Chapter 7-Mature T-Cell and NK-Cell Neoplasms

Classes of T Cells

n αβ T cells

n Two major subtypes: CD4+ (helper) and CD8+ (cytotoxic) T cells

n CD4+ T cells are mainly cytokine-secreting cells

o Th1 cells secrete Il-2 and interferon γ and provide help mainly to other T cells and macrophages

o Th2 cells secrete Il-4, 5, 6 and 10 and provide help to B cells in their production of antibodies

n γδ T cells

n Negative for both CD4 and CD8

n Comprise <5% of normal T cells and found mainly in the splenic red pulp, intestinal epithelium, and other epithelial sites.

T-Cell and NK-Cell Leukemia/Lymphoma

n Much less common than B cell lymphomas

n Significant variations in incidence in different geographical regions and racial populations

n More common in Asia

n HTLV-1 main risk factor in Japan and Caribbean

n Only about 11-12% of lymphomas overall (not including areas endemic for HTLV-1)

n T-Cell and NK-Cell Leukemia/Lymphoma

n Clinical features are very important in the diagnosis and classification of T and NK cell malignancies.

n No convenient immunophenotypic marker of clonality

n No specific antigenic profiles associated with most T cell lymphoma subtypes

n Antigen expression may not be specific (e.g., CD30 which is seen universally in T cell anaplastic large cell lymphoma, but may also be seen in other T cell lymphomas, some B cell lymphomas, and Hodgkin lymphoma)

n Many of the clinical manifestations of T cell lymphomas can be related to cytokine expression by the neoplastic cells.

n Hypercalcemia associated with Adult T Cell Leukemia/Lymphoma (ATLL) has been linked to secretion of factors with osteoclast-activation activity

n Hemophagocytic syndrome seen in T cell and NK cell malignancies has been associated with secretion of cytokines and chemokines.

n NK cells and cytotoxic T cells express cytotoxic proteins:

Perforin

Granzyme B

T-cell intracellular antigen (TIA-1)

NK cells

n Share some functions with cytotoxic T cells

n Share some markers with cytotoxic T cells:

n CD2, CD7, CD8, CD56 and CD57 positive

n Often positive for the epsilon chain of CD3

n Also usually positive for CD16

Types of mature T-Cell and NK cell neoplasms

n Leukemic/disseminated
T-cell prolymphocytic leukemia

T-cell large granular lymphocytic leukemia

Adult T-cell leukemia/lymphoma

n Nodal

Peripheral T-cell lymphoma, unspecified

Angioimmunoblastic T-cell lymphoma

Anaplastic large cell lymphoma

n Extranodal

Cutaneous
Mycosis fungoides/Sezary syndrome

Primary cutaneous CD30+ lymphoproliferative disorders, including

: Primary cutaneous anaplastic large cell lymphoma (C-ALCL)

Lymphomatoid papulosis

Borderline lesions

Subcutaneous panniculitis-like T-cell lymphoma

Non-cutaneous

Intestinal/Enteropathy-type T-cell lymphoma

Hepatosplenic T-cell lymphoma

Nasal type NK/T cell lymphoma

T-Cell Prolymphocytic Leukemia

n Relatively rare; ~2% of cases of SLL in adults >30 years

n Leukemic cells in the blood, bone marrow, lymph nodes, spleen, liver, skin

n Hepatosplenomegaly, generalized lymphadenopathy, skin infiltration in 20%

n Very high lymphocyte count, usually >100 x 10⁹/L; anemia and thrombocytopenia

n Serology for HTLV-1 negative

n Progressive clinical course; <1 year survival

n Small to medium-sized lymphoid cells

n Non-granular basophilic cytoplasm

n Round, oval or markedly irregular nuclei and a visible nucleolus

n May have cytoplasmic protrusions or blebs

n Nuclear outline may be very irregular, raising the possibility of ATLL (ruled out by HTLV-1 negativity) or Sezary syndrome (ruled out by clinical history and skin biopsy)

n Bone marrow diffusely infiltrated

n If skin is involved, there are dense dermal infiltrates, often around appendages, but without epidermotropism

n Immunophenotype

Mature T cell: CD2+, CD3+, CD7+

Negative for TdT and CD1a

60% CD4+, CD8-

25% CD4+, CD8+

15% CD4-, CD8+

n Cytogenetics: 80% with inversion of chromosome 14

T-Cell Large Granular Lymphocytic Leukemia

n Uncommon: 2-3% of cases of small lymphocytic leukemia

n Involves peripheral blood, bone marrow, liver and spleen; usually not lymph nodes.

n Most cases are indolent

n Severe neutropenia, with or without anemia. May have red cell hypoplasia due to cytokine production.

n Lymphocytosis usually not marked, 2,000-20,000.

n Moderate splenomegaly is the main physical finding.

n Rheumatoid arthritis, autoantibodies, circulating immune complexes and hypergammaglobulinemia are also common.

n Large granular lymphocytes with abundant cytoplasm and fine or coarse azurophilic granules

n Granules contain proteins involved in cytolysis such as perforin and granzyme B

n Bone marrow involvement is variable

n Can be divided into groups based on the predominant cell markers:

n Common variant (80% of cases)

o CD3+, TCRαβ+, CD4-, CD8+

n Rare variants

o CD3+, TCRαβ+, CD4+, CD8-

o CD3+, TCRαβ+, CD4+, and CD8+

o CD3+, TCRγδ+

n CD11b, CD56 and CD57 are variably expressed; CD57 is often expressed in the common type

n TIA-1 is usually positive

n Prognosis

May be indolent and nonprogressive, raising the possibility of a reactive
lymphocytosis which may be clonal in some circumstances.

Morbidity is associated with neutropenia, but usually not mortality

May progress to a more aggressive disease with transformation to a PTCL of large
cells

Aggressive N-K Cell Leukemia

· A systemic proliferation of NK cells

· Aggressive clinical course

· Epidemiology

o Rare

o More prevalent among Asians than Whites

o Mostly teenagers and young adults

o Slight male predominance

· Sites of Involvement

o Most common

§ PB, BM, liver and spleen

· Clinical Features

o Usually present with fever, constitutional symptoms, and a leukemic blood picture

o Number of circulating leukemic cells low or high (a few % to >80% of all leukocytes)

o Anemia, neutropenia, thrombocytopenia common

o Hepatosplenomegaly common, LAD sometimes

o Skin lesions uncommon

o Dx may be complicated y coagulopathy, HPS, or MOF (serum Fas ligand often markedly elevated)

· Etiology

o Little known

o Strong association with EBV

· Morphology

o Slightly larger than normal LGL

o Some contain irregular, hyperchromatic nuclei

o Nucleoli inconspicuous or distinct

o Ample amount of pale or lightly basophilic cytoplasm containing fine or course azurophilic granules

o BM shows massive, focal, or subtle infiltration with reactive histiocytes with hemophagocytosis

o In tissue sections, often monotonous, with round or irregular nuclei, condensed chromatin and small nucleoli; frequent admixed apoptotic bodies; necrosis common

· Immunophenotype

o CD2+, surface CD3-, CD3ε+, CD56+, and positive for cytotoxic molecules

o CD11b and CD16 may be expressed; CD57 usually negative

· Prognosis and predictive factors

o Most cases result in fatal outcome in 1 to 2 yrs

o Many pts die within days to weeks of initial presentation

Adult T-Cell Leukemia/Lymphoma

n Endemic in several regions: Japan, Caribbean basin, parts of Central Africa

n Sporadic in US and elsewhere

n Caused by HTLV-1

n Long latency; exposure to virus early in life

n Adults; median age 55 years; male to female ratio 1.5:1

n Widespread lymph node involvement

n Peripheral blood involvement

n Skin common site (>50%)

n Systemic with involvement of spleen, skin, lung, liver, GI tract, CNS

n Clinical Variants: Acute, Lymphomatous, Chronic, Smoldering

Acute variant

n Systemic illness with constitutional symptoms

n Leukemic phase with very high WBC count

n Skin rash

n Generalized lymphadenopathy and hepatosplenomegaly

n Hypercalcemia with or without lytic bone lesions

n May have immunodeficiency with infections

n In addition to acute variant, other clinical variants include:

Lymphomatous variant

n Prominent lymphadenopathy without PB involvement

n Advanced stage

n Hypercalcemia less often seen

Chronic variant

n Skin lesions, most commonly exfoliative rash

n Fewer atypical lymphocytes in PB

n No hypercalcemia

Smoldering variant

n WBC count normal with few atypical cells

n Skin or pulmonary lesions, but no hypercalcemia

n Long progression to acute disease in 25% of cases

Morphology

n Medium-sized to large cells with pronounced nuclear pleomorphism (polylobated “flower” cells)

n Patchy marrow infiltrates

n Osteoclastic activity may be prominent

n Skin: epidermal infiltrate with Pautrier-like microabscesses

Immunophenotype

· Express T-cell antigens: CD2, CD3, CD5

· Usually lack CD7

· Most cases: CD4-, CD8+, or double positive for CD4 and CD8

· CD25 expressed nearly all cases

· Large transformed cells may be positive for CD30, but ALK-

· TIA-1 and granzyme B negative

Prognostic factors:

n Clinical subtype

n Age

n Performance status

n Serum calcium

n LDH level

Survival:

n Acute and lymphomatous: two weeks to one year

n Chronic and smoldering: longer survival

Peripheral T-Cell Lymphoma, unspecified

n T-cell lymphomas that don’t meet the criteria for the more specific types

n About 50% of the T-cell lymphomas

n Mostly adults, but may occur in children

n Usually nodal, but may be extranodal

n Usually high stage at diagnosis

n Patients present with lymphadenopathy

n Constitutional symptoms often present

n Paraneoplastic features: eosinophilia, pruritus, hemophagocytic syndrome

n Aggressive clinical course

n Patients respond poorly to treatment

n Relapses are frequent

n Overall 5 year survival 20-30%

n Diffuse infiltration with effacement of lymph node architecture

n Broad cytologic spectrum: usually predominance of medium-sized or large cells with irregular nuclei

n Clear cells and Reed-Sternberg-like cells

n High endothelial venules increased

n Polymorphous inflammatory background

n T-zone variant

n Interfollicular growth pattern with preserved or even hyperplastic follicles

n Tumor cells predominantly small or medium-sized without nuclear pleomorphism

n Lymphoepithelial variant (Lennert lymphoma)

n Diffuse or interfollicular

n Numerous small clusters of epitheliod histiocytes

n Immunophenotype

n T-cell associated antigens (CD3, CD5, CD7)

n Often show loss of normal antigen expression

n Most nodal cases are CD4+, CD8-

n CD30 may be positive, but not cytotoxic granule associated proteins

n Some cases may express CD56, usually extranodal with cytotoxic T-cell phenotype

Genetics: TCR genes clonally rearranged in most cases

Angioimmunoblastic T-Cell Lymphoma

n Peripheral T-cell lymphoma characterized by:

n systemic disease

n polyclonal gammopathy

n polymorphous infiltrate in lymph nodes, with a prominent proliferation of high endothelial venules and follicular dendritic cells

n Occurs in middle age and elderly patients

n 15-20% of T cell lymphomas; 1-2% of NHL

n Generalized lymphadenopathy, hepatosplenomegaly, and frequent skin rash

n Bone marrow is commonly involved

n Other findings: edema, pleural effusion, arthritis, ascites

n Polyclonal gammopathy, circulating immune complexes, cold agglutinins, positive rheumatoid factor, anti-smooth muscle antibodies

n Progressive clinical course; survival <3 years

n Lymph node architecture partially effaced

n Paracortex diffusely infiltrated by polymorphous population of small to medium-sized lymphocytes, clear cells, some T-immunoblasts

n Minimal cytologic atypia

n Admixed small reactive lymphocytes, eosinophils, plasma cells, histiocytes, and increased dendritic cells

n High endothelial venules numerous

n Immunophenotype

n Mature T cells with CD4+ > CD8+ cells

n CD21+ dendritic cells

n Polyclonal plasma cells

n EBV+ B cells may be numerous

n Genetics: T-cell receptor genes rearranged in 75% of cases

Anaplastic Large Cell Lymphoma

n T-cell lymphoma composed of large atypical cells with abundant cytoplasm and pleomorphic nuclei

n About 3% of adult NHL; 10-30% of childhood NHL

n CD30 positive

n Express cytotoxic granule associated proteins

n Most cases positive for anaplastic large cell lymphoma kinase (ALK) protein

n ALK-positive ALCL most frequent in first three decades; male predominance (M:F 6.5:1)

n ALK-negative ALCL more common in older patients; M:F 0.9:1

n Frequently involves lymph nodes and extranodal sites (skin-21%, bone-17%, soft tissues-17%, lung-11%, liver-8%)

n Patients present with advanced stage; B symptoms, especially fever

n Broad morphologic spectrum but all cases contain “hallmark” cells – large or small cells with eccentric, horseshoe- or kidney-shaped nuclei