Figure 15.1. Overview of the Lymphatic System. Central lymphoid organs (red) are the bone marrow, where B-cell development occurs, and the thymus, where T-cell development occurs. Peripheral lymphoid organs (green) are the lymph nodes, spleen, and mucosa-associated lymphoid tissues (MALT). The major lymph node regions are shown (green clover).

NON-HODGKIN LYMPHOMA

NHL is the seventh most common cancer and the most common hematologic malignancy in the United States, with approximately 70,000 new cases diagnosed each year. NHL is also the seventh most common cause of cancer-related deaths in the United States, accounting for approximately 19,000 deaths per year.

CLINICAL PRESENTATION NHL

• Lymphadenopathy is present in over two-thirds of patients with NHL, with the rapidity of lymph node enlargement reflecting the aggressiveness of the underlying lymphoma.

• B symptoms are defined as fever greater than 38ºC (100.4ºF), drenching night sweats requiring a change of clothes, and weight loss of greater than 10% baseline body weight over a 6- to 12-month period. B symptoms are observed in about 45% of aggressive or highly aggressive NHL, and in less than 25% of indolent NHL; when present in the setting of an indolent NHL, B symptoms tend to indicate a large burden of disease or transformation into aggressive lymphoma.

• Local symptoms reflect the degree to which a lymphoma impairs the function of involved or adjacent tissues, with different NHLs displaying varying degrees of extranodal (i.e., external to the lymph nodes) involvement. Common sites of extranodal disease include the liver, spleen, gastrointestinal tract, skin, bone marrow, and central nervous system (CNS); rare sites include the kidneys, bladder, adrenals, heart (particularly the pericardial space), lungs, breast, testes, and thyroid.

EVALUATION OF NHL

Evaluation of a new or suspected diagnosis of NHL requires a thorough history, physical examination, laboratory evaluation, imaging analysis, and tissue sampling for pathology review (see Figure 15.2).

History

A comprehensive history in the evaluation of a new or suspected diagnosis of NHL should assess for B symptoms and for factors known to be associated with NHL, including:

• Autoimmune and inflammatory diseases. Examples are systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, dermatomyositis, and Sjögren syndrome, all of which may be associated with NHL and, occasionally, HL. Celiac disease is associated with enteropathy-associated T-cell lymphoma, autoimmune thyroiditis with extranodal marginal zone lymphoma, and cryoglobulinemia with NHL. Sarcoidosis is both associated with and may mimic NHL by virtue of lymphadenopathy.

• Viral infections. Examples include human immunodeficiency virus (HIV), associated with diffuse large B-cell lymphoma, Burkitt lymphoma, primary CNS lymphoma, primary effusion lymphoma, plasmablastic lymphoma, and HL; Epstein-Barr virus (EBV), associated with diffuse large B-cell lymphoma, Burkitt lymphoma, NK- and T-cell lymphomas, and HL; human T lymphotropic virus type I (HTLV-l), associated with adult T-cell lymphoma/leukemia; human herpesvirus 8 (HHV-8), associated with HIV+ primary effusion lymphoma and with HIV+ plasmablastic lymphoma; and hepatitis C virus (HCV), associated with splenic and extranodal marginal zone lymphomas.

• Bacterial infections. The major association of bacterial infections is with extranodal marginal zone lymphomas in various organs. The most common infections are Helicobacter pylori (stomach, a.k.a. gastric MALToma), Borrelia burgdorferi (skin), Campylobacter jejuni (small intestine), and Chlamydophila psittaci (eye).

• Medications. The most important medications associated with NHL are immunosuppressive agents (e.g., methotrexate, infliximab, 6-mercaptopurine, azathioprine, tacrolimus, cyclosporine, and mycophenolate) and targeted therapies against tumor necrosis factor-alpha (e.g., infliximab [Remicade], adalimumab [HUMIRA], and etanercept [Enbrel]).

• History of prior transplantation, associated with B- or T-cell posttransplant lymphoproliferative disease.

• Environmental exposure to pesticides, solvents, chemicals, or chemotherapy.

• Family history of lymphoma (particularly chronic lymphocytic leukemia), leukemia, or other hematologic diseases.

Physical Examination

• Lymph node examination. The major peripheral lymph node groups are the cervical (anterior and posterior), supraclavicular, axillary, epitrochlear, inguinal, and popliteal nodes. Features suggestive of malignancy include nodes that are >1 cm in diameter; have a firm, rubbery consistency; are fixed or immobile; are nontender to palpation; are located in the posterior cervical, supraclavicular, or epitrochlear chains; or are diffusely distributed.

• Liver and spleen examination. Every patient with a new or suspected diagnosis of NHL or HL should be evaluated for hepatomegaly or splenomegaly, as the liver and spleen are common sites of extranodal involvement.

• Oropharyngeal examination. Waldeyer’s ring, a region of lymphoid tissue encompassing the tonsils, base of tongue, and nasopharynx, may be involved by various lymphomas, particularly mantle cell lymphoma. Aphthous ulcers may rarely be manifestations of oral lymphoma. Oral petechiae may indicate thrombocytopenia or disseminated intravascular coagulation.

Laboratory Evaluation

• Complete blood count (CBC). Anemia or thrombocytopenia may reflect marrow infiltration or an associated autoimmune process such as autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP), both of which may be seen with chronic lymphocytic leukemia. The white blood cell (WBC) differential should be manually counted to assess for lymphocytosis. Peripheral blood smear should be examined for unusual lymphoid cell morphologies. In select cases, flow cytometry may be performed to evaluate for circulating monoclonal lymphoid populations.

• Comprehensive metabolic panel, phosphorus, and uric acid. Creatinine and liver function tests assess for end-organ damage due to lymphomatous infiltration. Calcium, potassium, phosphorus, and uric acid assess for tumor lysis, which may be seen with aggressive or highly aggressive lymphomas.

• Lactate dehydrogenase (LDH). The serum LDH level is a marker of tumor lysis in aggressive or highly aggressive NHL and serves as an important prognostic factor in many NHL subtypes. It may also be an indicator of transformation from indolent into aggressive NHL.

• Additional laboratory tests may include specific serologic, polymerase chain reaction, and culture studies for infectious or autoimmune processes as indicated by the clinical scenario. Examples are HIV, EBV, HTLV-l, hepatitis B virus, HCV, H. pylori, antinuclear antibody (ANA), rheumatoid factor (RF), serum protein electrophoresis, beta-2 microglobulin (B2M), cryoglobulin, and Coombs’ testing.

Imaging Evaluation

The imaging study of choice in the evaluation of NHL is a computed tomography (CT) scan of the chest, abdomen, and pelvis. CT scan of the neck may be performed if there is suspicion for cervical or upper oropharyngeal disease.

• For aggressive and highly aggressive NHL (and HL), whole-body fluorodeoxyglucose positron emission tomography in combination with CT (PET/CT) is routinely obtained in the initial staging and subsequent evaluation of response to therapy. In general, rapidly growing malignancies are exquisitely sensitive to detection on PET imaging due to robust uptake of fluorodeoxyglucose. The role of PET/CT in evaluation of indolent NHL is less clear.

• Transthoracic echocardiogram or cardiac multigated acquisition scan should be performed in all patients who will be receiving chemotherapy containing anthracyclines (e.g., doxorubicin or Adriamycin).

Tissue Evaluation

• Full excisional biopsy of an involved lymph node is the preferred procedure for obtaining tissue for pathologic review in evaluation of lymphoma. In patients with multiple enlarged peripheral lymph nodes, supraclavicular nodes have the highest diagnostic yield, followed by cervical or axillary nodes. Inguinal nodes are of low diagnostic utility, as their enlargement is often reactive.

• CT-guided core needle biopsy may be performed in cases where excisional lymph node biopsy is not feasible. Due to the small size of tissue obtained, diagnostic ability is reduced with core needle biopsy as compared to excisional biopsy.

• Fine needle aspiration of an involved lymph node is not recommended in evaluation of lymphoma, as cytology samples do not allow for evaluation of lymph node architecture.

• Bone marrow biopsy is performed in the majority of patients with aggressive or highly aggressive NHL and in some patients with indolent NHL.

• Lumbar puncture may be performed in patients with highly aggressive NHL who have suspicious neurologic manifestations or risk factors for CNS involvement (e.g., elevated LDH at initial presentation, involvement of more than one extranodal site, or infiltration of bone marrow, testes, or paranasal sinuses). In cases where the suspicion for CNS involvement is high, or where there may be concern for possible hematogenous seeding of the CNS by circulating lymphoma cells during lumbar puncture, intrathecal chemotherapy may be administered.

• Endoscopic evaluation of the gastrointestinal tract may be performed if there are suspicious gastrointestinal symptoms (e.g., dysphagia, abdominal pain, diarrhea, or constipation). At many academic centers endoscopy has become part of the routine staging evaluation of mantle cell lymphoma irrespective of symptoms, due to the high incidence of gastrointestinal involvement with this disease. Direct visualization and laryngoscopy may be performed if examination of Waldeyer’s ring is clinically indicated.

PATHOLOGIC CHARACTERIZATION OF NHL

• Histology. Pathologic characterization of NHL begins with a histologic review of tissue. Individual lymphoid and nonlymphoid cells are observed for malignant characteristics such as irregular shape, uniform or monotonous appearance, or nucleoli. Global lymphoid architecture is also evaluated, as normal follicular lymph node architecture is often preserved in follicular lymphoma and other indolent NHL subtypes but may be disrupted in diffuse large B-cell lymphoma, Burkitt lymphoma, and other aggressive or highly aggressive NHLs.

• Immunophenotyping (Figure 15.3). The immunophenotype is the unique signature of cell surface proteins displayed by each type of NHL. Immunophenotyping may be performed by immunohistochemistry or flow cytometry; these techniques measure binding of antibodies directed against specific molecular targets. For B-cell NHL the most important cell surface marker is CD20, which serves as the molecular target of the anti-CD20 antibody rituximab (Rituxan) used in treatment of a variety of B-cell NHLs.

• Cytogenetic analysis (Figure 15.3). Specific cytogenetic abnormalities, particularly translocations, are associated with different NHLs. Cytogenetic analysis is performed by karyotyping or fluorescent in situ hybridization (FISH).

• Ki-67 or MIB-1fraction. Staining for Ki-67 or MIB-1 identifies actively dividing cells. The Ki-67 index or MIB-1 fraction may help distinguish the clinical aggressiveness of different NHL subtypes and may have prognostic significance in specific NHLs (e.g., mantle cell lymphoma).

STAGING OF NHL

Staging for NHL (table 15.1) utilizes the Ann Arbor Staging System, originally devised for HL.

CLASSIFICATION OF NHL

The World Health Organization classifies NHL according to the parental cell type of origin and recognizes four broad categories of NHL: precursor lymphoid neoplasms, mature B-cell neoplasms, mature T-cell and NK-cell neoplasms, and posttransplant lymphoproliferative disorders. For practical reasons, and from the perspective of the general internist, the different NHL subtypes may be classified as indolent, aggressive, or highly aggressive (see box 15.1). Survival of untreated indolent NHL is generally on the order of years; aggressive NHL, months; and highly aggressive NHL, weeks. Major NHL subtypes are presented below.

Box 15.1 MAJOR NHL SUBTYPES CLASSIFIED BY CLINICAL AGGRESSIVENESS

Highly Aggressive NHL

B Lymphoblastic Leukemia/Lymphoma

    B lymphoblastic leukemia/lymphoma is the lymphomatous counterpart of pre-B acute lymphoblastic leukemia (pre-B ALL) and is evaluated and treated similarly. The disease is defined as leukemia if the bone marrow is more than 25% involved. B lymphoblastic leukemia/lymphoma is more common in children but may present in older adults. Both B lymphoblastic leukemia/lymphoma and pre-B ALL express terminal deoxynucleotidyl transferase (TdT), which is unique to these diseases and to T lymphoblastic leukemia/lymphoma, distinguishing these disorders from mature B-cell and T-cell lymphomas. B lymphoblastic leukemia/lymphoma and pre-B ALL are also associated with a number of translocations, the most important being the t(9;22) translocation (Philadelphia chromosome). Whereas pediatric cases have a favorable prognosis the clinical course in adult patients is generally unfavorable, particularly for t(9;22)+ disease. First-line treatment is a combined approach incorporating intensive chemotherapy, prophylactic CNS therapy, and allogeneic stem cell transplant; the tyrosine kinase inhibitor imatinib (Gleevec) is added in t(9;22)+ cases.

T Lymphoblastic Leukemia/Lymphoma

    T lymphoblastic leukemia/lymphoma is the T-cell counterpart to B lymphoblastic leukemia/lymphoma and is treated similarly. It typically presents in young males with a mediastinal mass.

Adult T-Cell Leukemia/Lymphoma

    Adult T-cell leukemia/lymphoma (ATLL) is caused by the HTLV-l virus, endemic to southern Japan and the Caribbean, and also found in Africa, Latin America, and the Middle East. About 5% of HTLV-1+ patients develop ATLL, usually following a latency period of over 30 years. Although there are indolent and smoldering subsets, the majority of patients present with aggressive disease and have a poor prognosis. Treatment approaches include intensive chemotherapy, allogeneic stem cell transplant, and in some cases antiviral agents such as interferon-alpha or zidovudine.

Burkitt Lymphoma

    Burkitt lymphoma (BL) represents more than half of pediatric NHL and less than 5% of all adult NHL in the United States.

    Pathologic features BL is characterized by medium-sized B cells with round nuclei containing multiple nucleoli and cytoplasmic vacuoles. Owing to a high proliferative rate, spontaneous cell destruction and necrosis are common, with macrophages recruited to remove cellular debris; the overall appearance is of sheets of lymphoma cells with interspersed macrophages, forming a “starry sky” pattern (Figure 15.4). By definition BL cells harbor translocations involving the c-myc proto-oncogene on chromosome 8, the most common being the t(8;14) translocation, which positions c-myc close to the Ig heavy chain enhancer on chromosome 14, leading to c-myc overexpression. The t(8;14) translocation accounts in part for the very high proliferative index of BL cells, with Ki-67 staining 100% of cells.

    Clinical presentation. The three major subtypes of BL are endemic, sporadic (nonendemic), and immunodeficiency-associated BL. Endemic BL is found in Africa, mostly in the pediatric population; is strongly associated with EBV infection; and presents as a jaw tumor with bone marrow, CNS, and other multiorgan involvement. Sporadic BL is found throughout the world, is associated with EBV in 30% of cases, and presents as disseminated disease with abdominal lymphadenopathy, ascites, and often bone marrow and/or CNS involvement. Immunodeficiency-associated BL occurs primarily in association with HIV, with only a subset being EBV+.

    Prognosis. BL is potentially curable, although bone marrow and CNS involvement at presentation are adverse features and predict a higher risk of relapse. Response rates to chemotherapy are very high, in part reflecting the high proliferative rate of BL cells. Children with BL have an excellent prognosis with high rates of durable remission, whereas adults have a less favorable course due to an increased risk of relapsed disease.

    Treatment: First-line treatment is intensive combination chemotherapy. Two commonly used chemotherapy regimens are hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) and the modified Magrath regimen (CODOX-M/IVAC: cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate, ifosfamide, cytarabine, etoposide), both of which incorporate prophylactic CNS therapy. Rituximab has recently been combined with both regimens, with encouraging results.

Aggressive NHL

Diffuse Large B-Cell Lymphoma

    Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL, accounting for approximately 30% of all NHLs.

    Pathologic features. DLBCL is characterized by heterogeneous large B cells that proliferate in a diffuse pattern, disrupting normal lymph-node architecture. The Ki-67 index is typically around 70%; cases with a Ki-67 index higher than 90% may occur, particularly in association with translocations involving or overexpression of c-myc, which can cloud histologic distinction from BL. About one-third of DLBCL cases bear the t(14;18) translocation of follicular lymphoma (FL), which may indicate transformation from an earlier FL.

    Clinical course. The median age of DLBCL is 64. The majority of patients present with advanced-stage (III or IV) disease. About 40% have extranodal involvement at the time of initial presentation, including gastrointestinal, skin, bone, CNS, thyroid, or testicular infiltration. Another 10–20% have bone marrow involvement. B symptoms and elevated LDH are common. In some cases, DLBCL may arise from a prior indolent NHL such as FL or CLL; the latter is known as Richter transformation and has an aggressive clinical course. Intravascular large B-cell lymphoma (ILCL) is a rare subtype of DLBCL in which the malignant cells infiltrate small blood vessels distributed across multiple organs; the classic presentation is of a “vasculitic disease without vasculitis,” with neurologic symptoms being common; prognosis is poor, in part because the disease is often not suspected until late in the course. Double-hit lymphoma is a subset of DLBCL characterized by concurrent chromosomal abnormalities affecting MYC (8q24) and BCL2 (18q21) or BCL6 (3q27). Prognosis is very poor, with resistance to standard chemotherapy and early disease relapse.

    Prognosis. Prognosis of DLBCL is determined by the International Prognostic Index (IPI; see table 15.2). Prior to the introduction of rituximab into standard therapy for DLBCL, 5-year overall survival of DLBCL ranged from 26% to 73% depending on the number of IPI risk factors. Both disease-free and overall survival have increased by 10–15% with the addition of rituximab to standard therapy for DLBCL.

Stay updated, free articles. Join our Telegram channel

Join