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

n Cells may resemble Reed-Sternberg cells

n May show sinusoidal pattern

n Common, lymphohistiocytic, and small cell variants recognized

n Immunophenotype

n CD30+ on cell membrane and in Golgi region

n ALK expression in 60-85% of cases; nuclear and/or cytoplasmic staining (very specific for ALCL)

n EMA+

n Usually express one or more T-cell antigens, but antigen loss may result in “null” phenotype

n Express cytotoxic associated proteins

n Genetics

n 90% show clonally rearranged TCR

n t(2:5) or variants involving the ALK gene

nPrognosis and Predictive Factors

ALK+ have better prognosis

5-year survival 80%

Relapses in 30% of cases

ALK- worse prognosis

5-year survival 40%

Blastic NK-cell Lymphoma

· Composed of cells with a lymphoblast-like morphology and evidence of commitment to the NK lineage

· Epidemiology

o Rare

o All ages; most pt’s are middle-aged or elderly

· Sites of Involvement and clinical features

o Tends to involve multiple sites, with a predilection for skin

o LN, soft tissue, PB or BM can also be involved

o Rarely, nasal cavity is the primary site

· Etiology

o Unknown

o Not related to EBV

· Morphology

o Diffuse monotonous infiltrate of medium-sized cells with fine chromatin, resembling lymphoblastic or myeloblastic leukemia

o A single-file pattern of infiltration can be identified in areas

o Uncommon to find coagulative necrosis and angiocentric infiltrate

o Tumor cell rosettes resembling Homer-Wright rosettes can be formed

o In Giemsa touch preps, azurophilic granules may or may not be found

· Immunophenotype

o Negative for surface CD3

o Positive for CD56

o CD4 and CD43 usually expressed

o CD2, CD7, cCD3ε, and cytotoxic molecules is variable, but usually negative

o Some cases TdT and/or CD34 positive

o The dx of blastic NK-cell lymphoma should only be made in the absence of commitment to the T-cell or myeloid lineages; thus, the neoplastic cells should be negative for surface CD3, MPO, and CD33, and the dx supported by absence of TCR rearrangement

· Prognosis and predictive factors

o Clinical course is aggressive with a poor response to regimens used for non-Hodgkin lymphomas

o Partial responses to “acute leukemia-like” regimens have been seen in rare cases

o Cases with localized skin lesions have a better prognosis

Mycosis Fungoides / Sezary Syndrome

n Mature T-cell lymphoma

n Rare (0.3 per 100,000 annual incidence)

n Most common subtype of T-cell lymphomas that arise primarily in skin

n Adults/elderly

n Male:Female = 2:1

n Presents in the skin with limited patches and/or plaques, frequently on the trunk

n Long natural history

n Usually progress to more generalized disease and to tumors

n Rare patients develop erythroderma and/or Sezary syndrome

n Epidermotropic infiltration of small to medium-sized T-cells with cerebriform nuclei

n Pautrier microabcesses sometimes seen

n Epidermal involvement with single cell exocytosis more common

n Dermal infiltrate may be bandlike, patchy or diffuse

n Grading of lymph node involvement in MF

n Category I – dermatopathic lymphadenopathy, no MF

n Category II – focal involvement by MF

n Category III – complete replacement by MF

n Immunophenotype

n CD2+, CD3+,TCRβ+, CD5+, CD4+, CD8-, CD7-

n Cytotoxic granule associated proteins not expressed

n Genetics

n T-cell receptor genes clonally rearranged

n Complex karyotypes may be seen

nMycosis Fungoides Variants

n Pagetoid reticulosis

Infiltrates strictly epidermal

Localized (Woringer-Kolopp disease)

Multiple (Ketron-Goodman disease)

Localized has excellent prognosis

Often CD30 positive

May be CD8+ or CD4+ or negative for both

n Mycosis fungoides-associated follicular mucinosis

Follicular, rather than epidermal, infiltrate

Mucinous degeneration of the hair follicles

Preferentially involves head and neck

Indolent course

n Granulomatous slack skin disease

May be seen with other types of lymphoma (e.g., Hodgkin) and may be separate entity

Slowly developing folds of atrophic skin

Preferentially involves axillae or groin

Granulomatous infiltrate with atypical T lymphocytes, macrophages, multinucleated giant cells

Elastophagocytosis

nClinical Course:

Most important factor is clinical stage

Patients with limited disease have nearly normal survival

Adverse prognostic findings:

Advanced stage

Skin tumors and/or extracutaneous spread

Age over 60 years

Elevated LDH

Transformation to large cell lymphoma

Primary Cutaneous Anaplastic Large Cell Lymphoma

n T-cell lymphoma with anaplastic morphology and CD30 positivity

n Limited to skin at time of diagnosis by careful staging

n Clinically important to distinguish from secondary skin involvement by other types of lymphoma

n Represents 25% of primary cutaneous T-cell lymphomas

n Predominantly seen in adults/elderly, rarely in children

n Male:Female = 1.5-2.0:1

n Solitary or localized skin lesions

n Tumors

n Nodules

n Papules (rarely)

n Multicentric cutaneous disease in 20%

n May partially or completely regress; cutaneous relapses frequent

n Extracutaneous dissemination in 10%

n Cytologic features similar to systemic ALCL

n Pleomorphic, multinucleated giant cells and R-S-like cells often more numerous

n Infiltrates diffuse, involving upper and deep dermis and subcutaneous tissue

n Epidermal invasion and ulceration may be seen, but epidermotropism less common

n Modest inflammatory background

n Immunophenotype

n T-cell antigens, usually CD4+

n CD30+ in majority of cells (>75%)

n Cytotoxic proteins in 70% of cases

n Variable loss of CD2, CD5, and/or CD3

n Usually negative for ALK and EMA

n Genetics

n TCR genes rearranged clonally in most

n t(2;5) not found

nClinical Course

Favorable for disease limited to skin – 90% survival rate at 5 years

Presence of extracutaneous disease is unfavorable indicator

Skin-directed therapy (radiotherapy or surgery) in limited disease

Multi-agent chemotherapy reserved for cases with extracutaneous disease

Lymphomatoid Papulosis

n Chronic, recurrent skin disease characterized by the appearance of spontaneously regressing (3-6 weeks) papules and an atypical T-cell infiltrate which can mimic T-cell lymphoma histologically

n Usually has a benign course, but lesions often recur

n Can be clonal and progresses to lymphoma in some cases

n Rare disease

n Predominantly affects adults/elderly

n Male:Female = 1.5:1

n Limited to skin

n Morphology

Wedge-shaped, dermal infiltrates consisting of atypical T lymphocytes admixed with
varying proportions of inflammatory cells (neutrophils, eosinophils, macrophages,
small lymphs)

T cells may resemble MF or RS-like cells

Type A: many RS-like cells and inflammatory cells

Type B: predominance of cells with cerebriform nuclei, only a few inflammatory cells

Both types may exist in individual patients

n Immunophenotype

n CD4+, CD8-

n Variable loss of pan-T-cell antigens

n CD30 positive in Type A lesions

n ALK negative

n Cytotoxic granules usually expressed

n Genetics

n Clonally rearranged TCR genes in about 50% of patients: most Type B lesions and some Type A lesions

n t(2;5) absent

n Clinical course: mostly benign course of long duration (years) with relapsing and
remitting lesions

n Treatment reserved for patients with large, numerous and/or scarring skin lesions

n Low-dose methotrexate and psoralen/UVA (PUVA)

n Lymphoma develops in 10-20% of patients

n MF

n C-ALCL

n Hodgkin lymphoma

n No known criteria to predict which patients will progress

Subcutaneous Panniculitis-like T-cell Lymphoma

n Lymphoma of cytotoxic T cells which preferentially infiltrates subcutaneous tissue

n Less than 1% of all non-Hodgkin lymphomas

n M:F = 1:1

n Multiple subcutaneous nodules of varying size, usually on extremities and trunk

n May have hemophagocytic syndrome with pancytopenia, fever, and hepatosplenomegaly

n Lymphadenopathy usually absent

n Neoplastic cells infiltrate diffusely through the subcutaneous tissue without sparing septae

n Overlying dermis and epidermis are typically uninvolved (except in gamma delta T-cell cases)

n Cells vary in size, may rim around fat cells

n Necrosis and karyorrhexis are common

n Immunophenotype

n Positive for cytotoxic granules

n Most derived from αβ cells, but 25% are from γδ cells

o αβ cases are usually CD8+

o γδ cases are usually CD4-, CD8-, CD56+

nGenetics: TCR genes rearranged

nClinical Course

Dissemination to lymph nodes and other organs uncommon, usually late in the clinical
course

Natural history aggressive, but often responds to combination chemotherapy

Hemophagocytic syndrome is frequent and usually precipitates downhill course

Intestinal / Enteropathy T-cell Lymphoma

n Tumor of intraepithelial T-lymphocytes

n Usually occurs in the jejunum or ileum

n Some patients have (or have history of) celiac disease

n Patients present with abdominal pain, often associated with intestinal perforation

n NK/T-cell lymphoma, nasal type, is in differential diagnosis

n Morphology

Usually presents with multiple ulcerating raised mucosal masses

May also present as one or more ulcers or as a large exophytic mass

Infiltrates intestinal wall with wide range of cytomorphology, usually medium-sized to
large monomorphic cells

May show marked pleopmorphism

Inflammatory cells (histiocytes & eos)

n Immunophenotype

n CD3+, CD5-, CD7+, CD8-/+, CD4-, CD103+

n Positive for cytotoxic proteins

n Varying number of CD30+ cells

n Subset of small to medium-sized cells is usually CD8+ and CD56+

n Genetics

n HLA DQA1*0501, DQB1*0201 genotype seen in celiac disease

n TCR β and γ genes clonally rearranged

n Clinical Course

Usually poor prognosis, but long term survivals recorded

Recurrences frequent in the small intestine

Death usually from abdominal complications

Hepatosplenic T-cell Lymphoma

n Extranodal and systemic lymphoma usually of cytotoxic T-cells of the γδ type

n Marked sinusoidal infiltration seen in the spleen, liver and bone marrow

n Patients present with marked hepatosplenomegaly but no lymphadenopathy

n Bone marrow nearly always involved

n More common in immunosuppressed pts

n Immunophenotype

n CD3+, CD4-, CD8-, CD5-

n TCRδ1+, TCRαβ-

n Positive for cytotoxic protein TIA-1, usually negative for perforin

n Minority of cases αβtype, considered a variant of the more common γδ form

n Genetics

n TCR γ gene rearrangement

n Isochromosome 7q in all cases studied

n Sometimes other abnormalities such as trisomy 8

Extranodal NK/T-cell Lymphoma, Nasal Type

n Predominantly extranodal lymphoma with broad morphologic spectrum

n Nasal cavity most common site, but may occur anywhere

n More prevalent in Asia, Mexico and Central and South America

n M>F

n May occur in immunosuppressed and post-transplant patients

n Present with nasal obstruction or epistaxis due to mass lesion or extensive mid-facial destructive lesions

n Variable presentation outside nasal cavity, e.g., skin ulceration, intestinal perforation

n May disseminate rapidly

n May have associated hemophagocytic syndrome

n May overlap with aggressive NK cell leukemia

n Mucosal sites show extensive ulceration

n Diffuse infiltrate

n Angiocentric and angiodestructive pattern common with fibrinoid changes in vessels

n Coagulative necrosis and apoptotic bodies

n Cytologic spectrum broad from small to large anaplastic cells

n Immunophenotype

n CD2+, CD56+, sCD3-, cCD3+

n Positive for cytotoxic proteins

n Positive for EBV

n Other T-cell and NK-cell antigens negative

n Genetics: Usually TCR and Ig genes germline