after surgery in early stage prostate cancer. In advanced stages of prostate cancer radiation is used to treat painful bone metastases. Radiation treatments also can be combined with hormonal therapy for intermediate risk disease, when radiation therapy alone is less likely to cure the cancer. Some radiation oncologists combine external beam radiation and brachytherapy for intermediate to high risk situations. One study found that the combination of six months of androgen suppressive therapy combined with external beam radiation had improved survival compared to radiation alone in patients with localized prostate cancer. Others use a "triple modality" combination of external beam radiation therapy, brachytherapy, and hormonal therapy.

Radiation therapy uses high-energy rays or particles to kill cancer cells. When delivered in the correct dosage, radiation can reduce the risk of recurrence.

Less common applications for radiotherapy are when cancer is compressing the spinal cord, or sometimes after surgery, such as when cancer is found in the seminal vesicles, in the lymph nodes, outside the prostate capsule, or at the margins of the biopsy.

Radiation therapy is often offered to men whose medical problems make surgery more risky. Radiation therapy appears to cure small tumors that are confined to the prostate just about as well as surgery. However, some issues remain unresolved, such as whether radiation should be given to the rest of the pelvis, how much the absorbed dose should be, and whether hormonal therapy should be given at the same time.

Side effects of radiation therapy might occur after a few weeks into treatment. Both types of radiation therapy may cause diarrhea and mild rectal bleeding due to radiation proctitis, as well as urinary incontinence and impotence. Symptoms tend to improve over time. Rates for impotence when comparing radiation to nerve-sparing surgery are similar. Radiation has lower rates of incontinence but higher rates of occasional mild rectal bleeding. Men who have undergone external beam radiation therapy may have a slightly higher risk of later developing colon cancer and bladder cancer.

Cryosurgery

Cryosurgery is another method of treating prostate cancer in which the prostate gland is exposed to freezing temperatures. It is less invasive than radical prostatectomy, and general anesthesia is less commonly used. Under ultrasound guidance, a method invented by Dr. Gary Onik, metal rods are inserted through the skin of the perineum into the prostate. Highly purified Argon gas is used to cool the rods, freezing the surrounding tissue at −186 °C (−302 °F). As the water within the prostate cells freeze, the cells die. The urethra is protected from freezing by a catheter filled with warm liquid. Cryosurgery generally causes fewer problems with urinary control than other treatments, but impotence occurs up to ninety percent of the time. When used as the initial treatment for prostate cancer and in the hands of an experienced cryosurgeon, cryosurgery has a 10 year biochemical disease free rate superior to all other treatments including radical prostatectomy and any form of radiation. Cryosurgery has also been demonstrated to be superior to radical prostatectomy for recurrent cancer following radiation therapy.

Hormonal therapy

Hormonal therapy in prostate cancer. Diagram shows the different organs (purple text), hormones (black text and arrows), and treatments (red text and arrows) important in hormonal therapy.

Hormonal therapy uses medications or surgery to block prostate cancer cells from getting dihydrotestosterone (DHT), a hormone produced in the prostate and required for the growth and spread of most prostate cancer cells. Blocking DHT often causes prostate cancer to stop growing and even shrink. However, hormonal therapy rarely cures prostate cancer because cancers which initially respond to hormonal therapy typically become resistant after one to two years. Hormonal therapy is therefore usually used when cancer has spread from the prostate. It may also be given to certain men undergoing radiation therapy or surgery to help prevent return of their cancer.

Hormonal therapy for prostate cancer targets the pathways the body uses to produce DHT. A feedback loop involving the testicles, the hypothalamus, and the pituitary, adrenal, and prostate glands controls the blood levels of DHT. First, low blood levels of DHT stimulate the hypothalamus to produce gonadotropin releasing hormone (GnRH). GnRH then stimulates the pituitary gland to produce luteinizing hormone (LH), and LH stimulates the testicles to produce testosterone. Finally, testosterone from the testicles and dehydroepiandrosterone from the adrenal glands stimulate the prostate to produce more DHT. Hormonal therapy can decrease levels of DHT by interrupting this pathway at any point. There are several forms of hormonal therapy:

Orchiectomy is surgery to remove the testicles. Because the testicles make most of the body's testosterone, after orchiectomy testosterone levels drop. Now the prostate not only lacks the testosterone stimulus to produce DHT, but also it does not have enough testosterone to transform into DHT.
Antiandrogens are medications such as flutamide, bicalutamide, nilutamide, and cyproterone acetate which directly block the actions of testosterone and DHT within prostate cancer cells.
Medications which block the production of adrenal androgens such as DHEA include ketoconazole and aminoglutethimide. Because the adrenal glands only make about 5% of the body's androgens, these medications are generally used only in combination with other methods that can block the 95% of androgens made by the testicles. These combined methods are called total androgen blockade (TAB). TAB can also be achieved using antiandrogens.
GnRH action can be interrupted in one of two ways. GnRH antagonists suppress the production of LH directly, while GnRH agonists suppress LH through the process of downregulation after an initial stimulation effect. Abarelix is an example of a GnRH antagonist, while the GnRH agonists include leuprolide, goserelin, triptorelin, and buserelin. Initially, GnRH agonists increase the production of LH. However, because the constant supply of the medication does not match the body's natural production rhythm, production of both LH and GnRH decreases after a few weeks.
A very recent Trial I study (N=21) found that Abiraterone Acetate caused dramatic reduction in PSA levels and Tumor sizes in aggressive end-stage prostate cancer for 70% of patients. This is prostate cancer that resists all other treatments (e.g., castration, other hormones, etc.). Officially the impacts on life-span are not yet known because subjects have not been taking the drug very long. Larger Trial III Clinical Studies are in the works. If successful an approved treatment is hoped for around 2011.

The most successful hormonal treatments are orchiectomy and GnRH agonists. Despite their higher cost, GnRH agonists are often chosen over orchiectomy for cosmetic and emotional reasons. Eventually, total androgen blockade may prove to be better than orchiectomy or GnRH agonists used alone.

Each treatment has disadvantages which limit its use in certain circumstances. Although orchiectomy is a low-risk surgery, the psychological impact of removing the testicles can be significant. The loss of testosterone also causes hot flashes, weight gain, loss of libido, enlargement of the breasts (gynecomastia), impotence and osteoporosis. GnRH agonists eventually cause the same side effects as orchiectomy but may cause worse symptoms at the beginning of treatment. When GnRH agonists are first used, testosterone surges can lead to increased bone pain from metastatic cancer, so antiandrogens or abarelix are often added to blunt these side effects. Estrogens are not commonly used because they increase the risk for cardiovascular disease and blood clots. The antiandrogens do not generally cause impotence and usually cause less loss of bone and muscle mass. Ketoconazole can cause liver damage with prolonged use, and aminoglutethimide can cause skin rashes.

Palliative care

Palliative care for advanced stage prostate cancer focuses on extending life and relieving the symptoms of metastatic disease. As noted above Abiraterone Acetate is showing some promise in treating advance stage prostate cancer. It causes a dramatic reduction in PSA levels and Tumor sizes in aggressive advanced-stage prostate cancer for 70% of patients. Chemotherapy may be offered to slow disease progression and postpone symptoms. The most commonly used regimen combines the chemotherapeutic drug docetaxel with a corticosteroid such as prednisone. Bisphosphonates such as zoledronic acid have been shown to delay skeletal complications such as fractures or the need for radiation therapy in patients with hormone-refractory metastatic prostate cancer.

Bone pain due to metastatic disease is treated with opioid pain relievers such as morphine and oxycodone. External beam radiation therapy directed at bone metastases may provide pain relief. Injections of certain radioisotopes, such as strontium-89, phosphorus-32, or samarium-153, also target bone metastases and may help relieve pain.

High Intensity Focused Ultrasound (HIFU)

HIFU for prostate cancer utilizes high intensity focused ultrasound (HIFU) to ablate/destroy the tissue of the prostate. During the HIFU procedure, sound waves are used to heat the prostate tissue thus destroying the cancerous cells. Essentially, ultrasonic waves are precisely focused on specific areas of the prostate to eliminate the prostate cancer with minimal risks of affecting other tissue or organs. Temperatures at the focal point of the sound waves can exceed 100 °C (212 °F). In lay terms, the HIFU technology is similar to using a magnifying glass to burn a piece of paper by focusing sunlight at a small precise point on the sheet. The ability to focus the ultrasonic waves leads to a relatively low occurrence of both incontinence and impotence. (0.6% and 0-20%, respectively) According to international studies, when compared to other procedures, HIFU has a high success rate with a reduced risk of side effects. Studies using the Sonablate 500 HIFU machine have shown that 94% of patients with a pretreatment PSA (Prostate Specific Antigen) of less than 10 ng/mL were cancer-free after three years. However, many studies of HIFU were performed by manufacturers of HIFU devices, or members of manufacturers' advisory panels.

HIFU was first used in the 1940s and 1950s in efforts to destroy tumors in the central nervous system. Since then, HIFU has been shown to be effective at destroying malignant tissue in the brain, prostate, spleen, liver, kidney, breast, and bone. Today, the HIF procedure for prostate cancer is performed using a transrectal probe. This procedure has been performed for over ten years and is currently approved for use in Japan, Europe, Canada, and parts of Central and South America.

Although not yet approved for use in the Unites States, many patients have received the HIFU procedure at facilities in Canada, and Central and South America. Currently, therapy is available using the Sonablate 500 or the Ablatherm. The Sonablate 500 is designed by Focus Surgery of Indianapolis, Indiana and is used in international HIFU centers around the world.

Prognosis

Prostate cancer rates are higher and prognosis poorer in developed countries than the rest of the world. Many of the risk factors for prostate cancer are more prevalent in the developed world, including longer life expectancy and diets high in red meat and dairy products (although it must be noted, that people who consume larger amounts of meat and dairy, also tend to consume fewer portions of fruits and vegetables. It's not currently known whether or not both of this factors, or just one of them, contributes to the occurrence of prostate cancer). Also, where there is more access to screening programs, there is a higher detection rate. Prostate cancer is the ninth most common cancer in the world, but is the number one non-skin cancer in United States men. Prostate cancer affected eighteen percent of American men and caused death in three percent in 2005. In Japan, death from prostate cancer was one-fifth to one-half the rates in the United States and Europe in the 1990s. In India in the 1990s, half of the people with prostate cancer confined to the prostate died within ten years. African-American men have 50–60 times more prostate cancer and prostate cancer deaths than men in Shanghai, China. In Nigeria, two percent of men develop prostate cancer and 64% of them are dead after two years.

In patients who undergo treatment, the most important clinical prognostic indicators of disease outcome are stage, pre-therapy PSA level and Gleason score. In general, the higher the grade and the stage, the poorer the prognosis. Nomograms can be used to calculate the estimated risk of the individual patient. The predictions are based on the experience of large groups of patients suffering from cancers at various stages.

Progression

In 1941, Charles Huggins reported that androgen ablation therapy causes regression of primary and metastatic androgen-dependent prostate cancer. Androgen ablation therapy causes remission in 80-90% of patients undergoing therapy, resulting in a median progression-free survival of 12 to 33 months. After remission an androgen-independent phenotype typically emerges, where the median overall survival is 23–37 months from the time of initiation of androgen ablation therapy. The actual mechanism contributes to the progression of prostate cancer is not clear and may vary between individual patient. A few possible mechanisms have been proposed. Scientists have established a few prostate cancer cell lines to investigate the mechanism involved in the progression of prostate cancer. LNCaP, PC-3, and DU-145 are commonly used prostate cancer cell lines. The LNCaP cancer cell line was established from a human lymph node metastatic lesion of prostatic adenocarcinoma. PC-3 and DU-145 cells were established from human prostatic adenocarcinoma metastatic to bone and to brain, respectively. LNCaP cells express androgen receptor (AR), however, PC-3 and DU-145 cells express very little or no AR. AR, an androgen-activated transcription factor, belongs to the steroid nuclear receptor family. Development of the prostate is dependent on androgen signaling mediated through AR, and AR is also important during the development of prostate cancer. The proliferation of LNCaP cells is androgen-dependent but the proliferation of PC-3 and DU-145 cells is androgen-insensitive.Elevation of AR expression is often observed in advanced prostate tumors in patients. Some androgen-independent LNCaP sublines have been developed from the ATCC androgen-dependent LNCaP cells after androgen deprivation for study of prostate cancer progression. These androgen-independent LNCaP cells have elevated AR expression and express prostate specific antigen upon androgen treatment. Androgens paradoxically inhibit the proliferation of these androgen-independent prostate cancer cells. Androgen at a concentration of 10-fold higher than the physiological concentration has also been shown to cause growth suppression and reversion of androgen-independent prostate cancer xenografts or androgen-independent prostate tumors derived in vivo model to an androgen-stimulated phenotype in athymic mice. These observation suggest the possibility to use androgen to treat the development of relapsed androgen-independent prostate tumors in patients. Oral infusion of green tea polyphenols, a potential alternative therapy for prostate cancer by natural compounds, has been shown to inhibit the development, progression, and metastasis as well in autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which spontaneously develops prostate cancer.

Epidemiology

Rates of prostate cancer vary widely across the world. Although the rates vary widely between countries, it is least common in South and East Asia, more common in Europe, and most common in the United States. According to the American Cancer Society, prostate cancer is least common among Asian men and most common among black men, with figures for white men in-between. However, these high rates may be affected by increasing rates of detection.

Prostate cancer develops most frequently in men over fifty. This cancer can occur only in men, as the prostate is exclusively of the male reproductive tract. It is the most common type of cancer in men in the United States, where it is responsible for more male deaths than any other cancer, except lung cancer. In the United Kingdom it is also the second most common cause of cancer death after lung cancer, where around 35,000 cases are diagnosed every year and of which around 10,000 die of it. However, many men who develop prostate cancer never have symptoms, undergo no therapy, and eventually die of other causes. That is because malignant neoplasms of the prostate are, in most cases, slow-growing, and because most of those affected are over 60. Hence they often die of causes unrelated to the prostate cancer, such as heart/circulatory disease, pneumonia, other unconnected cancers or old age. Many factors, including genetics and diet, have been implicated in the development of prostate cancer. The Prostate Cancer Prevention Trial found that finasteride reduces the incidence of prostate cancer rate by 30%. There had been a controversy about this also increasing the risk of more aggressive cancers, but more recent research showed this was not the case.

History

Andrzej W. Schally was awarded the 1977 Nobel Prize in Medicine for his research relating to prostate cancer.

Although the prostate was first described by Venetian anatomist Niccolò Massa in 1536, and illustrated by Flemish anatomist Andreas Vesalius in 1538, prostate cancer was not identified until 1853. Prostate cancer was initially considered a rare disease, probably because of shorter life expectancies and poorer detection methods in the 19th century. The first treatments of prostate cancer were surgeries to relieve urinary obstruction. Removal of the entire gland (radical perineal prostatectomy) was first performed in 1904 by Hugh H. Young at Johns Hopkins Hospital. Surgical removal of the testes (orchiectomy) to treat prostate cancer was first performed in the 1890s, but with limited success. Transurethral resection of the prostate (TURP) replaced radical prostatectomy for symptomatic relief of obstruction in the middle of the 20th century because it could better preserve penile erectile function. Radical retropubic prostatectomy was developed in 1983 by Patrick Walsh. This surgical approach allowed for removal of the prostate and lymph nodes with maintenance of penile function.

In 1941 Charles B. Huggins published studies in which he used estrogen to oppose testosterone production in men with metastatic prostate cancer. This discovery of "chemical castration" won Huggins the 1966 Nobel Prize in Physiology or Medicine. The role of the hormone GnRH in reproduction was determined by Andrzej W. Schally and Roger Guillemin, who both won the 1977 Nobel Prize in Physiology or Medicine for this work. Receptor agonists, such as leuprolide and goserelin, were subsequently developed and used to treat prostate cancer.

Radiation therapy for prostate cancer was first developed in the early 20th century and initially consisted of intraprostatic radium implants. External beam radiation became more popular as stronger radiation sources became available in the middle of the 20th century. Brachytherapy with implanted seeds was first described in 1983. Systemic chemotherapy for prostate cancer was first studied in the 1970s. The initial regimen of cyclophosphamide and 5-fluorouracil was quickly joined by multiple regimens using a host of other systemic chemotherapy drugs.

Pituitary adenoma

2008-12-23T08:42:00.000-08:00


Pituitary adenoma

Pituitary adenomas are tumors that occur in the pituitary gland, and account for about 10% of intracranial neoplasms. They often remain undiagnosed, and small pituitary tumors have an estimated prevalence of 16.7% (14.4% in autopsy studies and 22.5% in radiologic studies).

Types

Pituitary tumors were, historically, classed as basophilic, acidophilic, or chromophobic on the basis of whether or not they took up the stains hematoxylin and eosin. This classification has fallen into disuse, in favor of a classification based on what type of hormone is secreted by the tumor (though tumors which do not secrete any active hormone ("non-functioning tumors") are still sometimes called "chromophobic").

At present, classification of pituitary tumors is based on plasma hormone levels or immunohistochemical staining:

Type of adenoma	Secretion	Staining	Pathology
corticotrophic adenomas	secrete adrenocorticotropic hormone (ACTH) and pro-opiomelanocortin (POMC)	basophilic	Cushing's disease
somatotrophic adenomas	secrete growth hormone (GH)	acidophilic	acromegaly (gigantism)
adenomas thyrotrophic (rare)	secrete thyroid-stimulating hormone (TSH)	basophilic	occasionally hyperthyroidism, usually doesn't cause symptoms
gonadotrophic adenomas	secrete luteinizing hormone (LH), follicle-stimulating hormone (FSH) and their subunits	basophilic	usually doesn't cause symptoms
lactrotrophic adenomas or prolactinomas (most common)	secrete prolactin	acidophilic	galactorrhea, hypogonadism, amenorrhea, infertility, and impotence
null cell adenomas	do not secrete hormones	may stain positive for synaptophysin

Diagnosis

The diagnosis is generally entertained either on the basis of visual difficulties arising from the compression of the optic nerve by the tumor, or on the basis of manifestations of excess hormone secretion: the specifics depend on the type of hormone. The specific area of the visual pathway at which compression by these tumours occurs is at the optic chiasma.

The anatomy of this structure causes pressure on it to produce a defect in the temporal visual field on both sides, a condition called bitemporal hemianopia.

Tumors which cause visual difficulty are likely to be macroadenomata greater than 10 mm in diameter; tumors less than 10 mm are microadenomata.

Some tumors secrete more than one hormone, the most common combination being GH and prolactin.

Prolactinomas are frequently diagnosed during pregnancy, when the hormone progesterone increases the tumor's growth rate. Headaches may be present. The diagnosis is confirmed by testing hormone levels, and by radiographic imaging of the pituitary (for example, by CT scan or MRI).

Treatment

Treatment options depend on the type of tumor and on its size:

Prolactinomas are most often treated with bromocriptine or more recently, cabergoline which, unlike bromocriptine, decreases tumor size as well as alleviates symptoms, both dopamine agonists, and followed by serial imaging to detect any increase in size. Treatment where the tumor is large can be with radiation therapy or surgery, and patients generally respond well. Efforts have been made to use a progesterone antagonist for the treatment of prolactinomas, but so far have not proved successful.
Thyrotrophic adenomas respond to octreotide, a long-acting somatostatin analog, in many but not all cases according to a review of the medical literature. Unlike prolactinomas, thyrotrophic adenomas characteristically respond poorly to dopamine agonist treatment.

Additional images

Pinealoma

2008-12-23T08:38:00.000-08:00


Pinealoma
Pineocytoma

Pinealoma is a tumor of the pineal gland.

Presentation

The pineal gland produces the hormone melatonin which plays a role in regulating circadian rhythms. A pinealoma may disrupt production of this hormone, and insomnia may result.

Frequently, paralysis of upward gaze along with several ocular findings known collectively as Parinaud's syndrome are the only physical symptoms seen. This is caused by the compression of the vertical gaze center in the midbrain tectum at the level of the superior colliculus and cranial nerve III. Patients may also present with pupillary disturbances and eyelid retraction (Collier's sign).

A pinealoma may cause interruption of hypothalamic inhibiting pathways, sometimes leading to beta-hCG secretion and consequent Leydig's cell stimulation.

Other symptoms may include hydrocephalus, gait disturbances, and precocious puberty.

Etiology

Pinealomas can be due to proliferation of primary pineocytes (pineocytomas, pineoblastomas), astrocytes (astrocytoma), or germ cells (germinoma). Germinomas are the most common tumor in the pineal gland.

Prognosis

Of the different types of pinealomas, the type with the most favorable prognosis is the pineocytoma.

References

^ "eMedicine - Germinoma, Central Nervous System : Article by Daniel D Mais, MD". Retrieved on 2007-12-03.
^ Deshmukh VR, Smith KA, Rekate HL, Coons S, Spetzler RF (2004). "Diagnosis and management of pineocytomas". Neurosurgery 55 (2): 349–55; discussion 355–7. PMID 15271241.

Additional images

Carcinoma of the penis

2008-12-23T08:33:00.000-08:00

Carcinoma of the penis

Penile cancer is a malignant growth found on the skin or in the tissues of the penis. It is known to be most prominent among men who participate in dance. A Squamous cell carcinoma usually originating in the glans or foreskin is by far the most common type, occurring in 9 out of 10 cases. Penile cancer is very rare in Europe and North America, occurring in about one in 100,000 men in the latter. It accounts for 0.2% of cancers and 0.1% of deaths from cancer amongst males in the United States. However, in some parts of Africa and South America it accounts for up to 10% of cancers in men.

Symptoms

Redness, irritation, or a sore on the penis or a lump on the penis. Anyone with these symptoms should consult a doctor immediately.

Pathology

A. Precancerous Dermatologic Lesions
B. Carcinoma in Situ (Bowen Disease, Erythroplasia of Queyrat)
C. Invasive Carcinoma of the Penis

Staging

Like many malignancies, penile cancer can spread to other parts of the body. It is usually a primary malignancy, the initial place from which a cancer spreads in the body. Much less often it is a secondary malignancy, one in which the cancer has spread to the penis from elsewhere. Doctors use the extent of metastasis to estimate what stage the disease is in, to aid in treatment decisions and prognosis. The stages are assessed as follows:

Stage I - Cancer has only affected the glans and/or foreskin.
Stage II - Cancer has spread to the shaft of the penis.
Stage III - Cancer has affected the penis and surrounding lymph nodes.
Stage IV - Cancer has moved beyond the groin area to other parts of the body.
Recurrent - Cancer that has returned after treatment.

Prognosis can range considerably for patients, depending where on the scale they have been staged. Generally speaking, the earlier the cancer is diagnosed, the better the prognosis. The overall 5-year survival rate for all stages of penile cancer is about 50%.

Treatment

There are several treatment options for penile cancer, depending on staging. They include surgery, radiation therapy, chemotherapy, and biological therapy. The most common treatment is one of five types of surgery:

Wide local excision - The tumor and some surrounding healthy tissue are removed
Microsurgery - Surgery performed with a microscope is used to remove the tumor and as little healthy tissue as possible
Laser surgery - laser light is used to burn or cut away cancerous cells
Circumcision - cancerous foreskin is removed
Amputation (penectomy) - a partial or total removal of the penis, and possibly the associated lymph nodes. This is the most common and effective treatment.

Radiation therapy is usually used adjuvantly with surgery to reduce the risk of recurrence. With earlier stages of penile cancer, a combination of topical chemotherapy and less invasive surgery may be used. More advanced stages of penile cancer usually require a combination of surgery, radiation and chemotherapy.

Risk factors

The exact cause of penile cancer is unknown. The American Cancer Society provides the following as risk factors for penile cancer: human papillomavirus (HPV) infection, smoking, smegma, phimosis, treatment of psoriasis, age, and AIDS. The other etiologic factor most commonly associated with penile carcinoma is poor hygiene. There is some evidence that lichen sclerosus (also known as balanitis xerotica obliterans) may also be a risk factor.

Circumcision

There has been some debate over whether circumcision is a form of prevention.

The American Medical Association and the Royal Australasian College of Physicians say the use of infant circumcision in hope of preventing penile cancer in adulthood is not justified. The American Cancer Society has said that the suggestion that circumcision reduces penile cancer rates, were based on studies that were flawed because they failed to consider other factors that are now known to affect penile cancer risk. It concluded: "The current consensus of most experts is that circumcision should not be recommended as a prevention strategy for penile cancer."

One study reported a lifetime risk of a man in the United States developing invasive penile cancer (IPC) to be 1 in 600 if he is uncircumcised. though this study has been criticised. Several studies report that the risk is higher if a male was not circumcised neonatally, with relative risk estimates including 3.2 and 22 associated with the presence of a foreskin, and 0.41 associated with its absence. Several authors also state that there is a lower incidence of penile cancer in circumcised men. A few studies suggested that circumcision decreased the risk of HPV infection in males. A study that concluded circumcision did not prevent penile cancer was done by Wallerstein, which reported that the risk of penile cancer in Japan, Norway, and Sweden (countries with a low rate of circumcision) is about the same (1 in 100,000 per year) as in the US.

Vaccine

Infection with HPV is associated with some penile cancers. A quadri-valent vaccine (Gardasil) to prevent infection by some types of HPV has been developed, successfully tested and approved for women by the US Food and Drug Administration. Approval for men is expected in 2008. It is licensed and in production, and could substantially reduce the incidence of HPV infection in men, the incidence of genital warts and ano-genital cancers including penile cancer, and mortality.

Germ cell tumor

2008-12-23T08:21:00.000-08:00

Germ cell tumor

A germ cell tumor (GCT) is a neoplasm derived from germ cells. Germ cells normally occur inside the gonads (ovary and testis). Germ cell tumors that originate outside the gonads may be birth defects resulting from errors during development of the embryo.

Etiology

Some investigators suggest that this distribution arises as a consequence of abnormal migration of germ cells during embryogenesis. Others hypothesize a widespread distribution of germ cells to multiple sites during normal embryogenesis, with these cells conveying genetic information or providing regulatory functions at somatic sites.

Extragonadal germ cell tumors were thought initially to be isolated metastases from an undetected primary tumor in a gonad, but it is now known that many germ cell tumors are congenital and originate outside the gonads. The most notable of these is sacrococcygeal teratoma, the single most common tumor diagnosed in babies at birth.

Classification

Germ cell tumors are classified by their histology, regardless of location in the body.

Tumor	ICD-O	Peak Age (yr)	Benign or malignant	Histology	Tumor marker
Germinoma including dysgerminoma and seminoma	9060/3	40-50	Malignant	Sheets of uniform polygonal cells with cleared cytoplasm; lymphocytes in the stroma	10% have elevated hCG
Embryonal carcinoma	9070/3	20-30	Malignant	Poorly differentiated, pleomorphic cells in cords, sheets, or papillary formation	Pure tumors do not secrete hCG, AFP
Endodermal sinus tumor, also known as yolk sac tumor (EST, YST)	9071/3	3	Malignant	Poorly differentiated endothelium-like, cuboidal, or columnar cells	100% secrete AFP
Choriocarcinoma	9100/3	20-30	Malignant	Cytotrophoblast and syncytiotrophoblast without villus formation	100% secrete hCG
Teratoma including mature teratoma, dermoid cyst, immature teratoma, teratoma with malignant transformation	9080/0-9080/3	0-3, 15-30	Mature teratoma, dermoid cyst usually benign (but follow-up required); others usually malignant	Very variable, but "normal" tissues are common	Pure tumors do not secrete hCG, AFP
Polyembryoma	9072/3	15-25	?	?	?
Gonadoblastoma	9073/1	?	?	?	?
Mixed		15-30	Malignant	Depends on elements present	Depends on elements present

Germ cell tumors are broadly divided in two classes:

The germinomatous or seminomatous germ cell tumors (GGCT, SGCT) include only germinoma and its synonyms dysgerminoma and seminoma.
The nongerminomatous or nonseminomatous germ cell tumors (NGGCT, NSGCT) include all other germ cell tumors, pure and mixed.

The two classes reflect an important clinical difference. Compared to germinomatous tumors, nongerminomatous tumors tend to grow faster, have an earlier mean age at time of diagnosis (~25 years versus ~35 years, in the case of testicular cancers), and have a lower 5 year survival rate. The survival rate for germinomatous tumors is higher in part because these tumors are exquisitely sensitive to radiation, and they also respond well to chemotherapy. The prognosis for nongerminomatous has improved dramatically, however, due to the use of platinum-based chemotherapy regimens.

Mixed

Mixed germ cell tumors occur in many forms. Among these, a common form is teratoma with endodermal sinus tumor.

Teratocarcinoma refers to a germ cell tumor that is a mixture of teratoma with embryonal carcinoma, or with choriocarcinoma, or with both. This kind of mixed germ cell tumor may be known simply as a teratoma with elements of embryonal carcinoma or choriocarcinoma, or simply by ignoring the teratoma component and referring only to its malignant component: embryonal carcinoma and/or choriocarcinoma.

Location

Despite their name, germ cell tumors occur both within and outside the ovary and testis.

- inside the cranium — pineal and suprasellar locations are most commonly reported
- inside the mouth — a fairly common location for teratoma
1% to 5% in the mediastinum (mediastinal germ cell tumor)
pelvis, particularly sacrococcygeal teratoma

In females, germ cell tumors account for 30% of ovarian tumors, but only 1 to 3% of ovarian cancers in North America. In younger women germ cell tumors are more common, thus in patients under the age of 21, 60% of ovarian tumors are of the germ cell type, and up to one-third are malignant. In males, germ cell tumors of the testis occur typically after puberty and are malignant (testicular cancer). In neonates, infants, and children younger than 4 years, the majority of germ cell tumors are sacrococcygeal teratomas.

Males with Klinefelter's syndrome have a 50 times greater risk of germ cell tumors (GSTs). In these persons, GSTs usually contain nonseminomatous elements, present at an earlier age, and seldom are gonadal in location.

Prognosis

The 1997 International Germ Cell Consensus Classification is a tool for estimating the risk of relapse after treatment of malignant germ cell tumor.

A small study of ovarian tumors in girls reports a correlation between cystic and benign tumors and, conversely, solid and malignant tumors. Because the cystic extent of a tumor can be estimated by ultrasound, MRI, or CT scan before surgery, this permits selection of the most appropriate surgical plan to minimize risk of spillage of a malignant tumor.

Research

Germ cell tumors of children are the subject of clinical research by the worldwide Children's Oncology Group (COG), in a number of studies coordinated by Dr. John Cullen, MD.

Intracranial Germ Cell Tumors have been studied through the International CNS GCT Study Group. Under the direction of Jonathan Finlay, the program director, three international treatment studies have been initiated since 1990 with the goal to maintain a high rate of cure while minimizing the late effects of treatment.

Ovarian cancer

2008-12-23T08:11:00.000-08:00


Ovarian cancer (human)
Scheme showing the ovaries and other parts of the female reproductive system.

Ovarian cancer is a cancerous growth arising from an ovary. Although ovarian cancer is known to occur in many species, the majority of the medical literature and the focus of this article is on ovarian cancer in humans.

Ovarian cancer most commonly forms in the lining of the ovary (resulting in epithelial ovarian cancer) or in the egg cells (resulting in a germ cell tumor). Ovarian cancer is the fifth leading cause of death from cancer in women and the leading cause of death from gynecological cancer. A woman has a lifetime risk of ovarian cancer of around 1.5%, which makes it the second most common gynecologic malignancy (the first being breast cancer).

Ovarian cancer has been named 'the silent killer' because it frequently causes non-specific symptoms, which contribute to diagnostic delay, diagnosis in a late stage and a poor prognosis. Most women with ovarian cancer report one or more symptoms such as abdominal pain or discomfort, an abdominal mass, bloating, back pain, urinary urgency, constipation, tiredness and a range of other non-specific symptoms, as well as more specific symptoms such as pelvic pain, abnormal vaginal bleeding or involuntary weight loss. There can be a build-up of fluid in the abdominal cavity (this is called ascites).

The diagnosis of ovarian cancer can be suspected from an abnormal physical examination (including a pelvic examination), a blood test (for CA-125, more specifically) or from medical imaging studies. The diagnosis can be confirmed with a surgical procedure (open or keyhole surgery) to inspect the abdominal cavity, take biopsies (tissue samples for microscopic analysis) and look for cancer cells in the abdominal fluid. Treatment usually involves chemotherapy and surgery, and sometimes radiotherapy.

In most cases, the cause of ovarian cancer remains unknown. There is an increased risk of ovarian cancer in older women and in those who have a first or second degree relative with the disease. Hereditary forms of ovarian cancer can be caused by mutations in specific genes (most notably BRCA1 and BRCA2, but also in genes for hereditary nonpolyposis colorectal cancer). Infertile women and those with a condition called endometriosis, those who have never been pregnant and those who use postmenopausal estrogen replacement therapy are at increased risk. Use of oral contraceptive pills is a protective factor. The risk is also lower in women who have had their uterine tubes blocked surgically (tubal ligation).

Epidemiology

The exact cause is usually unknown. The disease is more common in industrialized nations, with the exception of Japan. In the United States, females have a 1.4% to 2.5% (1 out of 40-60 women) lifetime chance of developing ovarian cancer. Older women are at highest risk. More than half of the deaths from ovarian cancer occur in women between 55 and 74 years of age and approximately one quarter of ovarian cancer deaths occur in women between 35 and 54 years of age.

The risk of developing ovarian cancer appears to be affected by several factors. The more children a woman has, the lower her risk of ovarian cancer. Early age at first pregnancy, older ages of final pregnancy and the use of low dose hormonal contraception have also been shown to have a protective effect. Ovarian cancer is reduced in women after tubal ligation.

The relationship between use of oral contraceptives and ovarian cancer was shown in a summary of results of 45 case-control and prospective studies. Cumulatively these studies show a protective effect for ovarian cancers. Women who used oral contraceptives for 10 years had about a 60% reduction in risk of ovarian cancer. (risk ratio .42 with statistical significant confidence intervals given the large study size, not unexpected). This means that if 250 women took oral contraceptives for 10 years, 1 ovarian cancer would be prevented. This is by far the largest epidemiological study to date on this subject (45 studies, over 20,000 women with ovarian cancer and about 80,000 controls).

The link to the use of fertility medication, such as Clomiphene citrate, has been controversial. An analysis in 1991 raised the possibility that use of drugs may increase the risk of ovarian cancer. Several cohort studies and case-control studies have been conducted since then without providing conclusive evidence for such a link. It will remain a complex topic to study as the infertile population differs in parity from the "normal" population.

There is good evidence that in some women genetic factors are important. Carriers of certain mutations of the BRCA1 or the BRCA2 gene. The BRCA1 and BRCA2 gene account for 5%-13% of ovarian cancers and certain populations (e.g. Ashkenazi Jewish women) are at a higher risk of both breast cancer and ovarian cancer, often at an earlier age than the general population. Patients with a personal history of breast cancer or a family history of breast and/or ovarian cancer, especially if at a young age, may have an elevated risk.

A strong family history of uterine cancer, colon cancer, or other gastrointestinal cancers may indicate the presence of a syndrome known as hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch II syndrome), which confers a higher risk for developing ovarian cancer. Patients with strong genetic risk for ovarian cancer may consider the use of prophylactic i.e. preventative oophorectomy after completion of childbearing.

A Swedish study, which followed more than 61,000 women for 13 years, has found a significant link between milk consumption and ovarian cancer. According to the BBC, "[Researchers] found that milk had the strongest link with ovarian cancer - those women who drank two or more glasses a day were at double the risk of those who did not consume it at all, or only in small amounts." Recent studies have shown that women in sunnier countries have a lower rate of ovarian cancer, which may have some kind of connection with exposure to Vitamin D.

Other factors that have been investigated, such as talc use, asbestos exposure, high dietary fat content, and childhood mumps infection, are controversial and have not been definitively proven.

"Associations were also found between alcohol consumption and cancers of the ovary and prostate, but only for 50 g and 100 g a day."

Classification

A benign tumor of the ovary, discovered during a C-section; this is a 4 cm teratoma

Ovarian cancer is classified according to the histology of the tumor, obtained in a pathology report. Histology dictates many aspects of clinical treatment, management, and prognosis.

Surface epithelial-stromal tumour, also known as ovarian epithelial carcinoma, is the most common type of ovarian cancer. It includes serous tumour, endometrioid tumor and mucinous cystadenocarcinoma.
Sex cord-stromal tumor, including estrogen-producing granulosa cell tumor and virilizing Sertoli-Leydig cell tumor or arrhenoblastoma, accounts for 8% of ovarian cancers.
Germ cell tumor accounts for approximately 30% of ovarian tumors but only 5% of ovarian cancers, because most germ cell tumors are teratomas and most teratomas are benign (see Teratoma). Germ cell tumor tends to occur in young women and girls. The prognosis depends on the specific histology of germ cell tumor, but overall is favorable.
Mixed tumors, containing elements of more than one of the above classes of tumor histology.

Ovarian cancer can also be a secondary cancer, the result of metastasis from a primary cancer elsewhere in the body. Common primary cancers are breast cancer and gastrointestinal cancer (in which case the ovarian cancer is a Krukenberg cancer). Surface epithelial-stromal tumor can originate in the peritoneum (the lining of the abdominal cavity), in which case the ovarian cancer is secondary to primary peritoneal cancer, but treatment is basically the same as for primary surface epithelial-stromal tumor involving the peritoneum.

Symptoms

Studies on the accuracy of symptoms

Two case-control studies, both subject to results being inflated by spectrum bias, have been reported. The first found that women with ovarian cancer had symptoms of increased abdominal size, bloating, urge to pass urine and pelvic pain. The smaller, second study found that women with ovarian cancer had pelvic/abdominal pain, increased abdominal size/bloating, and difficulty eating/feeling full. The latter study created a symptom index that was considered positive if any of the six (6) symptoms "occurred >12 times per month but were present for <1>

Ovarian Cancer Symptoms Consensus Statement

In 2007, the Gynecologic Cancer Foundation, Society of Gynecologic Oncologists and American Cancer Society originated the following consensus statement regarding the symptoms of ovarian cancer.

Ovarian cancer is called a “silent killer” because symptoms were not thought to develop until the disease had advanced and the chance of cure or remission poor. However, the following symptoms are much more likely to occur in women with ovarian cancer than women in the general population. These symptoms include:

Bloating
Pelvic or abdominal pain
Difficulty eating or feeling full quickly
Urinary symptoms (urgency or frequency)
Pain during sex

Women with ovarian cancer report that symptoms are persistent and represent a change from normal for their bodies. The frequency and/or number of such symptoms are key factors in the diagnosis of ovarian cancer. Several studies show that even early stage ovarian cancer can produce these symptoms. Women who have these symptoms almost daily for more than a few weeks should see their doctor, preferably a gynecologist. Prompt medical evaluation may lead to detection at the earliest possible stage of the disease. Early stage diagnosis is associated with an improved prognosis.

Several other symptoms have been commonly reported by women with ovarian cancer. These symptoms include fatigue, indigestion, back pain, pain with intercourse, constipation and menstrual irregularities. However, these other symptoms are not as useful in identifying ovarian cancer because they are also found in equal frequency in women in the general population who do not have ovarian cancer.

Diagnosis

Ovarian cancer at its early stages(I/II) is difficult to diagnose until it spreads and advances to later stages (III/IV). This is due to the fact that most of the common symptoms are non-specific.

When an ovarian malignancy is included in the list of diagnostic possibilities, a limited number of laboratory tests are indicated. A complete blood count (CBC) and serum electrolyte test should be obtained in all patients.

The serum BHCG level should be measured in any female in whom pregnancy is a possibility. In addition, serum alpha-fetoprotein (AFP) and lactate dehydrogenase (LDH) should be measured in young girls and adolescents with suspected ovarian tumors because the younger the patient, the greater the likelihood of a malignant germ cell tumor.

A blood test called CA-125 is useful in differential diagnosis and in follow up of the disease, but it has not been shown to be an effective method to screen for early-stage ovarian cancer due to its unacceptable low sensitivity and specificity. However, this is the only available, widely-used marker currently.

Current research is looking at ways to combine tumor markers proteomics along with other indicators of disease (i.e. radiology and/or symptoms) to improve accuracy. The challenge in such an approach is that the very low population prevalence of ovarian cancer means that even testing with very high sensitivity and specificity will still lead to a number of false positive results (i.e. performing surgical procedures in which cancer is not found intra-operatively). However, the contributions of proteomics are still in the early stages and require further refining. Current studies on proteomics mark the beginning of a paradigm shift towards individually tailored therapy.

A pelvic examination and imaging including CT scan and trans-vaginal ultrasound are essential. Physical examination may reveal increased abdominal girth and/or ascites (fluid within the abdominal cavity). Pelvic examination may reveal an ovarian or abdominal mass. The pelvic examination can include a rectovaginal component for better palpation of the ovaries. For very young patients, magnetic resonance imaging may be preferred to rectal and vaginal examination.

To definitively diagnose ovarian cancer, a surgical procedure to take a look into the abdomen is required. This can be an open procedure (laparotomy, incision through the abdominal wall) or keyhole surgery (laparoscopy). During this procedure, suspicious areas will be removed and sent for microscopic analysis. Fluid from the abdominal cavity can also be analysed for cancerous cells. If there is cancer, this procedure can also determine its spread (which is a form of tumor staging).

Staging

Ovarian cancer staging is by the FIGO staging system and uses information obtained after surgery, which can include a total abdominal hysterectomy, removal of (usually) both ovaries and fallopian tubes, (usually) the omentum, and pelvic (peritoneal) washings for cytology. The AJCC stage is the same as the FIGO stage.

Stage I - limited to one or both ovaries
- IA - involves one ovary; capsule intact; no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings
- IB - involves both ovaries; capsule intact; no tumor on ovarian surface; negative washings
- IC - tumor limited to ovaries with any of the following: capsule ruptured, tumor on ovarian surface, positive washings
Stage II - pelvic extension or implants
- IIA - extension or implants onto uterus or fallopian tube; negative washings
- IIB - extension or implants onto other pelvic structures; negative washings
- IIC - pelvic extension or implants with positive peritoneal washings
Stage III - microscopic peritoneal implants outside of the pelvis; or limited to the pelvis with extension to the small bowel or omentum
- IIIA - microscopic peritoneal metastases beyond pelvis
- IIIB - macroscopic peritoneal metastases beyond pelvis less than 2 cm in size
- IIIC - peritoneal metastases beyond pelvis > 2 cm or lymph node metastases
Stage IV - distant metastases to the liver or outside the peritoneal cavity

Para-aortic lymph node metastases are considered regional lymph nodes (Stage IIIC).

Treatment

Surgical treatment may be sufficient for malignant tumors that are well-differentiated and confined to the ovary. Addition of chemotherapy may be required for more aggressive tumors that are confined to the ovary. For patients with advanced disease a combination of surgical reduction with a combination chemotherapy regimen is standard. Borderline tumors, even following spread outside of the ovary, are managed well with surgery, and chemotherapy is not seen as useful.

Surgery is the preferred treatment and is frequently necessary to obtain a tissue specimen for differential diagnosis via its histology. Surgery performed by a specialist in gynecologic oncology usually results in an improved result. Improved survival is attributed to more accurate staging of the disease and a higher rate of aggressive surgical excision of tumor in the abdomen by gynecologic oncologists as opposed to general gynecologists and general surgeons.

The type of surgery depends upon how widespread the cancer is when diagnosed (the cancer stage), as well as the presumed type and grade of cancer. The surgeon may remove one (unilateral oophorectomy) or both ovaries (bilateral oophorectomy), the fallopian tubes (salpingectomy), and the uterus (hysterectomy). For some very early tumors (stage 1, low grade or low-risk disease), only the involved ovary and fallopian tube will be removed (called a "unilateral salpingo-oophorectomy," USO), especially in young females who wish to preserve their fertility.

In advanced malignancy, where complete resection is not feasible, as much tumor as possible is removed (debulking surgery). In cases where this type of surgery is successful (i.e. <> 1 cm in diameter) are left behind. Minimally invasive surgical techniques may facilitate the safe removal of very large (greater than 10 cm) tumors with fewer complications of surgery.

Chemotherapy has been a general standard of care for ovarian cancer for decades, although with highly variable protocols. Chemotherapy is used after surgery to treat any residual disease, if appropriate. This depends on the histology of the tumor; some kinds of tumor (particularly teratoma) are not sensitive to chemotherapy. In some cases, there may be reason to perform chemotherapy first, followed by surgery.

For patients with stage IIIC epithelial ovarian adenocarcinomas who have undergone successful optimal debulking, a recent clinical trial demonstrated that median survival time is significantly longer for patient receiving intraperitoneal (IP) chemotherapy. Patients in this clinical trial reported less compliance with IP chemotherapy and fewer than half of the patients received all six cycles of IP chemotherapy. Despite this high "drop-out" rate, the group as a whole (including the patients that didn't complete IP chemotherapy treatment) survived longer on average than patients who received intravenous chemotherapy alone.

Some specialists believe the toxicities and other complications of IP chemotherapy will be unnecessary with improved IV chemotherapy drugs currently being developed.

Although IP chemotherapy has been recommended as a standard of care for the first-line treatment of ovarian cancer, the basis for this recommendation has been challenged.

Radiation therapy is not effective for advanced stages because when vital organs are in the radiation field, a high dose cannot be safely delivered.

Prognosis

Ovarian cancer usually has a poor prognosis. It is disproportionately deadly because it lacks any clear early detection or screening test, meaning that most cases are not diagnosed until they have reached advanced stages. More than 60% of patients presenting with this cancer already have stage III or stage IV cancer, when it has already spread beyond the ovaries. Ovarian cancers shed cells into the naturally occurring fluid within the abdominal cavity. These cells can implant on other abdominal (peritoneal) structures, included the uterus, urinary bladder, bowel and the lining of the bowel wall (omentum). These cells can begin forming new tumor growths before cancer is even suspected.

More than 50% of women with ovarian cancer are diagnosed in the advanced stages of the disease because no cost-effective screening test for ovarian cancer exists. The 5 year survival rate for all stages is only 35% to 38%. If a diagnosis is made early in the disease, five-year survival rates can reach 90% to 98%.

Germ cell tumors of the ovary have a much better prognosis than other ovarian cancers, in part because they tend to grow rapidly to a very large size, hence they are detected sooner.

Complications

Spread of the cancer to other organs
Progressive function loss of various organs
Ascites (fluid in the abdomen)
Intestinal obstructions

These cells can implant on other abdominal (peritoneal) structures, including the uterus, urinary bladder, bowel, lining of the bowel wall (omentum) and, less frequently, to the lungs.

Ovarian cancer in non-humans

Ovarian tumors have been reported in mares. Reported tumor types include teratoma, cystadenocarcinoma, and particularly granulosa cell tumor.

Neuroblastoma

2008-12-23T07:58:00.000-08:00


Neuroblastoma, NOS
microscopic view of a typical neuroblastoma with rosette formation

Sympathetic nervous system

Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 new cases per year in the US. Close to 50 percent of neuroblastoma cases occur in children younger than two years old. It is a neuroendocrine tumor, arising from any neural crest element of the sympathetic nervous system or SNS. A branch of the autonomic nervous system, the SNS is a nerve network that carries messages from the brain throughout the body and is responsible for the fight-or-flight response and production of adrenaline or epinephrine. Its solid tumors, which take the form of a lump or mass, commonly begin in one of the adrenal glands, though they can also develop in nerve tissues in the neck, chest, abdomen, or pelvis. Esthesioneuroblastoma, also known as olfactory neuroblastoma, is believed to arise from the olfactory epithelium and classification remains controversial. Since it is not a sympathetic nervous system malignancy it is a distinct clinical entity not to be confused with neuroblastoma.

The cause of neuroblastoma is unknown, though most physicians believe that it is an accidental cell growth that occurs during normal development of the adrenal glands.

Neuroblastoma is one of the rare human malignancies known to demonstrate spontaneous regression from an undifferentiated state to a completely benign cellular appearance.

Epidemiology

Neuroblastoma comprises 6-10% of all childhood cancers, and 15% of cancer deaths in children. The annual mortality rate is 10 per million children in the 0- to 4-year-old age group, and 4 per million in the 4- to 9-year old age group.

The highest incidence is in the first year of life, and some cases are congenital. The age range is broad, including older children and adults, but only 10% of cases occur in people older than 5 years of age.

Etiology

The etiology of neuroblastoma is not well understood. Several risk factors have been proposed and are the subject of ongoing research. Due to characteristic early onset many studies have focused on parental factors around conception and during gestation. Factors investigated have included occupation (i.e. exposure to chemicals in specific industries), smoking, alcohol consumption, use of medicinal drugs during pregnancy and birth factors, however results have been inconsistent.

Other studies have examined possible links with atopy and exposure to infection early in life, use of hormones and fertility drugs, and maternal use of hair dye.

Diagnosis

MRI showing orbital and skull vault metastatic NB in 2 year old

MIBG showing metastatic NB (salivary glands, liver, and bladder concentrate MIBG)

The first symptoms of neuroblastoma are often vague and may include fatigue, loss of appetite, and fever. Later symptoms depend on tumor locations:

In the abdomen, a tumor may cause a swollen belly and constipation.
A tumor in the chest may cause breathing problems.
Tumors pressing on the spinal cord cause a feeling of weakness.
Bone lesions in the legs and hips often cause bone pain and limping.
A tumor in the head may cause the eyes to start to swell outwards and turn black due to the pressure from behind.

Often because symptoms are so unclear, 50 to 60% of all neuroblastomas have already spread (metastasized) to other parts of the body by the time a diagnosis is made.

The diagnosis is usually confirmed by a surgical pathologist, taking into account the clinical presentation, microscopic findings, and other laboratory tests. On microscopy, the tumor cells are typically described as small, round and blue, and rosette patterns (Homer-Wright pseudo-rosettes) may be seen. A variety of immunohistochemical stains are used by pathologists to distinguish neuroblastomas from histological mimics, such as rhabdomyosarcoma, Ewing's sarcoma, lymphoma and Wilms' tumor. In February 2007, Althea Technologies announced the development of a molecular diagnostic capable of clearly differentiating various types of childhood cancers, developed in cooperation with the U.S. National Cancer Institute (NCI).

In about 90% of cases of neuroblastoma, elevated levels of catecholamines or its metabolites are found in the urine or blood. Catecholamines and their metabolites include dopamine, homovanillic acid (HVA), and/or vanillylmandelic acid (VMA).

Another way to detect neuroblastoma is the mIBG scan (meta-iodobenzylguanidine), which is taken up by 90 to 95% of all neuroblastomas, often termed "mIBG-avid." The mechanism is that mIBG is taken up by sympathetic neurons, and is a functioning analog of the neurotransmitter norepinephrine. When it is radio-ionated with I-131 or I-123 (radioactive iodine isotopes), it is a very good radiopharmaceutical for diagnosis and monitoring of response to treatment for this disease. With a half-life of 13 hours, I-123 is the preferred isotope for imaging sensitivity and quality. I-131 has a half-life of 8 days and at higher doses is an effective therapy as targeted radiation against relapsed and refractory neuroblastoma.

Histology

microscopic view of stroma-rich ganglioneuroblastoma

Neuroblastoma is one of the peripheral neuroblastic tumors (pNTs) that have similar origins and show a wide pattern of differentiation ranging from benign ganglioneuroma to stroma-rich ganglioneuroblastoma with differentiating neuroblastic cells intermixed or in nodules, to highly malignant neuroblastoma. This distinction in the pre-treatment tumor pathology is an important prognostic factor, along with age and mitosis-karyorrhexis index (MKI). This pathology classification system describes "favorable" and "unfavorable" tumors by the International Neuroblastoma Pathology Committee (INPC, also called Shimada system) which was established in 1999 and revised in 2003.

Stage and risk assignment

The "International Neuroblastoma Staging System" (INSS) established in 1986 and revised in 1988 stratifies neuroblastoma according to its anatomical presence at diagnosis:

Stage 1: Localized tumor confined to the area of origin.

Stage 2A: Unilateral tumor with incomplete gross resection; identifiable ipsilateral and contralateral lymph node negative for tumor.

Stage 2B: Unilateral tumor with complete or incomplete gross resection; with ipsilateral lymph node positive for tumor; identifiable contralateral lymph node negative for tumor.

Stage 3: Tumor infiltrating across midline with or without regional lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumor with bilateral lymph node involvement.

Stage 4: Dissemination of tumor to distant lymph nodes, bone marrow, bone, liver, or other organs except as defined by Stage 4S.

Stage 4S: Age <1>

Although international agreement on staging (INSS) has been used, the need for an international consensus on risk assignment has also been recognized in order to compare similar cohorts in results of studies. Beginning in 2005, representatives of the major pediatric oncology cooperative groups have met to review data for 8,800 neuroblastoma patients treated in Europe, Japan, USA, Canada, and Australia between 1990 and 2002. This task force has proposed the International Neuroblastoma Risk Group (INRG) classification system. Retrospective studies revealed the high survival rate of 12-18 month old age group, previously categorized as high-risk, and prompted the decision to reclassify 12-18 month old children without MYCN amplification to intermediate risk category.

The new INRG risk assignment will classify neuroblastoma at diagnosis based on a new International Neuroblastoma Risk Group Staging System (INRGSS):

Stage L1: Localized disease without image-defined risk factors.

Stage L2: Localized disease with image-defined risk factors.

Stage M: Metastatic disease.

Stage MS: Metastatic disease "special" where MS is equivalent to stage 4S.

The new risk stratification will be based on the new INRGSS staging system, age (dichotomized at 18 months), tumor grade, MYCN amplification, unbalanced 11q aberration, and ploidy into four pre-treatment risk groups: very low, low, intermediate, and high risk.

Screening

Urine catecholamine level can be elevated in pre-clinical neuroblastoma. Screening asymptomatic infants at three weeks, six months, and one year has been performed in Japan, Canada, and Germany since the 1980s. Japan began screening six-month olds for neuroblastoma via analysis of the levels of homovanillic acid and vanilmandelic acid in 1984. Screening was halted in 2004 after studies in Canada and Germany showed no reduction in deaths due to neuroblastoma, but rather caused an increase in diagnoses that would have disappeared without treatment, subjecting those infants to unnecessary surgery and chemotherapy.

Treatment

Current

When the lesion is localized, it is generally curable. However, long-term survival for children with advanced disease older than 18 months of age is poor despite aggressive multimodal therapy (intensive chemotherapy, surgery, radiation therapy, stem cell transplant, differentiation agent isotretinoin also called 13-cis-retinoic acid, and frequently immunotherapy with anti-GD2 monoclonal antibody therapy).

Biologic and genetic characteristics have been identified, which, when added to classic clinical staging, has allowed patient assignment to risk groups for planning treatment intensity. These criteria include the age of the patient, extent of disease spread, microscopic appearance, and several other biological features, most importantly MYCN oncogene amplification (MYCN regulates microRNAs), into low, intermediate, and high risk disease. A recent biology study (COG ANBL00B1) analyzed 2687 neuroblastoma patients and the spectrum of risk assignment was determined: 37% of neuroblastoma cases are low risk, 18% are intermediate risk, and 45% are high risk. (There is some evidence that the high- and low-risk types are caused by different mechanisms, and are not merely two different degrees of expression of the same mechanism.)

The therapy for these different risk categories is very different.

Low risk patients can frequently be observed without any treatment at all or cured with surgery alone.

Intermediate risk patients are treated with surgery and chemotherapy.

High risk neuroblastoma is treated with intensive chemotherapy, surgery, radiation therapy, bone marrow / Hematopoietic stem cell transplantation and biological-based therapy with 13-cis-retinoic acid (isotretinoin or Accutane).

With current treatments, patients with low and intermediate risk disease have an excellent prognosis with cure rates above 90% for low risk and 70%-90% for intermediate risk. In contrast, therapy for high-risk neuroblastoma results in cures only about 30% of the time.

Chemotherapy agents used in combination have been found to be effective against neuroblastoma. Agents commonly used in induction and for stem cell transplant conditioning are platinum compounds (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan), topoisomerase II inhibitor (etoposide), anthracycline antibiotics (doxorubicin) and vinca alkaloids (vincristine). Some newer regimens include topoisomerase I inhibitors (topotecan and irinotecan) in induction which have been found to be effective against recurrent disease.

Clinical trials for new frontline treatments

Recent focus has been to reduce therapy for low and intermediate risk neuroblastoma while maintaining survival rates at 90%. A study of 467 intermediate risk patients enrolled in A3961 from 1997 to 2005 confirmed the hypothesis that therapy could be successfully reduced for this risk group. Those with favorable characteristics (tumor grade and response) received four cycles of chemotherapy, and those with unfavorable characteristics received eight cycles, with three-year event free survival and overall survival stable at 90% for the entire cohort. Future plans are to intensify treatment for those patients with aberration of 1p36 or 11q23 chromosomes as well as for those who lack early response to treatment.

By contrast, focus the past 20 years or more has been to intensify treatment for high-risk neuroblastoma. Chemotherapy induction variations, timing of surgery, stem cell transplant regimens, various delivery schemes for radiation, and use of monoclonal antibodies and retinoids to treat minimal residual disease continue to be examined. Recent phase III clinical trials with randomization have been carried out to answer these questions to improve survival of high-risk disease:

1982-1985: European Neuroblastoma Study Group (ENSG1) enrolled 167 children and randomized to melphalan autologous bone marrow transplant or no further therapy (no radiation therapy given to any). Transplant and no-transplant arms each had 65 patients, and recent long-term follow-up report revealed significantly better 5 year event-free survival for stage 4 over 1 year old in melphalan-transplant group versus no further treatment: 33% versus 17% respectively.
1990-1999: European study (EU-20592 or CCLGNB-1990-11) randomized 262 high-risk children over 1 year old and revealed higher survival rate for rapid sequence induction (10-day cycle) versus standard induction (21-day cycle) with same total dose. Ten-year event free survival was 27% and 18% respectively with non-aggressive surgical approach, no radiotherapy, and melphalan-only autologous bone marrow or stem cell transplant for both groups.
1991-1996: Phase III trial with two sequential randomizations for 379 high-risk NB patients was carried out by the Children's Cancer Group (CCG-3891) which demonstrated improved survival with myeloablative therapy (with total body irradiation) and 13-cis-retinoic acid (Accutane) with 50 patients in each of the four arms of the study.
1996-2003: The German (GPOH) study NB97 compared outcomes of 295 high-risk NB patients randomized for stem cell transplant or consolidation chemotherapy. Results showed increased survival with transplant.
2000-2006: The recent study (COG-A3973) questioned the need for purged stem cells for CEM-LI (carboplatin, etoposide, melphalan, with local irradiation) transplant, and accrued 486 patients. Purging stem cells was not found to improve survival
2000-2012: An additional study (COG-ANBL0032) will determine if the antibody ch14.18 with interleukin 2 and GMCSF (studied retrospectively in German GPOH NB90 and NB 97 at a lower dose and without cytokines) improves survival, and will accrue a total of 423 patients.
2002-2008: SIOP (International Society of Paediatric Oncology) formed the European SIOP Neuroblastoma Group (ESIOP NB) in 1994 and activated a phase III high-risk NB protocol in 2002 (SIOP-EUROPE-HR-NBL-1) using “rapid” COJEC (8 cycles of chemotherapy given at 10-day intervals) followed by transplant randomization to CEM (carboplatin, etoposide, melphalan) or BuMel (busulfan, melphalan) and then randomization to with or without ch14.18 antibody treatment. This study will evaluate the use of growth factors as well as compare transplant regimens, with or without ch14.18 antibody, and all patients receive retinoic acid. This trial will accrue 1000 patients (175 per year). There are eight arms to this study.
2005-2010: The current German NB2004 randomization will include MIBG therapy and randomize topotecan use in up-front therapy and will accrue a total of 642 for all risk groups (roughly half will be high-risk). After transplant, the high-risk protocol includes six months of cis-retinoic acid, a three month break, and another three months of retinoic acid.
2007: The COG phase III ANBL0532 trial opened December 2007 for accrual of 495 and will compare single versus tandem transplants, and induction begins with two cycles of topotecan.

In addition to these phase III studies, research institutions such as Baylor College of Medicine/Texas Children's, St. Jude Children's Research Hospital (Memphis, Tennessee), and Memorial Sloan-Kettering Cancer Center in New York offer unique treatment protocols. Texas Children's uses a novel induction regimen which includes a method of giving chemotherapy called “chemo-switching” where cisplatin is given as high-dose pulse and etoposide is given at low-dose over several weeks for the first two cycles. St Jude's recently finished (2007) testing a new up-front chemotherapy regimen in 23 children which included irinotecan and gefitinib with 16 months of maintenance chemotherapy after stem cell transplant with alternating oral 13-cis-retinoic acid and topotecan. Sloan-Kettering offers treatment that includes a mouse-derived monoclonal antibody, 3F8, used in protocols since the mid 1980s. This antibody is used for treating minimal residual disease or consolidation instead of stem cell transplant.

Clinical trials for refractory and relapsed neuroblastoma

microscopic view of a NB cell line (SH-SY5Y) used in preclinical research for testing new agents

Some children (particularly in high-risk cases) do not respond completely to frontline treatment (with a complete response or very good partial response) and are labeled refractory. These children are removed from the frontline therapy (clinical trial) and are eligible for clinical trials using new therapies. Many high-risk children have a good response to frontline therapy and achieve a remission, but later the disease recurs (relapse). These children are also eligible for new therapies being tested in clinical trials. The protein p53 is believed to play a role in the development of resistance to chemotherapy.

Chemotherapy with topotecan and cyclophosphamide is frequently used in refractory setting and after relapse. A randomized study (2004) with 119 patients (comparing topotecan alone to topotecan and cyclophosphamide) revealed a 31% complete or partial response rate with two-year progression-free survival at 36% in the topotecan and cyclophosphamide group. Irinotecan (intravenous or oral) and oral temozolomide are also used in refractory and recurrent neuroblastoma.

Many phase I and phase II trials are currently testing new agents against neuroblastoma in children who have relapsed or are resistant to initial therapy. Investigators are studying targeted therapy, anti-angiogenesis agents, and new monoclonal antibodies such as hu14.18-IL2.

In November 2006, DRAXIS Health received approval from the U.S. Food and Drug Administration (FDA) to run two clinical trials using radioactive Iobenguane I-131 Injection (I-131 MIBG) to treat high-risk neuroblastoma and in May 2008 Molecular Insight Pharmaceuticals announced the opening of a Phase IIa trial of Azedra, the I-131 MIBG molecule radiolabeled using Molecular Insight's proprietary Ultratrace technology, which removes unnecessary nonradioactive molecules, effectively concentrating radiation in the neuroblastoma tumor cells. These trials are coordinated by a group of 11 children’s hospitals and two universities in the United States known as the New Advances in Neuroblastoma Therapy (NANT) consortium, and are continuations of earlier NANT studies. The NANT consortium is also currently offering trials using a tyrosine kinase inhibitor CEP-701 (lestaurtinib), new oral powder formulation of fenretinide, intravenous fenretinide, and bisphosphonate (Zometa).

In February 2007, a study in Sweden reported that a common painkiller, might inhibit the development of neuroblastoma and help make treatment of the disease more effective. Celecoxib, an analgesic, anti-inflammatory substance that works by inhibiting the effect of the inflammatory enzyme, Cox-2, and thus could affect neuroblastoma tumors, which depend on Cox-2 for their growth and proliferation. Clinical studies are now planned; research to date has been done only in animals and cell cultures.

Post-treatment prognosis and late-effects

Neuroblastoma frequently recurs in high-risk cases. Further treatment is available in phase I and phase II clinical trials that test new agents and combinations of agents against neuroblastoma, but the outcome remains very poor for relapsed high-risk disease.

Most long-term survivors alive today had low or intermediate risk disease and milder courses of treatment compared to high-risk disease. The majority of survivors have long-term effects from the treatment. Survivors of intermediate and high-risk treatment often experience hearing loss. Growth reduction, thyroid function disorders, learning difficulties, and greater risk of secondary cancers affect survivors of high-risk disease. An estimated two of three survivors of childhood cancer will ultimately develop at least one chronic and sometimes life-threatening health problem within 20 to 30 years after the cancer diagnosis.

Nasopharyngeal carcinoma

2008-12-22T08:57:00.000-08:00


Nasopharyngeal carcinoma
Metastatic nasopharyngeal carcinoma in a lymph node

Nasopharyngeal carcinoma (NPC) is a cancer originating in the nasopharynx, the uppermost region of the pharynx or "throat", where the nasal passages and auditory tubes join the remainder of the upper respiratory tract. NPC differs significantly from other cancers of the head and neck in its occurrence, causes, clinical behavior, and treatment. It is vastly more common in certain regions of East Asia and Africa than elsewhere, with viral, dietary, and genetic factors implicated in its causation.

Classification

Nasopharyngeal carcinoma, commonly known as nasopharyngeal cancer, is classified as a malignant neoplasm, or cancer, arising from the mucosal epithelium of the nasopharynx, most often within the lateral nasopharyngeal recess or fossa of Rosenmüller. There are three microscopic subtypes of NPC: a well-differentiated keratinizing type, a moderately-differentiated nonkeratinizing type, and an undifferentiated type, which typically contains large numbers of non-cancerous lymphocytes (chronic inflammatory cells), thus giving rise to the name lymphoepithelioma. The undifferentiated form is most common, and is most strongly associated with Epstein-Barr virus infection of the cancerous cells. Babe Ruth is the most famous sufferer of this type of cancer.

Undifferentiated nasopharyngeal carcinoma - low power

Undifferentiated nasopharyngeal carcinoma - med. power

Undifferentiated nasopharyngeal carcinoma - high power

Symptoms and Signs

Nasopharyngeal carcinoma produces few symptoms early in its course, with the result that most cases are quite advanced when detected. Once the tumor has expanded from its site of origin in the lateral wall of the nasopharynx, it may obstruct the nasal passages and cause nasal discharge or nosebleed. Obstruction of the auditory tubes may cause chronic ear infections, and patients may experience referred pain to the ear. Metastasis of cancer to the lymph nodes of the neck may also be the first noticeable sign of the disease.

Causes

Numerous studies have linked common subtypes of NPC to infection with the Epstein-Barr virus (EBV), which has also been implicated in the development of other cancers such as Hodgkin's disease, Burkitt's lymphoma, and HIV-associated lymphomas.

There is some evidence that genetic factors, such as HLA type may play a role in the susceptibility of certain ethnic groups to NPC.

Finally, dietary risk factors, such as the consumption of salt-cured fish high in nitrosamines, may play a role in the Asian endemic regions. Well-differentiated NPC, with a microscopic appearance most similar to other squamous cell cancers of the head and neck may be more closely associated with the standard risk factors for that disease, such as cigarette smoking.

Treatment

Because NPC occurs in an anatomical site which is poorly accessible to surgeons, and is often advanced at presentation, the most effective means of treatment is generally radiation therapy, either with or without concurrent chemotherapy. While the undifferentiated subtype of NPC is highly radiosensitive, this is less true of the more differentiated subtypes.

The Maxillary Swing approach, pioneered by the University of Hong Kong, provides an effective method for surgically resecting the nasopharyngeal tumour. The maxilla, severed from its bony connections, is swung laterally to provide exposure of the nasopharynx. Tumors in the nasopharynx and the paranasopharyngeal space can be adequately resected and tubings for afterloading brachytherapy can be positioned accurately during surgery.

Prognosis

The five-year survival rate of nonkeratinizing and undifferentiated nasopharyngeal carcinomas, with appropriate treatment, is about 65% overall. Cure is highly possible, even when disease has spread to the regional lymph nodes. The prognosis of keratinizing NPC is significantly worse, due to its greater resistance to radiation.

CD80 and CD86 are associated with a better prognosis.

Epidemiology

NPC is uncommon in the United States and most other nations, but is extremely common in southern regions of China, particularly in Guangdong accounting for 18% of all cancers in China. It is also quite common in Taiwan. This is largely due to the South East Asian diet which typically includes consumption of salted vegetables, fish and meat. While NPC is seen primarily in middle-aged persons in Asia, a high proportion of African cases appear in children. The cause of increased risk for NPC in these endemic regions is not entirely clear.

Mycosis fungoides

2008-12-22T08:45:00.001-08:00

Mycosis fungoides

(also known as Alibert-Bazin syndrome or granuloma fungoides), is the most common form of cutaneous T-cell lymphoma. It generally affects the skin, but may progress internally over time.

Mycosis fungoides was first described in 1806 by French dermatologist Jean-Louis-Marc Alibert. The name mycosis fungoides is somewhat misleading--it loosely means "mushroom-like fungal disease". The disease, however, is not a fungal infection but rather a type of non-Hodgkin's lymphoma. It was so named because Alibert described the skin tumors of a severe case as having a mushroom-like appearance.

Origins and causes

The cause of mycosis fungoides is unknown, but it is not believed to be hereditary or genetic. It is not contagious.

It is rare for the disease to appear before age 20, and it appears to be noticeably more common in males than females, especially over the age of 50, where the incidence of the disease (the risk per person in the population) does increase. The average age of onset is between 45 and 55 years of age for patients with patch and plaque disease only, but is over 60 for patients who present with tumours, erythroderma (red skin) or a leukemic form.

The disease is an unusual expression of CD4 T-cells, a part of the immune system. These T-cells are skin-associated, meaning that they biochemically and biologically are most related to the skin, in a dynamic manner. Mycosis fungoides is the most common type of 'Cutaneous T-cell Lymphoma' (CTCL), but there are many other types of CTCL that have nothing to do with mycosis fungoides and these disorders are treated differently.

Symptoms, diagnosis, and stages

Typical visible symptoms include rashlike patches, tumors, or lesions. Itching (pruritus) is common, perhaps in 20% of patients, and is not universal.

Diagnosis is sometimes difficult because the early phases of the disease often resemble eczema or even psoriasis. As with any serious disease, it is advisable to pursue the opinion of a medical professional if a case is suspected. Diagnosis is generally accomplished through a skin biopsy. Several biopsies are recommended, to be more certain of the diagnosis. The diagnosis is made through a combination of the clinical picture and examination, and is confirmed by biopsy.

To stage the disease, various tests may be ordered, to assess nodes, blood and internal organs, but most patients present with disease apparently confined to the skin, as patches (flat spots) and plaques (slightly raised or 'wrinkled' spots).

Treatments and cures

Mycosis fungoides can be treated in a variety of ways.

If treatment is successful the disease can go into a non-progressing state with clinically clear examination and various tests. This is called remission; it can last indefinitely. Treatments may also cause disease not to progress, while still present, and this is called stable disease; it may last indefinitely but is a more serious situation. Disease may also progress, to involve nodes, blood and internal organs, or transform into a higher-grade lymphoma.

Common treatments include simple sunlight, ultraviolet light, topical steroids, topical and systemic chemotherapies, local superficial radiotherapy, the histone deacetylase inhibitor vorinostat, total skin electron beam radiation, and biological therapies (e.g. interferons, retinoids, rexinoids). Treatments are often used in combination.

Selection of treatments typically depends on patient preference and access to therapies, as well as recommendations by physicians, the stage of the disease, established resistance to prior therapies, allergies of the patient, clinical evidence of a positive benefit:risk ratio, and so on.

It is debatable whether cures are reliably obtained through different types of treatments, but many patients experience prolonged periods of disease-control and at least half of all patients do not die from this disease, even if not truly cured. Quality of life is a major objective, in addition to cure, and maximizing periods of remission or stable disease, while minimizing treatments and toxicities, are two central concerns in clinical care.

Oral cancer

2008-12-22T08:38:00.000-08:00

Oral cancer

Oral cancer is any cancerous tissue growth located in the mouth. It may arise as a primary lesion originating in any of the oral tissues, by metastasis from a distant site of origin, or by extension from a neighboring anatomic structure, such as the nasal cavity or the maxillary sinus. Oral cancers may originate in any of the tissues of the mouth, and may be of varied histologic types: teratoma, adenocarcinoma derived from a major or minor salivary gland, lymphoma from tonsillar or other lymphoid tissue, or melanoma from the pigment producing cells of the oral mucosa. Far and away the most common oral cancer is squamous cell carcinoma, originating in the tissues that line the mouth and lips. Oral or mouth cancer most commonly involves the tissue of the lips or the tongue. It may also occur on the floor of the mouth, cheek lining, gingiva (gums), or palate (roof of the mouth). Most oral cancers look very similar under the microscope and are called squamous cell carcinoma. These are malignant and tend to spread rapidly.

Known risk factors

In 2008, in the US alone, about 34,000 individuals will be diagnosed with oral cancer. 66% of the time these will be found as late stage three and four disease. Low public awareness of the disease is a significant factor, but these cancers could be found at early highly survivable stages through a simple, painless, 5 minute examination by a trained medical or dental professional.

All cancers are diseases of the DNA in the cancer cells. Oncogenes are activated as a result of mutation of the DNA. The exact cause is often unknown. Risk factors that predispose a person to oral cancer have been identified in epidemiological studies.

Smoking and other tobacco use are associated with about 75 percent of oral cancer cases, caused by irritation of the mucous membranes of the mouth from smoke and heat of cigarettes, cigars, and pipes. Tobacco contains over 19 known carcinogens, and the combustion of it, and by products from this process, is the primary mode of involvement. Use of chewing tobacco or snuff causes irritation from direct contact with the mucous membranes.

In many Asian cultures chewing betel, paan and Areca is known to be a strong risk factor for developing oral cancer. In India where such practices are common, oral cancer represents up to 40% of all cancers, compared to just 4% in the UK.

Alcohol use is another high-risk activity associated with oral cancer. There is known to be a strong synergistic effect on oral cancer risk when a person is both a heavy smoker and drinker. Their risk is greatly increased compared to a heavy smoker, or a heavy drinker alone.

Some oral cancers begin as leukoplakia a white patch (lesion), red patches, (erythroplakia) or non healing sores that have existed for more than 14 days. In the US oral cancer accounts for about 8 percent of all malignant growths. Men are affected twice as often as women, particularly men older than 40/60. In Indian subcontinent Oral Submucous Fibrosis is very common.This condition is characterized by limited opening of mouth and burning sensation on eating of spicy food. This is a progressive lesion in which the opening of the mouth becomes progressively limited, and later on even normal eating becomes difficult. It occurs almost exclusively in India and Indian communities living abroad.

Human Papilloma Virus, (HPV) particularly version 16 (there are over 120 varieties) is a known risk factor and independent causative factor for oral cancer. (Gilsion et.al.Johns Hopkins) A fast growing segment of those diagnosed does not present with the historic stereotypical demographics. Historically that has been people over 50, blacks over whites 2 to 1, males over females 3 to 1, and 75% of the time people who have used tobacco products or are heavy users of alcohol. This new and rapidly growing sub population between 20 and 50 years old is predominantly non smoking, white, and males slightly outnumber females. Recent research from Johns Hopkins indicates that HPV is the primary risk factor in this new population of oral cancer victims. HPV16 (along with HPV18) is the same virus responsible for the vast majority of all cervical cancers and is the most common sexually transmitted infection in the US. Oral cancer in this group tends to favor the tonsil and tonsillar pillars, base of the tongue, and the oropharnyx. Recent data suggest that individuals that come to the disease from this particular etiology have some slight survival advantage.

Symptoms

Skin lesion, lump, or ulcer:

On the tongue, lip, or other mouth area
Usually small
Most often pale colored, may be dark or discolored
Early sign may be a white patch (leukoplakia) or a red patch (erythroplakia) on the soft tissues of the mouth
Usually painless initially
May develop a burning sensation or pain when the tumor is advanced

Additional symptoms that may be associated with this disease:

Tongue problems
Swallowing difficulty
Mouth sores that do not resolve in 14 days
Pain and paraesthesia are late symptoms.

Signs and tests

An examination of the mouth by the health care provider or dentist shows a visible and/or palpable (can be felt) lesion of the lip, tongue, or other mouth area. As the tumor enlarges, it may become an ulcer and bleed. Speech/talking difficulties, chewing problems, or swallowing difficulties may develop, particularly if the cancer is on the tongue.

While a dentist, physician or other medical professional may suspect a particular lesion is malignant, the only definitive method for determining this is through biopsy and microscopic evaluation of the cells in the removed sample. A tissue biopsy, whether of the tongue or other oral tissues, and microscopic examination of the lesion confirm the diagnosis of oral cancer.

Treatment

Surgical excision (removal) of the tumor is usually recommended if the tumor is small enough, and if surgery is likely to result in a functionally satisfactory result. Radiation therapy is often used in conjunction with surgery, or as the definitive radical treatment, especially if the tumour is inoperable.

Owing to the vital nature of the structures in the head and neck area, surgery for larger cancers is technically demanding. Reconstructive surgery may be required to give an acceptable cosmetic and functional result. Bone grafts and surgical flaps such as the radial forearm flap are used to help rebuild the structures removed during excision of the cancer.

Survival rates for oral cancer depend on the precise site, and the stage of the cancer at diagnosis. Overall, survival is around 50% at five years when all stages of initial diagnosis are considered. Survival rates for stage 1 cancers are 90%, hence the emphasis on early detection to increase survival outcome for patients.

Following treatment, rehabilitation may be necessary to improve movement, chewing, swallowing, and speech. Speech therapists may be involved at this stage.

Chemotherapy is useful in oral cancers when used in combination with other treatment modalities such as radiation therapy. It is seldom used alone as a monotherapy. When cure is unlikely it can also be used to extend life and can be considered palliative but not curative care. Biological agents, such as Cetuximab have recently been shown to be effective in the treatment of squamous cell head and neck cancers, and are likely to have an increasing role in the future management of this condition when used in conjunction with other treatments.

Treatment of oral cancer will usually be by a multidisciplinary team, with treatment professionals from the realms of radiation, surgery, chemotherapy, nutrition, dental professionals, and even psychology all possibly involved with diagnosis, treatment, rehabilitation, and patient care.

Complications

Postoperative disfigurement of the face, head and neck
Complications of radiation therapy, including dry mouth and difficulty swallowing
Other metastasis (spread) of the cancer

Melanoma

2008-12-22T08:27:00.000-08:00

Melanoma is a malignant tumor of melanocytes which are found predominantly in skin but also in the bowel and the eye (see uveal melanoma). It is one of the rarer types of skin cancer but causes the majority of skin cancer related deaths. Malignant melanoma is a serious type of skin cancer. It is due to uncontrolled growth of pigment cells, called melanocytes. Despite many years of intensive laboratory and clinical research, the sole effective cure is surgical resection of the primary tumor before it achieves a Breslow thickness greater than 1 mm.

Around 160,000 new cases of melanoma are diagnosed worldwide each year, and it is more frequent in males and caucasians. It is more common in caucasian populations living in sunny climates than other groups. According to a WHO Report about 48,000 melanoma related deaths occur worldwide per year.

Malignant melanoma accounts for 75 percent of all deaths associated with skin cancer.

The treatment includes surgical removal of the tumor; adjuvant treatment; chemo- and immunotherapy, or radiation therapy.

History

Although melanoma is not a new disease, evidence for its occurrence in antiquity is rather scarce. However, one example lies in a 1960s examination of nine Peruvian Inca mummies, radiocarbon dated to be approximately 2400 years old, which showed apparent signs of melanoma: melanotic masses in the skin and diffuse metastases to the bones.

John Hunter is reported to be the first to operate on metastatic melanoma in 1787. Although not knowing precisely what it was, he described it as a "cancerous fungous excrescence". The excised tumor was preserved in the Hunterian Museum of the Royal College of Surgeons of England. It was not until 1968 that microscopic examination of the specimen revealed it to be an example of metastatic melanoma.

The French physician René Laennec was the first to describe melanoma as a disease entity. His report was initially presented during a lecture for the Faculté de Médecine de Paris in 1804 and then published as a bulletin in 1806. The first English language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris in 1820. In his later work in 1857 he remarked that there is a familial predisposition for development of melanoma (Eight Cases of Melanosis with Pathological and Therapeutical Remarks on That Disease).

The first formal acknowledgment of advanced melanoma as untreatable came from Samuel Cooper in 1840. He stated that the only chance for benefit depends upon the early removal of the disease ...' More than one and a half centuries later this situation remains largely unchanged.

In 1956, Australian professor Henry Oliver Lancaster discovered that melanomas were directly associated with latitude (ie, intensity of sunlight); and that exposure to the sun was a very high factor in the development of the cancer.

Epidemiology & Causes

Generally, an individual's risk for developing melanoma depends on two groups of factors: intrinsic and environmental. "Intrinsic" factors are generally an individual's family history and inherited genotype, while the most relevant environmental factor is sun exposure.

Epidemiologic studies suggest that exposure to ultraviolet radiation (UVA and UVB) is one of the major contributors to the development of melanoma. UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell's genes. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor. Data from patients suggest that aberrant levels of Activating Transcription Factor in the nucleus of melanoma cells are associated with increased metastatic activity of melanoma cells; studies from mice on skin cancer tend to confirm a role for Activating Transcription Factor-2 in cancer progression. Occasional extreme sun exposure (resulting in "sunburn") is causally related to melanoma. Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure). The risk appears to be strongly influenced by socio-economic conditions rather than indoor versus outdoor occupations; it is more common in professional and administrative workers than unskilled workers. Other factors are mutations in or total loss of tumor suppressor genes. Use of sunbeds (with deeply penetrating UVA rays) has been linked to the development of skin cancers, including melanoma.

Possible significant elements in determining risk include the intensity and duration of sun exposure, the age at which sun exposure occurs, and the degree of skin pigmentation. Exposure during childhood is a more important risk factor than exposure in adulthood. This is seen in migration studies in Australia where people tend to retain the risk profile of their country of birth if they migrate to Australia as an adult. Individuals with blistering or peeling sunburns (especially in the first twenty years of life) have a significantly greater risk for melanoma. This does not mean that sunburn is the cause of melanoma. Instead it is merely statistically correlated. The cause is the exaggerated UV-exposure. It has been shown that sunscreen - while preventing the sunburn - does not protect from melanoma. Many researchers say that sunscreen can even increase the melanoma risk.

Fair and red-headed people, persons with multiple atypical nevi or dysplastic nevi and persons born with giant congenital melanocytic nevi are at increased risk.

A family history of melanoma greatly increases a person's risk because mutations in CDKN2A, CDK4 and several other genes have been found in melanoma-prone families. Patients with a history of one melanoma are at increased risk of developing a second primary tumour.

The incidence of melanoma has increased in the recent years, but it is not clear to what extent changes in behavior, in the environment, or in early detection are involved.

To understand how sunscreen can reduce sunburn and at the same time cause melanoma it is necessary to distinguish between direct DNA damage and indirect DNA damage. Genetic analysis has shown that 92% of all melanoma are caused by the indirect DNA damage. Although some people believe that dark-skinned people such as African Americans cannot get sunburns, they are in fact susceptible, and should use sunscreen accordingly. The recommended amount of sunscreen for adults is 1 oz, which is enough to fill a shot glass.

Genetics

Familial melanoma is genetically heterogeneous, and loci for familial melanoma have been identified on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to the pathogenesis of melanoma. The multiple tumor suppressor 1 (CDKN2A/MTS1) gene encodes p16INK4a - a low-molecular weight protein inhibitor of cyclin-dependent protein kinases (CDKs) - which has been localised to the p21 region of human chromosome 9. Today, melanomas are diagnosed only after they become visible on the skin. In the future, however, physicians will hopefully be able detect melanomas based on a patient’s genotype, not just his or her phenotype. Recent genetic advances promise to help doctors to identify people with high-risk genotypes and to determine which of a person’s lesions have the greatest chance of becoming cancerous. A number of rare mutations, which often run in families, are known to greatly increase one’s susceptibility to melanoma. One class of mutations affects the gene CDKN2A. An alternative reading frame mutation in this gene leads to the destabilization of p53, a transcription factor involved in apoptosis and in fifty percent of human cancers. Another mutation in the same gene results in a non-functional inhibitor of CDK4, a [cyclin-dependent kinase] that promotes cell division. Mutations that cause the skin condition Xeroderma Pigmentosum (XP) also seriously predispose one to melanoma. Scattered throughout the genome, these mutations reduce a cell’s ability to repair DNA. Both CDKN2A and XP mutations are highly penetrant. Other mutations confer lower risk but are more prevalent in the population. People with mutations in the MC1R gene, for example, are two to four times more likely to develop melanoma than those with two wild-type copies of the gene. MC1R mutations are very common; in fact, all people with red hair have a mutated copy of the gene. Two-gene models of melanoma risk have already been created, and in the future, researchers hope to create genome-scale models that will allow them to predict a patient’s risk of developing melanoma based on his or her genotype. In addition to identifying high-risk patients, researchers also want to identify high-risk lesions within a given patient. Many new technologies, such as optical coherence tomography (OCT), are being developed to accomplish this. OCT allows pathologists to view 3-D reconstructions of the skin and offers more resolution than past techniques could provide. In vivo confocal microscopy and fluorescently tagged antibodies are also proving to be valuable diagnostic tools.

Diagnosis

A melanoma showing irregular borders and colour, diameter over 10 mm and asymmetry (ie A, B, C and D.)

To detect melanomas (and increase survival rates), it is recommended to learn what they look like (see "ABCD" mnemonic below), to be aware of moles and check for changes (shape, size, color, itching or bleeding) and to show any suspicious moles to a doctor with an interest and skills in skin malignancy.

A popular method for remembering the signs and symptoms of melanoma is the mnemonic "ABCD":

Asymmetrical skin lesion.
Border of the lesion is irregular.
Color: melanomas usually have multiple colors.
Diameter: moles greater than 6 mm are more likely to be melanomas than smaller moles.

A weakness in this system is the D. Many melanomas present themselves as lesions smaller than 6 mm in diameter; and likely all melanomas were melanomas on day 1 of growth, which is merely a dot. An astute physician will examine all abnormal moles, including ones less than 6 mm in diameter. Unfortunately for the average person, many seborrheic keratosis breaks most if not all of the ABCD rules, and can not be distinguished from a melanoma without a trained eye or dermatoscopy.

Some will advocate the system A,B,C,D, E. With E for evolution. Certainly moles which changes and evolve will be a concern. Some will refer to E as elevation. But most melanomas detected today are in the very early stage, or in-situ stage. Elevation should absolutely not be a criteria to wait for, as it will be past in-situ and into the invasive stage.

A recent and novel method of melanoma detection is the "Ugly Duckling Sign" It is simple, easy to teach, and highly effective in detecting melanoma. Simply, correlation of common characteristics of a person's skin lesion is made. Lesions which greatly deviate from the common characteristics are labeled as an "Ugly Duckling", and further professional exam is required. The "Little Red Riding Hood" sign, suggests that individual with fair skin and light colored hair might have difficult to diagnose melanomas. Extra care and caution should be rendered when examining such individuals as they might have multiple melanomas and severely dysplastic nevi. A dermatoscope must be used to detect "ugly ducklings", as many melanomas in these individuals resemble non-melanomas or are considered to be "wolves in sheep clothing". These fair skinned individuals often have lightly pigmented or amelanotic melanomas which will not present with easy to observe color changes and variation in colors. The borders of these amelanotic melanomas are often indistinct, making visual identification without a dermatoscope (dermatoscopy) very difficult.

People with a personal or family history of skin cancer or of dysplastic nevus syndrome (multiple atypical moles) should see a dermatologist at least once a year to be sure they are not developing melanoma.

Prevention

Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds), following sun protection measures and wearing sun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. In the past it was recommended to use sunscreens with an SPF rating of 30 or higher on exposed areas as older sunscreen more effectively blocked UVA with higher SPF. Currently, newer sunscreen ingredients (avobenzone, zinc, and titanium) effectively block both UVA and UVB even at lower SPFs. However, there are questions about the ability of sunscreen to prevent melanoma.This controversy is well discussed in numerous review articles, and is refuted by most dermatologists. This correlation might be due to the confounding variable that individuals who used sunscreen to prevent burn, might have a higher lifetime exposure to either UVA or UVB. Please see Sunscreen controversy for further references and discussions. Tanning, once believed to help prevent skin cancers, actually can lead to increase incidence of melanomas Even though tanning beds emits mostly UVA, which causes tanning, it by itself might be enough to induce melanomas.

Rough rules of thumb to decreasing ultraviolet light exposure include avoiding the sun between the hours of 9 a.m. and 3 p.m. or avoiding the sun when your shadow is shorter than your height. These are rough rules of thumbs, and varies depending on your locality and your skin cancer risk.

Diagnosis

Moles that are irregular in color or shape are suspicious of a malignant or a premalignant melanoma. Following a visual examination and a dermatoscopic exam (an instrument that illuminates a mole, revealing its underlying pigment and vascular network structure), or an examination using other in vivo diagnostic tools, such as a confocal microscope, the doctor may biopsy the suspicious mole. If it is malignant, the mole and an area around it needs excision. It is unfortunate that as few as one in 4 dermatologists in the United States routinely use the dermatoscope in the detection of melanoma. However, the trend is improving. It is not adequate that a dermatologist has a dermatoscope in his or her office, it should be a routine part of the skin exam that the instrument is used.

The diagnosis of melanoma requires experience, as early stages may look identical to harmless moles or not have any color at all. A skin biopsy performed under local anesthesia is often required to assist in making or confirming the diagnosis and in defining the severity of the melanoma. Amelanotic melanomas and melanomas arising in fair skinned individuals (see the "Little Red Riding Hood" sign) are very difficult to detect as they fail to show many of the characteristics in the ABCD rule, and breaks the "Ugly Duckling" sign. These melanomas are often light brown, or pink in color - and very hard to distinguish from acne scarring, insect bites, dermatofibromas, or lentigines. There is no blood test for detecting melanomas.

Excisional skin biopsy is the management of choice; this is where the suspect lesion is totally removed with an adequate (but minimal, usually 1 or 2 mm) ellipse of surrounding skin and tissue. The preferred surgical margin for the initial biopsy should be narrow (1 mm) in order to prevent the disruption of the local lymphatic drainage. The biopsy will include the epidermal, dermal, and subcutaneous layers of the skin, enabling the histopathologist to determine the depth of penetration of the melanoma by microscopic examination. This is described by Clark's level (involvement of skin structures) and Breslow's depth (measured in millimeters). However, for large lesions such as suspected lentigo maligna, or for lesions in surgically difficult areas (face, toes, fingers, eyelids), a small punch biopsy (1.5 to 2 mm) in multiple representative areas will give adequate information and will not disrupt the final staging or depth determination. In no circumstances should the initial biopsy include the final surgical margin (0.5 cm, 1.0cm, or 2 cm), as a misdiagnosis can result in excessive scarring and morbidity from the procedure. Large initial excision will disrupt the local lymphatic drainage and can affect further lymphangiogram directed lymphnode dissection. A small punch biopsy can be utilized at anytime where for logistical and personal reasons a patient will refused more invasive excisional biopsy. Small punch biopsies are minimally invasive and heal quickly, usually without noticeable scarring.

Lactate dehydrogenase (LDH) tests are often used to screen for metastases, although many patients with metastases (even end-stage) have a normal LDH; extraordinarily high LDH often indicates metastatic spread of the disease to the liver. It is common for patients diagnosed with melanoma to have chest X-rays and an LDH test, and in some cases CT, MRI, PET and/or PET/CT scans. Although controversial, sentinel lymph node biopsies and examination of the lymph nodes are also performed in patients to assess spread to the lymph nodes.

Sometimes the skin lesion may bleed, itch, or ulcerate, although this is a very late sign. A slow-healing lesion should be watched closely, as that may be a sign of melanoma. Be aware also that in circumstances that are still poorly understood, melanomas may "regress" or spontaneously become smaller or invisible - however the malignancy is still present. Amelanotic (colorless or flesh-colored) melanomas do not have pigment and may not even be visible. Lentigo maligna, a superficial melanoma confined to the topmost layers of the skin (found primarily in older patients) is often described as a "stain" on the skin. Some patients with metastatic melanoma do not have an obvious detectable primary tumor.

Types of primary melanoma

The most common types of Melanoma in the skin:

superficial spreading melanoma (SSM)
nodular melanoma
acral lentiginous melanoma
lentigo maligna (melanoma-in-situ frequently on the face and arms of the elderly)
lentigo maligna melanoma invasive melanoma arising from a lentigo maligna

Any of the above types may produce melanin (and be dark in colour) or not (and be amelanotic - not dark). Similarly any subtype may show desmoplasia (dense fibrous reaction with neurotropism) which is a marker of aggressive behaviour and a tendency to local recurrence.

Elsewhere:

clear cell sarcoma (Melanoma of Soft Parts)
mucosal melano
mauveal melanoma

Prognostic factors

Features that affect prognosis are tumor thickness in millimeters (Breslow's depth), depth related to skin structures (Clark level), type of melanoma, presence of ulceration, presence of lymphatic/perineural invasion, presence of tumor infiltrating lymphocytes (if present, prognosis is better), location of lesion, presence of satellite lesions, and presence of regional or distant metastasis.

Certain types of melanoma have worse prognoses but this is explained by their thickness. Interestingly, less invasive melanomas even with lymph node metastases carry a better prognosis than deep melanomas without regional metastasis at time of staging. Local recurrences tend to behave similarly to a primary unless they are at the site of a wide local excision (as opposed to a staged excision or punch/shave excision) since these recurrences tend to indicate lymphatic invasion.

When melanomas have spread to the lymph nodes, one of the most important factors is the number of nodes with malignancy. Extent of malignancy within a node is also important; micrometastases in which malignancy is only microscopic have a more favorable prognosis than macrometastases. In some cases micrometastases may only be detected by special staining, and if malignancy is only detectable by a rarely-employed test known as the polymerase chain reaction (PCR), the prognosis is better. Macrometastases in which malignancy is clinically apparent (in some cases cancer completely replaces a node) have a far worse prognosis, and if nodes are matted or if there is extracapsular extension, the prognosis is still worse.

When there is distant metastasis, the cancer is generally considered incurable. The five year survival rate is less than 10%. The median survival is 6 to 12 months. Treatment is palliative, focusing on life-extension and quality of life. In some cases, patients may live many months or even years with metastatic melanoma (depending on the aggressiveness of the treatment). Metastases to skin and lungs have a better prognosis. Metastases to brain, bone and liver are associated with a worse prognosis.

There is not enough definitive evidence to adequately stage, and thus give a prognosis for ocular melanoma and melanoma of soft parts, or mucosal melanoma (e.g. rectal melanoma), although these tend to metastasize more easily. Even though regression may increase survival, when a melanoma has regressed, it is impossible to know its original size and thus the original tumor is often worse than a pathology report might indicate.

Staging

Also of importance are the "Clark level" and "Breslow depth" which refer to the microscopic depth of tumor invasion.

Melanoma stages:

Stage 0: Melanoma in Situ (Clark Level I), 99.9% Survival

Stage I/II: Invasive Melanoma, 85-95% Survival

T1a: Less than 1.00 mm primary, w/o Ulceration, Clark Level II-III
T1b: Less than 1.00 mm primary, w/Ulceration or Clark Level IV-V
T2a: 1.00-2.00 mm primary, w/o Ulceration

Stage II: High Risk Melanoma, 40-85% Survival

T2b: 1.00-2.00 mm primary, w/ Ulceration
T3a: 2.00-4.00 mm primary, w/o Ulceration
T3b: 2.00-4.00 mm primary, w/ Ulceration
T4a: 4.00 mm or greater primary w/o Ulceration
T4b: 4.00 mm or greater primary w/ Ulceration

Stage III: Regional Metastasis, 25-60% Survival

N1: Single Positive Lymph Node
N2: 2-3 Positive Lymph Nodes OR Regional Skin/In-Transit Metastasis
N3: 4 Positive Lymph Nodes OR Lymph Node and Regional Skin/In Transit Metastases

Stage IV: Distant Metastasis, 9-15% Survival

M1a: Distant Skin Metastasis, Normal LDH
M1b: Lung Metastasis, Normal LDH
M1c: Other Distant Metastasis OR Any Distant Metastasis with Elevated LDH

Based Upon AJCC 5-Year Survival With Proper Treatment

Treatment

Surgery is the first choice therapy for localized cutaneous melanoma. Depending on the stage a sentinel lymph node biopsy is done as well, although controversy exists around trial evidence for this procedure. Treatment of advanced malignant melanoma is performed from a multidisciplinary approach.

Surgery

Diagnostic punch or excisional biopsies may appear to excise (and in some cases may indeed actually remove) the tumor, but further surgery is often necessary to reduce the risk of recurrence.

Complete surgical excision with adequate margins and assessment for the presence of detectable metastatic disease along with short- and long-term followup is standard. Often this is done by a "wide local excision" (WLE) with 1 to 2 cm margins. Melanoma-in-situ and lentigo malignas are treated with narrower surgical margins, usually 0.2 to 0.5 cm. Many surgeons consider 0.5 cm the standard of care for standard excision of melanoma-in-situ, but 0.2 cm margin might be acceptable for margin controlled surgery (Mohs surgery, or the double bladed technique with margin control). The wide excision aims to reduce the rate of tumour recurrence at the site of the original lesion. This is a common pattern of treatment failure in melanoma. Considerable research has aimed to elucidate appropriate margins for excision with a general trend toward less aggressive treatment during the last decades.

Mohs surgery has been reported with cure rate as low as 77% and as high as 98% for melanoma-in-situ.

Melanomas which spread usually do so to the lymph nodes in the region of the tumor before spreading elsewhere. Attempts to improve survival by removing lymph nodes surgically (lymphadenectomy) were associated with many complications but unfortunately no overall survival benefit. Recently the technique of sentinel lymph node biopsy has been developed to reduce the complications of lymph node surgery while allowing assessment of the involvement of nodes with tumor.

Although controversial and without prolonging survival, "sentinel lymph node" biopsy is often performed, especially for T1b/T2+ tumors, mucosal tumors, ocular melanoma and tumors of the limbs. A process called lymphoscintigraphy is performed in which a radioactive tracer is injected at the tumor site in order to localize the "sentinel node(s)". Further precision is provided using a blue tracer dye and surgery is performed to biopsy the node(s). Routine H&E staining, and immunoperoxidase staining will be adequate to rule out node involvement. PCR tests on nodes, usually performed to test for entry into clinical trials, now demonstrate that many patients with a negative SLN actually had a small number of positive cells in their nodes. Alternatively, a fine-needle aspiration may be performed and is often used to test masses.

If a lymph node is positive, depending on the extent of lymph node spread, a radical lymph node dissection will often be performed. If the disease is completely resected, the patient will be considered for adjuvant therapy.

Adjuvant treatment

High risk melanomas may require adjuvant treatment. In the United States most patients in otherwise good health will begin up to a year of high-dose interferon treatment, which has severe side effects but may improve the patient's prognosis. This claim is not supported by all research at this time, and in Europe interferon is usually not used outside the scope of clinical trials.

Metastatic melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs, ultrasound, LDH testing and photoacoustic detection.

Chemotherapy and immunotherapy

Various chemotherapy agents are used, including dacarbazine (also termed DTIC), immunotherapy (with interleukin-2 (IL-2) or interferon (IFN)) as well as local perfusion are used by different centers. They can occasionally show dramatic success, but the overall success in metastatic melanoma is quite limited. IL-2 (Proleukin) is the first new therapy approved for the treatment of metastatic melanoma in 20 years. Studies have demonstrated that IL-2 offers the possibility of a complete and long-lasting remission in this disease, although only in a small percentage of patients. A number of new agents and novel approaches are under evaluation and show promise.

On June 23, 2008, Israeli scientists from the Oncology Institute of the Hadassa Medical Center in Jerusalem announced they developed a vaccine that prevents recurrences of the disease among previous sufferers and increases chances of survival for current ones.

Lentigo maligna treatment

Standard excision is still being done by most surgeons. Unfortunately, the recurrence rate is exceeding high (up to 50%). This is due to the ill defined visible surgical margin, and the facial location of the lesions (often forcing the surgeon to use a narrow surgical margin). The narrow surgical margin used, combined with the limitation of the standard bread loafing technique of fixed tissue histology - result in a high "false negative" error rate, and frequent recurrences. Margin controlled (peripheral margins) is necessary to eliminate the false negative errors. If breadloafing is utilized, distances from sections should approach 0.1 mm to assure that the method approaches complete margin control.

Mohs surgery has been done with cure rate reported to be 77% by Dr. Mikhail, and as high as 95% by another author The "double scalpel" peripheral margin controlled excision method approximates the Mohs method in margin control, but requires a pathologist intimately familiar with the complexity of managing the vertical margin on the thin peripheral sections and staining methods.

Some melanocytic nevi, and melanoma-in-situ (lentigo maligna) have resolved with an experimental treatment, imiquimod (Aldara) topical cream, an immune enhancing agent. Some dermasurgeons are combining the 2 methods: surgically excising the cancer and then treating the area with Aldara cream postoperatively for three months. Considering the very poor cure rate with standard excision, it might not be a bad idea to follow up all surgical excisions with topical imiquimod treatments.

Radiation and other therapies

Radiation therapy is often used after surgical resection for patients with locally or regionally advanced melanoma or for patients with unresectable distant metastases. It may reduce the rate of local recurrence but does not prolong survival.

In research setting other therapies, such as gene therapy, may be tested. Radioimmunotherapy of metastatic melanoma is currently under investigation. Experimental treatment developed at the National Cancer Institute (NCI), part of the National Institutes of Health in the US was used in advanced (metastatic) melanoma with moderate success. The treatment, adoptive transfer of genetically altered autologous lymphocytes, depends on delivering genes that encode so called T cell receptors (TCRs), into patient's lymphocytes. After that manipulation lymphocytes recognize and bind to certain molecules found on the surface of melanoma cells and kill them.

Complications

People with melanoma may not feel like eating especially if they are uncomfortable or tired. Foods may taste different than they did previously. Poor appetite, nausea, or vomiting are all side-effects of melanoma. Good nutrition however often helps people with cancer feel better and have more energy.

Future thought

One important pathway in melanin synthesis involves the transcription factor MITF. The MITF gene is highly conserved and is found in people, mice, birds, and even fish. MITF production is regulated via a fairly straightforward pathway. UV radiation causes increased expression of transcription factor p53 in keratinocytes, and p53 causes these cells to produce melanocyte stimulating hormone (MSH), which binds to melanocortin 1 receptors (MC1R) on melanocytes. Ligand-binding at MC1R receptors activates adenyl cyclases, which produce cAMP, which activates CREB, which promotes MITF expression. The targets of MITF include p16 (a CDK inhibitor) and Bcl2, a gene essential to melanocyte survival. It is often difficult to design drugs that interfere with transcription factors, but perhaps new drugs will be discovered that can impede some reaction in the pathway upstream of MITF. Studies of chromatin structure also promise to shed light on transcriptional regulation in melanoma cells. It has long been assumed that nucleosomes are positioned randomly on DNA, but murine studies of genes involved in melanin production now suggest that nucleosomes are stereotypically positioned on DNA. When a gene is undergoing transcription, its transcription start site is almost always nucleosome-free. When the gene is silent, however, nucleosomes often block the transcriptional start site, suggesting that nucleosome position may play a role in gene regulation. Finally, given the fact that tanning helps protect skin cells from UV-induced damage, new melanoma prevention strategies could involve attempts to induce tanning in individuals who would otherwise get sunburns. Redheads, for example, do not tan because they have MC1R mutations. In mice, it has been shown that the melanin production pathway can be rescued downstream of MC1R. Perhaps such a strategy will eventually be used to protect humans from melanoma.

Medulloblastoma

2008-12-22T08:21:00.000-08:00


Medulloblastoma
CT scan, showing a tumorous mass in the posterior fossa, giving rise to obstructive hydrocephalus, in a six year old girl.

Medulloblastoma is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa.

Originally considered to be a glioma, medulloblastoma is now known to be of the family of cranial primitive neuroectodermal tumors (PNET).

Tumors that originate in the cerebellum are referred to as infratentorial because they occur below the tentorium, a thick membrane that separates the cerebral hemispheres of the brain from the cerebellum. Another term for medulloblastoma is infratentorial PNET. Medulloblastoma is the most common PNET originating in the brain.

All PNET tumors of the brain are invasive and rapidly growing tumors that, unlike most brain tumors, spread through the cerebrospinal fluid (CSF) and frequently metastasize to different locations in the brain and spine.

Incidence

Brain tumors are the second most common malignancy among children less than 20 years of age. Medulloblastoma is the most common malignant brain tumor, comprising 14.5% of newly diagnosed cases. In adults, medulloblastoma is rare, comprising less than 2% of CNS malignancies.

The incidence of childhood medulloblastoma is higher in males (62%) than females (38%). Medulloblastoma and other PNET tumors are more prevalent in younger children than older children. 40% of medulloblastoma patients are diagnosed before the age of 5, 31% are between the ages of 5 and 9, 18.3% are between the ages of 10 and 14, and 12.7% are between the ages of 15 and 19.

Pathogenesis

Medulloblastomas usually form in the fourth ventricle, between the brainstem and the cerebellum. Tumors with similar appearance and characteristics originate in other parts of the brain, but they are not identical to medulloblastoma.

Although it is thought that medulloblastomas originate from immature or embryonal cells at their earliest stage of development, the exact cell of origin, or "medulloblast" has yet to be identified.

It is currently thought that medulloblastoma arises from cerebellar "stem cells" that have been prevented from dividing and differentiating into their normal cell types. This accounts from the varying histologic variants seen on biopsy. Rosette formation is highly characteristic of medulloblastoma and is seen in up to half of the cases.

Molecular genetics reveal a loss of genetic information on the distal part of chromosome 17, distal to the p53 gene, possibly accounting for the neoplastic transformation of the undifferentiated cerebellar cells. Medulloblastomas are also seen in Gorlin syndrome as well as Turcot syndrome. Another research has strongly implicated the JC virus, the virus that causes multifocal leukoencephalopathy.

Clinical manifestation

Symptoms are mainly due to secondary increased intracranial pressure due to blockage of the fourth ventricle and are usually present for 1 to 5 months before diagnosis is made. The child typically becomes listless, with repeated episodes of vomiting, and a morning headache, which may lead to a misdiagnosis of gastrointestinal disease or migraine. Soon, the child will develop a stumbling gait, frequent falls, diplopia, papilledema, and sixth cranial nerve palsy. Positional dizziness and nystagmus are also frequent and facial sensory loss or motor weakness may be present. Decerebrate attacks appear late in the disease.

Extraneural metastases to the rest of the body is rare, but usually only after craniotomy.

Diagnosis

The tumor is distinctive on T1 and T2-weighted MRI with heterogeneous enhancement and typical location adjacent to and extension into the fourth ventricle.

Histologically, the tumor is solid, pink-gray in color, and is well circumscribed. The tumor is very cellular, many mitoses, little cytoplasm, and has the tendency to form clusters and rosettes.

Correct diagnosis of medulloblastoma may require ruling out atypical teratoid rhabdoid tumor (ATRT) and primitive neuroectodermal tumor (PNET).

Treatment and prognosis

Treatment begins with maximal resection of the tumor. The addition of radiation to the entire neuraxis and chemotherapy may increase the disease-free survival. This combination may permit a 5 year survival in more than 80% of cases. The presence of desmoplastic features such as connective tissue formation offers a better prognosis. Prognosis is worse if the child is less than 3 years old, there is an inadequate degree of resection, or if presence of any CSF, spinal, supratentorial or systemic spread.

Increased intracranial pressure may be controlled with corticosteroids or a ventriculoperitoneal shunt

Model

Using gene transfer of SV40 large T-antigen in neuronal precursor cells of rats, a brain tumor model was established. The PNETs were histologically indistinguashabe from the human counterparts and have been used to identify new genes involved in human brain tumor carcinogenesis. The model was used to confirm p53 as one of the genes involved in human medulloblastomas, but since only about 10 % of the human tumors showed mutations in that gene, the model can be used to identify the other binding partners of SV40 Large T- antigen, other than p53.

References

^ George Jallo, MD, Medulloblastoma, eMedicine 2007.
^ Chris Hinz, Deneen Hesser, Focusing On Brain Tumors: Medulloblastoma, American Brain Tumor Association 2006, ISBN 0-944093-67-1.
^ James G. Gurney, Malcolm A. Smith, Greta R. Bunin, CNS and Miscellaneous Intracranial and Intraspinal Neoplasms, SEER Pediatric Monograph, National Cancer Institute
^ Selected Primary Brain and Central Nervous System Tumor Age-Specific Incidence Rates, Central Brain Tumor Registry of the United States, 1998-2002.
^ Selected Childhood Primary Brain and Central Nervous System Tumor Incidence Rates by Major Histology Groupings, Histology and Gender Central Brain Tumor Registry of the United States, 1998-2002.
^ Selected Childhood Primary Brain and Central Nervous System Tumor Age-Specific Incidence Rates, Central Brain Tumor Registry of the United States, 1998-2002.
^ Roger Packer M.D, Medulloblastoma Clinical Trials and Noteworthy Treatments for Brain Tumors 2002.
^ Burger PC; Yu I, Tihan T, et al (1998). "Atypical teratoid rhabdoid tumors of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group Study." (in English). Am J Surg Pathol 1998 (22:): 1083–92. doi:10.1097/00000478-199809000-00007.
^ Eibl RH, Kleihues P, Jat PS, Wiestler OD (1994) A model for primitive neuroectodermal tumors in transgenic neural transplants harboring the SV40 large T antigen. Am J Pathol. 1994 Mar;144(3):556-64.
^ Ohgaki H, Eibl RH, Wiestler OD, Yasargil MG, Newcomb EW, Kleihues P: p53 mutations in nonastrocytic human brain tumors. Cancer Res (1991) 51:6202-5

Additional images

Cerebellar medulloblastoma (1) in adult

Cerebellar medulloblastoma (2) in adult

Anaplastic large cell lymphoma

2008-12-22T08:15:00.000-08:00

Anaplastic large cell lymphoma (ALCL) is a type of non-Hodgkin lymphoma that features in the World Health Organisation (WHO) classification of lymphomas.

Signs and symptoms

It occurs in both nodal and extranodal locations. It typically presents at a late stage and is often associated with systemic symptoms ("B symptoms").

Diagnosis

To make this diagnosis under its present system of classification, the WHO the presence of "hallmark" cells and immunopositivity for CD30.

The classification acknowledges as typical, but does not require immunopositivity for ALK (anaplastic lymphoma kinase) protein. It specifically excludes primary cutaneous T-cell lymphomas and other specific types of anaplastic lymphoma (particularly those of B-cell lineage) with CD30 positivity.

The hallmark cells are of medium size and feature abundant cytoplasm (which may be clear, amphophilic or eosinophilic), kidney shaped nuclei, and a paranuclear eosinophilic region. Occasional cells may be identified in which the plane of section passes through the nucleus in such a way that it appears to enclose a region of cytoplasm within a ring; such cells are called "doughnut" cells.

By definition, on histological examination, hallmark cells are always present. Where they are not present in large numbers, they are usually located around blood vessels. Morphologic variants include the following types:

Common (featuring a predominance of hallmark cells)
Small cell (featuring smaller cells with the same immunophenotype as the hallmark cells)
Lymphohistiocytic
Sarcomatoid
Signet ring

Immunophenotype

The hallmark cells (and variants) show immunopositivity for CD30 (also known as Ki-1). True positivity requires localisation of signal to the cell membrane and/or paranuclear region (cyptolasmic positivity is considered non-specific and non-informative). Another useful marker which helps to differentiate this lesion from Hodgkin lymphoma is Clusterin. The neoplastic cells have a golgi staining pattern (hence paranuclear staining), which is characteristic of this lymphoma. The cells are also typically positive for a subset of markers of T-cell lineage. However, as with other T-cell lymphomas, they are usually negative for the pan T-cell marker CD3. Occasional examples are of null (neither T nor B) cell type. These lymphomas show immunopositivity for ALK protein in 70% of cases. They are also typically positive for EMA. In contrast to many B-cell anaplastic CD30 positive lymphomas, they are negative for markers of Epstein-Barr Virus (EBV).

Molecular biology

The majority of cases, greater than 90%, contain a clonal rearrangement of the T-cell receptor. This may be identified using PCR techniques, such as T-gamma multiplex PCR. Oncogeneic potential is conferred by upregulation of a tyrosine kinase gene on chromosome 2. Several different translocations involving this gene have been identified in different cases of this lymphoma. The most common is a chromosomal translocation involving the nucleophosmin gene on chromosome 5. The translocation may be identified by analysis of giemsa-banded metaphase spreads of tumour cells and is characterised by t(2;5)(p23;q35). The product of this fusion gene may be identified by immunohistochemistry using antiserum to ALK protein. Probes are available to identify the translocation by fluorescent in situ hybridization. The nucleophosmin component associated with the commonest translocation results in nuclear positivity as well as cytoplasmic positivity. Positivity with the other translocations may be confined to the cytoplasm.

Differential diagnosis and diagnostic pitfalls

As the appearance of the hallmark cells, pattern of growth (nesting within lymph nodes) and positivity for EMA may mimic metastatic carcinoma, it is important to include markers for cytokeratin in any diagnostic panel (these will be negative in the case of anaplastic lymphoma). Other mimics include CD30 positive B-cell lymphomas with anaplastic cells (including Hodgkin lymphomas). These are identified by their positivity for markers of B-cell lineage and frequent presence of markers of EBV. Primary cutaneous T-cell lymphomas may also be positive for CD30; these are excluded by their anatomic distribution. ALK positivity may also be seen in some large cell B-cell lymphomas and occasionally in rhabdomyosarcomas.

Treatment

Managed under "Aggressive Lymphoma" guidelines
- CHOP is first line of treatment, CHOP-Rituxan in the unlikely scenario that CD20 is positive, given that CD20 is a B-cell marker.
- Radiation therapy as per institutional preference (based on ECOG, SWOG, and GELA trials), but usually added for bulky disease
Overall better prognosis than other "Aggressive Lymphomas"
- ALK+ 5-year survival 70-80%
- ALK- 5-year survival 30-50%

Prognosis

During treatment, relapses may occur but these typically remain sensitive to chemotherapy.

Those with ALK positivity have a better prognosis. It is possible that ALK-negative anaplastic large cell lymphomas represent other T-cell lymphomas that are morphologic mimics of ALCL in a final common pathway of disease progression. It is possible that existing systems of classification will be revised in the future to exclude such lymphomas from this specific diagnosis.

Epidemiology

The lymphoma is more common in the young and in males.

Cutaneous T cell lymphoma

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Cutaneous T-Cell lymphoma (CTCL) is a class of non-Hodgkin's lymphoma, which is a type of cancer of the immune system. Unlike most non-Hodgkin's lymphomas (which are generally B-cell related), CTCL is caused by a mutation of T cells. The malignant T cells in the body are pushed to the surface of the skin in a biological process used to rid the body of offending material, causing various lesions to appear on the skin. These lesions change shape as the disease progresses, typically beginning as what appears to be a rash and eventually forming plaques and tumors before metastasizing to other parts of the body.

Types

Though there are many types of CTCL and presentation can vary from individual to individual, there are two main forms:

mycosis fungoides (MF)
Sézary syndrome (SS)

There is some dispute over whether SS is an advanced form of MF or a different type of CTCL entirely - in either case, the prognosis for SS patients is substantially poorer than for those of MF.

Treatment

There is no cure for CTCL, but there are a variety of treatment options available and some CTCL patients are able to live somewhat normal lives with this cancer, although symptoms can be debilitating and painful, even in earlier stages.

Treatments include: Topical Corticosteroids, Bexarotene Gel, Carmustine(Nitrogen Mustard), Mechlorethamine, Phototherapy (Broad & Narrow Band UVB or PUVA), Local & Total Skin Electron Beam Radiation, Conventional Radiation Therapy, Oral Corticosteroids, Bexarotene (Targretin) Capsules, Photopheresis, Interferons, Denileukin Diftitox (Ontak), Alemtuzumab (Campath-1H), Vorinostat (Zolinza), Methotrexate, Pentostatin & other purine analogues (Fludarabine, 2- deoxychloroadenosine), Liposomal doxorubicin (Doxil), Gemcitabine (Gemzar), Cyclophosphamide, oral, Bone marrow/Stem cell, and Allogenic Transplantation.

Epidemiology

Of all cancers involving the same class of blood cell, 2% of cases are cutaneous T cell lymphomas.

References

^ Turgeon, Mary Louise (2005). Clinical hematology: theory and procedures. Hagerstown, MD: Lippincott Williams & Wilkins. p. 283. ISBN 0-7817-5007-5. "Frequency of lymphoid neoplasms. (Source: Modified from WHO Blue Book on Tumour of Hematopoietic and Lymphoid Tissues. 2001, p. 2001.)".

Chronic lymphocytic leukemia

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Chronic lymphocytic leukemia
Peripheral blood smear showing CLL cells

Chronic lymphocytic leukemia (also known as "chronic lymphoid leukemia" or "CLL"), is a type of leukemia, or cancer of the white blood cells (lymphocytes). CLL affects a particular lymphocyte, the B cell, which originates in the bone marrow, develops in the lymph nodes, and normally fights infection. In CLL, the DNA of a B cell is damaged, so that it can't fight infection, but it grows out of control and crowds out the healthy blood cells that can fight infection.

CLL is an abnormal neoplastic proliferation of B cells. The cells accumulate mainly in the bone marrow and blood. Although not originally appreciated, CLL is now felt to be identical to a disease called small lymphocytic lymphoma (SLL), a type of non-Hodgkin's lymphoma which presents primarily in the lymph nodes. The World Health Organization considers CLL and SLL to be "one disease at different stages, not two separate entities".

CLL is a disease of adults. Most (>75%) people newly diagnosed with CLL are over the age 50, and the majority are men. In the United States during 2007, it is estimated there will be 15,340 new cases diagnosed and 4,500 deaths, but because of prolonged survival, many more people are living with CLL.

Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but as it advances CLL results in swollen lymph nodes, spleen, and liver, and eventually anemia and infections. Early CLL is not treated, and late CLL is treated with chemotherapy and monoclonal antibodies. Survival varies from 5 years to more than 25 years. It is now possible to diagnose patients with short and long survival more precisely by examining the DNA mutations, and patients with slowly-progressing disease can be reassured and may not need any treatment in their lifetimes.

Classification and prognosis

Clinical staging

Staging, determining the extent of the disease, is done with the Rai staging system or the Binet classification and is based primarily on the presence, or not, of a low platelet or red cell count. Early stage disease does not need to be treated.

Gene mutation status

Recent publications suggest that two or three prognostic groups of CLL exist based on the maturational state of the cell. This distinction is based on the maturity of the lymphocytes as discerned by the immunoglobulin variable-region heavy chain (IgVH) gene mutation status. High risk patients have an immature cell pattern with few mutations in the DNA in the IgV_H antibody gene region whereas low risk patients show considerable mutations of the DNA in the antibody gene region indicating mature lymphocytes.

Since assessment of the IgV_H antibody DNA changes is difficult to perform, the presence of either cluster of differentiation 38 (CD38) or Z-chain–associated protein kinase-70 (ZAP-70) may be surrogate markers of high risk subtype of CLL. Their expression correlates with a more immature cellular state and a more rapid disease course.

Fluorescence in situ hybridization (FISH)

In addition to the maturational state, the prognosis of patients with CLL is dependent on the genetic changes within the neoplastic cell population. These genetic changes can be identified by fluorescent probes to chromosomal parts using a technique referred to as fluorescent in situ hybridization (FISH). Four main genetic aberrations are recognized in CLL cells that have a major impact on disease behavior.

Deletions of part of the short arm of chromosome 17 (del 17p) which target the cell cycle regulating protein p53 are particularly deleterious. Patients with this abnormality have significantly short interval before they require therapy and a shorter survival. This abnormality is found in 5-10% of patients with CLL.
Deletions of the long arm on chromosome 11 (del 11q) are also unfavorable although not to the degree seen with del 17p. The abnormality targets the ATM gene and occurs infrequently in CLL (5-10%).
Trisomy 12, an additional chromosome 12, is a relatively frequent finding occurring in 20-25% of patients and imparts an intermediate prognosis.
Deletion of the long arm of chromosome 13 (del 13q) is the most common abnormality in CLL with roughly 50% of patients with cells containing this defect. These patients have the best prognosis and most will live many years, even decades, without the need for therapy. The gene targeted by this deletion is a segment that likely produces small inhibitory RNA molecules that affect expression of important death inhibiting gene products.

Related diseases

In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, it is now recognized that these so-called T-cell CLLs are in fact a separate disease group and are currently classified as T-cell prolymphocytic leukemias.

CLL should not be confused with acute lymphoblastic leukemia, (ALL) a highly aggressive and highly treatable leukemia most commonly diagnosed in children.

Symptoms and signs

Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count. Uncommonly, CLL presents as enlargement of the lymph nodes without a high white blood cell count or no evidence of the disease in the blood. This is referred to as small lymphocytic lymphoma. In some individuals the disease comes to light only after the neoplastic cells overwhelm the bone marrow resulting in anemia producing tiredness or weakness.

Diagnosis

The disease is easily diagnosed. CLL is usually first suspected by the presence of a lymphocytosis, an increase in one type of the white blood cell, on a complete blood count (CBC) test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 4000 cells per mm3 (microliter) of blood but can be much higher. The presence of a lymphocytosis in an elderly individual should raise strong suspicion for CLL and a confirmatory diagnostic test, in particular flow cytometry, should be performed unless clinically unnecessary.

The diagnosis of CLL is based on the demonstration of an abnormal population of B lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of molecules on the cell surface. This atypical molecular pattern includes the co-expression of cells surface markers cluster of differentiation 5 (CD5) and cluster of differentiation 23 (CD23). In addition, all the CLL cells within one individual are clonal, that is genetically identical. In practice, this is inferred by the detection of only one of the mutually exclusive antibody light chains, kappa or lambda, on the entire population of the abnormal B cells. Normal B lymphocytes consist of a stew of different antibody producing cells resulting in a mixture of both kappa and lambda expressing cells. The lack of the normal distribution of kappa and lambda producing B cells is one basis for demonstrating clonality, the key element for establishing a diagnosis of any B cell malignancy (B cell Non-Hodgkin lymphoma).

The combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by flow cytometry to confirm clonality and marker molecule expression is needed to establish the diagnosis of CLL. Both are easily accomplished on a small amount of blood. A flow cytometer is an instrument that can examine the expression of molecules on individual cells in fluids. This requires the use of specific antibodies to marker molecules with fluorescent tags recognized by the instrument. In CLL, the lymphocytes are genetically clonal, of the B cell lineage (express marker molecules cluster of differentiation 19 (CD19) and CD20), and characteristically express the marker molecules CD5 and CD23. Morphologically, the cells resemble normal lymphocytes under the microscope, although slightly larger, and are fragile when smeared onto a glass slide giving rise to many broken cells (smudge cells).

Differential diagnosis

Hematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include mantle cell lymphoma, marginal zone lymphoma, B cell prolymphocytic leukemia, and lymphoplasmacytic lymphoma.

B cell prolymphocytic leukemia (B PLL), is a related but more aggressive disorder, has cells with similar phenotype but that are significantly larger than normal lymphocytes and have a prominent nucleolus. The distinction is important as the prognosis and therapy differs from CLL.
Hairy cell leukemia is also a neoplasm of B lymphocytes but the neoplastic cells have a distinct morphology under the microscope (hairy cell leukemia cells have delicate, hair-like projections on their surface) and unique marker molecule expression.

All the B cell malignancies of the blood and bone marrow can be differentiated from one another by the combination of cellular microscopic morphology, marker molecule expression, and specific tumor-associated gene defects. This is best accomplished by evaluation of the patient's blood, bone marrow and occasionally lymph node cells by a pathologist with specific training in blood disorders. A flow cytometer is necessary for cell marker analysis and the detection of genetic problems in the cells may require visualizing the DNA changes with fluorescent probes by fluorescent in situ hybridization (FISH).

Treatment

While generally considered incurable, CLL progresses slowly in most cases. Many people with CLL lead normal and active lives for many years - in some cases for decades. Because of its slow onset, early-stage CLL is generally not treated since it is believed that early CLL intervention does not improve survival time or quality of life. Instead, the condition is monitored over time to detect any change in the disease pattern. Chronic Lymphocytic Leukemia may transform into Richter's Syndrome _ a term used to describe the development of high-grade non-Hodgkin lymphoma, prolymphocytic leukemia, Hodgkin disease, or acute leukemia in a patient who has chronic lymphocytic leukemia. Its incidence is estimated to be around 5%.

The decision to start CLL treatment is taken when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life.

CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. CLL is treated by chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Symptoms are sometimes treated surgically (splenectomy removal of enlarged spleen) or by radiation therapy ("de-bulking" swollen lymph nodes).

Clinical "staging systems" such as the Rai 4-stage system and the Binet classification can help to determine when and how to treat the patient.

Determining when to start treatment and by what means is often difficult; studies have shown there is no survival advantage to treating the disease too early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.

Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. There are dozens of agents used for CLL therapy, and there is considerable research activity studying them individually or in combination with each other.

Purine analogues

Although the purine analogue fludarabine was shown to give superior response rates than chlorambucil as primary therapy, there is no evidence that early use of fludarabine improves overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease.

Monoclonal antibodies

Monoclonal antibodies are alemtuzumab (directed against CD52) and rituximab (directed against CD20).

Combination chemotherapy

Combination chemotherapy options are effective in both newly-diagnosed and relapsed CLL. Recently, randomized trials have shown that combinations of purine analogues (fludarabine) with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents:

FC (fludarabine with cyclophosphamide)
FR (fludarabine with rituximab)
FCR (fludarabine, cyclophosphamide, and rituximab)
CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone)

Stem cell transplantation

Allogeneic bone marrow (stem cell) transplantation is rarely used as a first-line treatment for CLL due to its risk. There is increasing interest in the use of reduced intensity allogeneic stem cell transplantation, which offers the prospect of cure for selected patients with a suitable donor.

Refractory CLL

"Refractory" CLL is a disease that no longer responds favorably to treatment. In this case more aggressive therapies, including lenalidomide, flavopiridol, and bone marrow (stem cell) transplantation, are considered. The monoclonal antibody, alemtuzumab (directed against CD52), may be used in patients with refractory, bone marrow-based disease.

Epidemiology

CLL is a disease of older adults and is rarely encountered in individuals under the age of 40. Thereafter the disease incidence increases with age. Subclinical "disease" can be identified in 3.5% of normal adults, and in up to 8% of individuals over the age of 70. That is, small clones of B cells with the characteristic CLL phenotype can be identified in many healthy elderly persons. The clinical significance of these cells is unknown.

Of all cancers involving the same class of blood cell, 7% of cases are CLL/SLL.

Complications: hypogammaglobulinemia leading to recurrent infection, warm auto imune haemolytic anaemia in 10-15% of patients, transformation to high grade lymphoma, Richter's transformation.