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.