Indolent and Aggressive Mature T-Cell and Natural Killer–Cell Lymphomas

Overview and Incidence

T-cell prolymphocytic leukemia (T-PLL) is an aggressive, mature T-cell malignancy affecting predominantly older adults and accounts for 2% of chronic leukemias. There is an approximate 3:1 male predominance. Patients with ataxia telangiectasia show an increased incidence of T-PLL.

Etiology and Histopathology

The peripheral blood and bone marrow demonstrate a proliferation of small- to medium-sized lymphocytes, with round to oval nuclei, mature chromatin, characteristic blebbing of the cytoplasm, and usually a prominent nucleolus, although in a minor subset of cases the nucleoli may not be visible (small cell variant) ( Fig. 13.1 ). ^, The bone marrow typically shows effacement with variable reticulin fibrosis. The liver, spleen, and lymph nodes can additionally be involved. The neoplastic cells are positive for most T-cell markers, including CD2, CD3, CD5, and CD7. The CD4 ⁺ /CD8 ⁻ immunophenotype is present in 60% of cases, the CD4 ⁺ /CD8 ⁺ in 25%, and the remaining 15% are CD4 ⁻ /CD8 ⁺ . CD52 is frequently expressed and is a targetable antigen.

A recurrent cytogenetic abnormality involving chromosome 14 can be detected in almost 75% of T-PLL cases, more commonly inv(14)(q11q32) and less commonly t(14;14)(q11q32), both of which juxtapose the TRA locus with the TCL1A and TCL1B oncogenes. This leads to overexpression of TCL1 , which can be detected by immunohistochemistry, aiding in the diagnosis. Mutations in genes involved in the JAK/STAT pathway are frequent ( JAK1, JAK3, STAT5B ).

Clinical Features

Patients are often asymptomatic but can present with hepatosplenomegaly, lymphadenopathy, and circulating disease with associated cytopenias. Cutaneous involvement and pleural effusions can be seen on occasion. The clinical course is typically very aggressive, with poor response to conventional chemotherapy and median survival of 1 to 2 years. ^,

Diagnostic Studies

Examination of the peripheral blood is a key diagnostic test, and flow cytometry (FC) is often helpful in establishing the immunophenotype. T-cell leukemia/lymphoma 1 (TCL1) oncoprotein overexpression and demonstration of inv(14)(q11q32) or t(14;14)(q11q32) can also be used to support the diagnosis.

Current Clinical and Radiologic Staging

T-PLL does not have a formal staging scheme.

Overview and Incidence

T-cell large granular lymphocytic (T-LGL) leukemia accounts for 2% to 6% of chronic lymphoproliferative disorders, characterized by a persistent increase in large granular lymphocytes (LGLs) that are clonal and not attributable to a secondary identifiable cause. It is a disease of older adults, with a median age of 60 years. ^,

Etiology and Histopathology

The pathogenesis of T-LGL leukemia is not entirely clear, although there is some thought that it may arise as the result of chronic antigenic stimulation, because it is associated with autoimmune diseases, in particular rheumatoid arthritis. T-LGL leukemia is characterized by increased circulating peripheral blood neoplastic LGLs (usually 2–20 ×10 ⁹ /L), which show similar morphologic features as reactive LGLs (enlarged nuclei with mature chromatin, abundant pale cytoplasm, with azurophilic granules) ( Fig. 13.2 ). The bone marrow and spleen can also be involved classically in a sinusoidal pattern ( Fig. 13.2 ). T-LGL leukemia typically shows a cytotoxic T-cell immunophenotype, with expression of CD2, CD3, CD8, CD16, and CD57, and α-β T-cell receptor (TCR). Rarely, CD4 ⁺ or γ-δ TCR variants are seen. CD5 and CD7 partial or complete loss can be seen, and CD56 expression is uncommon. Although no recurrent cytogenetic abnormality has been identified, the majority of cases demonstrate activating mutations in STAT3 and a subset show activating mutations in STAT5B .

Clinical Course

T-LGL leukemia often presents with peripheral blood lymphocytosis and can cause splenomegaly, although a significant percentage of patients are asymptomatic, and their disease is discovered incidentally. Patients can present with neutropenia and associated bacterial infections. Patients who are asymptomatic and without significant disease-related cytopenias may not require treatment at diagnosis. The majority of cases show an indolent course, with 5-year survival noted at 89% according to a large French study.

Diagnostic Studies

Most frequently, T-LGL leukemia is diagnosed on a peripheral blood smear, showing persistent large granular lymphocytosis. FC and TCR clonality studies are often used to aid in the diagnosis. Some caveats: although technically a T-LGL count of less than 2 × 10 ⁹ /L could be diagnosed according to current criteria as T-LGL leukemia (provided other parameters are met), it is controversial whether these cases truly represent a malignancy. Furthermore, it is important to bear in mind that clonal expansions of T-LGLs can be seen in the setting of bone marrow transplants or in association with other malignancies, and it is only when other causes are excluded that a diagnosis of T-LGL leukemia can confidently be made.

Current Clinical and Radiologic Staging

No formal staging system is used for T-LGL leukemia.

Overview and Incidence

Aggressive natural killer–cell leukemia (ANKL) is an exceptionally rare neoplasm of mature natural killer (NK) cells. The majority of cases have been reported in East Asia, Central America, and South America in young to middle-aged adults, with two peaks: one in the third and the other in the fifth decade of life. There is no definite sex predilection. ^,

Etiology and Histopathology

The pathophysiology of this disease remains elusive; however, there is a strong association with Epstein-Barr virus (EBV), supportive of a critical role in its development. Morphologically, the peripheral blood and bone marrow (and often the liver and spleen) show involvement by an atypical mononuclear cell infiltrate, which can show variable morphology. Cells generally show a moderate amount of cytoplasm with sparse, variably prominent granules, and the nuclear features can range from mature (resembling large granular lymphocytes) to blastic (with some cases morphologically indistinct from acute myeloid leukemia) ( Fig. 13.3 ). Nucleoli are variably prominent. The degree of bone marrow involvement and burden of circulating disease are also highly variable. The bone marrow is typically involved in an interstitial pattern and can be associated with necrosis. There is a high association with hemophagocytosis, in which the macrophages may obscure the ANKL.

The neoplastic cells in ANKL are positive for CD2, CD3 (cytoplasmic, but not surface), CD56, T-cell intracellular antigen 1 (TIA-1), and EBER by in situ hybridization. CD5 is typically negative and CD16 is frequently positive. The morphology and immunophenotype can be similar to that of extranodal NK/T-cell lymphoma (NKTCL), nasal type; however, NKTCL affects older patients and primarily the nasal cavity and nasopharynx and is typically CD16 negative. ^,

Clinical Course

Patients typically present with systemic symptoms (fever, malaise, night sweats, weight loss), hepatosplenomegaly, lymphadenopathy, and circulating disease. The clinical course is highly aggressive and is often complicated by disseminated intravascular coagulopathy, multiorgan failure, and hemophagocytic lymphohistiocytosis. Durable remissions are rare. There is no standard of care for treatment of this disease. Rarely, ANKL can evolve from a long-standing chronic lymphoproliferative disorder of NK cells and can be EBV ⁻ .

Diagnostic Studies

Examination of the peripheral blood and/or bone marrow is typically used for diagnosis. Immunohistochemistry (with EBER in situ hybridization) and FC can be quite useful in identifying subtle infiltrates.

Current Clinical and Radiologic Staging

There is currently no formal clinical staging scheme for ANKL.

Overview and Incidence

Chronic lymphoproliferative disorder of NK cells (CLPD-NKs) is defined as a sustained increased in peripheral blood mature NK cells of 2 × 10 ⁹ /L or more for longer than 6 months without a clear cause (i.e., reactive etiologies must be excluded). This is a rare entity, which typically affects older adults (median age 60 years). There is no known sex predilection.

Etiology and Histopathology

Unlike many other NK cell disorders, CLPD-NKs is not associated with EBV. There is some speculation that NK cell activation via chronic infection plays a role, but this is not confirmed. The blood and bone marrow are involved by a population of large granular lymphocytes with enlarged nuclei, mature chromatin, moderate to abundant pale cytoplasm, and azurophilic granules ( Fig. 13.4 ). Although these features resemble T-LGL leukemia morphologically, the immunophenotype is that of a mature NK cell, with expression of cytoplasmic CD3, but not surface CD3, CD16, CD56 (often dim), CD2, TIA-1, and granzyme. CD2, CD5, CD7, and CD57 are often dim or absent. ^, Aggressive NK cell leukemia may also be in the differential diagnosis. However, CLPD-NK is not associated with EBV; the clinical features differ between these two entities. Clonality can be demonstrated by restricted expression of killer cell immunoglobulin-like receptors (KIRs); however, in some cases of CLPD-NK, restricted KIR expression is absent. In recent years activating STAT3 and STAT5B mutations have been identified in this neoplasm.

Clinical Course

Many patients are asymptomatic and are incidentally diagnosed by an abnormal routine complete blood cell count (CBC). Others present with symptoms related to cytopenias. Hepatosplenomegaly and lymphadenopathy are rare. The natural history is indolent in most cases, with no treatment necessary, although transformation to an aggressive NK disorder can be seen.

Diagnostic Studies

An abnormal increase in circulating mature NK cells can generally be demonstrated through morphologic and immunophenotypic evaluation of the peripheral blood by FC. This finding, in the appropriate clinical setting, is diagnostic of CLPD-NKs. KIR studies can be pursued to establish clonality, which may be helpful in establishing the diagnosis. Of note, bone marrow involvement may be subtle, and staining for CD3 and TIA-1 prove helpful in identifying focal infiltrates.

Current Clinical and Radiologic Staging

No formal staging system is used for CLPD-NKs.

Overview and Incidence

Adult T-cell leukemia/lymphoma (ATLL) is an uncommon mature helper T-cell malignancy causally linked to human T-cell leukemia virus (HTLV)-1. As such, it is largely restricted to endemic HTLV-1 areas, including central Africa, southwestern Japan, Iran, and the Caribbean basin. Owing to a long latency period after infection, ATLL is a disease of adults.

Etiology and Histopathology

A postthymic helper T-cell infected with HTLV-1 expresses the viral protein p40 tax, which has various downstream cellular functions transcription of genes that mediate proliferation and resistance to apoptosis (including activation of nuclear factor-κB (NF-κB), Akt signaling, and cyclin-dependent kinases, and silence of p53 functions). In additional, the HTLV-1 basic leucine zipper factor (HBZ) is thought to play a role in maintenance of T-cell proliferation and oncogenesis after the initiating events.

ATLL is characterized by blood and bone marrow involvement by a population of atypical lymphocytes with morphology that can be quite variable ( Fig. 13.5 ). The neoplastic cells can range in size from small to large and can show blastic or mature chromatin. The prototypical ATLL cell is medium to large, shows mature chromatin, and a distinctive nuclear lobation, sometimes referred to as a “flower cell.” The neoplastic cells typically show a helper T-cell immunophenotype, with expression of CD4, although rarely CD4 ⁻ /CD8 ⁺ , CD4 ⁺ /CD8 ⁺ , and CD4 ⁻ /CD8 ⁻ variants have been described. CD2, CD3, and CD5 are typically retained, but loss of CD7 is common and associated with poor prognosis. ^, CD25 is strongly expressed in virtually all cases.

Clinical Course

ATLL can be subdivided into multiple forms: smoldering, chronic, lymphomatous, and acute (leukemic). The smoldering form is defined by more than 5% abnormal T-cell lymphocytes in the peripheral blood, in the setting of a normal lymphocyte count, lactate dehydrogenase (LDH), calcium, and absence of lymphadenopathy, hepatosplenomegaly, and bone marrow infiltration. The chronic form is similar to the smoldering form except it can be associated with lymphocytosis, slightly increased LDH, and mild hepatosplenomegaly and lymphadenopathy. The lymphomatous form presents with diffuse involvement of the lymph nodes. The acute (leukemic) form presents with constitutional symptoms (fever, weight loss), as well as elevated LDH, hypercalcemia, and lytic bone lesions. Multiple organs may be involved, and hepatosplenomegaly and bone marrow infiltration are common. Of these, the lymphomatous and acute leukemic forms are typically aggressive, with a median overall survival of less than 1 year. By comparison, the chronic and smoldering forms have a more indolent clinical course, but they can also progress to a more aggressive form in a subset of patients.

Diagnostic Studies

A careful clinical history demonstrating HTLV-1 exposure or demonstration of positive HTLV-1 serology in conjunction with evaluation of the peripheral blood, bone marrow, and lymph nodes with ancillary testing (FC immunophenotyping, immunohistochemistry) can lead to the diagnosis of ATLL.

Current Clinical and Radiologic Staging

There is no formal staging scheme for ATLL; however, the four clinical variants of ATLL (see previous section) can provide significant prognostic information.

Overview and Incidence

Mycosis fungoides (MF) and Sézary syndrome (SS) are variant presentations of a peripheral T-cell lymphoma. MF primarily involves the skin, whereas SS is defined by a triad of erythroderma, diffuse lymphadenopathy, and circulating disease. MF is the most common type of cutaneous T-cell lymphoma, affecting primarily adults and the elderly, and accounts for 50% of all cases of primary cutaneous lymphoma.