Lymphomas are a diverse group of malignancies that originate in the lymphoid system. This system includes the lymph nodes as well as extranodal sites, such as bone marrow, the spleen, the tonsils and adenoids, the thymus gland, and Peyer’s patches in the small intestine. There are two major types of lymphoma: Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL). HD makes up 15% of lymphomas and is characterized by the Reed-Sternberg cell. NHL diseases are very heterogeneous and consist of approximately 23 different histologic types (see Table 18-1 for types of lymphoma). Although each type of NHL is biologically different, there are two major categories of NHL: indolent and aggressive (see Table 18-2 for characteristics of uncommon NHL types).
A. Incidence: NHL is the sixth leading site of cancer among men and women. According to the American Cancer Society (2003), there were an estimated 53,400 new cases of NHL in 2003. The incidence of lymphoma has increased steadily since the 1970s. This rapid rise is in part due to the increase in human immunodeficiency virus (HIV) and subsequent NHL development in this patient population. A decrease in the incidence of HIV-related NHL may be seen as the use of highly effective antiretroviral therapy (HAART) increases. HAART increases the immunocompetence of people with HIV, thereby potentially lowering their increased cancer risk. Improved diagnostics and chronic immunosuppression (eg, organ transplantation patients) have also been implicated in the rising incidence of lymphoma. NHL is more common and the mortality rates are greater than those of HD. The American Cancer Society (2003) reports an estimated 7,600 new cases of HD in 2003. HD has a bimodal incidence that peaks in youth, between the ages of 18 and 24, and then peaks again at 50 to 70 years of age. NHL has a peak incidence of 50 years. Males are at greater risk of lymphoma than females.
B. Morbidity and Mortality Statistics: The American Cancer Society (2003) reports an estimated 1,300 deaths in 2003 from HD, and there will be an estimated 23,400 deaths in 2003 from NHL. HD is highly curable with chemotherapy. NHL is the fifth leading cause of death among men and the sixth leading cause of death among women. Many of the indolent NHL diseases have a natural course lasting 10 to 15 years, whereas the more aggressive NHL course can lead to death quickly if left untreated. Higher mortality is seen in urban and higher socioeconomic populations.
TABLE 18-1 Revised European-American Lymphoma (REAL)/World Health Organization (WHO) Classification of Lymphoid Neoplasms
Anaplastic large cell lymphoma, T/null cell, primary cutaneous type
Peripheral T-cell lymphoma, not otherwise characterized
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma, T/null cell, primary systematic type
Harris, N. L., Jaffe, E. S., Diebold, J., et al. (1999). The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia.
TABLE 18-2 Characteristics of Uncommon NHL Types
Type
Characteristics
Small lymphocytic lymphoma
Morphologically indistinguishable from CLL 10% to 20% progress to CLL
5% transform to an aggressive form of lymphoma treated with fludarabine, cyclophosphamide, chlorambucil, prednisone, CVP
Gastric MALT lymphoma
Associated with chronic gastritis and H pylori, which is a bacteria that induces gastric ulcers
May be treated with antibiotics, local radiation, gastrectomy, chemotherapy
Burkitt’s lymphoma
Rapid doubling time ˜1 day
Need immediate treatment
High risk for tumor lysis syndrome
Patients often present with high LDH and bulky disease
20% to 30% risk of CNS disease
IT prophylaxis
High-risk patients may need blood or marrow transplantation if chemotherapy responsive
Mantle cell lymphoma
Presents in older patients >50 years of age
Median survival 3 to 5 years
80% are males
Difficult to treat
Metastasizes to the liver, spleen, bone marrow, and GI tract
Blood and marrow transplantation are under investigation
AIDS-related lymphoma
T-cell destruction leads to immunosuppression
Poor survival
Aggressive, present with advanced disease, more severe side effects from treatment
Often need dose reductions in chemotherapy regimens
20% to 53% have bone marrow involvement
20% to 45% have CNS involvement
Most are diffuse B-cell and Burkitt’s
˜50% may be EBV related
Primary CNS lymphoma is more common in AIDS patients who have low CD4 counts
Performance status and CD4 count at diagnosis are prognostic indicators
T-cell lymphomas
Lymphoblastic—aggressive, most present with large mediastinal masses, bone marrow, and CNS involvement
Treatment is patterned after ALL +/− radiation
Mycosis fungoides—cutaneous T-cell lymphomas
Initial indolent course with wide dissemination
Cure is uncommon
Should be considered for clinical trials
Poor prognosis if visceral and blood/marrow involvement
T-cell lymphomas
Treatment includes topical therapies, photopheresis, electron beam therapy, interferon A, psoralen plus ultraviolet A radiation (PUVA), monoclonal antibody treatments (eg, Ontak-CD 25 MAB)
Skin eruptions, nodular/necrotic tumors, and visceral involvement occur
Patients experience significant body image changes, depression
Infection is a common cause of death in these patients
CNS lymphoma
Rare
NHL confined to the central nervous system
Most are high-grade, diffuse, B-cell type
Incidence is on the rise
25% of patients have ocular involvement
Treatment includes whole brain radiation and/or high-dose methotrexate with leucovorin rescue
II. Etiology
A. Risk Factors
1. Immunodeficiency disorders such as rheumatoid arthritis and systemic lupus erythematosus are associated with lymphoma.
2. Patients who have undergone organ transplantation and who are on chronic immunosuppression have a higher risk of NHL.
3. Inherited immunodeficiency syndromes increase one’s risk of developing a lymphoma (eg, Klinefelter’s syndrome, telangiectasia, and ataxia).
4. Treatments for cancer, including chemotherapy and radiation therapy, can cause second malignancies, which often present as a lymphoma or leukemia.
5. Viral infections are known to be associated with the development of lymphomas.
a. Epstein Barr virus (EBV) infection occurs earlier in childhood in underdeveloped countries and is associated with Burkitt’s lymphoma in those areas. In developed countries, EBV is associated with post-transplantation lymphoproliferative disorders. Some scientists believe that HD is caused by EBV infection.
b. The incidence of NHL in HIV-positive patients is approximately 60 times greater than that of the general population (Tulpule & Levine, 1999). HIV infection is also associated with HD but to a lesser extent.
c. Human T-cell leukemia/lymphoma virus (HTLV-1) is associated with NHL. This virus is most common in Japan and the Caribbean; however, incidence is on the rise in some parts of the United States.
6.Helicobacter pylori is a bacteria associated with the development of primary gastric NHL.
7. There is some indication that benzene compounds, insecticides, and herbicides may increase the risk of lymphomas; however, the data are not yet conclusive.
III. Patient Management
A. Assessment: Symptoms are commonly associated with compression of structures adjacent to nodal groups, decreased lymphatic function, and systemic infiltration of the disease.
1. Complete history and physical examination are obtained with a special emphasis on lymphatic areas and extranodal sites that may be involved.
2. Performance status scales, such as the Karnofsky or Eastern Cooperative Oncology Group (ECOG) scale, have proven to be a key factor in prognosis of aggressive NHL. In 1993, a group of physicians developed the International Prognostic Index (IPI) to help determine therapy in aggressive lymphomas. The IPI includes age >60 years, LDH >1 × normal, performance status 2-4, stage III or IV, and extranodal involvement >1 site. IPI levels of 4 or 5 are at high risk of relapse. (International Non-Hodgkin’s Lymphoma Prognostic Factors Project, 1993)
3. Lymphadenopathy of the cervical, supraclavicular, axillary, inguinal, or mediastinal areas is the most common presenting symptom. This reflects the increased growth of cancer cells in the lymph nodes. Growth is often rapid; nodes are painless and may be unilateral or bilateral. About 20% of patients report pain of the enlarged lymph nodes after alcohol ingestion. HD spreads in a contiguous manner along lymph node chains, whereas NHL spreads in a less predictable manner to lymph nodes and to extranodal sites not adjacent to the original site.
4. Fever, fatigue, night sweats, pruritus, frequent infections, and weight loss are symptoms associated with altered immune response patterns and systemic involvement. The definition of “B symptoms” includes an unexplained fever for greater than 1 month, unintentional weight loss of >10%, and night sweats for more than 1 month. Pruritus is another presenting symptom in some lymphoma patients. The presence of B symptoms indicates a poor prognosis in HD patients, and these symptoms can also be a harbinger of relapse and advanced disease. “A symptoms” refers to the absence of “B symptoms.”
5. Cough, dyspnea, dysphagia, and superior vena cava syndrome are symptoms that may result from the tumor causing pressure or obstructing an adjacent area. These symptoms are most often seen when mediastinal nodes are involved.
6. Abdominal pain in the left upper quadrant suggests enlargement of the spleen.
7. Jaundice can result from bile duct obstruction.
8. General abdominal pain and bowel or bladder dysfunction can be caused by retroperitoneal adenopathy.
9. Cytopenias are common, and it is important to differentiate between treatment-related aplasia, autoimmune disorders, and lymphoma infiltration of the bone marrow in order to direct treatment.
10. Confusion, lethargy and cranial nerve palsies are associated with central nervous system (CNS) NHL.
IV. Diagnostic Parameters
A. Lymph Node Biopsy: Lymphadenopathy can result from allergic reactions, infections, and other nonspecific causes. If the enlarged node persists for several weeks, a lymph node biopsy is indicated. Cervical lymph node excisional biopsies are more diagnostic than inguinal nodes, which often demonstrate benign reactivity instead of malignancy.
1. The Reed-Sternberg cell is a large, binucleated cell that is thought to be derived from a B-cell. This characteristic cell is required for the diagnosis of HD. See Table 18-3 for HD histopathologic classifications.
2. The pathologic diagnosis of NHL depends on the type of malignant lymphocyte found. In 1994, the International Lymphoma Study Group (ILSG) introduced a new classification system for lymphoid neoplasms called the Revised European-American Lymphoma Classification of Lymphoid Neoplasms (REAL). The World Health Organization (WHO) also updated its classification. The REAL/WHO classification is now the standard for classification in lymphoma. See Table 18-1 for the REAL/WHO classifications. Classification depends on the architecture of the lymph node, immunophenotype, and molecular characteristics. For example, affected lymph nodes in follicular lymphoma retain their follicular appearance, whereas lymph nodes affected by diffuse large cell lymphoma have no resemblance to a lymph node under the microscope. NHL can arise primarily from the B-cell (85%) and the T-cell (15%).
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