Chapter 67: Mature T-Cell and Natural Killer Cell Lymphomas

• The lymphomas of mature T cells and natural killer (NK) cells are shown in Table 67–1. The cutaneous forms are discussed in Chap. 66.

T-Cell Prolymphocytic Leukemia

• Prolymphocytes (large [T] lymphocytes usually with prominent nucleoli) represent at least 50 percent of lymphocytes in the blood. They often have nuclear convolutions.

• T-prolymphocytes characteristically express pan-T-cell markers: CD2, CD3, CD5, and CD7.

• In the majority of cases, prolymphocytes express CD4 but not CD8 (i.e., malignant cell of T-helper cell origin). In occasional morphologically identical cases, CD4 may be weakly expressed or absent and CD8 may be weakly positive. CD52 is highly expressed and can be a target of therapy.

• Inversion of chromosome 14 is the most common cytogenetic abnormality and is found in 80 percent of patients. The t(14;14) occurs in 10 percent of patients. Associated abnormalities of chromosome 8 (e.g., t(8;8)) are common as well. Several other chromosomes (e.g., 6, 11, 17) may also be abnormal.

• Represents 20 percent of prolymphocytic leukemias; the remainder have a B-cell phenotype.

• The male:female ratio is 1.5:1.

• The tissue (e.g., lymphatic tissue) involvement and blood involvement coexist and are striking in both locations.

• Most patients have generalized lymphadenopathy and hepatosplenomegaly with marrow replacement and lymphoma cells dominating the white cell count (usually >100 × 10⁹/L).

• Anemia and thrombocytopenia are nearly always evident at diagnosis.

• Skin involvement occurs in approximately 20 percent of patients.

• Serology for the human lymphocytotropic virus-1 is negative.

• The clinical course is usually rapid. Median survival is less than 1 year.

• No standard chemotherapeutic treatment program has been developed. For example, cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine (Oncovin), prednisone (CHOP) therapy does not produced long-term remissions.

• Pentostatin and cladrabine can induce responses in approximately 40 percent of patients; but, complete remissions are infrequent (~10%) and long-term responses (>1 year) are uncommon.

• Alemtuzamab, a humanized monoclonal antibody against CD52, given three times weekly, has induced good responses in over 50 percent of patients.

• Allogeneic hematopoietic stem cell transplantation can induce a long-term remission of the disease.

• Occasional patients may have a chronic course of a few years but then evolve to a rapidly progressive phase.

T-Cell Large Granular Lymphocytic Leukemia

Demographic Features

• Accounts for approximately 3 percent of all T cell/NK cell neoplasms (see also Chap. 58).

• Median age of onset is 60 years.

• Approximately 85 percent of cases in Western countries are indolent.

• An aggressive variant (15% of cases) occurring in younger patients is most prevalent in Asia and South America.

Clinical Findings

• Persistence of elevated numbers of large granular lymphocytes in the blood (usually > 0.2 × 10⁹/L). The absolute large granular lymphocyte count may be lower and a clonal proliferation still be present based on T-cell receptor chain gene rearrangement studies.

• Marrow may show prominent infiltrate of large granular lymphocytes.

• Anemia occurs in 50 percent and neutropenia in 80 percent of patients. Severe neutropenia (< 0.5 × 10⁹/L) occurs in half the patients. Mild thrombocytopenia occurs in 20 percent of patients.

• Recurrent bacterial infections are notable in patients with severe neutropenia.

• Splenomegaly in about 35 percent at diagnosis, principally from massive accumulation of neoplastic cells in the spleen.

• Pure red cell aplasia occurs in approximately 15 percent of cases.

• One-third of cases associated with clinical evidence of rheumatoid arthritis (thought to reflect immune system dysregulation).

• In patients in which evidence of rheumatoid arthritis is present, the clinical features are indistinguishable from Felty syndrome.

• Circulating immune complexes, autoantibodies to various tissues, and polyclonal hypergammaglobulinemia also highlight the immune dysregulation.

• T-cell receptor chain gene rearrangement is a diagnostic hallmark along with clinical features.

• The large granular lymphocyte immunophenotype is CD3+CD8+CD57+.

Treatment

• Treatment may not be necessary initially. Severe neutropenia with recurrent infections, severe anemia or thrombocytopenia, or symptomatic splenomegaly may require therapy. No standard approach has been set in phase III clinical trials.

• Methotrexate, 10 mg/m² orally weekly, combined with prednisone, 1 mg/kg per day orally for 1 month and then tapered is one approach. A majority so treated have marked improvement.

• Cyclosporine, 7.0 mg/kg per day orally, or cyclophosphamide, 100 mg per day orally, may be used. Taper and use minimum required, once cell counts reach acceptable levels.

• Several early trials of various agents (e.g., tipifarnib, an oral farnesyltransferase inhibitor) and monoclonal antibodies (e.g., siplizumab, an anti-CD2) are under way.

• Although infrequent cases with an aggressive course may occur, most cases are indolent and the clonal abnormality remains relatively stable. The median survival is approximately 13 years.

Aggressive NK Cell Leukemia

• Represents less than 1 percent of all T-cell lymphomas.

• The Epstein-Barr virus implicated in its pathogenesis.

• Compared with most lymphomas, affects younger patients; median age at diagnosis 40 years.

• Most common among Asians or those of Asian ancestry.

• Usually fulminant presentation with fever, night sweats, cytopenias, hepatosplenomegaly.

• Disseminated intravascular coagulation (see Chap. 86), hemophagocytic syndrome (see Chap. 37), and multiorgan failure may be evident.

• Lymphadenopathy is often evident.

• Cutaneous involvement is not a feature.

• Lymphocytosis is present in the blood and marrow, but percent of neoplastic lymphocytes in the blood is quite variable from low to markedly elevated.

• Immunophenotype of lymphocytes by flow cytometry is CD2+CD3+CD8+ CD56+CD57–.

• Deletions of 17p13 and 6q21-25 most common cytogenetic abnormalities. Isochromosome 7 also occurs. 17p13 is site of the p53 gene.

• Serum lactic acid dehydrogenase markedly elevated.

• Standard multidrug chemotherapy is ineffective for this aggressive disease.

• Multidrug therapy (as used for poor-risk acute lymphocytic leukemia for initial therapy, including central nervous system prophylaxis, followed by high-dose consolidation therapy, in anticipation of allogeneic hematopoietic stem cell transplantation) is an intensive approach that can lead to a prolonged response.

• Anti-CD2 antibody, siplizumab, has been effective in only 1 of 16 patients in a phase I trial.

• An indolent form of NK cell leukemia, not separately classified as yet, exists. It presents as a chronic lymphocytosis with NK cell markers and no other signs or symptoms; easily distinguished clinically from the fulminant, prevalent form described above.

Adult T-Cell Leukemia/Lymphoma

Epidemiology and Pathogenesis

• Viral-induced lymphoproliferative disease with foci of occurrence in areas of Japan, South America, the Caribbean Basin, and equatorial Africa.

• Caused by a retrovirus, human lymphocytotropic virus (HTLV)-1, prevalent in the same regions as the clinical disease.

• Among HTLV-1 carriers, the lifetime risk of the disease is about 4 percent.

• Male:female ratio of disease 1.2:1 and median age of onset is approximately 60 years.

• Virus can be transmitted by blood-borne routes (e.g., transfusion), breast milk (mother to infant), and sexual intercourse.

Clinical Findings

• The presentation is variable: (a) smoldering disease, (b) chronic process with leukemic phase, (c) an aggressive lymphoma without overt blood involvement, (d) an aggressive leukemia with extensive marrow and blood lymphocytosis, or (e) a leukemic and lymphomatous presentation simultaneously.

• Lymphadenopathy, splenomegaly without overt leukemic involvement of blood and marrow may be evident in the lymphomatous presentation, although blood and marrow involvement frequently develops later.

• Lymph node enlargement occurs in virtually all patients although the nodes may be small, initially. Generalized lymphadenopathy is the rule and most have retroperitoneal adenopathy but mediastinal lymphadenopathy is very infrequent.

• The lymph node histopathology may mimic (a) diffuse large-cell lymphoma, (b) mixed large and small cell lymphoma, (c) large-cell immunoblastic lymphoma but no correlation exists with these different patterns of node effacement and clinical course.

• Blood lymphocytosis and marrow infiltration marks the leukemic phenotype. The lymphocyte count at diagnosis may range from 5 × 10⁹/L to >100 × 10⁹/L.

• The lymphoid cells have characteristic clefted and lobulated nuclear shapes (Fig. 67–1) and express a mature T-helper cell phenotype, CD2+CD3+CD4+ and often CD25. Clonal rearrangement of the T-cell receptor β-chain is characteristic.

• Anemia and thrombocytopenia are not prominent features at the time of diagnosis.

• Extranodal sites of involvement include the skin; lungs; gastrointestinal tract, especially the liver; and central nervous system.

• Skin involvement occurs in two-thirds of patients. Erythematous patches, plaques, papules, erythroderma, nodules or tumors alone or in combination may develop. Epidermal T-cell infiltration and lesions mimicking Pautrier microabscesses are found on histologic examination.

• The skin lesions may be indistinguishable from mycosis fungoides on inspection or even histologic examination but usually can be distinguished by serology for HTLV-1.

• Meningeal involvement may be evident by lymphocytosis in the cerebrospinal fluid.

• Spinal cord myelopathy and spastic paraparesis are two neurologic syndromes associated with this disorder.

• Decrease in B-cell function occurs through induction of suppressor cells; opportunistic infections are common even in the indolent forms.

• Hypercalcemia is often a feature and results from paraneoplastic production of parathyroid hormone-related proteins by osteoclasts. The osteoclastogenesis is mediated by the neoplastic T cells.

• The hypercalcemia is associated with polydipsia, polyuria, weakness, lethargy, and confusion.

• Radionuclide bone scans show a diffuse uptake throughout the skeleton, findings not usually seen in other lymphomas.

• Isolated osteolytic lesions may also occur.

Treatment

• Anthracycline-containing, multidrug therapy can induce a complete remission in approximately 30 percent of patients; however, it does not confer an increase in survival.

• Several other multidrug regimens (up to eight drugs) have been tried with complete remission rates of approximately 35 percent but the median survival with several different combinations has not exceeded 1 year.

• Allogeneic hematopoietic stem cell transplantation has had a high fatality rate (40%). The median survival of patients treated was less than 2 years.

• Interferon-α and zidovudine have resulted in partial remissions, some lasting several years.

• Monoclonal antibodies to CD25 with or without attached radionuclides have shown promising results.

• Denileukin diftitox (interleukin-2 coupled with diphtheria toxin) has induced complete remissions in pretreated patients.

• There is as yet no standardized approach that can be used as a basis for providing the treatment most likely to lead to long-term, disease-free survival.

Course

• Median survival for the lymphomatous or leukemic form of the disease is about 1 year.

• The "indolent" form, which is largely expressed in the skin, with little organ, marrow, or blood involvement, has a median survival of 2 years. (This form can be confused with cutaneous T-cell lymphoma described in Chap. 66)

Anaplastic Large Cell Lymphoma

Epidemiology and Pathogenesis

• Accounts for 5 percent of T-cell lymphomas.

• Has a bimodal age distribution: children and adolescents and older persons.

• Cells react with anti-CD30 and sometime referred to as CD30+ lymphomas.

• The cells in 65 percent of cases are positive for anaplastic lymphoma kinase (ALK).

• ALK-positive anaplastic large cell lymphoma cells contain a t(2;5)(p23;q35) fusing the NPM and ALK genes. The resultant NPM-ALK fusion gene encodes a p80 fusion oncoprotein. A small proportion of cases have translocations of ALK with other partners.

• Genomic and protein expression patterns indicate that the ALK-positive and ALK-negative anaplastic large cell lymphoma are two different diseases, although similar histopathologically.

Clinical and Laboratory Findings

• The cells of T-cell variants of anaplastic large-cell lymphoma are CD2+CD3+ CD4+CD5+CD7+.

• The cells of T-cell variants of anaplastic large cell lymphoma express granzyme B and perforin but have T-cell receptor gene rearrangements indicating its T-cell origin.

• Cutaneous CD30+ anaplastic large-cell lymphoma is a distinct entity and is discussed in Chap. 66.

• This type of lymphoma is usually an aggressive disease presenting with systemic symptoms of fever, chills, and weight loss, and nodal and extranodal involvement.

• The T-cell variant has a greater predilection for skin involvement and less predilection for marrow (and blood) and extranodal sites than does the null-cell variant.

• There are some distinctions between the ALK-positive and ALK-negative type. The former has a better prognosis.

• Ninety percent of children have the ALK-positive cell type.

• Marrow involvement is overt in about 30 percent of cases but if marrow is stained for CD30-positive or ALK-positive cells, approximately 60 percent of cases have marrow involvement.

• The histopathology is made up of large pleomorphic lymphoma cells in approximately 85 percent of cases, small to medium sized cells in 7 percent and a mixed small and large cell-sized variant with frequent macrophages in 7 percent. In each case, the cells stain for CD30.

Treatment

• Usually behaves as an aggressive lymphoma but is among the most responsive T-cell lymphomas to multidrug therapy containing an anthracycline antibiotic.

• Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or high-dose methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) each result in a 70 percent complete remission rate and a 5-year overall survival rate of 60 percent.

• There has not been a large experience with allogeneic hematopoietic stem cell transplantation but it can be very effective, even in patients with refractory or relapsed disease after multiagent chemotherapy.

Peripheral T-Cell Lymphoma (Unspecified)

• These T-cell lymphomas do not fit into a specified World Health Organization category of T-cell lymphoma.

• They represent about 30 percent of all T-cell lymphomas in Western countries.

• They are uncommon in children. Males are two-fold more likely than females to be affected.

• They are considered more aggressive than diffuse large B-cell lymphoma.

• Usually present with prominent (bulky) lymphadenopathy and widespread disease.

• Extranodal sites and marrow may be involved but blood involvement at presentation is uncommon.

• Patients have a high frequency of fever, night sweats, and weight loss.

• Pruritus, eosinophilia, or the hemophagocytic syndrome (see Chap. 37) may be present.

• Neoplastic cells express a CD4 or CD8 αβ T-cell phenotype but deletion of any of the pan-T cell antigens is common.

• Rearrangement of the T-cell receptor β chain gene is present in the neoplastic T cells.

• Elevated serum lactic acid dehydrogenase is very frequent.

• Use of multidrug lymphoma regimens that include an anthracycline antibiotic results in very few long-term survivors. These lymphoma cells are chemotherapy-resistant with current regimens that contain alkylating agents, anthracycline antibiotics, or topoisomerase II inhibitors.

• Use of high-dose consolidation therapy with autologous stem cell rescue for patients who have entered a remission on multidrug chemotherapy has increased 5-year overall survival for that subset of patients.

• There is little experience with allogeneic hematopoietic stem cell transplantation but transplantation-related mortality is considerable.

Angioimmunoblastic T-Cell Lymphoma

• Represents approximately 20 percent of T-cell lymphomas and 1 percent of all lymphomas.

• Median age of onset approximately 65 years. Males are affected slightly more often than females.

• Two types can occur: one evolving from angioimmunoblastic lymphadenopathy with dysproteinemia and the other arising de novo.

• Lymph node histopathology is characterized by nodal effacement and loss of germinal centers with a pleomorphic cellular infiltrate that in addition to neoplastic T cells has a background of plasma cells, immunoblasts, eosinophils, and macrophages. Small arborizing blood vessels are an important and prominent feature in the node.

• The neoplastic cells are CD4+ αβ T cells with β or γ T-cell receptor rearrangement (CD4+ follicular helper T cells). Pan T-cell markers are evident (e.g., CD2, CD3, CD5).

• The neoplastic T cells express CD10 in about 90 percent of cases, a marker characteristic of this type of lymphoma.

• CD8 cellular staining is present, but on reactive T cells in the background.

• Immunoglobulin gene rearrangements may be found in 20 percent of cases; but, they represent expanded clones of Epstein Barr virus-carrying B cells.

• Epstein-Barr virus-positive B cells are frequently present scattered throughout the node and is thought to be a secondary infection related to immunodeficiency.

• Patients present with widespread lymphadenopathy and splenomegaly with frequent involvement of marrow, liver, and skin. Pruritus may accompany the rash.

• Fever, night sweats, weight loss are very common at diagnosis.

• Pleural and peritoneal effusions (ascites) and arthritic manifestations may be present.

• Laboratory abnormalities include polyclonal hypergammaglobulinemia, immune complexes, cold agglutinins, rheumatoid factor, and other anti-tissue antibodies.

• The most frequent cytogenetic abnormalities are trisomy 3, trisomy 5, and involvement of the X chromosome. Complex karyotypes are a poor prognostic sign.

• Most patients are treated with anthracycline antibiotic-containing multidrug regimens. As in most other T-cell lymphomas, the initial response rate is about 40 percent, but survival is not extended significantly by such treatment.

• The course is usually aggressive and median survival is approximately 3 years.

• Poor prognostic signs are male sex, mediastinal lymphadenopathy, anemia, and complex cytogenetic patterns at the time of diagnosis.

• Large B-cell lymphoma may supervene, often Epstein Barr virus-positive.

Extranodal NK/T-cell Lymphoma

• Although most cases are NK cell malignancies, the cells in some cases have a cytotoxic T cell phenotype. Hence, the double nomenclature of NK/T cell.

• Nasal type (formerly called midline granuloma) always associated with Epstein-Barr virus infection and the blood titer of viral DNA is positively correlated with extent of the disease and a poor prognosis.

• More prevalent in Native Americans, Mexicans, and in Central and South Americans than those of European descent. Cases are more common in males than females and more prevalent at middle age (median age 50 years). Children can be affected.

• Nasal form 5-fold more common than extranasal form.

• Nasal form involves midline facial structures. The tumor induces vascular damage and necrosis.

• The neoplastic cellular histopathology is quite varied but the cells usually are CD2+CD56+CD3– but with CD3ε+ cytoplasmic staining. Cytotoxic molecules such as granzyme and perforin are positive. In situ hybridization for Epstein-Barr virus encoded RNA (EBER) is positive in all tumor cells and a negative reaction should result in consideration of other possible diagnoses.

• Patients present with symptoms of nasal obstruction or with epistaxis. Nasal examination shows a mass lesion and destruction of midline structures (e.g., nasal septum), but the tumor can extend to paranasal sinuses, orbit, palate, and oropharynx.

• Although typically localized to the nasopharynx and neighboring structures at presentation, the disease can spread to cervical lymph nodes, skin, gastrointestinal tract, and testes.

• Extranodal NK/T-cell lymphomas may also occur without initial confinement to the nasopharynx.

• These extranodal and extrapharyngeal lymphoma presentations are variable. Nodular ulcerating skin lesions are frequent. Intestinal involvement with perforation is common. Numerous other extranodal sites may be involved. Lymph node involvement may be present. Marrow and blood involvement can occur and can overlap with NK cell leukemia.

• The hemophagocytic syndrome may develop in the setting of this T-cell lymphoma.

• Local radiation and multidrug chemotherapy, including an anthracycline antibiotic, is usually used. One example of a useful intensive regimen is prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide (ProMace) coupled with cytarabine, bleomycin, vincristine, methotrexate with leucovorin rescue (CytaBOM) with or without local radiation.

• Approximately 50 percent of patients may have a complete remission. The median overall survival is approximately 12 months but the 5-year free-survival was as high as 25 percent in some studies.

• High-dose chemotherapy with autologous stem cell rescue has been useful, occasionally.

• There is limited experience with allogeneic hematopoietic stem cell transplantation.

Enteropathic-Associated T-cell Lymphoma

• Accounts for less than 1 percent of lymphomas but for 25 percent of all intestinal lymphomas.

• Often preceded by gluten-sensitive enteropathy (celiac disease). Therefore, prevalent in geographic regions in which celiac disease is prevalent (Northern Europe) but can occur, sporadically, worldwide.

• A disease of adults. Median age at diagnosis 55 years. Male:female ratio is 3:1.

• Relapse while on a gluten-free diet may precede onset of lymphoma in patients with preceding celiac disease.

• Lymphoma is confined to the jejunum and ileum with invasion of the mucosa by interepithelial neoplastic T cells. Macroscopically, lesions appear as raised mucosal masses with ulcerations. May appear as a solitary mass.

• A preceding history of celiac disease may be described but is not invariable. Weight loss, small bowel diarrhea (steatorrhea), nausea and vomiting are usual, either as a result of the relapse of celiac disease or the malabsorptive effects of the infiltrating small bowel lymphoma.

• The diagnosis is usually made by histologic examination of the resected or biopsied portion of small bowel.

• Therapy is difficult because of the associated enteropathy. Many patients put on a multidrug lymphoma regimen cannot complete therapy.

• Complications while on therapy are common. These include gastrointestinal bleeding, small bowel perforation, and enterocolonic fistulae.

• Some patients may require enteral or parenteral feeding during therapy.

• A very good response in some studies has occurred in 35 percent of patients; but, relapse occurs at a median interval of 6 months and the 5-year relapse-free survival is under 20 percent.

• Most patients die either of complications of therapy or disease progression.

Hepatosplenic T-Cell Lymphoma

• Represents less than 1 percent of lymphomas.

• One-fifth of cases arise on background of immunodeficiency (e.g., immunosuppressive therapy for solid organ transplantation).

• The neoplastic cells are CD3+CD56+CD4–CD8– T-cells.

• T cells express γδ receptor chains and clonal rearrangement of the T-cell receptor δ-chain is present. Granzyme M is expressed but usually not granzyme B or perforin.

• The typical patient is a young male (median age 35 years) who presents with prominent splenomegaly and hepatomegaly without lymphadenopathy.

• Fever, night sweats, weight loss, and cytopenias (marked thrombocytopenia, leukopenia, anemia) as a result of marrow involvement are very common.

• An elevated serum lactic acid dehydrogenase is common.

• The most common cytogenetic abnormality in the lymphoma cells is isochromosome 7 (i(7)(q10) with trisomy 8. The i(7) is so common it may be a marker for this disease and the genetic effects responsible for the phenotype.

• Intensive multidrug therapy fails in most cases. Complete remissions occur in approximately 5 percent of patients with anthracycline antibiotic–containing regimens. Responses are usually short-lived. The median survival is 8 months.

• Allogeneic hematopoietic stem cell transplantation has been used uncommonly but some success has been reported.

Subcutaneous Panniculitis-Like T-Cell Lymphoma

• A very uncommon form of lymphoma occurring in less than 1 percent of cases.

• The median age of presentation is 30 years and 20 percent of cases are under age 20 years.

• About one-fifth of patients have an associated autoimmune disease, usually disseminated lupus erythematosus.

• Most common presentation is that of multiple, painful subcutaneous nodules on the trunk and extremities without other apparent sites of involvement. The nodules may range from 0.5 to several centimeters in diameter and may become necrotic.

• The lesions may regress, only to reappear later.

• Fever, night sweats, and weight loss is present in 50 percent of patients. Cytopenias may be present at diagnosis.

• The hemophagocytic syndrome may accompany this lymphoma in as many as 20 percent of patients.

• The cells have a mature αβ T-cell phenotype and usually are CD8+ and express granzyme B, and perforin.

• Dissemination to lymph nodes is very unusual.

• The 5-year survival is approximately 80 percent. However, onset of the hemophagocytic syndrome is a very bad prognostic sign.

• Multidrug lymphoma therapy has been the mainstay of treatment but studies indicate less intensive regimens (e.g., chlorambucil, prednisone, cyclosporine) may be as useful.

• A distinction from cutaneous γδ T-cell lymphoma is important because the latter does not have as favorable a prognosis.

• Blood eosinophilia of >1 × 10⁹/L occurs in approximately 20 percent of T-cell lymphomas and about 20 percent of patients with the hypereosinophilic syndrome have a clonal T-cell expansion as the underlying cause.

• The neoplastic T-cells secrete IL-5, the principal eosinophilopoietin. Intratumoral IL-5 elaboration is closely correlated with blood eosinophilia.

• The clonal expansion of T cells, manifest principally by blood hypereosinophilia progress to overt and progressive T-cell lymphoma in >25 percent of patients over 10 years of observation.