Lauren C. Pinter-Brown and Dennis A. Casciato
EVALUATION OF SUSPECTED LYMPHOMA
I. SYMPTOMS AND SIGNS
A. History
1. Painless lymphadenopathy, involving any of the superficial lymph nodes, is the most common chief complaint of patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).
2. Systemic symptoms. Fevers, night sweats, and weight loss are characteristic in advanced presentations of HL and aggressive NHL but may be encountered in all stages and pathologic types of lymphoma. Marked fatigue and general weakness may also be reported, not always correlating with the degree of anemia.
a. Pruritus, often intense, may be the presenting symptom in HL, particularly the nodular sclerosis subtype, and may antedate diagnosis by months or years.
b. Pel-Ebstein fever is periodic and uncommon but characteristic of HL.
3. Pain
a. Alcohol-induced pain in areas of involvement is infrequent but is characteristic of HL.
b. Abdominal pain or discomfort may be due to splenomegaly, bowel dysfunction due to adenopathy or bowel involvement, or hydronephrosis.
c. Bone pain may reflect localized areas of bone destruction or invasion or diffuse marrow infiltration.
d. Neurogenic pain is caused by spinal cord compression, plexopathies, nerve root infiltration, meningeal involvement, and complicating varicella zoster.
e. Back pain suggests massive retroperitoneal nodal involvement, often with psoas muscle invasion.
B. Physical examination. should evaluate for hepatosplenomegaly, the presence of effusions, evidence of neuropathy, and signs of obstruction (e.g., extremity edema, superior vena cava syndrome, spinal cord compression, hollow viscera dysfunction). Lymph node chains must be carefully examined, including the submental, supraclavicular, infraclavicular, epitrochlear, iliac, femoral, and popliteal nodes.
1. The lymph nodes are examined for size, multiplicity, consistency, and tenderness. Lymphomatous involvement typically imparts a rubbery consistency, not the rock-hard quality of carcinoma.
2. The tonsils and oropharynx are thoroughly examined. Waldeyer ring involvement mandates complete evaluation of the nasopharynx, oropharynx, and hypopharynx by endoscopy.
II. DIFFERENTIAL DIAGNOSIS (Table 21.1) compares clinical features of HL and NHL.
Table 21.1 Comparison of Hodgkin and Non-Hodgkin Lymphomas
A. Lymphadenopathy
1. Infections. Patients, particularly young children with apparent viral or other infections, may develop striking lymphadenopathy. Such patients should be evaluated for infectious processes and observed for clear-cut resolution. Microorganisms associated with prominent lymphadenopathy include Epstein-Barr virus (EBV; infectious mononucleosis), cytomegalovirus (CMV), human immunodeficiency virus (HIV), hepatitis virus, secondary syphilis, mycobacteria, some fungi, and Toxoplasma, Brucella, and Rochalimaea species infection. In some cases, biopsy is required for diagnosis of specific infectious diseases.
2. Systemic immune disorders, such as rheumatoid arthritis, Sjögren syndrome, and systemic lupus erythematosus, are associated with both benign lymphadenopathy and lymphoma. Progressive or asymmetric lymphadenopathy mandates biopsy.
3. Patients at risk for HIV infection present problems requiring individualization in management. Persistent generalized lymphadenopathy is a part of the acquired immunodeficiency syndrome (AIDS) spectrum, but lymphadenopathy can also be caused by opportunistic infections, Kaposi sarcoma, or lymphoma.
4. Lymph nodes that are usually benign
a. Occipital. Consider scalp infection.
b. Posterior auricular. Usually viral or scalp infection
c. Shotty inguinal nodes. Often present with no obvious cause but may suggest external genital or lower extremity infections
5. Cervical nodes. Patients with isolated enlargement of high or middle cervical lymph nodes often harbor occult primary carcinoma of the head and neck. The special approach required for these patients is discussed in Chapter 7, Section X.
B. Midline masses
1. Retroperitoneal masses (see Chapter 19, Section II)
2. Mediastinal masses may occur in a variety of nonneoplastic and neoplastic (both primary and metastatic) conditions (see Chapter 19, Section I).
3. Hilar masses. Isolated symmetric bilateral hilar lymphadenopathy (without mediastinal mass) is strongly suggestive of sarcoidosis, and many experts believe that observation alone could suffice in this clinical setting. Unilateral hilar masses are frequently secondary to lung cancer; metastatic disease must also be considered. Coccidioidomycosis and histoplasmosis enter the differential diagnosis in the appropriate clinical and geographic milieu.
C. Splenomegaly. The diagnosis can usually be made with careful history taking and physical examination, laboratory evaluation, CT scans of abdomen, bone marrow biopsy or aspiration with flow cytometric analysis, and, occasionally, liver biopsy. When a diagnosis cannot be established by these means, careful follow-up of the patient is warranted. Splenectomy should be considered for diagnosis in patients with massive or progressive isolated splenomegaly.
1. Normal. A palpable spleen is occasionally seen in otherwise healthy young adults of thin body habitus.
2. Infections include most pathogens listed in Section II.A.1, bacterial endocarditis, malaria, and abscess.
3. Secondary to portal hypertension (congestive splenomegaly). Patients with chronic liver disease or portal or splenic vein thrombosis may have no other findings to direct the diagnostic search. Portal hypertension may be documented by ultrasound of the abdomen with Doppler or by liver–spleen scanning, which reveals redistribution of the radionuclide to the spleen and marrow.
4. Storage diseases, particularly Gaucher disease, may produce prominent splenomegaly; characteristic cells are seen in the bone marrow in most cases.
5. Tumors are predominantly hematologic, including lymphomas and leukemias. Metastases, particularly from melanoma and breast cancer, and primary splenic sarcomas may also occur.
6. Myeloproliferative disorders such as polycythemia vera, agnogenic myeloid metaplasia (myelofibrosis), and chronic myelogenous leukemia may cause marked splenomegaly.
7. Autoimmune disorders. Rheumatoid arthritis (Felty syndrome), systemic lupus erythematosus, and autoimmune hemolytic anemia may produce splenomegaly (not isolated autoimmune thrombocytopenia) and can usually be diagnosed by history and associated laboratory findings.
8. Miscellaneous. Splenic cysts, thyrotoxicosis, sarcoidosis, chronic nonimmune hemolysis, and amyloidosis are unusual causes of splenomegaly.
III. BIOPSY PROCEDURES
A. Sites and methods of diagnostic biopsy. Tissues or organs that are suspected of involvement are subjected to generous open biopsy for primary diagnosis wherever possible. Fine-needle aspiration cytology is mainly used for staging evaluation or for proving recurrence but may sometimes allow cytologic diagnosis if expertise in interpretation is available.
1. Peripheral node biopsy. One of the largest accessible lymph nodes is excised whenever peripheral lymphadenopathy is present. Small lymph nodes may be more readily removed but may be uninvolved.
2. Inguinal lymph nodes are frequently enlarged because of chronic inflammatory processes in the lower extremities. These nodes should be excised only when other sites are not suspected or when pathologic involvement is clearly anticipated.
3. Bone marrow biopsy combined with aspiration is used for staging and may lead to diagnosis, particularly in the presence of abnormal circulating cells or cytopenias.
4. Mediastinoscopy or limited thoracotomy (e.g., Chamberlain procedure) for definitive diagnosis is required for a substantial proportion of patients with mediastinal masses.
5. Laparotomy is used to diagnose some cases of lymphoma restricted to the abdomen and may include biopsies of the liver and random lymph nodes, as well as the primary area in question.
6. Laparoscopy assesses the liver and peritoneum and allows extensive biopsy, obviating the need for laparotomy in some patients.
7. Endoscopic gastric biopsy with staining for Helicobacter pylori may be helpful in the diagnosis of gastric MALToma. Repeated attempts with deeper biopsies and immunoperoxidase staining for leukocyte common antigen and keratin intermediate filaments may be helpful in the differential diagnosis between lymphoma and carcinoma. Small bowel involvement beyond the duodenum usually requires open biopsy, although capsule biopsies may be suggestive of lymphoma in some cases.
8. Retroperitoneal and mesenteric masses may be evaluated by imaging-guided Trucut biopsy or fine-needle aspiration with immunologic analysis of the specimens, obviating the need for laparotomy.
B. Handling the biopsy material. The procured biopsy specimen is submitted to the pathologist directly and not placed in a fixative by the operating surgeon to ensure the best use of the available tissue. Prior communication with the pathologist is advantageous. Maintaining frozen sections is preferable for subsequent analysis. Pathology tissue processing includes the following procedures:
1. Touch preparations (imprints), which provide cytologic detail and material for immunologic phenotyping
2. Immunologic phenotyping with monoclonal antibodies can be crucial to diagnosis. Lymphoid cells are characterized immunologically using flow cytometry. Discriminatory immunophenotypes in lymphoma are shown in Appendix C5. A common NHL panel should include assessment of expression of CD2 or CD3, CD5, CD19 or CD20, and CD23 in blood, bone marrow, or biopsy specimens. Classic Reed-Sternberg (RS) cells are usually CD15-positive and CD30-positive. More surface markers may need to be analyzed if this screening is inconclusive or if rare entities (such as natural killer [NK] cell or hairy cell leukemia) are considered.
3. Special handling of tissues for procedures that may occasionally be used in difficult diagnostic problems or research such as cytogenetics, molecular genetic analysis, and electron microscopy
4. Microbial culture of submitted material when the clinical picture or tissue suggests infection
IV. CLINICAL EVALUATION. The extent of the staging evaluation is determined by the individual case presentation, the histopathologic diagnosis, and the effect of the stage on treatment planning.
A. Evaluation of blood tests
1. Hematologic manifestations are discussed in Chapter 34.
2. Diagnostically abnormal circulating lymphoid cells or lymphocytosis is seen in some patients with either indolent or aggressive forms of NHL. Lymphoid cells are characterized immunologically using flow cytometry, and monoclonality may be established by k:λ ratios (B cell) or gene rearrangement technology (T and B cell); these techniques are capable of detecting minute clones of circulating lymphoma cells not detectable by inspection of the blood smears.
3. Acute-phase reactants, such as the erythrocyte sedimentation rate (ESR), fibrinogen, haptoglobin, and serum copper levels, may parallel disease activ ity, especially in HL.
4. Liver function tests are unreliable in predicting lymphomatous involvement of the liver. Marked elevation of alkaline phosphatase and occasionally frank cholestatic jaundice may complicate HL as a paraneoplastic event without direct liver involvement. Extrahepatic biliary obstruction may also occur with lymphoma caused by enlarged nodes in the porta hepatis.
5. Renal function tests. Elevated creatinine and blood urea nitrogen levels suggest ureteral obstruction and, less commonly, direct renal involvement. Uric acid nephropathy or hypercalcemia may contribute to renal insufficiency. Frank nephrotic syndrome as a paraneoplastic phenomenon may complicate HL and other lymphomas (see Chapter 31).
6. Serum uric acid. Hyperuricemia is a common manifestation of high-turnover-rate (aggressive) NHL and may also be seen with extensive lower grade lymphomas. Treatment of high-grade NHL or treatment of sensitive bulky low-grade lymphoma may provoke brisk tumor lysis, leading to further elevation of uric acid and renal shutdown (see Chapter 27, Section XIII). Hypouricemia may be seen in HL.
7. Hypercalcemia has been noted in some cases of lymphoma and may be secondary to production of parathyroid hormone–related peptide or activation of vitamin D by lymphoma tissue.
8. Serum lactate dehydrogenase (LDH) levels reflect tumor bulk and turnover, particularly in the aggressive NHL, and are considered an independent prognostic factor.
9. Serum immunoglobulins. Polyclonal hypergammaglobulinemia is commonly seen in HL and NHL. Hypogammaglobulinemia is particularly common in the small lymphocytic lymphomas (SLLs) and late in the disease. Monoclonal spikes are seen occasionally in NHL patients.
B. Evaluation of the chest
1. Chest radiographs may demonstrate mediastinal and hilar lymphadenopathy, pleural effusions, and parenchymal lesions. A cavitating lesion is more typical of infection than lymphomas.
2. CT scans tend to replace chest x-rays because they can demonstrate parenchymal and mediastinal abnormalities in more detail.
3. Thoracentesis and pleural biopsy may demonstrate direct lymphomatous involvement of the pleura. Obstruction of mediastinal lymphatic–venous drainage may result in cytologically negative or chylous effusions.
C. Evaluation of the abdomen and retroperitoneum
1. CT scans are useful in delineating abnormal enlargement of nodes in retroperitoneal, mesenteric, portal, and other lymph node sites. The CT scan also detects splenomegaly and, with constant enhancement, may define space-occupying lesions in the liver, spleen, and kidneys.
2. Bipedal lymphangiography has been abandoned because of improvements and availability of alternative imaging techniques and because expertise in performance and evaluation is frequently unavailable.
3. Abdominal ultrasonography is too insensitive to be useful in routinely assessing abdominal lymphadenopathy. It is occasionally helpful in distinguishing hepatic or splenic lesions (cystic vs. solid) and in excluding an obstructive basis for renal insufficiency and jaundice.
4. MRI with contrast may be useful in distinguishing benign from malignant hepatic lesions.
D. Evaluation of the gastrointestinal (GI) tract. Direct involvement of the GI tract is uncommon in HL but is common in NHL. Patients with Waldeyer ring lymphoma, suggestive GI symptoms, extensive abdominal nodal involvement, unexplained iron deficiency, or GI bleeding are evaluated with upper GI series and complete small bowel follow-through. Barium enema may be necessary. Endoscopic examination and biopsy of accessible abnormalities are performed. Routine GI tract evaluation for patients with mantle cell lymphoma is performed in some centers.
E. Evaluation of the central nervous system (CNS). Spinal fluid examination is routinely used to exclude occult lymphomatous involvement of the meninges in patients with Burkitt lymphoma (BL) or lymphoblastic lymphoma and is often performed in patients with intermediate-grade or high-grade lymphoma involving the testes or paranasal sinuses (B-cell histology), with extensive bone marrow involvement, or with multiple sites of extranodal involvement and elevated LDH. In these cases, the incidence of CNS disease is in the 5% range. Patients with AIDS-related lymphoma may require CT or MRI scans of the brain and spinal fluid analysis. Symptoms suggestive of intracranial, spinal cord, or peripheral nerve involvement require immediate diagnostic evaluation.
F. Nuclear scans
1. Positron emission tomography (PET) using 18F-fluorodeoxyglucose scans tends to replace gallium scans. It seems to be more sensitive in detecting unsuspected metastasis or in differentiating active versus uninvolved nodes with accuracy approaching 95% depending on nodal histology. Similar to gallium scans, PET is somewhat less reliable in indolent lymphoma. False-positive results can be produced by any inflammation, whereas faint normal uptake of muscles, the bowel, and bone marrow recovering from chemotherapy should be differentiated from involvement. The advent of combined PET/CT scan is thought to increase the accuracy of the procedure and may eventually become the gold standard for staging and following patients.
2. Gallium scans. 67Ga scans are primarily used in assessing residual radiographic mediastinal and, less often, retroperitoneal abnormalities after therapy. Persistent 67Ga uptake in these areas strongly suggests residual tumor instead of fibrosis or necrosis. To be useful in such follow-up, a 67Ga body scan is recommended before therapy. 67Ga scans can be unreliable below the diaphragm because of competing uptake in the GI tract, liver, and spleen.
HODGKIN LYMPHOMA
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. HL accounts for about 1% of new cancer cases annually in the United States, or 7,000 cases per year.
1. Age. HL demonstrates a bimodal age–incidence curve in the United States and some industrialized European nations. The first peak, constituting predominantly the nodular sclerosis subtype, occurs in the 20s and the second peak occurs after 50 years of age. In Third World countries, the first peak is absent, but there is a significant incidence of mixed cellularity and lymphocyte-depleted HL in men.
2. Sex. About 85% of children with HL are boys. In adults, the nodular sclerosing subtype of HL shows a slight female predominance, whereas the other histologic subtypes are more common in men.
B. Risk factors. In Western countries, the first peak of HL is associated with a higher social class, advanced education, and small family size; a delayed exposure to a common infectious or other environmental agent has been suggested. HL may be associated with EBV infection, but the significance of this association is unclear. A slightly increased incidence of HL has been demonstrated with HIV infection; HIV-associated HL (see Chapter 36, Section III) often presents with constitutional symptoms, advanced stage, and unusual sites of involvement (e.g., marrow, skin, leptomeninges).
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. The pathologic diagnosis of HL depends on the presence of RS cells and their variants in an appropriate pathologic milieu. The bulk of lymphatic tissue involved by HL is not composed of neoplastic cells but rather a variety of normal-appearing lymphocytes, plasma cells, eosinophils, neutrophils, and histiocytes existing in different proportions in the various histologic subtypes. Important variants of RS cells include L&H (lymphocyte and histiocyte) cells, lacunar cells, and RS-like cells (see Appendix C5. Discriminatory Immunophenotypes for Lymphocytic Neoplasms).
1. The Rye classification for HL relates the histopathologic subtypes to clinical behavior and prognosis. This older classification system comprises lymphocyte-predominant (LP), nodular sclerosing (NS), mixed-cellularity (MC), and the uncommon lymphocyte-depleted (LD) varieties of HL. The LP subtype was further divided into nodular LP and diffuse LP subtypes. Immunohistochemistry, however, has resulted in deletion of the diffuse LP subtype and redefinition of the nodular LP subtype (see Section II.A.2).
2. The World Health Organization (WHO) classification divides HL into nodular LP HL and classical HL. Classical HL in this newer classification system comprises the lymphocyte-rich, NS, MC, and LD varieties.
a. Nodular LP HL with its L&H cells, which are not classical RS cells, is now clearly recognized to be most like an indolent B-cell NHL and not true HL. For that reason, nodular LP HL is distinguished from classical HL in the WHO classification. Table 21.2 shows this classification system with distinguishing histopathologic features, clinical correlates, and immunophenotypes.
b. Diffuse LP HL in the Rye classification has disappeared as an entity. In the new WHO classification of lymphocytic neoplasms (see Appendix C6), what was thought to be diffuse LP HL is now classified as lymphocyte-rich classical HL (with true RS cells that are CD30-positive), Lennert lymphoma (lymphoepithelioid peripheral T-cell lymphoma), T-cell–rich B-cell lymphoma, or other entities.
Table 21.2 Pathologic and Clinical Features of Hodgkin Lymphoma Subtypesa
aWorld Health Organization classification system
bL&H cells immunophenotype: CD15−, CD30−, CD20+, CD45+, EMA±, CD79a+
cClassical HL–RS immunophenotype: CD15+, CD30+, CD20±, CD45−, EMA−, ALK-1−
HL, Hodgkin lymphoma; L&H, lymphocytic and histiocytic cells; CHL, classical HL; RS, Reed-Sternberg cells; EMA, epithelial membrane antigen; ALK-1, anaplastic lymphoma kinase.
3. RS cells and their variants
a. RS cells are giant cells that have more than one nucleus and large, eosinophilic, inclusion-like nuclei. Single-cell polymerase chain reaction analysis has shown that the RS cells are B cells that originate in the germinal centers of lymph nodes. RS cells and the accompanying mononuclear Hodgkin cell variants are the neoplastic cells in HL and are surrounded by a reactive cellular infiltrate. Classic RS cells usually express CD15 and CD30. CD30 (Ki-1) is an antigen that is also expressed in anaplastic large cell lymphoma and occasionally in other forms of NHL (e.g., large B-cell lymphoma [LBCL], peripheral T-cell lymphoma [PTCL]). RS cells express CD20 infrequently, but not CD45 (leukocyte common antigen).
b. The lacunar cell is a variant of the RS cell and has the same immunophenotype. It characterizes NS HL and is often far more plentiful than classic RS cells in that subtype.
c. L&H cells are RS-like but have a different immunophenotype. L&H cells manifest B-cell markers (CD20, CD45, and CD79a), but not CD15 or CD30. Although the L&H cells are believed to be of monoclonal origin, the surrounding B-cell infiltrates may be polyclonal. L&H cells were identified in nodular LP HL, which is now considered a separate entity because of its distinct immunophenotype.
d. RS-like cells are found in a variety of infectious, inflammatory, and neoplastic disorders, including infectious mononucleosis, lymphoid hyperplasia associated with phenytoin therapy, and immunoblastic lymphomas.
B. Mode of spread (see Table 21.1). HL almost always originates in a lymph node. Whenever a primary diagnosis of HL is made in an extranodal site without contiguous nodal involvement, the diagnosis should be highly suspect. For much of its natural history, HL appears to spread in an orderly fashion through the lymphatic system by contiguity. Histologic types other than NS, however, often skip the mediastinum, and disease appears in the neck and upper abdomen. The axial lymphatic system is almost always affected in HL, whereas distal sites (e.g., epitrochlear and popliteal nodes) are rarely involved. Hematogenous dissemination occurs late in the course of disease and is characteristic of the LD subtype.
C. Sites of involvement
1. Peripheral lymph nodes. Cervical or supraclavicular lymphadenopathy occurs in >70% of cases. Axillary and inguinal lymph nodes are less frequently involved. Generalized lymphadenopathy is atypical of HL. Left supraclavicular lymphadenopathy is more strongly associated with abdominal involvement (specifically, splenic involvement) than is right-sided disease.
2. Thorax
a. The anterior mediastinum is a prime location for NS HL. Mediastinal precedes hilar lymph node involvement.
b. Lung involvement may occur by direct contiguity with hilar involvement in HL as well as by hematogenous dissemination. Pulmonary involvement by HL may produce discrete nodules and irregular, interstitial, or even lobar infiltrates.
c. Pleural effusion may occur secondary to mediastinal compression of vascular–lymphatic drainage and by direct pleural involvement. Chylous effusions occasionally occur.
d. Pericardial involvement may be found on CT scans, but overt cardiac tamponade is uncommon.
e. Superior vena cava syndrome is more frequent in NHL than in HL.
3. Spleen, liver, and upper abdomen
a. The spleen, splenic hilar nodes, and celiac nodes are the earliest abdominal sites of involvement in infradiaphragmatic HL. Mesenteric lymph nodes are rarely involved in HL.
b. At least 25% of spleens not clinically enlarged harbor occult HL at laparotomy, and as many as half of spleens believed to be enlarged on physical examination or radiologic assessment are histologically normal.
c. Liver involvement is uncommon at diagnosis and is almost always associated with infiltration of the spleen.
4. Retroperitoneal lymph node involvement tends to occur relatively late in the course of supradiaphragmatic HL and after spleen, splenic hilar, and celiac nodal involvement. Periaortic involvement without splenic involvement is uncommon. The retroperitoneal nodes are, however, affected early in the course of inguinal presentations of HL.
5. The bone marrow is rarely involved at the time of diagnosis of HL. Patients with advanced-stage disease, systemic symptoms, and MC or LD histologies have a higher risk for bone marrow involvement. Biopsy is mandatory to evaluate the bone marrow because HL is difficult to diagnose on marrow aspirates. Granulomatous changes or fibrosis may be seen, which is not diagnostic of HL involvement.
6. Bone. Osseous involvement of HL usually produces an osteoblastic reaction mimicking prostatic carcinoma. Extradural masses may result in spinal cord compression. Sternal erosion by mediastinal NS HL may occur.
7. Other extranodal sites are rarely involved in HL. Liver or skin involvement is rare and usually a late manifestation of disease. CNS involvement is very uncommon with the exception of extrinsic spinal cord compression. Clinical involvement of meninges, brain, Waldeyer ring, GI tract, kidney, and other extranodal sites usually suggests an alternative diagnosis.
III. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Staging is the most crucial determinant of prognosis and treatment in HL. The Ann Arbor Staging System had previously been universally used but has been modified to take into account important prognostic factors, particularly mediastinal bulk. The modified system is called the Cotswolds Staging Classification and is shown in Table 21.3.
Table 21.3 Cotswolds Staging Classification of Hodgkin Lymphoma
B. Prognostic factors
1. Stage is clearly the single most important prognostic factor in HL. Within each stage, the presence of B symptoms confers a poorer prognosis. About 60% of patients with HL in the United States have stage I or II disease at the time of diagnosis. The percentage of patients with stage III or IV disease is generally higher in Third World countries and in lower socioeconomic enclaves.
2. Histopathology. With advances in therapy, the value of histopathologic subtype as an independent prognostic variable (apart from stage) is less clearly defined than it was in the past.
3. Adverse prognostic factors were evaluated by an international group in a multivariate retrospective analysis of 4,695 patients, mostly with extensive disease (see Hasenclever et al. 1998 in “Suggested Reading”). Patients with no adverse factors had an 84% freedom from progression, whereas the presence of each factor depressed the freedom from progression curve plateau by about 8%. Interestingly, neither tumor bulk nor histology emerged as independent factors. The seven independent prognostic factors identified were as follows:
4. Independent adverse prognostic factors for NS HL include eosinophilia, lymphocyte depletion, and RS cell atypia.
5. Adverse prognostic factors in early stage HL include ESR ≥50 mm/h, four or more separate sites of nodal involvement, bulky mediastinal mass (defined as >33% of the maximum intrathoracic diameter) or any mass ≥10 cm, or extranodal sites of disease.
IV. DIAGNOSIS
A. Clinical evaluation. See “Evaluation of Suspected Lymphoma,” Sections I through IV.
B. Staging evaluation
1. Adequate surgical biopsy reviewed by experienced hematopathologist. Fine-needle aspiration is not an adequate means of initial diagnosis.
2. Thorough history and physical examination
3. Laboratory tests: CBC with differential and platelet count, serum chemistries including LDH, ESR, urinalysis
4. CT scan of the neck, chest, abdomen, and pelvis with contrast
5. Bone marrow aspiration and biopsy (bilateral iliac crest) unless clinical stage IA to IIA with no anemia or other blood count depression
6. Bone scan in presence of bone pain, or elevated serum alkaline phosphatase or calcium level
7. PET scans are optional but are useful in follow-up of residual masses on chest radiograph or CT scan after therapy, given the propensity of treated HL nodes to remain visible on CT scans.
8. HIV testing should be considered in patients whose disease presentation is primarily extranodal.
9. Pregnancy test and fertility counseling in patients of childbearing age should be performed with staging evaluation.
C. Staging laparotomy. Systematic evaluation by staging laparotomy revealed that at least 25% of patients with supradiaphragmatic presentations and negative clinical subdiaphragmatic evaluations had occult HL discovered at laparotomy (predominantly in the spleen, splenic hilar nodes, or celiac lymph nodes). Liver involvement was extremely uncommon in the absence of extensive splenic involvement.
The main purpose of staging laparotomy and splenectomy was to save patients with truly supradiaphragmatic or stage III1A disease from the long-term complications of alkylator-based chemotherapy (MOPP regimen in Appendix D1and equivalents). Patients with a negative laparotomy or limited upper abdominal disease would be treated with radiation alone. The advent of improved diagnostic modalities, less toxic curative chemotherapy (ABVD regimen in Appendix D1 and equivalents), and the success of combined-modality approaches have eliminated the need for surgical staging.
V. MANAGEMENT: PRIMARY THERAPY
A. Treatment philosophy. More than one treatment approach may be used in the management of cases of HL. The challenge is to determine a course of therapy that preserves cure while minimizing long-term complications.
B. Surgery is limited to diagnosis, possibly laparotomy, and laminectomy for spinal cord compression.
C. RT alone is still used in the United States to treat many patients with stage IA or possibly IIA disease nonclassical HL. However, it is increasingly replaced in the treatment of classical HL with combined-modality treatment.
1. Radiation dose. HL may be locally sterilized in almost all cases with 3,000 to 4,400 cGy given at a rate of about 1,000 cGy per week. Lesser doses may be adequate as consolidation after chemotherapy.
2. Radiation fields (Fig. 21.1)
a. Mantle field encompasses the cervical, supraclavicular, infraclavicular, axillary, hilar, and mediastinal lymph nodes to the level of the diaphragm. Preauricular fields are added for patients with high cervical lymphadenopathy. The lungs and much of the heart are shielded by lead blocks, although many radiotherapists administer some radiation (≤1,500 cGy) to the lung on the involved side, if hilar lymph nodes are enlarged. The whole heart may be treated if the pericardium is involved. A small gap must be left between the inferior border of the mantle field and the superior border of the periaortic field to obviate potential severe spinal cord injury caused by overlap.
b. Inverted-Y field includes the spleen or splenic pedicle and the celiac, periaortic, iliac, inguinal, and femoral lymph nodes. The kidneys, much of the pelvic marrow, and the testes are shielded.
c. Spade and pelvic fields. The inverted-Y field may be divided into a spade field, encompassing the splenic pedicle (or spleen) and periaortic nodes, and a pelvic field, including the iliac, inguinal, and femoral lymph nodes.
d. Subtotal nodal or subtotal lymphoid irradiation consists of mantle and spade fields.
e. Total nodal or total lymphoid irradiation is uncommonly used and consists of mantle and inverted-Y fields.
f. Involved-field radiation therapy (IFRT) consists of sites of known disease only and is used with curative intent only in combination with chemotherapy. It has become the most common use of RT in HL with other fields previously described of mostly historical interest. Doses given in combined-modality therapy range from 2,000 to 3,600 cGy.
Figure 21.1. Radiation fields used in Hodgkin lymphoma. Stippled area is the area irradiated. See text for descriptions.
D. Combination chemotherapy is the mainstay modality for all stages of classical HL and advanced stages of nonclassical HL. Chemotherapy, often in combination with RT, is also preferable for patients with early-stage disease and/or bulky disease. The selection among the available regimens is often guided by the desire to avoid long-term toxicities associated with specific treatments. The advent of the nonleukemogenic, gonadal-sparing ABVD chemotherapy regimen expanded the use of chemotherapy to patients with earlier stages and obviated the need for laparotomy; it has replaced the historic MOPP. More aggressive regimens such as BEACOPP (Appendix D1, Section II) may improve on ABVD (see Section V.D.3), especially in patients with advanced disease. Maintenance therapy is not recommended.
1. Useful chemotherapy regimens for HL are shown in Appendix D1. These regimens must be strictly followed because delays in therapy or reduction in dosages not indicated by the protocol can clearly compromise results. The total dose and dose rate (dose intensity) are important in achieving cure. Regimens used as salvage therapy in HL are shown in Appendix D3.
2. MOPP or COPP regimen (Appendix D1, Section I). The National Cancer Institute (NCI) recommends that vincristine should not be limited to a 2-mg maximum dosage in this regimen, but most clinicians sustain the 2-mg limit. Treatment is administered in 28-day cycles for two additional cycles beyond the attainment of a restaged complete response (CR) and a minimum of six cycles (6 months).
a. The CR rate using the MOPP regimen is between 70% and 80% for stages III and IV HL. About 60% to 70% of CR cases are durable, with relapses rare after 42 months. More than 80% of patients with stage IIIA or IVA disease survive 10 years without recurrence of disease. Histologic subtype appears to have little effect on results with MOPP.
b. The MOPP regimen is particularly emetogenic, and it is associated with myelosuppression neuropathy, leukemogenesis, and infertility. It is believed that COPP (replacing mechlorethamine with cyclophosphamide) may be better tolerated.
3. ABVD regimen (Appendix D1, Section I) is superior to the MOPP regimen and causes much less leukemia and infertility. Potential cardiac toxicity caused by doxorubicin and pulmonary toxicity caused by bleomycin (particularly with the concomitant use of granulocyte growth factors) have been occasional problems using this schedule. The concern is heightened when combined with mediastinal RT. ABVD-based treatment has replaced MOPP as the standard regimen for HL.
a. Generally, the same therapeutic rules as with the MOPP regimen apply: 6 to 8 monthly cycles are usually administered and at least two cycles beyond maximum response.
b. Pulmonary function should be monitored. If dyspnea, pneumonitis, or significant reduction to <40% of predicted lung diffusion capacity is noted, bleomycin should be discontinued. Bleomycin pneumonitis usually responds to corticosteroids and mandates discontinuation of bleomycin. As there is a concern that the use of myeloid growth factors may increase the risk for bleomycin pulmonary toxicity, their use has been discouraged.
c. Cardiac function should be monitored in patients with pre-existing heart disease and in those receiving high cumulative doses of doxorubicin. A baseline measurement of left ventricular ejection fraction is suggested before beginning doxorubicin administration.
4. MOPP and ABVD in alternating cycles and the MOPP/ABV hybrid have both been found to be less satisfactory than ABVD alone. While MOPP/ABV and ABVD were equally efficacious, the hybrid regimen was associated with increased acute toxicity, myelodysplastic syndrome, and leukemia in a randomized trial. While MOPP/ABVD and ABVD were both superior regimens to MOPP alone, ABVD was less myelotoxic than the combined regimen.
5. Dose-intense regimens have been developed with the hope of improving outcome, especially in patients with high-risk HL. The value of these regimens remains unclear.
a. BEACOPP. This aggressive 3-week cycle regimen has been compared favorably to COPP–ABVD in randomized prospective and mature studies. Higher response rates and progression-free survival are reported with dose escalation and mandatory use of growth factors, possibly with a higher risk for secondary leukemia. The effect on sterility is not fully evaluated.
b. Stanford V (Appendix D1, Section II). Excellent results achieved with this weekly regimen in phase II studies at a single institution have not yet been confirmed in multicenter randomized trials.
c. High-dose chemotherapy followed by autologous stem cell transplantation (SCT) for patients in first remission is not generally recommended.
6. Compared effectiveness
a. A large, randomized trial conducted by a cooperative group showed that ABVD alone may be as effective as MOPP plus ABVD and more effective than MOPP alone in the management of most patients with advanced HL. ABVD is considered the standard first-line treatment for most patients and is superior to MOPP in efficacy and toxicity profile.
b. A three-arm randomized clinical study compared COPP–ABVD with standard-dose BEACOPP and escalated-dose BEACOPP (see Diehl et al. 2003, in “Suggested Reading”). The 5-year relapse-free rates were 69% for COPP–ABVD, 76% for standard BEACOPP, and 87% for escalated BEACOPP. The 5-year survival rate was 83% for the COPP–ABVD arm, 88% for the standard-dose BEACOPP arm, and 91% for the escalated-dose BEACOPP arm. Patients with advanced HL and adverse prognostic factors appear to derive benefit from dose escalation. BEACOPP in one of its forms can clearly be considered the treatment of choice for selected patients with high-risk HL.
7. Combined-modality treatment is becoming popular in the management of early-stage disease. The advantage of this approach is the limitation of radiation to the involved area only (and thus the reduction of the total dose), reducing long-term radiation-related complications.
a. IFRT can complement an abbreviated course of chemotherapy in patients with clinical stage I or II and nonbulky disease.
b. IFRT may be prescribed after a full course of chemotherapy to consolidate previously bulky areas of disease, especially those that respond only partially to chemotherapy. IFRT to prior sites of disease, however, may not be helpful for patients who achieve a CR with chemotherapy.
E. Treatment controversies and recommendations in classical HL (Table 21.4)
1. Stages IA and IIA
a. Supradiaphragmatic disease. Traditionally, most patients used to undergo staging laparotomy and, if found to have pathologic stage I or II disease, would receive subtotal nodal irradiation. This approach resulted in an 80% probability of disease-free survival. Overall survival, on the other hand, may not be affected because most patients who relapse after RT can be salvaged by chemotherapy.
Excellent disease-free survival, however, has been documented after treatment with an abbreviated course of chemotherapy (two to four cycles) followed by IFRT. ABVD regimen or the Stanford V regimen (Appendix D1, Sections I and II) is often used. In a randomized study using four cycles of ABVD, there was no difference in outcome between groups irradiated with 2,000 or 4,000 cGy, suggesting that the dose of radiation can also be reduced.
b. Infradiaphragmatic disease. Generally, similar principles apply for early disease. Most patients could be treated with a combined-modality approach or full-course combination chemotherapy.
c. Current studies intend to assess the minimum number of cycles of a first-line regimen, such as ABVD, that can be given without compromising outcome. Less aggressive chemotherapy may suffice for patients with no risk factors, such as anemia, elevation of ESR, or bulky disease.
2. Stages IB and IIB management is somewhat controversial. Early-stage B disease has a nearly 50% relapse rate when treated with radiation monotherapy. It is preferable to treat such patients with a full course of chemotherapy, although a combined-modality approach may be considered.
3. Bulky mediastinal presentations. About 60% of patients with stage IA to IIB disease and bulky mediastinal masses fail treatment with RT alone; relapses occur predominantly in the mediastinum and lungs. Full-course combination chemotherapy and IFRT are recommended for these patients. Patients with bulky mediastinal disease and more advanced stages (IIIA to IVB) may also receive mediastinal RT at the end of chemotherapy. Using both modalities, results approaching the cure rate for patients without large mediastinal masses may be attained.
4. Stage IIIA. The 10-year disease-free survival rate using chemotherapy alone is 80%. Such results are superior to RT alone and probably cannot be improved by combined-modality therapy.
5. Stage IIIB or IV. The ABVD regimen is probably adequate management for most patients, although medically fit patients with adverse features may benefit from BEACOPP.
6. E (extranodal) presentations. Patients with contiguous limited extranodal disease (such as a single bone involved adjacent to an involved lymph node) can sometimes be managed by radiation alone or more frequently in combination with chemotherapy. Multiple E lesions and extensive E disease (such as a large pulmonary lesion) are best managed with chemotherapy or a combined approach.
7. HIV and HL. Patients with HIV usually present with stage IV disease involving the bone marrow. The desired intensity of the treatment should be weighed against the patient’s tolerance. Full-course chemotherapy should be tried with curative intent in patients with good performance status and controlled viremia (see Chapter 36, Section III).
Table 21.4 Hodgkin Lymphoma: Recommended Treatment According to Clinical Presentation
HL, Hodgkin lymphoma; IFRT, involved field radiation therapy; NLP, nodular lymphocyte-predominant; RT, radiation therapy; CS, clinical stage.
VI. MANAGEMENT AFTER PRIMARY THERAPY
A. Restaging. All CRs resulting from either irradiation or chemotherapy must be verified by a restaging evaluation that consists of the repetition of all examinations that were initially abnormal.
1. The initial restaging occurs 2 to 3 months after completion of radiation and traditionally after three or four cycles of chemotherapy, provided that all palpable and radiographic disease has disappeared.
2. Restaging mandates repeat biopsy of previously involved and accessible stage IV sites, such as liver or bone marrow.
3. Persistent and stable abnormalities on chest radiograph or CT scan in the mediastinum are not uncommon (particularly in patients treated for NS). Occasionally, persistent stable abdominal masses or palpable nodal masses may also occur. These abnormalities demand close follow-up. In most cases, however, these findings represent only fibrosis and do not require biopsy. PET scanning is useful in distinguishing viable HL from fibrosis.
B. Follow-up. Most relapses after therapy occur within the first 2 to 5 years, although later recurrences have been observed.
1. Follow-up should occur every 2 to 4 months the first 2 years and every 3 to 6 months for the next 3 to 5 years. Follow-up examinations include
a. History and physical examination
b. CBC, chemistry panel, ESR, chest radiographs
c. CT scans every 3 to 6 months for the first 3 years
d. Thyroxine and thyroid-stimulating hormone (TSH) levels at least annually (see Section VII.A.1) if radiation to the neck has been administered
2. Health maintenance counseling and cancer screening are imperative for long-term survivors of HL. Smoking cessation and avoidance of additional practices associated with increased risk for cancer should be encouraged. If irradiation above the diaphragm was administered, women should be encouraged to start annual mammograms 5 to 8 years after treatment, or earlier if 40 years of age (whichever comes first). Some groups have suggested the addition of breast MRI for screening in this high-risk population.
3. PET scanning is not recommended for surveillance due to the high false-positive rate. Any management decisions should not be based on PET scanning alone but require clinical or pathologic correlation. PET scanning after two cycles of treatment is currently being investigated as a possible determinant in decision making for continued treatment (e.g., total number of cycles of ABVD, escalation of ABVD to BEACOPP, de-escalation of BEACOPP).
C. Salvage therapies
1. RT failures are generally treated with combination chemotherapy with results at least as successful as with de novo chemotherapy.
2. Chemotherapy failures
a. Failure to achieve a CR with effective combination chemotherapy is associated with a poor prognosis. Although alternate combinations may be temporarily useful, long-term disease control is unlikely. Such patients should be referred for autologous SCT or less likely for allogeneic SCT. The decision depends on the age of the patient, the availability of a donor, bone marrow status, and responsiveness to a salvage chemotherapy regimen.
b. Relapses after chemotherapy-achieved CR. The initial combination can be used again (provided there is no cardiotoxicity risk) if the unmaintained CR lasts >1 year, but it should not be used again if the CR lasts <1 year. No known available regimen is capable of producing long-term disease-free survival in >10% to 20% of chemotherapy relapsed cases. Patients who respond to salvage chemotherapy should be referred for consideration of autologous SCT.
c. Patients who are resistant to MOPP and ABVD may experience brief (although occasionally long) responses to alternate chemotherapy. Single-agent therapy with a nitrosourea, vinca alkaloid, etoposide (possibly the oral form), or combinations of these and other agents may be helpful. Gemcitabine is an active agent, particularly in combination with vinorelbine or platinum. Gemcitabine-based regimens are shown in Appendix D3. Other second-line and third-line combination chemotherapy regimens are also shown in Appendix D3. Chemotherapy failures with predominantly nodal relapses may benefit from extended-field irradiation, which results in some long-term disease-free survival. Allogeneic SCT can be considered for young patients. Experimental trials would also be appropriate to consider for the treatment of this patient population.
3. Intensive chemoradiotherapy with autologous SCT has undergone extensive study. High doses of chemotherapy (potentially myeloablative), often combined with total-body irradiation, are administered (“conditioning regimen”), and either autologous bone marrow or peripheral stem cells (mobilized by growth factors) are used to rescue the patient from prolonged myelosuppression. This procedure is performed in most centers with a mortality rate of <5%; the hospital stay averages 3 weeks. Candidates include patients who have either relapsed after a CR or never achieved a CR with adequate combination chemotherapy. About 60% of chemosensitive candidates and 40% of patients failing induction chemotherapy achieve prolonged disease-free survival.
4. Other therapies. Immunoconjugates, such as anti-CD30 conjugated to a chemotherapeutic agent, have been tested in patients with HL in phase II studies, with promising results so far. Rituximab is being used for nodular LP HL. Several agents with activity in the relapsed setting are currently being examined in the front-line setting in combination with ABVD or as maintenance therapy after autologous SCT in high-risk patients and include rituximab, lenalidomide, panobinostat, and SGN-35.
VII. SPECIAL CLINICAL PROBLEMS IN HL
A. Sequelae and complications of therapy
1. Hypothyroidism. Overt hypothyroidism can be expected in 10% to 20% of patients and elevation of serum TSH in up to 50% of patients treated with mantle-field RT or neck irradiation. Replacement therapy corrects the problem.
2. Sterility. RT poses problems for female patients who receive pelvic irradiation without oophoropexy and appropriate gonadal shielding. The testes are shielded during irradiation. MOPP and similar therapies produce near-universal sterility in male patients and can be anticipated to produce sterility in women in their late 20s or older. ABVD is not associated with sterility. BEACOPP is expected to cause sterility in many patients, although the incidence is unknown. Sperm banking is encouraged in male patients about to receive MOPP, BEACOPP, autologous SCT, or similar therapies.
3. Lung damage
a. Radiation pneumonitis. Mantle-field irradiation routinely produces a paramediastinal fibrosis that is usually not clinically significant. When large ports are necessitated by large mediastinal–hilar masses, the potential for more severe reaction exists. In addition, patients given MOPP who have a prior history of mantle-field irradiation may experience an abrupt episode of pneumonitis, presumably secondary to steroid withdrawal. Therefore, prednisone is avoided after mantle-field irradiation, even if the radiation was administered years earlier.
b. Bleomycin pulmonary toxicity. Almost all patients treated with bleomycin (in ABVD and the like) experience a reduction in their lung diffusion capacity. This reduction is usually asymptomatic and slowly improves after treatment. Severe idiopathic pulmonary toxicity is occasionally seen at bleomycin doses of >50 mg, although it usually does not occur until cumulative doses exceed 200 mg/m2.
Even more severe pulmonary toxicity (pulmonary infiltrates, restrictive defects, exertional dyspnea) is reported when bleomycin is given in combination with mediastinal RT. These adverse effects depend partly on the total dose of bleomycin and the radiation field. Caution is needed in patients who already have compromised lung function.
4. Cardiac damage
a. Radiation. The risk for radiation pericarditis is relatively small when modern anteroposterior weighted radiation ports are used and when large portions of the heart are not radiated. Radiation pericarditis with or without pericardial effusion or tamponade can develop, however. Constrictive pericarditis is a rare complication of RT.
b. Chemotherapy. Doxorubicin, which is a component of ABVD and related regimens, is a well-known cardiotoxic agent. The incidence of cardiotoxicity is related to the cumulative dose and probably to peak serum levels. The cumulative dose of doxorubicin in ABVD is usually 300 mg/m2, below the clinically significant cardiotoxic level when given without radiation. Administration of mediastinal and/or neck RT, however, increases the chance of cardiomyopathy, pericarditis, or coronary artery disease and other accelerated atherosclerotic disease and valvular disorders as well as the potential for delayed cardiomyopathy.
5. Aseptic necrosis of the femoral heads has been reported and is probably secondary to prednisone therapy in MOPP.
6. Depressed cellular immunity. Progressive loss of cell-mediated immunity with the development of cutaneous anergy, lymphocytopenia, and increased susceptibility to a variety of organisms is associated with advancing HL, even in the absence of therapy. Treatment with chemotherapy, corticosteroids, and RT accentuates these abnormalities. Late in the course of HL, hypogammaglobulinemia may also develop.
a. Infections associated with depressed cell-mediated immunity and therapy (particularly corticosteroids) include Listeria, Toxoplasma, and Mycobacterium spp., fungi, and slow viruses (such as progressive multifocal leukoencephalopathy). Patients treated with corticosteroids are at particularly increased risk for infections with Pneumocystis carinii and CMV.
b. Herpes zoster appears in >25% of patients, particularly in patients with irradiated dermatomes and in those undergoing splenectomy. Generalized cutaneous involvement is not uncommon, but visceral involvement is rare.
c. Splenectomy-related infections involve encapsulated micro-organisms, particularly pneumococci, and less commonly Haemophilus influenzae and Salmonella sp., especially in children. Pneumococcal infection in an asplenic host can be rapidly fatal. Vaccination with polyvalent pneumococcal vaccine, haemophilus, and meningococcus is recommended before splenectomy, although its effectiveness in this population is not certain. Early, aggressive treatment with antibiotics of all febrile patients after splenectomy is mandatory.
7. Secondary neoplasms
a. Acute myelogenous leukemia, often preceded by a prodrome of myelodysplastic syndrome, develops in 2% to 10% of patients treated with MOPP or similar combined-modality therapy containing alkylating agents. The problem appears to be greatest in patients older than 40 years of age and may be increased in patients undergoing splenectomy. The leukemia generally occurs between 3 and 10 years after treatment, is often associated with total or partial deletion of chromosomes 5 and 7, and has an extremely poor prognosis. Acute leukemia is extremely uncommon in patients treated with RT alone and appears to be rare in patients treated with ABVD.
b. NHL may occur during the course of HL and may represent an evolution of the natural history of disease rather than a treatment complication. Most reported cases are high-grade B-cell tumors, with a particularly high incidence in cases of nodular LP HL. As previously noted, LP HL may be a B-cell lymphoma (see Section II.A.2). High-grade peripheral T-cell lymphomas and mycosis fungoides have also complicated HL, particularly the NS type.
c. Epithelial tumors and sarcomas are being increasingly reported as complications of RT and possibly of combined-modality therapy, and actuarial statistics suggest a rate of second neoplasms exceeding 20% with prolonged follow-up. Tumors may include breast cancer, sarcoma, melanoma, lung cancer, and other solid tumors. The relative risk for cancer appears to be higher for younger patients and synergistic to other predisposing factors. This significant risk applies to a patient population treated in the 1960s and 1970s; modern strategies limiting radiation exposure may reduce this risk.
8. Neurologic complications
a. Lhermitte sign, which follows thoracic irradiation for HL, is an innocuous but worrisome finding for the patient. It consists of shock-like sensations down the back and legs, often precipitated by flexing the neck, and it gradually disappears.
b. Transverse myelopathy is a rare but serious complication of RT that is usually caused by failure to leave an appropriate gap between the mantle and abdominal ports.
9. Retroperitoneal fibrosis has been described as a complication of HL treatment.
B. Synchronous neoplasms. HL is said to be associated with an increased risk for simultaneous Kaposi sarcoma, leukemia, NHL, and myeloma.
C. Nephrotic syndrome, as a remote effect of malignancy, occurs most often in patients with HL. Lipoid nephrosis is typical (see Chapter 31, Section IV). Other paraneoplastic phenomena that have been described in the setting of HL include autoimmune hemolysis, immune thrombopenia, neurologic deficits, and jaundice.
D. Pregnancy in HL. See Chapter 26.
E. Ichthyosis. Adult-onset ichthyosis is associated with HL in 75% of cases (see Chapter 28, Section II.I).
NON-HODGKIN LYMPHOMA
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. NHL occurs with increasing frequency, with about 60,000 new cases annually in the United States. The incidence is rising dramatically for unknown reasons.
B. Age and sex. Small lymphocytic lymphomas occur in the elderly. Lymphoblastic lymphoma has a predilection for male adolescents and young adults. Follicular lymphomas occur mainly in middle-adult life. BL occurs in children and young adults.
C. Etiology. Viral etiology and abnormal immune regulation have been implicated in the development of lymphomas. The two mechanisms may be interrelated. An etiologic agent, however, can be identified in only a minority of cases.
1. Pathogens
a. RNA viruses. The human T-cell lymphotrophic virus type 1 (HTLV-1) is associated with adult T-cell leukemia–lymphoma (ATLL). HIV produces AIDS, and the resultant immune deficiency is associated with high-grade B-cell lymphomas. Chronic hepatitis C virus infection has been associated with indolent B-cell lymphoma.
b. DNA viruses. EBV has been found in the genome of African BL cells. EBV is also detected in biopsies of nasal T-cell and NK-cell lymphoma. This virus has also been associated with lymphomas in situations characterized by reduced immune surveillance, such as in patients with the X-linked lymphoproliferative syndrome, organ transplantation, the elderly, and, in many instances, HIV-associated lymphoma.
c. Chronic H. pylori infection of the gastric mucosa is clearly associated with gastric lymphoma. Eradication of the infection produces remission in more than two-thirds of patients.
2. Immunodeficiency or immune dysregulation states associated with development of lymphomas include the following:
a. AIDS
b. Organ transplant recipients
c. Congenital immunodeficiency syndromes (e.g., agammaglobulinemia, ataxia–telangiectasia, Wiskott-Aldrich syndrome)
d. Autoimmune disorders (e.g., Sjögren syndrome, rheumatoid disease, lupus erythematosus, Hashimoto thyroiditis)
e. Phenytoin may cause a spectrum from benign lymphoproliferation to frank lymphoma.
f. Elderly patients with “senescent” immune systems
3. Treatment-related. The potential role of chemotherapy or RT in the development of NHL after HL and myeloproliferative disorders remains uncertain.
4. Toxins. Exposure to toxins such as Agent Orange utilized during the Vietnam War is associated with increased lymphoma risk.
5. Genetics. Approximately 10% of patients with small lymphocytic lymphoma/chronic lymphocytic leukemia will have more than one family member with that or other lymphoproliferative disorders.
II. PATHOLOGY AND NATURAL HISTORY
A. Two complementary classification systems for NHL have been used: the Working Formulation (WF) and the WHO classification, which was based on the Revised European American Lymphoma (REAL) classification. The WF captures and describes the most common lymphomas in terms of biologic behavior or “grades.” The REAL/WHO classifications intend to distinguish lymphoma entities based on their unique clinical, pathologic, immunologic, and/or genetic characteristics and include the uncommon lymphomas. Because of its dependence on immunophenotypic and cell lineage analysis, the REAL/WHO system is more reproducible.
B. The WF was previously the most commonly used system for the classification of NHL in the United States. This scheme was developed in 1982 as the result of a consensus panel made up of distinguished hematopathologists, each previously espousing his or her own classification. The WF attempts to associate clinical behavior with descriptive histopathologic features of NHL. However, it does not incorporate accepted information regarding B-cell or T-cell origin of lymphomas and does not recognize a large variety of newly described clinicopathologic entities. Table 21.5 shows the WF with the frequencies, some clinical correlates, and median survival rates for the various types of NHL using prerituximab chemotherapeutic regimens.
Table 21.5 The Working Formulation Classification of Non-Hodgkin Lymphomaa
Extracted from Rosenberg SA, Berard CW, Braun BW Jr et al. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas. Summary and description of a working formulation for clinical usage. Cancer 1982;49:2112.
aThe Working Formulation was based on a study of 1,014 patients. It does not include cutaneous T-cell lymphomas, adult T-cell leukemia–lymphoma, diffuse intermediately differentiated lymphocytic lymphoma, and malignant histiocytosis, which constitute 12% of cases
1. Grades. The WF divides NHLs into low, intermediate, and high grades that reflect their biologic aggressiveness. The dividing lines between these categories are sometimes arbitrary.
a. In general, small cell size, round or cleaved nuclei, and a low mitotic rate characterize low-grade NHLs. The intermediate-/high-grade NHLs usually manifest larger cell size, prominent nucleoli, and a higher mitotic rate.
b. Clinically, it is useful to consider low-grade NHLs as being indolent or nonaggressive, whereas the intermediate-grade and high-grade NHLs are aggressive diseases with a short, untreated natural history. Many clinicians approach immunoblastic lymphomas in a similar fashion to the intermediate-grade NHLs and consider lymphoblastic lymphomas and the small noncleaved NHLs, particularly the Burkitt variant, as high-grade NHLs requiring special management.
2. Survival curves based on the WF are shown in Figure 21.2.
Figure 21.2. Actuarial survival curves for the National Cancer Institute’s Working Formulation subtypes of lymphomas. Each of the three major prognostic categories (grades) is significantly different from the other (p <0.0001). Table 21.5 defines the histopathologic subtypes A through J for the grades. (From Rosenberg SA et al. National Cancer Institute sponsored study of classifications of non-Hodgkin lymphomas. Summary and description of a working formulation for clinical usage. Cancer 1982;49:2112, with permission)
C. The WHO/REAL classification was established after a consensus meeting of hematopathologists in 1993. It incorporates immunophenotypic characteristics to determine cell lineage and to define subtypes by a more scientific method. It continues to evolve, recognizing several less common entities that were unclassifiable by the WF. The WHO accepted the REAL proposal with some additions and should be the current classification standard. The WHO classification, which serves as a common language among hematologists, is shown in Appendix C6.
1. WHO/REAL entities may include lymphomas of various clinical behaviors, provided that they originate from the same cell type. Leukemias are considered to be an extreme of the spectrum of certain lymphoproliferative disorders.
2. Acute lymphocytic leukemias and lymphoblastic lymphomas are grouped together.
3. Chronic lymphocytic leukemia (CLL) is classified together with small lymphocytic lymphoma (SLL) because they both consist of small, round, B lymphocytes that are positive for CD5 and CD23.
4. All follicular lymphomas constitute one group with grade designation (grades 1 to 3).
5. Mantle cell lymphoma (MCL) is recognized as a separate entity with its distinct features and clinical aggressiveness. MCL was previously described as small lymphocytic lymphoma, diffuse small cleaved cell lymphoma, or at times follicular lymphoma in the WF.
6. Immunoblastic lymphoma is classified as diffuse large cell lymphoma and is no longer recognized as a separate entity.
7. Detailed classification of T-cell and NK-cell malignancies is attempted in this system. Such lymphomas were not recognized by the WF.
8. Because about two-thirds of the NHL histologies are follicular or diffuse large cell, clinical decisions often rely on WF principles.
D. Pathogenesis
1. Monoclonal antibodies can identify epitopes on lymphoid cells characteristic of developmental stages of B-cell and T-cell ontogeny. The antibodies are used with flow cytometry in cell suspensions and with indirect immunoperoxidase labeling in frozen sections. Some of the most useful antibodies are shown in Appendix C5. Monoclonality of B-cell lymphomas is usually established by showing marked dominance of a single light chain (κ or λ) type.
2. Gene rearrangements. B cells and T cells must rearrange DNA to assemble antigen-specific receptors. Each clone rearranges its genes in a unique way that can be differentiated from the germ line pattern by Southern blot techniques. Identification of gene rearrangements for immunoglobulin and T-cell receptor loci can establish cellular lineage, monoclonality, and sometimes stage of differentiation for lymphoid neoplasms. The application of the polymerase chain reaction method may enable detection of down to one clonal cell in one million using amplification of breakpoint regions by specific primers.
3. Specific chromosomal translocations (Table 21.6) have been associated with histologically distinct lymphoma types. The genetic material found at or near the breakpoint of each translocated chromosome is frequently highly informative and provides clues regarding pathogenesis. For example, in BL, the transforming c-myc cellular oncogene found on chromosome 8 is involved in a translocation within or adjacent to the heavy chain gene on chromosome 14 or to one of the light chain genes (κ on chromosome 2 or λ on chromosome 22).
In the follicular lymphomas, the translocation also involves the heavy chain gene on chromosome 14, which is this time juxtaposed with the so-called BCL-2 gene on chromosome 18. Twhe BCL-2 gene appears to be significantly involved in the abrogation of apoptosis (programmed cell death). Thus, the activation of the BCL-2 gene by translocation in follicular lymphomas may result in the excessive longevity or accumulation of lymphoma cells, implying a defect in cell death rather than a pure problem of proliferation in that disease. In MCL, the heavy chain gene on chromosome 14 and the BCL-1 gene on chromosome 11 are brought into proximity. The BCL-1 gene encodes cyclin-D1, which is involved in the cell cycle.
Such cytogenetic abnormalities can be demonstrated with the use of florescence in situ hybridization techniques to analyze specific genetic abnormalities that a tumor may possess.
Table 21.6 Chromosomal Translocations in Lymphoma
Key: CD5, Leu-1 or T-101; CD10, common acute lymphocytic leukemia antigen (CALLA); Sig, surface immunoglobulin; Cig, cytoplasmic immunoglobulin; TdT, terminal deoxynucleotidyl transferase. See Appendix C4 for leukocyte differentiation antigens and Appendix A for glossary of cytogenetic nomenclature.
4. Production of lymphokines by tumor cells may be related to the symptoms or manifestations of specific lymphomas. For example, production of interleukin (IL)-4 by T cells in Lennert lymphoma may explain the exuberant proliferation of histiocytes in that disease, whereas in angioimmunoblastic lymphomas, IL-6 production may result in plasmacytosis and hypergammaglobulinemia.
5. The pattern of surface antigens (Appendix C5) found on lymphoma cells when flow cytometry or immunohistochemical staining is used may help identify or corroborate certain lymphoma types. For example, the CD5 antigen, a pan T-cell antigen expressed by a small minority of B lymphocytes, is found on the neoplastic cells of patients with small cell lymphocytic lymphoma and MCL but is absent from the cells of follicular lymphomas and monocytoid B-cell lymphoma.
III. NATURAL HISTORY. NHL exhibits a remarkable range of natural histories, with doubling times varying between days (e.g., BL) and years (some low-grade NHLs). Treatment tends to have a much more dramatic effect on intermediate-/high-grade NHLs (collectively also called aggressive) than on low-grade NHLs. Early bone marrow involvement and hematogenous and noncontiguous dissemination characterizes NHL, particularly the low-grade types, in sharp contrast to the distribution in HL. Extra-axial nodes, including epitrochlear and mesenteric nodes, are often involved, again in distinction to HL (Table 21.1). Intermediate-grade and high-grade NHLs often present in extranodal sites, including Waldeyer ring, GI tract, skin, bone, and CNS.
A. B-cell lymphomas: low grade (see Appendixes C5 and C6)
1. Small lymphocytic lymphoma (SLL) is the tissue or nodal counterpart of CLL and classically presents with diffuse lymphadenopathy and marrow involvement. Cells are positive for CD5, CD20, and CD23. CLL and chronic B-cell prolymphocytic leukemia are discussed in Chapter 23, in “Chronic Lymphocytic Leukemia.”
2. Lymphoplasmacytic lymphomas, including Waldenström macroglobulinemia, may manifest monoclonal IgM spikes in the serum. The cellular composition of plasmacytoid lymphocytic lymphoma is made up of lymphocytes, plasma cells, and hybridized forms with features of both. Cells are usually CD20-positive, in contrast to frank plasma cells. Hyperviscosity syndrome caused by the IgM protein that forms asymmetric pentamers or neuropathy may dominate the clinical picture in Waldenström macroglobulinemia, which is discussed in detail in Chapter 22.
3. Follicular lymphoma. The follicular lymphomas include lymphocytic infiltrates that are composed mostly of small cleaved cells with increasing numbers of large cells with increasing grade. Cells are positive for CD10 and CD20 and negative for CD5.
a. Cytogenetics. Follicular lymphomas bear the t(14;18) translocation that results in upregulation of BCL-2 expression. The BCL-2 gene product is considered a potent inhibitor of apoptosis.
b. Follicular lymphoma subtype, according to the WHO classification, is defined by the average number of large cells (centroblasts) in a high-power field (hpf):
Grade 1, if <5 large cells/hpf
Grade 2, if 5 to 15 large cells/hpf
Grade 3, if >15 large cells/hpf
c. Aggressiveness. Follicular lymphomas grades 1 and 2 are generally considered to be low grade. The rarer follicular large cell type, or grade 3, is considered by most as intermediate grade, although it is not clear that the natural history is distinct. Cytologic transformation to intermediate-grade or high-grade NHL may occur at any point in the disease and is often characterized by p53 mutation. A similar transformation may take place in other forms of low-grade NHL.
d. Behavior. The follicular lymphomas tend to present as nodal disease. About 85% of cases are stage III or IV at presentation, with frequent bone marrow involvement (>50% of cases). The liver, spleen, and mesenteric nodes are often involved. Follicular lymphomas often progress slowly and may not require immediate therapy. Temporary spontaneous regressions are observed in up to 30% of cases. Follicular lymphomas are highly responsive to therapy, but the effect of any specific treatment on survival is modest, and few patients are cured. Average survival times vary between 6 and 10 years in the past, with possible increases in median survival times in the “rituximab era.”
4. Marginal-zone lymphoma is believed to be derived from parafollicular or marginal-zone cells that surround the mantle zone. Cells are negative for CD10 and CD5 and positive for CD20.
a. MALTomas (MALT: mucosa-associated lymphoid tissue) are a group of extranodal lymphomas that frequently present as localized tumors in the stomach, lung, ocular adnexa, thyroid, skin, and other extranodal sites.
(1) In some cases, a pre-existing organ-associated autoimmune disease is noted (e.g., Sjögren syndrome or Hashimoto thyroiditis). Many of these were designated pseudolymphomas in the past.
(2) The natural history includes prolonged survival without widespread dissemination and suggests a role for RT or surgery in management.
(3) Gastric MALToma is clearly associated with H. pylori infection and regresses in two-thirds of the patients after its eradication.
b. Splenic lymphomas are an uncommon form of marginal-zone lymphomas. These are characterized by pronounced splenic enlargement, often without systemic disease, and with blood and/or bone marrow involvement. Cells often have villi (splenic lymphoma with villous lymphocytes).
c. Nodal marginal zone lymphomas may also be called monocytoid lymphomas because of their appearance.
5. Hairy cell leukemia is characterized by an indolent course, hypersplenism, and neutropenia. Characteristic lymphocytes may be seen with the tartrate-resistant acid phosphatase (TRAP) stain. Cells are characteristically positive for CD103, CD22, CD11c, and often CD25. This disease is discussed in Chapter 23, in “Hairy Cell Leukemia.”
B. B-cell lymphomas: intermediate grade and high grade (see Appendixes C5 and C6)
1. Mantle cell lymphoma (MCL) is a unique B-cell lymphoma with an adverse prognosis. It is derived from CD5-positive, CD20-positive, and CD23-negative lymphocytes surrounding the germinal center. It is associated with the t(11;14) translocation, which results in up-regulation of cyclin D1, a promoter of cell cycling.
a. MCL may present with a variety of histologic variations ranging from a pseudofollicular pattern to a blastic form. The most common appearance is a diffuse, small cell, slightly irregular infiltrate.
b. MCL usually presents at advanced stage with B symptoms and involvement of the GI tract and bone marrow. Conventional chemotherapy usually produces disappointingly short remissions and a median survival of about 2.5 years.
c. Mantle-zone lymphoma with a “mantle zone pattern” is an uncommon indolent variety of MCL without invasion of the follicular center of the involved lymph nodes.
2. Diffuse large B-cell lymphomas (DLBCL). About 30% of cases originate in extranodal sites, such as the GI tract and Waldeyer ring, sinuses, bone, or CNS. In contrast to most low-grade NHLs, localized presentations (stage I and II disease) are common, and bone marrow involvement is less frequent (<25% of cases). Localized presentations (stage I and II disease) may be curable in up to 80% of cases, whereas disseminated disease (stage III and IV disease) is curable 50% of the time.
a. AIDS-related NHLs are almost universally intermediate-grade or high-grade B-cell lymphomas (see Chapter 36, Section II). Most patients present with extranodal disease, often including the GI tract, bone, jaw, and CNS (as parenchymal involvement), but almost any organ can be involved. Dissemination to bone marrow and meninges is characteristic.
b. Posttransplantation lymphoproliferative disorders describe a spectrum of oligoclonal lymphoproliferation following intense, often iatrogenic, immunosuppression in organ transplant recipients and also occurring in other immunocompromised patients. It is believed that polyclonal or oligoclonal B-cell proliferation is initially driven by EBV infection escaping immune surveillance. Ongoing proliferation results in true malignant transformation and development of monoclonal aggressive NHL.
The disease typically manifests with hectic fever, malaise, and cytopenias. Nodal involvement may or may not be noted at presentation. These lymphomas share similar histology and a proclivity for extranodal involvement with AIDS lymphomas. This disorder may respond to withdrawal of immunosuppression in early stages, but systemic chemotherapy and/or monoclonal antibody therapy may be required. The prognosis depends largely on comorbid conditions and the length of the time from transplant to diagnosis of the lymphoma.
c. Primary effusion lymphoma is an aggressive lymphoma originating in serosa and presenting with effusions. Dissemination of disease is the rule. It has been strongly associated with presence of the human herpes virus type 8 (HHV-8) and HIV infection.
3. The “high-grade” B-cell lymphomas are rapidly proliferating lesions with an extremely high mitotic rate and doubling times as brief as 24 hours. Many lymphomas associated with AIDS or organ transplantation are of this type.
a. Burkitt lymphoma has a distinctive morphology, natural history, and behavior and is divided into African (endemic), sporadic, and immunosuppressive types. The cells are all nearly equal in size and contain prominent small nucleoli and cytoplasmic lipid vacuoles. In the non-Burkitt type of small noncleaved lymphoma, the cells have a less homogeneous cellular size and composition. BL is discussed later in Section VIII.E.
b. B-cell lymphoblastic lymphoma is classified with B-lineage acute lymphoblastic leukemia (ALL) and is approached similarly (see Chapter 25, “Acute Leukemia” section).
C. T-cell NHLs constitute about 20% of NHLs in Western societies. T-cell lymphomas have been analyzed in detail by the REAL/WHO classifications (see Appendix C6), despite the difficulty arising from the rarity of certain categories.
1. Precursor T-cell lymphoblastic leukemia/lymphomas (including T-cell ALL) are malignancies of immature T cells that occur predominantly in male adolescents and young adults. The nuclei are often convoluted in appearance, and the mitotic rate is high.
a. Terminal deoxynucleotidyl transferase (TdT) activity is characteristically positive in these patients. TdT positivity is generally restricted to lymphoblastic lymphoma, ALL (pre-B, T, and null subtypes), and the lymphoid blast crisis of chronic myelogenous leukemia; it is not seen in other NHLs.
b. Clinical aspects. Patients usually present with anterior mediastinal masses and often manifest pleural effusion, pericardial effusion, or superior vena cava syndrome. Bone marrow and peripheral blood involvement are frequent, and the syndrome then merges with T-cell ALL. Meningeal involvement is anticipated unless CNS prophylaxis is used. Therapy that is similar to that used for ALL may cure half of the cases of lymphoblastic lymphoma.
2. Peripheral T-cell and NK-cell neoplasms refer to all NHLs of T-cell or NK-cell origin except precursor T-cell lymphoblastic leukemia/lymphoma. The spectrum includes low-grade disorders, such as mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, and a variety of other more aggressive clinicopathologic syndromes. With the exception of MF and large granular lymphocytic leukemia, T-cell lymphomas tend to be clinically aggressive even if the morphology suggests a low-grade behavior. It appears that the noncutaneous peripheral T-cell lymphomas (PTCLs) have a poorer prognosis than intermediate-/high-grade B-cell NHLs stage for stage. Occasionally, hemophagocytic syndrome can occur.
a. The pathologic manifestations of PTCL often include infiltration of T-cell lymph node regions (paracortical) and increased atypical epithelioid venules. The pleomorphic tumor cells often exhibit clear cytoplasm and occasionally resemble RS cells. These tumors frequently contain an admixture of interdigitating cells, epithelioid cells, eosinophils, and plasma cells. Many peripheral T-cell lymphomas would be placed in the diffuse mixed category of the WF.
b. Clinical aspects of PTCL. PTCLs often develop in middle-aged to elderly patients, who present with constitutional symptoms (B symptoms). Most patients have nodal-based stage III or IV disease with frequent hepatosplenomegaly. Pulmonary and skin involvement are not uncommon. Eosinophilia and polyclonal hypergammaglobulinemia develop in some cases.
D. Peripheral T-cell and NK-cell entities (see Appendixes C5 and C6)
1. Adult T-cell leukemia–lymphoma (ATLL) was initially described in southwestern Japan but has been subsequently seen throughout the world, including the United States. The HTLV-1 virus apparently causes the disease. Cutaneous involvement, lymphadenopathy, organomegaly, a leukemic blood picture, hypercalcemia with osteolytic bone lesions, and pulmonary involvement characterize ATLL. The cells frequently show a remarkable “knobby” configuration of the nuclei. Immunologically, the cells are CD4-positive. The response to treatment has been poor; combinations of zidovudine and interferon (IFN) may be useful. A prodromal, less aggressive chronic and smoldering phase is also recognized, which may clinically appear indistinguishable from MF, but with positive serology for the causative agent, HTLV-1.
2. Aggressive NK-cell leukemia–lymphoma is a rare and rapidly fatal NK-cell malignancy. It is more prevalent among Asians than whites. The immunophenotype is identical to extranodal nasal-type NK-/T-cell lymphomas.
3. T-cell prolymphocytic leukemia is discussed in Chapter 23, Section VI.B of “Chronic Lymphocytic Leukemia”.
4. T-cell or NK-cell large granular lymphocytic leukemia is an indolent disease with subtle lymphocytosis of the blood or bone marrow and paraneoplastic neutropenia. It usually does not require treatment. Responses to cyclosporine have been reported. This is also discussed in Chapter 23, Section III.D.6 of “Chronic Lymphocytic Leukemia”.
5. Anaplastic large cell lymphoma (ALCL) is usually of T-cell origin. Occasional cases appear to be of undefined lineage (null cell). The large anaplastic cells are positive for Ki-1 (CD30), an antigen initially described in HL but later found to be present in some neoplastic cells in a variety of aggressive NHLs. It is often associated with t(2;5), which results in fusion of the nucleophosmin gene NPM to a tyrosine kinase, ALK (anaplastic lymphoma kinase). The presence of t(2;5) and ALK positivity is believed to confer a better prognosis.
Pathologically, the cases are frequently confused with epithelial tumors (carcinomas) or melanoma. The confusion is sometimes compounded by positive staining for epithelial membrane antigen and by a sinusoidal distribution, which is characteristic of carcinomas or melanomas. Pathologically, it can be confused with HL, with lymphomatoid papulosis (a relatively benign cutaneous condition with similar histology and spontaneous regressions), or with cutaneous anaplastic lymphoma, which has an excellent prognosis with local treatment despite almost always being ALK-negative. Treatment of ALK positive ALCL is similar to that of large cell B-cell lymphoma and is believed to have a slightly better outcome.
6. Angioimmunoblastic T-cell lymphoma. Immunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) were originally described as abnormal immune reactions clinically characterized by fever, skin rash, autoimmune hemolytic anemia, polyclonal hypergammaglobulinemia, and generalized lymphadenopathy. Pathology revealed diffuse effacement of lymph node architecture, involvement by immunoblasts and plasma cells, and often an abnormal vascular network. Immunohistochemistry and gene rearrangement studies have indicated that many of these patients have underlying T-cell lymphomas from the onset. The course may vary in aggressiveness, with occasional spontaneous remissions. Satisfactory and prolonged responses to corticosteroids or cyclosporine can be seen. More often, patients require treatments similar to aggressive NHL.
7. Nasal-type NK-cell and T-cell lymphomas include the former angiocentric lymphoma and lethal midline granuloma (malignant midline reticulosis). The neoplastic cells in these disorders involve vessels and lead to an angiodestructive necrotizing process. Nasal NK-/T-cell lymphoma involves the palate and sinuses, but metastasis can occur. The course can be indolent but is more commonly aggressive, particularly if disseminated. It is uncommon in the United States and more common in Asia. In contrast to aggressive diffuse large cell B-cell lymphoma of the nasal cavity, nasal NK-/T-cell lymphoma does not usually extend to the CNS. Cells usually are positive for T-cell markers and CD56. Chemotherapy and RT can be curative for localized disease.
8. Hepatosplenic T-cell lymphoma is characterized by sinusoidal infiltration of the liver by cytotoxic T cells expressing the γ–δ rather than the most common α–β T-cell receptor complex. The bone marrow is nearly always involved and lymph nodes are rarely involved. This rare form of NHL is often associated with a hemophagocytic syndrome. Despite the bland appearance of the cells, the clinical course is usually relentless. A possible relationship between treatment of adolescents and young adults with TNF blocking agents, azathioprine, and 6-mercaptopurine is being further investigated.
9. Enteropathy-type T-cell lymphoma presents with ulcerative intestinal lesions in patients with gluten-sensitive (celiac disease) or other enteropathy most commonly. Patients present with abdominal pain, often associated with perforation. It is uncommon in the United States.
10. Subcutaneous panniculitis-like T-cell lymphoma is rare and is characterized by infiltration of the subcutaneous tissue with cytotoxic T cells, expressing the α–β T-cell receptor complex. Patients present with multiple subcutaneous nodules, usually in the absence of other sites of disease. A hemophagocytic syndrome is a possible complication and often the harbinger of an aggressive clinical course.
11. Mycosis fungoides and the Sézary syndrome are described separately (see Section VIII.B).
E. Histiocytic and dendritic cell neoplasms represent a rather confusing category of ill-defined very rare diseases. The cells of origin, histiocytes and accessory cells, have a major role in the processing and presentation of antigen to both T and B cells.
1. Malignant histiocytosis–hemophagocytic syndrome (fever, jaundice, hepatosplenomegaly, coagulopathy, and hemophagocytosis) has been described and most often represents a complication of T-cell lymphoma. Etoposide and sometimes cyclosporine have been reported to control this syndrome. (see Chapter 34 Cytopenia. Section III).
2. Langerhans cell histiocytosis is a condition caused by clonal proliferation of Langerhans cells. Most cases occur in childhood. Langerhans cell histiocytosis is associated with both HL and NHL. It may be localized or generalized with variable aggressiveness. Unifocal disease occurs in a majority of cases (eosinophilic granuloma), usually involving bone. Multifocal, unisystem disease (Hand-Schüller-Christian disease) involves several sites in one organ system (usually the bone). Combination chemotherapy may be necessary for multiple system involvement.
F. Immunologic abnormalities
1. Hypogammaglobulinemia is typically seen in small lymphocytic lymphoma but may develop in other lymphomas, particularly after treatment with rituximab.
2. Paraprotein spikes, often IgM, are seen particularly in lymphoplasmacytic lymphomas but are also noted in other B-cell malignancies and in AILD.
3. Warm or cold antibody immune hemolytic anemias may be seen with any B-cell malignancy, particularly in the small lymphocytic type.
4. Additional autoimmune phenomena, such as circulating anticoagulants (e.g., acquired von Willebrand disease) or angioedema (associated with C′1 esterase deficiency), may occur, especially in the small lymphocytic lymphomas.
5. Polyclonal hypergammaglobulinemia is commonly observed in patients with AIDS or PTCL.
6. Defects in T-cell function are prominent in ATLL even before treatment and in other lymphomas after treatment.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. The Ann Arbor Staging System was used for HL and is applied to NHL, but histopathologic subtype is the prime determinant of survival in NHL. MF has a different staging system (see Section VIII.B).
B. Survival (see Fig. 21.2 and Table 21.5)
1. Low-grade lymphomas are rarely curable and appear to cause a steady percentage of deaths annually. It is possible that the rare, early stages of low-grade NHL (stage I or II) may be curable in some cases, but even this is uncertain. Survival time averaged between 6 and 10 years for follicular lymphomas in the prerituximab era.
2. Intermediate-grade and high-grade lymphoma survival curves generally display two components: a rapid falloff in the first 1 to 2 years followed by an eventual plateau representing a presumptively cured population. About 80% to 90% of patients with stage I or early stage II disease and 50% with stage III or IV intermediate-/high-grade lymphomas may be curable.
3. MCL survival curve shows a rapid and steady decline, with no survival plateau, and a median survival time of 2 to 2.5 years with conventional chemotherapy.
C. Prognostic factors. Extent of disease at presentation and survival rates are shown in Table 21.5.
1. Low-grade lymphomas
a. Sensitivity to therapy is a prognostic sign in that the attainment of a CR or an excellent partial response (PR) with duration of over 1 year identifies patients who are likely to do well.
b. Early stage. Stage I and II cases constitute <15% of all patients with low-grade lymphoma. In one small series, 80% of stage I and II patients younger than 40 years of age who were treated with RT were disease-free 10 years after diagnosis.
c. Follicular mixed (grade 2) lymphomas. It is unclear whether there is a difference in long-term outcome based on grade.
d. The FLIPI scale (Follicular Lymphoma International Prognostic Index) may be helpful to determine prognosis of patients with follicular lymphoma. Variables (score one point per variable) included in this score are as follows (mnemonic: NOLASH):
Greater than 4 Nodal areas of involvement
Abnormal LDH
Age >60 years
Stage III or IV
Hemoglobin <12 g/dL
Those with a low FLIPI score (0 to 1) have a 5-year survival of 90%, and those with a high score (3 or greater) have a 53% 5-year survival in the prerituximab era.
e. The international prognostic index (IPI) described in Section IV.C.2.a is also useful in stratifying patients with indolent lymphoma.
2. Intermediate-/high-grade lymphomas. Stage I or II presentations, constituting 30% to 40% of these lymphomas, are highly curable (about 80%), although tumor bulk (>10 cm in largest diameter) adversely affects outcome.
a. The IPI has established five independently important prognostic factors. The 5-year survival rate was 73% for patients manifesting none or one of the adverse risk factors and 26% for patients with four or five risk factors in the prerituximab era. In the postrituximab era, even those with 3 to 5 points have a 4-year progression-free survival of 55%. These important adverse risk factors are as follows (mnemonic: APLES):
(1) Age older than 60 years
(2) Performance status (ECOG > 1; see inside back cover)
(3) LDH abnormal
(4) Extranodal sites more than one
(5) Stage III or IV
b. Gene profiling. Retrospective microarray analysis of gene expression has identified subgroups of DLBCL with distinct gene cluster expression patterns. Recognized subgroups may resemble the expression profile of the follicular center cells, which confers better prognosis, or the expression pattern of activated lymphocytes, which confers a worse outcome in the prerituximab era. This association is independent of the IPI and may explain why treatment fails in certain patients who have a favorable IPI score. In addition to prognostic information, the evolution of gene profiling is expected to offer significant insight into the pathophysiology of the disease and in the identification of putative therapeutic targets.
c. Gene Overexpression. Overexpression of c-myc in patients with diffuse large B-cell lymphoma appears to confer a worse prognosis.
V. STAGING EVALUATION
A. Clinical evaluation. See “Evaluation of Suspected Lymphoma,” Sections I through IV.
B. Initial staging evaluation
1. The staging evaluation as outlined in “Hodgkin Lymphoma” Section IV.B is generally applicable in NHL. Laboratory evaluation should also include uric acid, serum protein electrophoresis, hepatitis B and C testing, and HIV if diagnosis is high-grade B-cell malignancy. β2-Microglobulin may be substituted for ESR.
2. Flow cytometry on the peripheral blood and bone marrow in low-grade lymphomas may define a clonal excess and suggest hematogenous involvement, even when circulating lymphoma cells are not seen.
3. Diagnostic spinal tap is indicated in lymphoblastic lymphoma, lymphomas occurring in AIDS, BL, and probably in intermediate-/high-grade lymphomas with extensive marrow, sinus, or testicular involvement or with any parameningeal focus.
4. Upper GI and small bowel series should be performed in patients with GI symptoms, unexplained iron deficiency, and/or Waldeyer ring involvement. Endoscopic evaluation is performed as indicated, particularly in MCL.
C. Restaging evaluation is performed to verify CR (all lymph nodes that were ≥1.5 cm). All abnormal studies are repeated, including biopsies of accessible previously involved sites, particularly with potentially curable histologies.
Patients with intermediate-grade or high-grade lymphomas and residual masses on CT scans or radiographs should be followed closely with serial studies; stable residual masses usually do not contain lymphoma. PET is often used to ensure negativity of the presumed inert residual mass. The frequent presence of residual masses has resulted in the definition of “unconfirmed CR” (CRu), whereby all the requirements for CR exist except that a residual lymph node may be >1.5 cm, provided it has been reduced by >75% in the bidimensional product. This designation has been largely eradicated by the use of PET scanning in staging.
VI. THERAPY FOR INDOLENT LYMPHOMAS
A. True stage I and II disease (15% cases): RT to a dose of 2,400 to 3,600 cGy may be administered to all known sites of disease (including draining lymph nodes in E presentation). Large RT fields do not increase the cure rate and may decrease tolerance to chemotherapy later. Prolonged disease-free survival has been reported in some patients. Observation in select patients may also be a reasonable option.
B. Stage III and IV disease
1. No treatment. Most patients with advanced indolent disease may be observed with no therapy and without adverse influence on survival. Spontaneous remissions may occur during the period of no therapy. Therapy is instituted in the presence of any systemic symptoms, rapid nodal growth, or imminent complications of the disease, such as significant cytopenias, obstructive phenomena, or effusions. The median times for “requiring therapy” vary from 16 months for the follicular mixed group, to 48 months for the follicular small cleaved group, and to 72 months for the small lymphocytic group.
2. Single-agent chemotherapy with chlorambucil or cyclophosphamide gives good responses in indolent NHL. Cyclophosphamide has the disadvantages of alopecia and hemorrhagic cystitis. The purine analogs, fludarabine and cladribine, exhibit activity rivaling the alkylating agents; up to 50% of patients with previously treated low-grade lymphomas respond to these purine analogs. Dosages are as follows:
a. Chlorambucil, 2 to 6 mg/m2 PO daily
b. Fludarabine, 25 mg/m2 IV daily for 5 days every 4 weeks
c. Cladribine, 0.14 mg/kg/d IV over 2 hours for 5 days every 4 weeks or 0.1 mg/kg/d by continuous IV infusion for 7 days every 4 weeks
d. Bendamustine, 90 mg/m2 IV, on day 1 and 2 when combined with rituximab every 3 to 4 weeks
3. Combination chemotherapy. Multiagent therapy may be used if a more rapid response is required. Chlorambucil or cyclophosphamide plus corticosteroids in pulse doses and fludarabine plus mitoxantrone combinations are commonly used regimens (see Chl & P, CVP, and FMD in Appendix D-2, Section I for regimens and dosages).
Single-agent or combination chemotherapy produces CRs or excellent PRs in 60% to 80% of patients. Doxorubicin-containing regimens have no clear advantages for low-grade NHL and are often reserved for later stages of the disease or adverse presentations. Treatment is generally continued until a maximum response is achieved. Maintenance chemotherapy does not prolong survival, may compromise further treatment, and is potentially leukemogenic.
4. Rituximab (Rituxan, MabThera) is a chimeric humanized anti-CD20 monoclonal antibody approved for the treatment of refractory or relapsed indolent B-cell lymphoma, and the first-line therapy of follicular lymphoma when combined with CVP. It is believed to mediate cytotoxicity through activation of antibody-dependent cytotoxic T cells, possibly by activation of complement, and by mediating direct intracellular signaling.
a. An overall 50% response rate with a median duration of about 1 year is expected for indolent B-cell lymphomas with rituximab monotherapy. Small lymphocytic lymphoma may be less responsive than follicular NHL because of lower expression of CD20 antigen. Responses of about 30% have been reported in large cell lymphoma that is relapsed or refractory to treatment or occurs in patients that have not been treated but are over age 60. Combinations of rituximab with a variety of chemotherapy regimens are feasible and are believed to be synergistic, with documented increased disease-free survival. Rituximab allows for flexibility in its coadministration with chemotherapy, with no particular schedule known to be more advantageous.
b. The established dose of rituximab is 375 mg/m2 IV weekly for 4 or 8 weeks. The maximum tolerated dose has not been defined, but it is doubtful that higher doses improve outcome. There are no criteria for choosing the 4- or 8-week dosing.
Retreatment on progression is feasible with an expected response rate of 40%. Given its lack of cytotoxicity, maintenance regimens have been investigated and usually demonstrate considerable delay of progression; however, given the frequently successful retreatment on progression, it is unclear whether maintenance with rituximab really delays the time to refractoriness to this agent.
c. Mild infusion-related fever or rigors are common, particularly during the first infusion. Cytopenias develop occasionally. Reactions resulting in death (anaphylaxis, tumor lysis syndrome, adult respiratory distress syndrome) have also been seen, mainly in patients with circulating lymphoma cells or the elderly; slow escalation of the dose as tolerated is recommended for such patients. Reactivation of latent viruses has been reported, as well as immune phenomena such as serum sickness and lupus-like syndromes. The resulting B-cell depletion for 6 months or more seems to be well tolerated but may contribute to ongoing hypogammaglobulinemia. Precipitation of hyperviscosity on lymphoplasmacytoid lymphomas has been seen.
5. Radioactive monoclonal antibodies offer the advantage of targeted radio-immunotherapy. Responses rates of 50% to 80% have been reported in previously treated patients. 131I-labeled anti-CD20 (tositumomab [Bexxar]) and 90Y-labeled anti-CD20 (ibritumomab tiuxetan [Zevalin]) are available.
a. A randomized study of Zevalin versus rituximab demonstrated a higher response rate (80% vs. 55%) and a higher CR rate (30% vs. 15%) for the radioimmunoconjugate.
b. The treatment is given once and is well tolerated with the exception of cytopenias. Grade IV cytopenia occurs in one-third of the patients. Nadirs occur during the sixth and seventh weeks following therapy. Patients are excluded from this treatment with >25% involvement or hypocellularity in the bone marrow, with platelets <100,000/μL, or with neutrophil counts <1,500/μL.
c. Radiation hazard with Zevalin is negligible, whereas lead shielding and more stringent release instructions are needed for Bexxar.
6. IFN-α has been used in several randomized studies as part of either induction or maintenance therapy for previously untreated patients. No clear-cut dose schedule is superior, and doses as low as two to three million units three times weekly may produce responses in up to 40% to 60% of patients.
The place of IFN-α in the routine management of follicular lymphoma is not clear. Results of some series suggest a potentiation of response rates, a prolongation of remission duration, and possibly an effect of IFN-α on survival.
7. Palliative RT is used for sites of bulky disease and to relieve obstruction or pain. RT alone may be used when most of the disease sites do not require treatment but one or two areas are troublesome. However, multiple courses of RT exhaust the marrow and are discouraged when chemotherapy is an effective alternative.
C. Histologic conversion. Indolent lymphomas that transform to an aggressive cell type usually have a poor prognosis. Limited, relatively asymptomatic presentations, however, may respond well to treatment used for intermediate-/high-grade NHL. The CNS can be involved (particularly the meninges) in transformed NHL and is rarely affected in low-grade NHL. High-dose chemotherapy and stem cell support for cases of transformed chemosensitive low-grade NHL should be considered.
D. Primary cutaneous B-cell lymphoma (CBCL) is defined as having no extracutaneous dissemination at presentation and for 6 months thereafter (see Appendix C6, Section II for classification of cutaneous lymphomas). They are most commonly follicular and indolent with a good prognosis. Localized CBCL is treated with RT, even for multifocal disease. Polychemotherapy or monoclonal antibody therapy is reserved for noncontiguous anatomic sites or extracutaneous spread. The diagnosis of primary cutaneous LBCL, leg type, confers a poorer prognosis and may mandate a different treatment approach.
E. Experimental therapies
1. Monoclonal antibodies of several types, in addition to rituximab, have been used in the treatment of low-grade (and some aggressive) NHL. Targets include B-cell antigens (e.g., CD23, CD19, CD20, CD22) or more generalized common antigens (CD5, CD25, CD80, CD40).
a. Alemtuzumab (Campath-1H) is a humanized antibody against CD52 (present in B cells, T cells, and monocytes) and is believed to have satisfactory activity in CLL, prolymphocytic leukemia, and certain T-cell lymphomas but modest action against indolent NHL.
b. Immunotoxins have been under investigation.
c. Novel agents. Bortezomib (a proteosome inhibitor) and lenalidomide (an immunomodulatory agent) have demonstrated single-agent activity in follicular lymphomas and are currently in randomized trials. Bortezomib is also active in mantle cell lymphoma.
2. Idiotype vaccines have been used in a limited fashion to stimulate cellular and humoral immune response against the idiotype of the lymphoma cells. Generation of idiotype vaccines is labor intensive. Infusion of autologous dendritic cells pulsed with idiotype have been used for the same purpose. Although an immune response is produced in most patients with minimal disease, the magnitude of clinical benefit is unclear.
3. Antisense oligonucleotide treatment against BCL-2 or other targets is undergoing investigation.
4. Selective inhibitors. Several agents targeting selected processes, such as angiogenesis, signal transduction, cyclins, histone deacetylase enzymes, and inhibitors of the mTOR, B-cell receptor/spleen tyrosine kinase, and protein kinase C-beta pathways are under active investigation.
5. Autologous bone marrow or peripheral stem cell support following high-dose chemotherapy is undergoing extensive study in patients with relapsed or newly diagnosed low-grade NHL. Although no convincing data support high-dose therapy in the routine management of low-grade NHL, it can be used in relatively young patients with adverse presentations in an effort to prolong remissions.
6. Allogeneic SCT is proposed by certain centers for the treatment of refractory young patients with related donors and should probably be reserved as a last resort. The use of nonmyeloablative, less toxic preparative regimens has been shown to be a particularly useful allogeneic transplant approach in patients with indolent lymphoma with excellent early disease-free survival.
VII. THERAPY FOR AGGRESSIVE NHL. Therapy for special lymphoma subtypes is discussed in Section VIII. Therapy for AIDS-associated lymphoma is discussed in Chapter 36, Section II. Useful combination chemotherapy regimens for these malignancies are shown in Appendixes D2 and D3.
A. Localized presentations of intermediate-/high-grade NHL. Nonbulky (<10 cm) stages IA and IIA cases, including extranodal (E) presentations, can be successfully managed by three cycles of a doxorubicin-containing regimen (i.e., CHOP) followed by IFRT (equivalent to 3,000 cGy in 10 fractions). Virtually all patients achieve CR, and the actuarial relapse-free survival exceeds 80%. Another approach is full-course chemotherapy with or without subsequent RT.
B. Stage I to II (bulky), III, and IV diseas e is treated with full-course CHOP chemotherapy (Appendix D2, Section II). For areas of bulky disease, IFRT may benefit the patient if all bulky disease that was present before giving chemotherapy can be safely encompassed by the radiation ports.
Pursuant to the results of the randomized Groupe d’Etude des Lymphomes de l’Adulte (GELA) study in which elderly patients with aggressive NHL demonstrated a survival advantage (see Coiffier et al. 2002 in “Suggested Reading”), rituximab is added to each cycle of CHOP. The addition of rituximab to CHOP increased the overall survival at 3 years from 49% to 62% when compared with treatment with CHOP alone. One can expect long-term disease control (“cure”) in roughly 50% of patients with advanced-stage, intermediate-/high-grade NHL treated with R-CHOP and similar programs.
Despite claims to the contrary, there is no proof that any of the more complex and more toxic regimens are superior to CHOP. Some of these alternative regimens (m-BACOD, M-BACOD, MACOP-B, ProMACE/CytaBOM) are shown in Appendix D2, Section II. The results of an intergroup trial comparing CHOP with three of the purportedly more effective combinations showed CHOP to be equally active and less toxic. The claims for improved outcome reported in single-institution trials using other regimens are likely the result of incomplete follow-up and selection bias.
1. Complete restaging to assess completeness of response is mandatory. Restaging is usually done after three to four cycles of CHOP and again after six cycles. Patients are generally given at least two additional cycles of therapy after attainment of CR (usually a total of six to eight cycles). Ideally, patients should be in CR after the fourth cycle.
2. CNS prophylaxis using intrathecal chemotherapy, sometimes complemented by cranial irradiation, appears to be indicated in situations associated with a high risk for meningeal relapse. This strategy is particularly advised in cases of involvement of the paranasal sinuses, when there is contiguous spread to the CNS, and in the small noncleaved lymphomas (especially the Burkitt type). Other indications may include lymphoblastic lymphoma, primary testicular lymphoma, and intermediate-/high-grade lymphomas that involve the bone marrow extensively, and those with multiple extranodal sites and elevated LDH, although the latter indications are more controversial.
3. Autologous SCT has been proposed as consolidation during first remission for high-risk patients but is of no proven efficacy in multiple randomized trials.
4. Maintenance therapy does not enhance survival and thus is not advised.
C. Refractory or relapsed intermediate-/high-grade lymphomas
1. Refractory patients failing to achieve a CR may be salvaged with consolidation RT if the involved area is not extensive. Salvage chemotherapy, followed by autologous SCT, is the preferred approach, if feasible. Patients achieving a PR may have a 20% to 40% chance of cure, but the long-term survival rate of truly refractory patients is in the 10% range, so that high-dose chemotherapy is not generally recommended. Allogeneic SCT can be considered for these patients.
2. Salvage chemotherapy regimens often employ high-dose cytosine arabinoside, corticosteroids, and cisplatin with or without etoposide (see ESHAP in Appendix D3). Combinations employing ifosfamide (ICE, MINE) and other potentially helpful regimens (CEPP-B, EVA, mini-BEAM, VAPEC-B, and infusional EPOCH) are also shown in Appendix D3. Any of these regimens could be combined with rituximab, but the impact of this practice is unclear. These programs generally produce significant but short-lasting remissions in 40% to 50% of patients. A small proportion of patients, probably fewer than 10%, have prolonged responses.
3. High-dose chemotherapy plus RT with autologous bone marrow or stem cell support. A similar strategy to that employed in HL has been adopted for intermediate-grade NHL after relapse from standard CHOP-like chemotherapy. A conditioning regimen based on high-dose chemotherapy, sometimes combined with total-body irradiation, is used and followed by reinfusion of cryopreserved peripheral blood progenitor cells (stem cells) mobilized by growth factors. The results of this strategy are best in chemosensitive recurrences, in which about 40% of patients may derive long-term, disease-free survival. The results are far less optimistic in patients whose disease is chemoresistant or in patients who have never achieved remission. The relative merits of salvage chemotherapy followed by autologous SCT have been convincingly proved in a multicenter randomized European study (the PARMA study).
4. Allogeneic SCT differs from autologous SCT in that a potential graft-versus-lymphoma immune reaction may complement the effects of the conditioning regimen. The degree to which this effect exists in lymphoma is subject to debate and may vary with the type of lymphoma. Allogeneic SCT may be most reasonable in young patients who have a suitable donor match and who do not fall into the favorable categories for benefit from autologous transplantation.
5. Experimental therapies. Monoclonal antibody approaches similar to those employed in low-grade NHL are under investigation.
D. Therapy for MCL with standard chemotherapy regimens has generally been ineffective at achieving long-term remissions. The hyper-CVAD regimen (see Appendix D2, Section III) alternated with high-dose methotrexate plus high-dose cytarabine has been proposed for treatment of MCL by the M.D. Anderson Cancer Center. Rituximab has been supplemented to the regimen. Allogeneic or autologous transplantation after two or four rounds of chemotherapy is considered for patients younger than 65 years of age. Aggressive approaches to MCL such as this may have shifted the survival curve to the right, but it still remains unclear if long-term remission is possible. Patients who relapse may receive palliative treatment with agents such as rituximab, bortezomib, and/or radioimmunotherapy.
E. Therapy for lymphoblastic lymphoma is patterned after therapy for the closely related ALL. Overall results of therapy indicate a 40% long-term, disease-free survival, with the best prognosis seen in patients who have minimal or no marrow involvement, no CNS involvement, and normal serum LDH levels. Patients with poor prognostic presentations of lymphoblastic lymphoma are being considered for early allogeneic SCT or more intensive primary chemotherapy programs.
Stanford University researchers reported a 94% freedom-from-relapse rate at 5 years for patients without the previously named adverse prognostic factors with a regimen that involves 1 month of induction therapy, 1 month of CNS prophylaxis, 3 months of consolidation, and, finally, 7 months of maintenance therapy, as follows:
Cyclophosphamide, 400 mg/m2 PO for 3 days, on weeks 1, 4, 9, 12, 15, and 18
Doxorubicin, 50 mg/m2 IV, on weeks 1, 4, 9, 12, 15, and 18
Vincristine, 2 mg IV, on weeks 1, 2, 3, 4, 5, 6, 9, 12, 15, and 18
Prednisone, 40 mg/m2 daily for 6 weeks (tapered off); then for 5 days on weeks 9, 12, 15, and 18
CNS prophylaxis consists of whole-brain RT (2,400 cGy in 12 fractions) and intrathecal methotrexate (12 mg for each of six doses) given between weeks 4 and 9
L-Asparaginase, 6,000 U/m2 IM (maximum, 10,000 U) for five doses at the beginning of CNS prophylaxis
Maintenance therapy consists of methotrexate (30 mg/m2 PO weekly) and 6-mercaptopurine (75 mg/m2 PO daily) during weeks 23 to 52.
F. Therapy for ATLL with polychemotherapy has been largely ineffective. A combination of zidovudine (AZT) and IFN-α has been stated to show promise. Occasionally, patients may benefit briefly from combination chemotherapy programs used in intermediate-/high-grade NHL or from 2-deoxycoformycin, a purine analog. Investigational agents, such as anti-CCR4 antibodies, are attractive treatment options for this group of patients.
G. Therapy of peripheral T-cell lymphomas. Patients with non–B-cell aggressive lymphomas usually relapse after aggressive chemotherapy and fare worse than patients with B-cell NHL. Often the remissions may last only for a few weeks (kinetic failure). Aggressive approaches with autologous or allogeneic SCT are justified. Participation in clinical trials is highly recommended for this group of patients. Histology-specific treatments are being developed such as that described for enteropathy type T-cell lymphoma (see Sieniawski Met al. 2010 in Selected Reading) as well as lineage-specific drugs such as pralatrexate and/or histone deacetylase inhibitors.
1. Angioimmunoblastic lymphoma (AILD) has been managed with generally poor results by conventional chemotherapy or corticosteroids, although occasional long-term responses or spontaneous regressions have occurred. More recently, responses to IFN-α, cyclosporine, or high-dose chemotherapy with stem cell support have been described in small series or case reports.
2. T/NK lymphoma, nasal type with localized involvement of the palate and sinuses (“lethal midline granuloma”) may benefit from RT followed by chemotherapy. Specific chemotherapy regimens, such as the SMILE regimen employing L-asparaginase and non–multidrug-resistant drugs, are especially attractive in this patient group (see Yamaguchi M et al. 2008 in Selected Reading).
3. Primary cutaneous CD30 (Ki-1)-positive T-cell disorders comprise a spectrum of closely related skin lesions that, although they may look identical microscopically, can be distinguished on physical examination of the patient’s skin.
a. Lymphomatoid papulosis has the best prognosis and is often a self-limited disease. It appears as crops of <2-cm nodules that may have central ulceration and leave scars but spontaneously resolve within 6 to 8 weeks.
b. Cutaneous anaplastic large cell lymphoma (C-ALCL), which appears as single >2-cm skin lesions often with ulcerative centers, can be treated with local irradiation or surgery or, if multiple, single-agent chemotherapy (cyclophosphamide or weekly low-dose methotrexate) with or without corticosteroids or RT. Spontaneous remission can occur in up to 30% of cases within 6 to 8 weeks. It can often be confused with ALCL, which is treated as a common aggressive lymphoma.
VIII. SPECIAL LYMPHOMA SYNDROMES
A. Systemic Castleman disease. Initially, Castleman disease referred to localized giant lymph node hyperplasia, usually involving the mediastinum or abdomen. The disease is associated with infection with HHV-8 and probably promoted by viral IL-6 production. A disorder exhibiting the histopathologic features of the plasma cell type of Castleman disease but with a generalized presentation has been described.
1. Clinical features
a. Fever, malaise, and weakness
b. Lymphadenopathy, usually generalized
c. Organomegaly
d. Edema, anasarca, and effusions
e. Pulmonary and CNS involvement
f. Anemia, thrombocytopenia, polyclonal hypergammaglobulinemia, and elevated ESR
2. Histopathology shows preservation of lymph node architecture, but with prominent germinal centers, either hyperplastic or hyalinized, and diffuse marked plasma cell infiltration.
3. Clinical course is either persistent or episodic with remissions and exacerbations. Lymphoma or Kaposi sarcoma occasionally develops. The median survival time is 30 months.
4. Treatment. Corticosteroids and antitumor agents used in NHL have met with occasional responses. IL-6 has been implicated in the pathogenesis of this disorder, with a reported clinical response to treatment with an anti–IL-6 antibody.
B. Mycosis fungoides (MF) and Sézary syndrome (SS) are CTCLs (see Appendix C6 Section II for classification of CTCL). Both are malignant cutaneous lymphoproliferative disorders of helper T cells (CD4-positive). Approximately 15% to 20% transform to CD30-positive or CD 30-negative large cell lymphoma.
1. Dermatologic presentation is in localized patches or plaques evolving into tumor nodules in MF and diffuse exfoliative erythroderma associated with abnormal circulating cells in SS.
2. Histopathology shows atypical T cells with irregular cerebriform nuclei (MF cells) infiltrating the epidermis and the upper dermis, forming characteristic Pautrier microabscesses. Enlarged lymph nodes do not always show overt lymphomatous infiltration, but techniques such as T-cell–receptor gene arrangement may be positive.
3. Natural history. A long history of undiagnosed skin disease often precedes the specific diagnosis.
a. Cutaneous stages of MF
(1) Patch stage
(2) Plaque stage
(3) Tumor stage
b. Lymph node involvement occurs with increasing skin involvement. Histologically confirmed lymph node involvement with complete lymph node effacement on microscopic examination conveys a poor prognosis.
c. Visceral involvement. Almost any organ can be involved late in the disease, particularly the liver, spleen, lung, and GI tract, but the marrow is relatively spared. A peculiar epitheliotropic pattern of dissemination may be observed.
4. Staging system. A variety of systems have been proposed, including a TNM system. One example is the following:
5. Prognosis. About 90% of patients with stage IA survive >15 years with treatment; median survival is not different from age-matched controls. Median survival time is 2 to 4 years from onset of tumor stage or lymph node involvement and <2 years from visceral involvement.
6. Topical treatment
a. Topical corticosteroids frequently achieve good responses.
b. Topical nitrogen mustard is useful in the patches or plaque stages. It can be used for involved skin only or in a total body application. Cutaneous allergic reactions may develop.
c. Psoralen with ultraviolet light A (PUVA) or narrow band UVB repeated two to three times a week is effective for the patch or plaque phase. Long-term benefits and side effects are poorly defined.
d. Bexarotene (Targretin) gel is a retinoid that selectively binds to the retinoid X-receptor (RXR) family of retinoid receptors. The response rate of localized patch or plaque disease to the gel is >60%. Bexarotene is the only retinoid that has been approved for this indication.
e. Electron-beam RT to the total skin is technically demanding but has produced durable remissions, particularly in early stages of disease. Local electron-beam RT can be used in the treatment of tumors, especially if they are few in number.
7. Systemic chemotherapy and investigational approaches have resulted in short-term responses without an effect on survival.
a. Systemic chemotherapy is recommended only for patients with advanced disease. A variety of single agents (e.g., methotrexate, corticosteroids, alkylating agents, gemcitabine, etoposide, doxorubicin, pegylated liposomal doxorubicin) achieve temporary responses in 30% of patients. The purine analogs 2-deoxycoformycin (pentostatin), cladribine, and fludarabine have all also shown response rates of about 30%. Combination chemotherapy is advocated for those with disease transformation to large cell lymphoma.
b. Bexarotene (Targretin) is an oral rexinoid that is approved in the treatment of CTCL. The most common side effects are hypertriglyceridemia, central hypothyroidism, and myelosuppression.
c. IFN-α has response rates of 15% to 50% in MF/SS.
d. Denileukin diftitox (DAB389-IL-2, Ontak) is a fusion protein between IL-2 and diphtheria toxin that was approved for the treatment of CTCLs failing other treatments. Most common side effects include vascular capillary leak syndrome, abnormal liver function tests, and infusion reactions.
e. Antibody therapy. Transient responses to monoclonal T-cell antibodies, such as alemtuzumab (Campath), have been observed in CTCL.
f. Extracorporeal photophoresis (ECP), a systemic form of PUVA therapy, is an effective immunoadjuvant therapy for CTCL. The procedure involves exposure of leukapheresed mononuclear cells to a psoralen photoactivating agent and UVA ex vivo followed by reinfusion of the treated cells. ECP induces an anti-idiotype cytotoxic T-cell response against circulating tumor cells. ECP is most effective with the erythrodermic phase (SS) of CTCL.
g. Histone deacetylase inhibitors (HDI). Vorinostat (Zolinza), an oral HDI, and romidepsin (Istodax), an IV HDI, have been approved for the treatment of the skin manifestations of CTCL. The most common side effects are GI, thrombopenia, and constitutional.
C. Primary CNS lymphoma (PCNSL) is essentially always of high histologic grade (large cell, immunoblastic) and of B-cell origin. Lesions are primarily parenchymal and involve deep periventricular structures. Multiple lesions occur in 20% to 40% of cases. The leptomeninges are involved in 30% of cases at diagnosis and in most cases at autopsy.
1. Etiology and epidemiology
a. PCNSL accounts for about 1% of brain tumors and 1% of extranodal lymphomas. The disease is associated with advanced age (>60 years), AIDS, drug-induced immunosuppression (e.g., for transplantation), and congenital immunodeficiency syndromes.
b. PCNSL accounts for roughly 50% of all lymphomas seen in transplant recipients and occurs at a somewhat lower frequency in AIDS. In AIDS cases, PCNSL appears in a setting of severe CD4 depression, with counts frequently <50/μL.
c. Relationship to EBV infection is suggested by discovery of the EBV genome in some cases of PCNSL arising in transplant recipients and AIDS patients.
2. Clinical presentations include headache, personality changes, and hemiparesis. Symptoms of meningeal infiltration or spinal cord compression are less common. Associated systemic lymphoma is rare. Ocular lymphoma (appearing as uveitis) may precede or follow the diagnosis of CNS lymphoma. PCNSL complicating AIDS is associated with a median survival time of <3 months.
3. Evaluation. The diagnosis can usually be made with stereotactic biopsy and without formal surgical exploration.
a. Brain CT scan. Deep periventricular lesions often involve the corpus callosum, basal ganglia, or thalamus and often appear hyperdense before contrast dye injection. Contrast often produces generalized intense enhancement, unlike the picture of gliomas and metastases. In AIDS patients, the precontrast scan may be hypodense.
b. Brain MRI may reveal additional lesions not seen by CT scan.
c. Lumbar puncture. Nonspecific elevation of cerebrospinal fluid (CSF) protein is common. Abnormal cells may be found in 25% to 35% of patients undergoing lumbar puncture at diagnosis. Identification of malignant cells may be enhanced by immunofluorescent techniques with monoclonal antibodies.
d. Ophthalmologic examination, including slit-lamp examination
e. HIV antibody; HIV titer if positive
f. Enumeration of the CD4 count
g. Abdominal CT scan, chest radiograph
h. Bone marrow biopsy
4. Therapy
a. Corticosteroids are extremely effective in PCNSL. Lesions may disappear on steroids alone and preclude histologic diagnosis after steroids are given.
b. Whole-brain RT (WBRT) was previously the preferred treatment for PCNSL. Doses of 4,000 to 5,000 cGy appear necessary, with 1,000 to 1,500 cGy focal boost to the tumor bed. However, WBRT is associated with severe delayed neurotoxicity. Up to 90% of patients over 60 years of age develop totally debilitating dementia, gait ataxia, and urinary dysfunction within 1 year of treatment, if they survive. Delayed treatment-related cerebrovascular disease, alone or in combination with progressive leukoencephalopathy, has been observed in younger patients 7 to 10 years after WBRT.
c. Chemotherapy with high doses of methotrexate (>3 g/m2) has become the preferred treatment because it improves disease-free survival significantly and because it is not associated with the high rate of neurotoxicity from combined-modality treatment. The response rate to high doses of methotrexate is 70% to 95%, with an expected 2-year survival rate of 60% and median survival of 32 months. Relapses are treated with WBRT and/or salvage chemotherapy. Intrathecal chemotherapy is not given unless CSF cytology is positive. Approaches utilizing high-dose methotrexate, cytarabine, and autologous stem cell transplant are being investigated.
D. Primary gastrointestinal lymphoma (PGL) is the most common form of solitary extranodal disease and may occur in the stomach, small bowel, and large bowel.
1. Associated diseases. The incidence of enteropathy-type T-cell lymphoma is increased in patients with ulcerative colitis, regional enteritis, or celiac disease. α-Heavy chain disease is present in some patients with the Mediterranean type of PGL. MALToma of the stomach is associated with H. pylori infection.
2. Histopathology. PGL may originate from either T cells or B cells. MALToma, follicular lymphoma, MCL, or other aggressive lymphomas may be found anywhere along the GI tract. B-cell PGL tends to present at lower stages, have fewer complications, and have a better prognosis than T-cell PGL.
3. Symptoms and physical findings. Anorexia, nausea, vomiting, weight loss, GI bleeding, or abdominal pain is present in most patients. An abdominal mass may be present, but peripheral lymphadenopathy is not common.
4. Complications. Obstruction may complicate the course of PGL. Perforation or hemorrhage may be either a presenting sign or a complication of treatment for PGL. Therapy can cause perforation by the lysis of the lymphoma’s involvement of the full thickness of the wall of the organ involved.
5. Diagnosis. Endoscopy or barium contrast radiographs usually show large mucosal folds, ulceration, masses, lumen narrowing, or annular strictures. Gastric lymphomas may be indistinguishable from peptic ulcer by both radiologic and endoscopic criteria. Undifferentiated carcinoma or adenocarcinoma of the GI tract may be confused with intermediate-/high-grade lymphoma even after expert histologic evaluation; immunohistochemical verification of diagnosis is mandatory. Multiple sites of involvement should be excluded by barium follow-through or endoscopy.
6. Management of PGL
a. Surgical management. Laparotomy may be needed to establish the diagnosis or treat complications. Resection of bowel should be considered in cases with solitary lesions, intractable bleeding, or high risk of perforation. Subtotal gastrectomy for gastric lymphoma is rarely performed.
b. Medical management should be based on histologic subtype and extent of disease. Intermediate-/high-grade lesions are treated primarily with combination chemotherapy, such as CHOP. The 2-year survival after CHOP is better than 90% for B-cell PGL and 25% to 35% for T-cell PGL.
7. Gastric MALToma. H. pylori–associated MALToma of the stomach usually has low-grade histology. Occasionally, transformation to a large cell lymphoma may occur. Significant mucosal thickening may be present before spread to regional or distant nodes. H. pylori can usually be found in endoscopic biopsies.
a. Treatment of H. pylori. MALToma usually regresses after eradication of H. pylori. At least a 70% CR is expected but may be observed up to 6 months after treatment. A t(11;18) translocation is a predictor for no response to antibiotic therapy. The following 2-week regimen can be used for H. pylori (amoxicillin may be used instead of metronidazole in case of intolerance):
Clarithromycin (Biaxin), 500 mg b.i.d.
Metronidazole (Flagyl), 500 mg b.i.d.
Omeprazole (Prilosec), 20 mg b.i.d.
b. Antineoplastic therapy. Patients with a large cell component, deeply penetrating disease, or with metastatic disease are not expected to respond to antimicrobial therapy. IFRT is used for disease localized to the stomach (3,000 to 3,300 cGy). Gastrectomy is probably not superior to RT for local control and has been abandoned. Rituximab can also be used if RT is contraindicated. Systemic chemotherapy is used for more advanced disease that is symptomatic or bulky.
E. Burkitt lymphoma (BL) is a specific subtype of the small, noncleaved cell, high-grade NHL. The cells in BL are very uniform with round or oval nuclei, two to five prominent nucleoli, and cytoplasm rich in RNA. The cells are of B lineage, expressing monoclonal surface IgM with c-myc overexpression. A consistent series of cytogenetic translocations (Table 21.6) and explosive growth characterizes BL.
1. Epidemiology and etiology
a. BL is endemic in certain regions of equatorial Africa and other tropical locations. A sporadic form of BL occurs in the United States and throughout the world. The disease occurs predominantly in childhood but can be seen in young adults, particularly in the sporadic form.
b. EBV has been found in the genome of endemic BL but rarely in the sporadic form. Very high EBV antibody titers are seen in the endemic form.
2. Clinical features of BL are shown in Table 21.7.
Table 21.7 Clinical Features of Burkitt Lymphoma
3. Staging system. A variety of systems have been proposed. The NCI system is as follows:
|
Stage |
Disease Distribution |
|
A |
Single solitary extra-abdominal site |
|
AR |
Intra-abdominal: >90% of tumor resected |
|
B |
Multiple extra-abdominal sites |
|
C |
Intra-abdominal tumor |
|
D |
Intra-abdominal plus one or more extra-abdominal sites |
4. Prognosis. Before effective treatment, only 30% of sporadic cases survived. Using combination chemotherapy and CNS prophylaxis, the survival rate is at least 60%. Children and young adults with limited-stage (A, AR, B) disease have an excellent prognosis with a 90% survival rate. Bone marrow and CNS involvement carry a poor prognosis. Adult cases of BL, particularly those of advanced stage, do more poorly than childhood cases. So-called double hit BL that contains both 8;14 and 14;18 translocations have a worse prognosis.
5. Treatment
a. Cyclophosphamide therapy alone has been curative for many localized presentations in Africa.
b. Multiagent, aggressive regimens are necessary for the sporadic form as well as for Burkitt-like NHL. One such program would be hyper-CVAD with or without rituximab. Another appropriate treatment alternates two cycles of CODOX-M with two cycles of IVAC (see Appendix D2, Section III) in patients with Burkitt-like NHL, with excellent results. Low-risk patients (those with normal LDH and complete resection of an abdominal tumor or single extra-abdominal mass) may be treated with CODOX-M alone combined with intrathecal prophylaxis. CHOP is not adequate therapy for this group of patients.
c. Because of the extremely rapid growth rate, massive acute destruction of tumor with initial chemotherapy usually results in tumor lysis syndrome and mandates prophylaxis for tumor lysis syndrome when the patient is initially treated (see Chapter 27, Section XIII).
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