Waldenström's macroglobulinemia

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

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

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
Pelvic exam
Pap smear
• Biopsy
Colposcopy

Uterine sarcoma

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

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

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

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
  Lymphoma
  • 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

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

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

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
• 
  
Hematocele
• 
  
Varicocele

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">
• 
  
Gonadoblastoma

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

• 
  
Lymphoma
• 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.