SM
Uploaded bySwetha Mulukala
PPTX, PDF1,739 views

T cell lymphomas - By Dr MULUKALA SWETHA

This document provides an overview of T-cell lymphomas, detailing their classification, clinical features, and pathophysiology. It highlights various types, including precursor T-cell neoplasms and mature T-cell neoplasms, along with diagnostic criteria and immunophenotyping characteristics. The document emphasizes the aggressive nature of these malignancies and their association with viral infections, particularly in specific populations.

Embed presentation

Downloaded 46 times
T CELL LYMPHOMAS BY: Dr. M.Swetha
CONTENTS • INTRODUCTION • PRECURSOR T-CELL NEOPLASM • MATURE T-CELL NEOPLASMS • SUMMARY
INTRODUCTION • Mature T- and Natural killer (NK)- cell malignancies are rare, accounting for 10 – 12% of all Non-Hodgkin's lymphoma. • More common in Asia and linked to EBV viral infection (NK-cell lymphomas) and human T-cell leukaemia virus (HTLV-1) (adult T-cell leukaemia/lymphoma). • More aggressive than B-cell lymphomas.
WHO CLASSIFICATION OF PRECURSOR LYMPHOID NEOPLASMS • T-Lymphoblastic leukemia/lymphoma • Early T-cell Precursor lymphoblastic leukemia • Nk-lymphoblastic leukemia/lymphoma
T-LYMPHOBLASTIC LEUKEMIA/LYMPHOMA (Precursor T-lymphoblastic leukaemia/ lymphoma) • Definition : Refers to neoplasm of immature lymphoid cells (lymphoblasts) of T-cell lineage. • Age : Most common in adolescents and young adults Median age of 28 years. • SEX: Males > Females. • Clinical findings : Widespread lymphadenopathy (neck, axillae and supraclavicular). • Mediastinal mass is common • Hepatosplenomegaly often present.
T-Lymphoblastic leukemia T-ALL T-LBL • Involving Bone marrow and Blood • 15% of childhood ALL cases • 25% of cases of adult ALL • Involving Thymus or Nodal or Extra nodal • 85–90% of all LBLs
Peripheral blood smear and Bone Marrow • Anemia • Granulocytopenia, • Lymphoblasts >25% • Thrombocytopenia
LYMPH NODE • Architecture : Effaced • Capsule & Para cortex : Involved • Pattern : Multinodular – mimicking Follicular lymphoma. Starry Sky - mimicking Burkitt lymphoma. • Lymphoblasts : Medium sized- round or Convoluted nuclei - High N: C ratio, Frequent mitotic figures.
TdT, CD34, CD1a & CD99 are positive (suggest Precursor T-lymphoblasts) CD7, CD3(cytoplasmic), CD2, CD5 (Immature markers) are often positive. CD4, CD8 & CD10 are Positive • The most common recurrent cytogenetic abnormality involves the αδ TR loci at 14q11.2. • β locus at 7q35, and the γ locus at 7p14-15, with a variety of partner genes • Deletions of (9q) CYTOGENETICS
CRITERIA FOR DIAGNOSIS 1. Frequently associated with mediastinal mass 2. Relatively uniform cell population with high mitotic rate 3. Variable number of round - convoluted (deeply indented) nuclei 4. Dense, finely granular chromatin, mostly inconspicuous nucleoli 5. Scanty, pale, fragile cytoplasm. 6. Immunophenotype: TdT, most often CD3 (cytoplasmic) and CD7; Often CD4 and CD8 double positive or double negative; variable positivity with CD1a, CD34, CD10. 7. 50-70% abnormal karyotype.
WHO CLASSIFICATION • Mycosis fungoides • Sézary syndrome • Primary cutaneous CD30+ T cell lymphoproliferative disorders • Lymphomatoid papulosis • Primary cutaneous anaplastic large cell lymphoma • Primary cutaneous gamma delta cell lymphoma • Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphoma • Primary cutaneous acral CD8+ T cell lymphoma* • Primary cutaneous CD4+ small / medium T cell lymphoproliferative disorder* • Peripheral T cell lymphoma, NOS • Angioimmunoblastic T cell lymphoma • Follicular T cell lymphoma* • Nodal peripheral T cell lymphoma with T follicular helper phenotype* • Anaplastic large cell lymphoma, ALK+ • Anaplastic large cell lymphoma, ALK-* • Breast implant associated anaplastic large cell lymphoma* MATURE T-CELL AND NK CELL NEOPLASMS • T cell prolymphocytic leukemia • T cell large granular lymphocytic leukemia • Chronic lymphoproliferative disorder of NK cells • Aggressive NK cell leukemia • Systemic Epstein-Barr virus+ T cell lymphoma of childhood* • Hydroa vacciniforme-like lymphoproliferative disorder* • Adult T cell leukemia / lymphoma • Extranodal NK / T cell lymphoma, nasal type • Enteropathy associated T cell lymphoma • Monomorphic epitheliotropic intestinal T cell lymphoma* • Indolent T cell lymphoproliferative disorder of the GI tract* • Hepatosplenic T cell lymphoma • Subcutaneous panniculitis-like T cell lymphoma
FREQUENCY OF T- cell LYMPHOMAS
NODAL T- CELL LYMPHOMAS
ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA (Lymphogranulomatosis-x) • DEFINITION: Neoplasm of Mature T follicular helper (TFH) cells characterized by Systemic disease & Lymphadenopathy with polymorphous infiltrate involving lymph nodes with prominent proliferation of high endothelial venules (HEV’s) & Follicular dendritic cells (FDC’s) • AGE : Elderly individuals. • SEX : Males > Females • LOCALIZATION : Lymph node(Primary site), Spleen, liver, skin, and bone marrow . • CLINICAL FEATURES : Generalised lymphadenopathy, hepatosplenomegaly and polyclonal hypergammaglobulinemia
PATHOGENESIS
MICROSCOPIC • Lymph node: Three most common features are 1. Diffuse pattern with Partial or complete architecture effacement. 2. Numerous arborizing blood vessels, lined by hyperplastic endothelial cells. 3. Polymorphous population of cells with a variable number of small and large size with Hyperchromatic nuclei and clear cytoplasm. 4. Numerous reactive cells including plasma cells, eosinophils, immunoblasts, small lymphocytes and follicular dendritic cells.
• Subdivided into 3 histological patterns TYPE-I • Architecture- Partially preserved and hyperplastic follicles with tingible body macrophages and indistinct mantle zones • Seen in 10-20% of cases TYPE- II • Architecture- Preserved mostly with residual follicles. • In half of the cases TYPE-III • Architecture- Completely effaced without residual follicles. • In remaining cases.
IMMUNOPHENOTYPE • T cell antigens: εCD3, CD4, CD5 and CD7. • Follicular dendritic cells: CD21, CD23, CD35 • TFH markers: CXCL13, CD10, PD1 & BCL6 • EBER (Epstein-Barr virus encoded small RNAs) • Loss of sCD3 is more common in bone marrow and peripheral blood compared to lymph nodes. • CD8 –Ve and loss of CD7 is also observed
CYTOGENETICS/MOLECULAR STUDIES • Karyotypic abnormalities in 90% of the cases. • Trisomy of chromosomes 3,5 and 21. Gain of chromosome X. • Monoclonal T-cell receptor gene rearrangements γ or β in 80%-90% of AILT cases. • Next generation sequencing panel showed TET2, DNMT3, RHOA and IDH2 mutations. DIFFERENTIAL DIAGNOSIS • Reactive lymphoid hyperplasia • Classic hodgkins lymphoma, mixed cellularity • Peripheral T cell lymphoma –NOS • EBV+ diffuse large B cell lymphoma, NOS
ANAPLASTIC LARGE – CELL LYMPHOMA-ALK POSITIVE (Malignant Histiocytosis) • Definition: A peripheral T cell lymphoma consisting of large lymphoid cells with abundant amphophilic cytoplasm, often horseshoe shaped nuclei, an ALK (anaplastic lymphoma kinase) gene translocation, expression of ALK protein (CD246) and CD30 • Constitutes 10-20% of childhood lymphomas. • Age : First 3 decades of life • SEX : M: F - 1.5 :1 • LOCALIZATION : Lymph nodes & extra nodal sites.
PATHOGENESIS • Neoplastic cells are activated mature cytotoxic T cells (CD30+) • Oncogenic translocations result in constitutive activation of the ALK tyrosine kinase • Resulting fusion proteins are shown to be involved in different downstream signalling pathways including RAS/ERK, PI3K/Akt and JAK/STAT.
MICROSCOPY • Small-medium-large anaplastic cells • Interfollicular T zones and subcapsular sinuses infiltration • Cohesive growth pattern • Intrasinusoidal infiltration pattern • Anaplastic large cells with abundant cytoplasm, wreath-like or multiple nuclei, open chromatin, multiple nucleoli, perinuclear eosinophilic region (prominent Golgi zone) • Cells with horseshoe / kidney / embryo shaped nuclei are referred to as “hallmark cells”. • Brisk mitotic activity
• Lympho histiocytic (10%) • Numerous histiocytes and small lymphocytes, occasional erythrophagocytosis • Small cell (5 - 10%) • Predominantly small cells with irregular nuclei, hallmark cells present (tend to be perivascular), occasional fried egg cells, rare signet ring cells • Hodgkin-like (1 - 3%) • Mimics nodular sclerosis classic Hodgkin lymphoma; • Hypocellular • Small cell types may have hypocellular, granulation tissue-like appearance • Composite pattern (10 - 20%) • More than one pattern. VARIANTS
IMMUNOPHENOTYPING Positive stains: • ALK1 • CD30 • CD2 • CD4 • CD5 • TIA1 • Granzyme B • Perforin Negative stains : • PAX5 • CD15 • CD20 • CD79a • EBER
CYTOGENETICS /MOLECULAR DIAGNOSIS • Clonal T cell receptor (TCR) gene rearrangement seen in 90% • All translocations result in upregulation of ALK protein • ALK translocation results in activation of the downstream oncogenic transcription factor, STAT3 • STAT3 activation regulates availability of hypoxia inducible factors involved in tumor growth and metastasis • t(2;5)(p23;q35): ALK and NPM (75 - 85%) • t(1;2)(q25;p23): tropomyosin 3 (TPM3) and ALK (13%) • inv(2)(p23;q35): ALK and ATIC (1%)
DIFFERENTIAL DIAGNOSIS • ALK –ve anaplastic large cell lymphoma • Hodgkins lymphoma • Histiocytic sarcoma
ALK NEGATIVE ANAPLASTIC LARGE CELL LYMPHOMA • Morphologically similar to ALK +ALCL but is ALK negative. • Common in Adults (40-65 years) • Sites: Both lymph nodes and extra nodal sites, including bone, soft tissue and skin • Etiology : Unknown PATHOPHYSIOLOGY: • Recurrent rearrangement involving the TP63 gene • STAT3 activating mutations • DUSP22 rearrangements
MICROSCOPY • Morphologically indistinguishable from ALCL, ALK positive • Effaced architecture with solid, cohesive sheets of neoplastic cells • May show preserved lymph node architecture with neoplastic cells growing intrasinusoidally or only within the T cell areas • Large cells with round to indented nuclei, deeply staining cytoplasm, with prominent Golgi zone • Hallmark cells (cells with eccentric, horseshoe or kidney shaped nuclei) • Cases with DUSP22 rearrangements show smaller, monomorphic cells with central nuclear pseudo inclusions (doughnut cells)
IMMUNOPHENOTYPING POSITIVE STAINS • CD30 • CD43 • CD45 • CD2 NEGATIVE STAINS • ALK • CD3 • CD5 • CD15 • EBV (EBER & LMP)
DIFFERENTIAL DIAGNOSIS • ALK + ALCL • Classic Hodgkins lymphoma • Peripheral T – Cell lymphoma (NOS)
PERIPHERAL T-CELL LYMPHOMA (NOS) (lymphoepithelioid lymphoma; Lennert lymphoma) • Definition: Mature T cell lymphoma that does not meet WHO classification criteria of other mature T cell lymphoma entities • Heterogeneous category of nodal and extra nodal mature T-cell lymphomas. (Wastebasket category) • AGE : Adults, and has an aggressive clinical course. • PTCL-U can be preceded by an immunologic disorder such as Hashimotos thyroiditis, Immune thrombocytopenic purpura and Rheumatoid arthritis. • Cell of origin: Activated mature T cells (CD4+ memory T cell)
LYMPH NODE • Effacement of the normal architecture. • Para cortical or diffuse infiltrates • Polymorphous to monomorphic. • Most cases consist of medium-large cells with irregular, pleomorphic, hyperchromatic, or vesicular nuclei; prominent nucleoli; and many mitotic figures. • Clear cells and Reed- Sternberg―like cells can also be seen. Rare cases have a predominance of small lymphoid cells with atypical, irregular nuclei. • An inflammatory background is often present.
MOLECULAR SUBTYPES •GATA3 subtype (35% of PTCL, NOS): • ≥ 50% tumor cells positive for GATA3 or CXCR3 by IHC • Associated with monomorphic morphology with minimal inflammatory background • Very poor overall survival •TBX21 subtype (58% of PTCL, NOS): • ≥ 20% tumor cells positive for TBX21 or CCR4 by IHC • Associated with polymorphous morphology • Longer overall survival
Lymphoepithelioid variant •Typically shows a diffuse infiltrate of small cells with subtle nuclear atypia numerous epithelioid histiocytes which often form clusters •Correlates with TBX21 molecular subtype •May have better prognosis than other PTCL, NOS subsets
• Extra nodal – Diffuse infiltration with similar cells • SKIN : Infiltration in the dermis and subcutis, often producing nodules, which may undergo central necrosis. Epidermotropism, angiocentricity, and adnexal involvement are sometimes seen.
IMMUNOPHENOTYPING • Pan T cell antigens CD3, CD5 and/or CD7 +ve. • CD4+/CD8- • Cases may be double positive or double negative for CD4 and CD8 • TCR alpha/beta • CD30 : Variable (heterogeneous) • ALK –ve • T follicular helper markers -ve (CD10, BCL6, PD1, CXCL13) • EBER -ve
MOLECULAR DIAGNOSIS • PCR demonstrates clonal rearrangement of TCR genes. • Next generation sequencing shows recurrent alterations of TP53, TET2, CDKN2A ... DIFFERENTIAL DIAGNOSIS • Classic hodgkins lymphoma • ALK negative Anaplastic large cell lymphoma • Angioimmunoblastic T cell lymphoma • Adult T cell leukemia/ lymphoma • Mycosis fungoides
EXTRANODAL T-CELL LYMPHOMAS
EXTRA NODAL NK /T CELL LYMPHOMA –NASAL TYPE (Polymorphic reticulosis/Malignant midline reticulosis/Lethal midline granuloma/Angiocentric T cell lymphoma) • DEFINITION : Aggressive extranodal lymphoma of NK / T cell origin characterized by angiotropism and angiodestruction, necrosis and association with Epstein-Barr virus (EBV) • AGE : 5th to 7th decade. • SEX : M:F – 2:1 • SITES : Nasal cavity (mc), GIT, Skin, Testis, Lung, Spleen and liver • Clinical features : Nasal / upper airways obstruction, purulent discharge, epistaxis and facial mass with surrounding edema, Pleural effusion and elevated serum LDH
PATHOPHYSIOLOGY • Nk cells infected by EBV secrete IL9 and IL10 which promote cell activation and proliferation. • Frequent 30 base pair deletion in LMP1 gene leads to a decrease in immune recognition
LYMPH NODE • Monotonous population of cells • Paracortex or medullary infiltration. • Moderate cytoplasm, folded nuclei and indistinct nucleoli. • Coagulative necrosis • Frequent mitosis
SKIN • Dense and atypical lymphoid infiltrate in dermis and subcutis • Frequent mitoses, necrosis and angioinvasion • Association with microthrombi • Involvement of hair follicles and sweat glands
CD56 CD7 cCD3 EBER
ENTEROPATHY ASSOCIATED T CELL LYMPHOMAS • Definition : Intestinal lymphoma derived from intraepithelial T cells which occurs in patients with celiac disease • Age : 6th to 7th decade • SEX : M=F In few areas Female preponderance. • SITES : Small intestine more frequent Jejunum > Ileum or Duodenum • Clinical features : Abdominal pain, diarrhoea and vomiting, Malabsorption, Fever, Fatigue, Weight loss.
MICROSCOPY • Intestinal involvement: Ulcerated lesion with diffuse and pleomorphic infiltrate of medium to large cells , angulated nuclei, prominent nucleoli and abundant cytoplasm. Mitotic figures and necrosis are common. Angiotropism. Background inflammatory cells. Features of celiac disease – Mucosa adjacent to EATL. • Lymph node : Sinusoidal pattern.
MONOMORPHIC EPITHELIOTROPHIC INTESTINAL T-CELL LYMPHOMA • Definition : Previously known as Type-II enteropathy associated T-cell lymphoma, is a mature intestinal T-cell lymphoma. • Arise from intraepithelial T-lymphocytes & lacks association with Celiac disease. • Rare, aggressive disease • Median age in the sixth decade • M:F = 2:1 • Sites : Small bowel, especially the jejunum, followed by ileum • Clinical features : Abdominal pain, Obstruction or Perforation, weight lss, diarrhea & gastro intestinal bleeding.
GROSS • Neoplastic lymphocytes are relatively monotonous, intermediate in size, with round or slightly irregular nuclear contours, dispersed chromatin, inconspicuous nucleoli and scant rim of pale cytoplasm • Prominent epitheliotropism as well as transmural infiltrate are characteristic • Few inflammatory cells are noted in the background. MICROSCOPY
• Spleen tyrosine kinase (SYK) was overexpressed in MEITL. • Extra signals for MYC at 8q24 are commonly seen • Proliferation index (Ki67) was approximately 90% Differential Diagnosis • Enteropathy associated T cell lymphoma (EATL) • Mycosis fungoides with gastrointestinal involvement Positive: surface CD3, CD8, CD56, granzyme B and TCRδγ Negative: CD4, CD5, surface TCRαβ Cytogenetics/Molecular diagnosis
HEPATOSPLENIC T CELL LYMPHOMA (Erythrophagocytic Tγ lymphoma) • Definition : Rare, aggressive extra nodal neoplasm that originates from cytotoxic T cells; it usually expresses the T cell receptor (TCR) γδ (gamma delta) • More common in young adult men, median age ~35 years. • M > F • Clinical findings : Hepatomegaly and splenomegaly, Moderate anemia, Thrombocytopenia and Neutropenia, Lymphadenopathy is uncommon.
Pathophysiology • Neoplastic clonal proliferation of γδ T cells induced by the upregulation of the JAK / STAT (STAT3 and STAT5B) and PI3K signaling pathways (Or) • Mutations of chromatin modifiers (SETD2, INO80 and ARID1B)
MICROSCOPY
Cytogenetics/Molecular diagnosis • Gamma delta origin: biallelic rearrangement of TRG • Mutations in JAK / STAT pathway • Isochromosome (7q) or ring chromosome 7 • Trisomy 8 Differential Diagnosis • Splenic marginal zone lymphoma • T-cell large granular lymphocytic leukemia TCRγδ in 80% of cases CD2+, CD3+, CD7+, CD56+, CD8+/-, CD4-, CD5-, Variable CD16 and CD94 (dim or negative)
LEUKEMIC LYMPHOMAS
ADULT T CELL LEUKEMIA/LYMPHOMA • Definition : Aggressive T cell neoplasm of mature CD4+ T cells associated with human T lymphotropic virus 1 (HTLV1) • SITES : Widespread lymph node involvement in most • Systemic: Spleen and extranodal sites including the skin, peripheral blood. • Age : Adults average 58 years • SEX : M: F – 1.5:1
PATHOPHYSIOLOGY • Cell of origin is peripheral CD4+ T regulatory αβ T cell (CD4+ CD25+ FoxP3+) • ATLL patients suffer from profound immunodeficiency
Clinical manifestation Acute (mc) Lymphomatous Smouldering Chronic Lymphocytosis Increased No No Mildly increased Blood abnormal lymphocyte Increased No* > 5% Mildly increased Increased LDH Yes No No Minimal Hypercalcemia Yes Variable No No Skin rash Variable: > 50% Variable: > 50% Erythematous rash Rash, papules Lymphadenopathy Generalized Yes No Mild Hepatosplenomegaly Usually present Often present No Mild Bone marrow infiltration May be present No No No Median survival < 1 year < 1 year > 2 years > 2 years SHIMOYAMA CLASSIFICATION FOR CLINICAL VARIANTS
MICROSCOPY PERIPHERAL BLOOD: • Medium to large sized lymphocytes with multilobulated nuclei (flower cells), condensed chromatin, absent or small nucleoli, scant slightly basophilic cytoplasm
BONE MARROW • Pattern of marrow involvement can be diffuse, interstitial or sinusoidal • Often evidence of bone resorption and osteoclastic activity • Bone trabeculae: may show remodelling • Lytic bone lesions can be present even in the absence of tumoral bone infiltration
LYMPH NODE • Involves paracortical T cell zones • Diffuse architectural effacement • May be subdivided according to cell type and pattern • Pleomorphic medium and large cell type / pattern (most common) • Anaplastic large cell-like • Hodgkin lymphoma-like: seen in early phase of some adult T cell lymphoma
SKIN LESIONS • Epidermal infiltration with Pautrier-like micro-abscesses is common. • Hyperparakeratosis is variably present in the overlying epidermis • Dermal infiltration: mainly perivascular but larger tumor nodules with extension to subcutaneous fat may be observed • Papules and nodules: composed of larger cells that replace dermis
IMMUNOPHENOTYPING • ATLL is neoplasm of mature T cells, CD2+, CD3+, CD5+,TCR αβ+, CD1a-, CD7-, CD10-, PD-1- • ~ 90% of cases are CD4+ CD8- DIFFERENTIAL DIAGNOSIS • Peripheral T cell lymphoma –NOS • Angioimmunoblastic T-cell lymphoma • Anaplastic large cell lymphoma
T-PROLYMPHOCYTIC LEUKEMIA (T cell chronic lymphocytic leukemia (small cell variant of T cell prolymphocytic leukemia) • Definition : Aggressive, mature T cell leukemia, composed of small to medium sized mature T cells, with high white blood cell (WBC) count and widespread organ involvement • Rare (2% of mature lymphocytic leukemias) • Adults and elderly (> 30 years) Median age: 65 years • Sites : Peripheral blood, bone marrow, lymph nodes, spleen, liver, skin • Clinical picture : Hepatosplenomegaly, lymphadenopathy, Anemia & thrombocytopenia, high leukocyte count (>100 x 109/L) with skin and mucosal lesions.
Pathophysiology • Overexpression of TCL1 family of proteins (which stimulate AKT / protein kinase B driven proliferation) • Functional deficit of ATM
PERIPHERAL SMEAR • Lymphocytosis with small to medium sized lymphocytes with cytoplasmic blebs, clumped chromatin and variably prominent central nucleolus • Small cell variant in 25% • Cerebriform variant in 5%
LYMPH NODE Effaced with Monotonous lymphoid aggregates Intermediate sized atypical cells CD3+ TCL1A+
Cytogenetics/Molecular diagnosis • Clonal T cell receptor gene rearrangements • TCL1A / TCL1B rearrangement: inv(14)(q11;q32) in 80%, t(14;14)(q11;q32) in 10% • Rarely MTCP1 rearrangement t(X;14)(q28;q11) • Complex karyotype in 70 - 80%; • Mutations in ATM gene on 11q23 in 80 - 90% Differential diagnosis • Adult T-cell leukemia/ lymphoma • T-cell large granular lymphocytic leukemia Mature CD3 positive T cells, usually express pan T markers CD2, CD5 and CD7; positive for CD52 CD4+, CD8- in 60%
T-CELL LARGE GRANULAR LYMPHOCYTIC LEUKEMIA • DEFINITION: A chronic T cell lymphoproliferative disorder- clonal proliferation of mature cytotoxic T cells without an identified cause. Presenting with cytopenia. • 2 - 5% of mature lymphocytic leukemias • Gender : M = F • Age : Elderly with a median age of 60 years • SITES : Peripheral blood, bone marrow, spleen, liver • Clinical Features : • Majority have neutropenia or anemia • 30% are asymptomatic but regular complete blood count reveals lymphocytosis and cytopenia • Splenomegaly , autoimmune disorders- Rheumatoid arthritis(most common) • Associated with other hematologic malignancies such as B cell lymphoma, myelodysplastic syndrome and aplastic anemia
PATHOPHYSIOLOGY • Oligo clonal expansion of cytotoxic large granular T cells in response to antigen stimulation • Upregulation of cellular survival signals or downregulation of apoptotic pathways • STAT3 / STAT5b mutation as a secondary event • Other secondary events - Resistance to Fas / FasL mediated cell death.
BONE MARROW CD3+ CD8+ granzyme B+ TIA1+ No abnormal lymphocytic infiltration by H&E IHC demonstrates Intra-sinusoidal pattern
PERIPHERAL SMEAR • Increased lymphocytes containing small to intermediate sized reticulated nuclei and fine to coarse azurophilic cytoplasmic granules
Cytogenetics/Molecular studies • Clonal T cell receptor (TCR) gene rearrangements • STAT3 mutation in 40 - 50% of T cell large granular lymphocytic leukemia • STAT5b mutation in 2% of T cell large granular lymphocytic leukemia Differential diagnosis • Chronic lymphoproliferative disorder of NK cells • Peripheral T cell lymphoma Mature CD3 positive T cells, usually coexpress NK cell associated markers (CD16 and CD57) CD4- CD8+
CUTANEOUS T –CELL LYMPHOMAS
MYCOSIS FUNGOIDES • DEFINITION : Peripheral T cell lymphoma derived from Mature, post- thymic T lymphocytes • Presents as cutaneous patches and can progress to plaques, tumors and erythroderma • EPIDEMIOLOGY : M>F ; Median age - 50yrs • SITES: Bathing trunk distribution. • CELL OF ORIGIN: Effector Memory T cells
MICROSCOPY • Early lesions are histologically indistinguishable from inflammatory skin diseases • Band-like papillary dermal lymphoid infiltrate • Intraepidermal lymphocytes out of proportion with spongiosis (epidermotropism) ± Pautrier microabscesses • Lymphocytes in the junction and within the epidermis may have haloes & variable nuclear pleomorphism, nuclear contour irregularity (cerebriform cytomorphology can be difficult to appreciate on biopsies) and hyperchromasia
VARIANTS Folliculotropic MF Granulomatous slack skin Pagetoid reticulosis
STAGING (ISCL & EORTC) Skin T1 Limited patches, papules or plaques covering < 10% of the skin surface: T1a: patch only T1b: plaque with or without patch T2 Patches, papules or plaques covering ≥ 10% of the skin surface: T2a: patch only T2b: plaque with or without patch T3 One or more tumors (≥ 1cm diameter) T4 Confluence of erythema covering ≥ 80% body surface area Node N0 No clinically abnormal peripheral lymph node N1 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 1 or NCI LN0-2 N1a: clone negative N1b: clone positive N2 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN3 N2a: clone negative N2b: clone positive N3 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 3 - 4 or NCI LN4; clone positive or negative Nx Clinically abnormal peripheral lymph nodes with no histological confirmation Visceral M0 No visceral organ involvement M1 Visceral involvement (must have pathological confirmation) Peripheral Blood (PB) B0 Absence of significant blood involvement: ≤ 5% Sézary cells in PB B0a: clone negative B0b: clone positive B1 Low blood tumor burden: > 5% Sézary cells in PB and does not meet criteria of B2 B1a: clone negative B1b: clone positive B2 High blood tumor burden: ≥ 1000/µL Sézary cells in PB with clone positive
IMMUNOHISTOCHEMISTRY • Diagnosis of exclusion • Mature T cell phenotype ( CD45RO+, TCRβ+, CD2+, CD3+, CD4+ [frequent], CD5+, CD7+) is most commonly observed • Loss of CD2 or CD5 favors mycosis fungoides • Partial loss of CD7 is common. • TCR gamma, CD8 & EBER are negative.
SEZARY SYNDROME • Definition : Leukemic variant of cutaneous T cell lymphoma (CTCL) defined by the presence of erythroderma, generalized lymphadenopathy and clonal T cells with cerebriform nuclei (Sézary cells) • If same clone expressed in skin, lymph node and Peripheral blood – Stronger diagnosis • Cell of origin : Effector memory T cells (CD45RO)
PATHOPHYSIOLOGY • Abnormalities in pathways: NFκB / JAK STAT activation, cell cycle dysregulation / apoptosis and DNA structural dysregulation affecting gene • Chemokine receptors: CCR4/CCR10 • Overexpression of CD47 CLINICAL FEATURES • Erythroderma • Alopecia • Nail dystrophy • Pruritis Note: Clinical presentation with erythroderma with < 1 x 109/L is defined as pre-Sézary and some patients progress to SS
MICROSCOPY • SS is histologically similar to mycosis fungoides but sometimes epidermotropism is not present • May range from limited to superficial perivascular lymphocytic and eosinophilic dermatitis with or without spongiosis (atopic-like lesions) • Pautrier microabscesses are not common • Peripheral blood • Sézary cells: Atypical lymphocytes of intermediate to large size and cerebriform nuclei • Lymph node • Complete effacement of the nodal architecture by monotonous infiltrating population of Sézary cells • Large cell or blastoid morphology may occur in advanced stages.
LYMPH NODE
IMMUNOPHENOTYPING • Positive for CD3, CD4, CD5 and CD45RO • Negative for CD2, CD7 and CD30. DIFFERENTIAL DIAGNOSIS • Non-neoplastic Erythroderma • Adult T – cell leukemia/lymphoma
SUMMARY
REFERENCES • WHO HEMATOLYMPHOID NEOPLASMS, Revised 4th edition • IAOCHIMS LYMPH NODE PATHOLOGY 4th edition • WASHINGTON MANUAL BOOK OF SURGICAL PATHOLOGY
T cell lymphomas - By Dr MULUKALA SWETHA

More Related Content

PPTX
who 5th hematolymphoid B cell neoplasm.pptx
byDrKomalBhairo
 
PPTX
Unusual type and site of Lymphoma(Extranodal Lymphoma) Dr.Argha Baruah
byArgha Baruah
 
PPTX
T cell lymphomas ppt
byRiddhi Karnik
 
PDF
Mature T/NK cell Neoplasms
byAhmed Makboul
 
PPTX
Approach to lymphoma
byGarimaAgarwalSUSMRAs
 
PDF
Mature B-cell Neoplasms
byAhmed Makboul
 
PPTX
Chronic lymphoproliferative disorders
byVeena Raja
 
PPT
Molecular pathology of lymphoma by dr ramesh
byRamesh Purohit
 
who 5th hematolymphoid B cell neoplasm.pptx
byDrKomalBhairo
 
Unusual type and site of Lymphoma(Extranodal Lymphoma) Dr.Argha Baruah
byArgha Baruah
 
T cell lymphomas ppt
byRiddhi Karnik
 
Mature T/NK cell Neoplasms
byAhmed Makboul
 
Approach to lymphoma
byGarimaAgarwalSUSMRAs
 
Mature B-cell Neoplasms
byAhmed Makboul
 
Chronic lymphoproliferative disorders
byVeena Raja
 
Molecular pathology of lymphoma by dr ramesh
byRamesh Purohit
 

What's hot

PPTX
Cutaneous lymphoproliferative disorders
bykanwalpreet15
 
PPT
Minimal residual disease
byAppy Akshay Agarwal
 
PPTX
Milan cytology reporting
byArgha Baruah
 
PPTX
Approach to undifferentiated tumors
byDr. Varughese George
 
PPTX
Small round cell tumors
byDr Niharika Singh
 
PPTX
Cutaneous pseudolymphoma
byDr Daulatram Dhaked
 
PPTX
The bethesda system for reporting thyroid cytopathology
bydhanya89
 
PPTX
Cutaneous T Cell Lymphomas
byJerriton Brewin
 
PPTX
Non hodgkin lymphoma
bytashagarwal
 
PPT
Small round cell_tumor_DR NARMADA
byNarmada Tiwari
 
PPTX
The Paris System for Reporting Urinary Cytology
byRawa Muhsin
 
PPT
Embryonal brain tumours in children
byAppy Akshay Agarwal
 
PPTX
approach to lymph node cytology part 1
byKamalesh Lenka
 
PPTX
PEComas
byVikram Prabhakar
 
PPTX
Role of ihc on soft tissue tumours
byariva zhagan
 
PPTX
Tensins 123
bySpoorthy Gurajala
 
PPTX
MALToma
byArgha Baruah
 
PPTX
Gross of thyroid gland
byMonika Nema
 
PPTX
Ig g 4 related disease
byGarimaAgarwalSUSMRAs
 
PPT
Acute lymphoblastic leukemia dr narmada
byNarmada Tiwari
 
Cutaneous lymphoproliferative disorders
bykanwalpreet15
 
Minimal residual disease
byAppy Akshay Agarwal
 
Milan cytology reporting
byArgha Baruah
 
Approach to undifferentiated tumors
byDr. Varughese George
 
Small round cell tumors
byDr Niharika Singh
 
Cutaneous pseudolymphoma
byDr Daulatram Dhaked
 
The bethesda system for reporting thyroid cytopathology
bydhanya89
 
Cutaneous T Cell Lymphomas
byJerriton Brewin
 
Non hodgkin lymphoma
bytashagarwal
 
Small round cell_tumor_DR NARMADA
byNarmada Tiwari
 
The Paris System for Reporting Urinary Cytology
byRawa Muhsin
 
Embryonal brain tumours in children
byAppy Akshay Agarwal
 
approach to lymph node cytology part 1
byKamalesh Lenka
 
PEComas
byVikram Prabhakar
 
Role of ihc on soft tissue tumours
byariva zhagan
 
Tensins 123
bySpoorthy Gurajala
 
MALToma
byArgha Baruah
 
Gross of thyroid gland
byMonika Nema
 
Ig g 4 related disease
byGarimaAgarwalSUSMRAs
 
Acute lymphoblastic leukemia dr narmada
byNarmada Tiwari
 

Similar to T cell lymphomas - By Dr MULUKALA SWETHA

PPTX
nodular T cell.pptx
bySwarnimc
 
PPTX
NHL.pptx
byDeepikaGupta967065
 
PPTX
Non Hodgkin Lymphoma pathology pathology.pptx
bySubramanianM44
 
PPTX
ROUND CELL TUMOR.pptx
byDrPurvaPihulkar
 
PPTX
Hodgkins lymphoma ppt.pptx
byLekhraajgautamChetry
 
PPTX
T cell and NK-cell neoplasms
byAbdullah Hashish
 
PPTX
lymphoma.hematology.pptxncncnjcncncnncjcjcncjcjn
byqyj52hn9jb
 
PPTX
WHO 2016 lymphoma classification
byChandan K Das
 
PPTX
approach to lymph node cytology part 2
byKamalesh Lenka
 
PPTX
LYMPHOPROLIFERATIVE DISORDERS AND ITS ORAL MANIFESTATIONS.pptx
byKasthuriVenkatesan1
 
PPTX
Hodgkin lymphoma
bytashagarwal
 
PPTX
lymphoma-150127113120-conversion-gate01.pptx
byfaisalmd10
 
PPTX
NHL.pptx presentation of sixty three slides
byShreyanshSoni22
 
PPTX
Lymphoma Sitabile and Thelma at the CDH lusaka
byMuluseMuluti
 
PPT
Lymphomas 1-nhl
byPrasad CSBR
 
PPTX
Lymphoma
bySaugat Chapagain
 
PPTX
Lymphoproliferative disorders (lecture)
byssuserb26cfc
 
PPTX
Week 6 presentation
bySarahSaeedAhmed
 
PPTX
Lymphomas+ Multiple Choice Questions
byMojgan Talebian
 
PPTX
Lymphoma
byIrshad Ali
 
nodular T cell.pptx
bySwarnimc
 
NHL.pptx
byDeepikaGupta967065
 
Non Hodgkin Lymphoma pathology pathology.pptx
bySubramanianM44
 
ROUND CELL TUMOR.pptx
byDrPurvaPihulkar
 
Hodgkins lymphoma ppt.pptx
byLekhraajgautamChetry
 
T cell and NK-cell neoplasms
byAbdullah Hashish
 
lymphoma.hematology.pptxncncnjcncncnncjcjcncjcjn
byqyj52hn9jb
 
WHO 2016 lymphoma classification
byChandan K Das
 
approach to lymph node cytology part 2
byKamalesh Lenka
 
LYMPHOPROLIFERATIVE DISORDERS AND ITS ORAL MANIFESTATIONS.pptx
byKasthuriVenkatesan1
 
Hodgkin lymphoma
bytashagarwal
 
lymphoma-150127113120-conversion-gate01.pptx
byfaisalmd10
 
NHL.pptx presentation of sixty three slides
byShreyanshSoni22
 
Lymphoma Sitabile and Thelma at the CDH lusaka
byMuluseMuluti
 
Lymphomas 1-nhl
byPrasad CSBR
 
Lymphoma
bySaugat Chapagain
 
Lymphoproliferative disorders (lecture)
byssuserb26cfc
 
Week 6 presentation
bySarahSaeedAhmed
 
Lymphomas+ Multiple Choice Questions
byMojgan Talebian
 
Lymphoma
byIrshad Ali
 

Recently uploaded

PDF
Dr. David Ford Wilson - Provides Holistic Mental Health Care
byDr. David Ford Wilson
 
PDF
Seminario Biología Molecular - UNVEILING THE THERAPEUTIC POTENTIAL OF SUYIN ...
bytrabajosupbmdg
 
PPTX
ACTINOMYCETES- Introduction,Pathogenesis,clinical manifestations,Epidemiology...
byAmeenKhan59
 
PPTX
PERI-PROSTHETIC FRACTURE NAIL-PLATE CONSTRUCT [NPC].pptx
bydrashraf369
 
PPTX
Venous cutdown for Surgery Viva, MBBS Students
byCBME SURGERY
 
PPTX
PRODUCTION OF ANTIBIOTICS e.g (Penicillin)
bySadaqat Ahmed
 
PPTX
Sympathetic Nervous System in Pain Medicine | Anatomy, CRPS & Sympathetic Blo...
byDaradia: The Pain Clinic
 
PPTX
BENIGN BREAST DISEASES BBD/ Fibroadenoma, Fibrocystic Diseases/ ANDI.pptx
byDr Sushil Gyawali
 
PPTX
Introduction to Geriatric Nursing,Theory
bynabina paneru
 
PDF
The Doctor's Balance Sheet By Dr Kanhu Charan Patro
byKanhu Charan
 
PDF
Preparing Medicare Cost Reports Seems Easy Until It's Not
byNMP Professional Services, Inc
 
PDF
SEMINARIO BIOMOL.pdf (Samuel Cantillo y Karen Bohorquez)
bySamuelCantillo7
 
PPTX
Template for presentation of patients at the MDT Meeting
byNasri937947
 
PPTX
Left Ventricular Assist Devices.(New Gen)
bySyedFaisalAhmed12
 
PPTX
History and Evolution of Microbiology.pptx
byVijayaRengan4
 
PPTX
muscles of facial expressions and mastication.pptx
byClevin Aswani
 
PPTX
CTEV [ clubfoot] DR ARUN LAL ,DR MOHAMED ASHRAF travancore medical college k...
bydrashraf369
 
PPTX
Atrial Fibrillation and difference with Atrial flutter
byrashamarei
 
PPTX
Anatomy of temporal & infratemporal fossa.pptx
byClevin Aswani
 
PPTX
sinusitis.....................................pptx
by62cjjqfcvg
 
Dr. David Ford Wilson - Provides Holistic Mental Health Care
byDr. David Ford Wilson
 
Seminario Biología Molecular - UNVEILING THE THERAPEUTIC POTENTIAL OF SUYIN ...
bytrabajosupbmdg
 
ACTINOMYCETES- Introduction,Pathogenesis,clinical manifestations,Epidemiology...
byAmeenKhan59
 
PERI-PROSTHETIC FRACTURE NAIL-PLATE CONSTRUCT [NPC].pptx
bydrashraf369
 
Venous cutdown for Surgery Viva, MBBS Students
byCBME SURGERY
 
PRODUCTION OF ANTIBIOTICS e.g (Penicillin)
bySadaqat Ahmed
 
Sympathetic Nervous System in Pain Medicine | Anatomy, CRPS & Sympathetic Blo...
byDaradia: The Pain Clinic
 
BENIGN BREAST DISEASES BBD/ Fibroadenoma, Fibrocystic Diseases/ ANDI.pptx
byDr Sushil Gyawali
 
Introduction to Geriatric Nursing,Theory
bynabina paneru
 
The Doctor's Balance Sheet By Dr Kanhu Charan Patro
byKanhu Charan
 
Preparing Medicare Cost Reports Seems Easy Until It's Not
byNMP Professional Services, Inc
 
SEMINARIO BIOMOL.pdf (Samuel Cantillo y Karen Bohorquez)
bySamuelCantillo7
 
Template for presentation of patients at the MDT Meeting
byNasri937947
 
Left Ventricular Assist Devices.(New Gen)
bySyedFaisalAhmed12
 
History and Evolution of Microbiology.pptx
byVijayaRengan4
 
muscles of facial expressions and mastication.pptx
byClevin Aswani
 
CTEV [ clubfoot] DR ARUN LAL ,DR MOHAMED ASHRAF travancore medical college k...
bydrashraf369
 
Atrial Fibrillation and difference with Atrial flutter
byrashamarei
 
Anatomy of temporal & infratemporal fossa.pptx
byClevin Aswani
 
sinusitis.....................................pptx
by62cjjqfcvg
 

T cell lymphomas - By Dr MULUKALA SWETHA

  • 1.
  • 2.
    CONTENTS • INTRODUCTION • PRECURSORT-CELL NEOPLASM • MATURE T-CELL NEOPLASMS • SUMMARY
  • 8.
    INTRODUCTION • Mature T-and Natural killer (NK)- cell malignancies are rare, accounting for 10 – 12% of all Non-Hodgkin's lymphoma. • More common in Asia and linked to EBV viral infection (NK-cell lymphomas) and human T-cell leukaemia virus (HTLV-1) (adult T-cell leukaemia/lymphoma). • More aggressive than B-cell lymphomas.
  • 9.
    WHO CLASSIFICATION OFPRECURSOR LYMPHOID NEOPLASMS • T-Lymphoblastic leukemia/lymphoma • Early T-cell Precursor lymphoblastic leukemia • Nk-lymphoblastic leukemia/lymphoma
  • 10.
    T-LYMPHOBLASTIC LEUKEMIA/LYMPHOMA (Precursor T-lymphoblasticleukaemia/ lymphoma) • Definition : Refers to neoplasm of immature lymphoid cells (lymphoblasts) of T-cell lineage. • Age : Most common in adolescents and young adults Median age of 28 years. • SEX: Males > Females. • Clinical findings : Widespread lymphadenopathy (neck, axillae and supraclavicular). • Mediastinal mass is common • Hepatosplenomegaly often present.
  • 11.
    T-Lymphoblastic leukemia T-ALL T-LBL •Involving Bone marrow and Blood • 15% of childhood ALL cases • 25% of cases of adult ALL • Involving Thymus or Nodal or Extra nodal • 85–90% of all LBLs
  • 12.
    Peripheral blood smearand Bone Marrow • Anemia • Granulocytopenia, • Lymphoblasts >25% • Thrombocytopenia
  • 13.
    LYMPH NODE • Architecture: Effaced • Capsule & Para cortex : Involved • Pattern : Multinodular – mimicking Follicular lymphoma. Starry Sky - mimicking Burkitt lymphoma. • Lymphoblasts : Medium sized- round or Convoluted nuclei - High N: C ratio, Frequent mitotic figures.
  • 14.
    TdT, CD34, CD1a& CD99 are positive (suggest Precursor T-lymphoblasts) CD7, CD3(cytoplasmic), CD2, CD5 (Immature markers) are often positive. CD4, CD8 & CD10 are Positive • The most common recurrent cytogenetic abnormality involves the αδ TR loci at 14q11.2. • β locus at 7q35, and the γ locus at 7p14-15, with a variety of partner genes • Deletions of (9q) CYTOGENETICS
  • 15.
    CRITERIA FOR DIAGNOSIS 1.Frequently associated with mediastinal mass 2. Relatively uniform cell population with high mitotic rate 3. Variable number of round - convoluted (deeply indented) nuclei 4. Dense, finely granular chromatin, mostly inconspicuous nucleoli 5. Scanty, pale, fragile cytoplasm. 6. Immunophenotype: TdT, most often CD3 (cytoplasmic) and CD7; Often CD4 and CD8 double positive or double negative; variable positivity with CD1a, CD34, CD10. 7. 50-70% abnormal karyotype.
  • 16.
    WHO CLASSIFICATION • Mycosisfungoides • Sézary syndrome • Primary cutaneous CD30+ T cell lymphoproliferative disorders • Lymphomatoid papulosis • Primary cutaneous anaplastic large cell lymphoma • Primary cutaneous gamma delta cell lymphoma • Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T cell lymphoma • Primary cutaneous acral CD8+ T cell lymphoma* • Primary cutaneous CD4+ small / medium T cell lymphoproliferative disorder* • Peripheral T cell lymphoma, NOS • Angioimmunoblastic T cell lymphoma • Follicular T cell lymphoma* • Nodal peripheral T cell lymphoma with T follicular helper phenotype* • Anaplastic large cell lymphoma, ALK+ • Anaplastic large cell lymphoma, ALK-* • Breast implant associated anaplastic large cell lymphoma* MATURE T-CELL AND NK CELL NEOPLASMS • T cell prolymphocytic leukemia • T cell large granular lymphocytic leukemia • Chronic lymphoproliferative disorder of NK cells • Aggressive NK cell leukemia • Systemic Epstein-Barr virus+ T cell lymphoma of childhood* • Hydroa vacciniforme-like lymphoproliferative disorder* • Adult T cell leukemia / lymphoma • Extranodal NK / T cell lymphoma, nasal type • Enteropathy associated T cell lymphoma • Monomorphic epitheliotropic intestinal T cell lymphoma* • Indolent T cell lymphoproliferative disorder of the GI tract* • Hepatosplenic T cell lymphoma • Subcutaneous panniculitis-like T cell lymphoma
  • 17.
    FREQUENCY OF T-cell LYMPHOMAS
  • 18.
    NODAL T- CELLLYMPHOMAS
  • 19.
    ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA (Lymphogranulomatosis-x) •DEFINITION: Neoplasm of Mature T follicular helper (TFH) cells characterized by Systemic disease & Lymphadenopathy with polymorphous infiltrate involving lymph nodes with prominent proliferation of high endothelial venules (HEV’s) & Follicular dendritic cells (FDC’s) • AGE : Elderly individuals. • SEX : Males > Females • LOCALIZATION : Lymph node(Primary site), Spleen, liver, skin, and bone marrow . • CLINICAL FEATURES : Generalised lymphadenopathy, hepatosplenomegaly and polyclonal hypergammaglobulinemia
  • 20.
  • 21.
    MICROSCOPIC • Lymph node:Three most common features are 1. Diffuse pattern with Partial or complete architecture effacement. 2. Numerous arborizing blood vessels, lined by hyperplastic endothelial cells. 3. Polymorphous population of cells with a variable number of small and large size with Hyperchromatic nuclei and clear cytoplasm. 4. Numerous reactive cells including plasma cells, eosinophils, immunoblasts, small lymphocytes and follicular dendritic cells.
  • 22.
    • Subdivided into3 histological patterns TYPE-I • Architecture- Partially preserved and hyperplastic follicles with tingible body macrophages and indistinct mantle zones • Seen in 10-20% of cases TYPE- II • Architecture- Preserved mostly with residual follicles. • In half of the cases TYPE-III • Architecture- Completely effaced without residual follicles. • In remaining cases.
  • 24.
    IMMUNOPHENOTYPE • T cellantigens: εCD3, CD4, CD5 and CD7. • Follicular dendritic cells: CD21, CD23, CD35 • TFH markers: CXCL13, CD10, PD1 & BCL6 • EBER (Epstein-Barr virus encoded small RNAs) • Loss of sCD3 is more common in bone marrow and peripheral blood compared to lymph nodes. • CD8 –Ve and loss of CD7 is also observed
  • 25.
    CYTOGENETICS/MOLECULAR STUDIES • Karyotypicabnormalities in 90% of the cases. • Trisomy of chromosomes 3,5 and 21. Gain of chromosome X. • Monoclonal T-cell receptor gene rearrangements γ or β in 80%-90% of AILT cases. • Next generation sequencing panel showed TET2, DNMT3, RHOA and IDH2 mutations. DIFFERENTIAL DIAGNOSIS • Reactive lymphoid hyperplasia • Classic hodgkins lymphoma, mixed cellularity • Peripheral T cell lymphoma –NOS • EBV+ diffuse large B cell lymphoma, NOS
  • 26.
    ANAPLASTIC LARGE –CELL LYMPHOMA-ALK POSITIVE (Malignant Histiocytosis) • Definition: A peripheral T cell lymphoma consisting of large lymphoid cells with abundant amphophilic cytoplasm, often horseshoe shaped nuclei, an ALK (anaplastic lymphoma kinase) gene translocation, expression of ALK protein (CD246) and CD30 • Constitutes 10-20% of childhood lymphomas. • Age : First 3 decades of life • SEX : M: F - 1.5 :1 • LOCALIZATION : Lymph nodes & extra nodal sites.
  • 27.
    PATHOGENESIS • Neoplastic cellsare activated mature cytotoxic T cells (CD30+) • Oncogenic translocations result in constitutive activation of the ALK tyrosine kinase • Resulting fusion proteins are shown to be involved in different downstream signalling pathways including RAS/ERK, PI3K/Akt and JAK/STAT.
  • 29.
    MICROSCOPY • Small-medium-large anaplasticcells • Interfollicular T zones and subcapsular sinuses infiltration • Cohesive growth pattern • Intrasinusoidal infiltration pattern • Anaplastic large cells with abundant cytoplasm, wreath-like or multiple nuclei, open chromatin, multiple nucleoli, perinuclear eosinophilic region (prominent Golgi zone) • Cells with horseshoe / kidney / embryo shaped nuclei are referred to as “hallmark cells”. • Brisk mitotic activity
  • 30.
    • Lympho histiocytic(10%) • Numerous histiocytes and small lymphocytes, occasional erythrophagocytosis • Small cell (5 - 10%) • Predominantly small cells with irregular nuclei, hallmark cells present (tend to be perivascular), occasional fried egg cells, rare signet ring cells • Hodgkin-like (1 - 3%) • Mimics nodular sclerosis classic Hodgkin lymphoma; • Hypocellular • Small cell types may have hypocellular, granulation tissue-like appearance • Composite pattern (10 - 20%) • More than one pattern. VARIANTS
  • 32.
    IMMUNOPHENOTYPING Positive stains: • ALK1 •CD30 • CD2 • CD4 • CD5 • TIA1 • Granzyme B • Perforin Negative stains : • PAX5 • CD15 • CD20 • CD79a • EBER
  • 33.
    CYTOGENETICS /MOLECULAR DIAGNOSIS •Clonal T cell receptor (TCR) gene rearrangement seen in 90% • All translocations result in upregulation of ALK protein • ALK translocation results in activation of the downstream oncogenic transcription factor, STAT3 • STAT3 activation regulates availability of hypoxia inducible factors involved in tumor growth and metastasis • t(2;5)(p23;q35): ALK and NPM (75 - 85%) • t(1;2)(q25;p23): tropomyosin 3 (TPM3) and ALK (13%) • inv(2)(p23;q35): ALK and ATIC (1%)
  • 34.
    DIFFERENTIAL DIAGNOSIS • ALK–ve anaplastic large cell lymphoma • Hodgkins lymphoma • Histiocytic sarcoma
  • 35.
    ALK NEGATIVE ANAPLASTICLARGE CELL LYMPHOMA • Morphologically similar to ALK +ALCL but is ALK negative. • Common in Adults (40-65 years) • Sites: Both lymph nodes and extra nodal sites, including bone, soft tissue and skin • Etiology : Unknown PATHOPHYSIOLOGY: • Recurrent rearrangement involving the TP63 gene • STAT3 activating mutations • DUSP22 rearrangements
  • 36.
    MICROSCOPY • Morphologically indistinguishablefrom ALCL, ALK positive • Effaced architecture with solid, cohesive sheets of neoplastic cells • May show preserved lymph node architecture with neoplastic cells growing intrasinusoidally or only within the T cell areas • Large cells with round to indented nuclei, deeply staining cytoplasm, with prominent Golgi zone • Hallmark cells (cells with eccentric, horseshoe or kidney shaped nuclei) • Cases with DUSP22 rearrangements show smaller, monomorphic cells with central nuclear pseudo inclusions (doughnut cells)
  • 37.
    IMMUNOPHENOTYPING POSITIVE STAINS • CD30 •CD43 • CD45 • CD2 NEGATIVE STAINS • ALK • CD3 • CD5 • CD15 • EBV (EBER & LMP)
  • 38.
    DIFFERENTIAL DIAGNOSIS • ALK+ ALCL • Classic Hodgkins lymphoma • Peripheral T – Cell lymphoma (NOS)
  • 39.
    PERIPHERAL T-CELL LYMPHOMA(NOS) (lymphoepithelioid lymphoma; Lennert lymphoma) • Definition: Mature T cell lymphoma that does not meet WHO classification criteria of other mature T cell lymphoma entities • Heterogeneous category of nodal and extra nodal mature T-cell lymphomas. (Wastebasket category) • AGE : Adults, and has an aggressive clinical course. • PTCL-U can be preceded by an immunologic disorder such as Hashimotos thyroiditis, Immune thrombocytopenic purpura and Rheumatoid arthritis. • Cell of origin: Activated mature T cells (CD4+ memory T cell)
  • 40.
    LYMPH NODE • Effacementof the normal architecture. • Para cortical or diffuse infiltrates • Polymorphous to monomorphic. • Most cases consist of medium-large cells with irregular, pleomorphic, hyperchromatic, or vesicular nuclei; prominent nucleoli; and many mitotic figures. • Clear cells and Reed- Sternberg―like cells can also be seen. Rare cases have a predominance of small lymphoid cells with atypical, irregular nuclei. • An inflammatory background is often present.
  • 41.
    MOLECULAR SUBTYPES •GATA3 subtype(35% of PTCL, NOS): • ≥ 50% tumor cells positive for GATA3 or CXCR3 by IHC • Associated with monomorphic morphology with minimal inflammatory background • Very poor overall survival •TBX21 subtype (58% of PTCL, NOS): • ≥ 20% tumor cells positive for TBX21 or CCR4 by IHC • Associated with polymorphous morphology • Longer overall survival
  • 42.
    Lymphoepithelioid variant •Typically showsa diffuse infiltrate of small cells with subtle nuclear atypia numerous epithelioid histiocytes which often form clusters •Correlates with TBX21 molecular subtype •May have better prognosis than other PTCL, NOS subsets
  • 43.
    • Extra nodal– Diffuse infiltration with similar cells • SKIN : Infiltration in the dermis and subcutis, often producing nodules, which may undergo central necrosis. Epidermotropism, angiocentricity, and adnexal involvement are sometimes seen.
  • 44.
    IMMUNOPHENOTYPING • Pan Tcell antigens CD3, CD5 and/or CD7 +ve. • CD4+/CD8- • Cases may be double positive or double negative for CD4 and CD8 • TCR alpha/beta • CD30 : Variable (heterogeneous) • ALK –ve • T follicular helper markers -ve (CD10, BCL6, PD1, CXCL13) • EBER -ve
  • 45.
    MOLECULAR DIAGNOSIS • PCRdemonstrates clonal rearrangement of TCR genes. • Next generation sequencing shows recurrent alterations of TP53, TET2, CDKN2A ... DIFFERENTIAL DIAGNOSIS • Classic hodgkins lymphoma • ALK negative Anaplastic large cell lymphoma • Angioimmunoblastic T cell lymphoma • Adult T cell leukemia/ lymphoma • Mycosis fungoides
  • 46.
  • 47.
    EXTRA NODAL NK/T CELL LYMPHOMA –NASAL TYPE (Polymorphic reticulosis/Malignant midline reticulosis/Lethal midline granuloma/Angiocentric T cell lymphoma) • DEFINITION : Aggressive extranodal lymphoma of NK / T cell origin characterized by angiotropism and angiodestruction, necrosis and association with Epstein-Barr virus (EBV) • AGE : 5th to 7th decade. • SEX : M:F – 2:1 • SITES : Nasal cavity (mc), GIT, Skin, Testis, Lung, Spleen and liver • Clinical features : Nasal / upper airways obstruction, purulent discharge, epistaxis and facial mass with surrounding edema, Pleural effusion and elevated serum LDH
  • 48.
    PATHOPHYSIOLOGY • Nk cellsinfected by EBV secrete IL9 and IL10 which promote cell activation and proliferation. • Frequent 30 base pair deletion in LMP1 gene leads to a decrease in immune recognition
  • 49.
    LYMPH NODE • Monotonouspopulation of cells • Paracortex or medullary infiltration. • Moderate cytoplasm, folded nuclei and indistinct nucleoli. • Coagulative necrosis • Frequent mitosis
  • 50.
    SKIN • Dense andatypical lymphoid infiltrate in dermis and subcutis • Frequent mitoses, necrosis and angioinvasion • Association with microthrombi • Involvement of hair follicles and sweat glands
  • 51.
  • 52.
    ENTEROPATHY ASSOCIATED TCELL LYMPHOMAS • Definition : Intestinal lymphoma derived from intraepithelial T cells which occurs in patients with celiac disease • Age : 6th to 7th decade • SEX : M=F In few areas Female preponderance. • SITES : Small intestine more frequent Jejunum > Ileum or Duodenum • Clinical features : Abdominal pain, diarrhoea and vomiting, Malabsorption, Fever, Fatigue, Weight loss.
  • 53.
    MICROSCOPY • Intestinal involvement: Ulceratedlesion with diffuse and pleomorphic infiltrate of medium to large cells , angulated nuclei, prominent nucleoli and abundant cytoplasm. Mitotic figures and necrosis are common. Angiotropism. Background inflammatory cells. Features of celiac disease – Mucosa adjacent to EATL. • Lymph node : Sinusoidal pattern.
  • 54.
    MONOMORPHIC EPITHELIOTROPHIC INTESTINALT-CELL LYMPHOMA • Definition : Previously known as Type-II enteropathy associated T-cell lymphoma, is a mature intestinal T-cell lymphoma. • Arise from intraepithelial T-lymphocytes & lacks association with Celiac disease. • Rare, aggressive disease • Median age in the sixth decade • M:F = 2:1 • Sites : Small bowel, especially the jejunum, followed by ileum • Clinical features : Abdominal pain, Obstruction or Perforation, weight lss, diarrhea & gastro intestinal bleeding.
  • 55.
    GROSS • Neoplastic lymphocytesare relatively monotonous, intermediate in size, with round or slightly irregular nuclear contours, dispersed chromatin, inconspicuous nucleoli and scant rim of pale cytoplasm • Prominent epitheliotropism as well as transmural infiltrate are characteristic • Few inflammatory cells are noted in the background. MICROSCOPY
  • 57.
    • Spleen tyrosinekinase (SYK) was overexpressed in MEITL. • Extra signals for MYC at 8q24 are commonly seen • Proliferation index (Ki67) was approximately 90% Differential Diagnosis • Enteropathy associated T cell lymphoma (EATL) • Mycosis fungoides with gastrointestinal involvement Positive: surface CD3, CD8, CD56, granzyme B and TCRδγ Negative: CD4, CD5, surface TCRαβ Cytogenetics/Molecular diagnosis
  • 58.
    HEPATOSPLENIC T CELLLYMPHOMA (Erythrophagocytic Tγ lymphoma) • Definition : Rare, aggressive extra nodal neoplasm that originates from cytotoxic T cells; it usually expresses the T cell receptor (TCR) γδ (gamma delta) • More common in young adult men, median age ~35 years. • M > F • Clinical findings : Hepatomegaly and splenomegaly, Moderate anemia, Thrombocytopenia and Neutropenia, Lymphadenopathy is uncommon.
  • 59.
    Pathophysiology • Neoplastic clonalproliferation of γδ T cells induced by the upregulation of the JAK / STAT (STAT3 and STAT5B) and PI3K signaling pathways (Or) • Mutations of chromatin modifiers (SETD2, INO80 and ARID1B)
  • 60.
  • 61.
    Cytogenetics/Molecular diagnosis • Gammadelta origin: biallelic rearrangement of TRG • Mutations in JAK / STAT pathway • Isochromosome (7q) or ring chromosome 7 • Trisomy 8 Differential Diagnosis • Splenic marginal zone lymphoma • T-cell large granular lymphocytic leukemia TCRγδ in 80% of cases CD2+, CD3+, CD7+, CD56+, CD8+/-, CD4-, CD5-, Variable CD16 and CD94 (dim or negative)
  • 62.
  • 63.
    ADULT T CELLLEUKEMIA/LYMPHOMA • Definition : Aggressive T cell neoplasm of mature CD4+ T cells associated with human T lymphotropic virus 1 (HTLV1) • SITES : Widespread lymph node involvement in most • Systemic: Spleen and extranodal sites including the skin, peripheral blood. • Age : Adults average 58 years • SEX : M: F – 1.5:1
  • 64.
    PATHOPHYSIOLOGY • Cell oforigin is peripheral CD4+ T regulatory αβ T cell (CD4+ CD25+ FoxP3+) • ATLL patients suffer from profound immunodeficiency
  • 65.
    Clinical manifestation Acute(mc) Lymphomatous Smouldering Chronic Lymphocytosis Increased No No Mildly increased Blood abnormal lymphocyte Increased No* > 5% Mildly increased Increased LDH Yes No No Minimal Hypercalcemia Yes Variable No No Skin rash Variable: > 50% Variable: > 50% Erythematous rash Rash, papules Lymphadenopathy Generalized Yes No Mild Hepatosplenomegaly Usually present Often present No Mild Bone marrow infiltration May be present No No No Median survival < 1 year < 1 year > 2 years > 2 years SHIMOYAMA CLASSIFICATION FOR CLINICAL VARIANTS
  • 66.
    MICROSCOPY PERIPHERAL BLOOD: • Mediumto large sized lymphocytes with multilobulated nuclei (flower cells), condensed chromatin, absent or small nucleoli, scant slightly basophilic cytoplasm
  • 67.
    BONE MARROW • Patternof marrow involvement can be diffuse, interstitial or sinusoidal • Often evidence of bone resorption and osteoclastic activity • Bone trabeculae: may show remodelling • Lytic bone lesions can be present even in the absence of tumoral bone infiltration
  • 68.
    LYMPH NODE • Involvesparacortical T cell zones • Diffuse architectural effacement • May be subdivided according to cell type and pattern • Pleomorphic medium and large cell type / pattern (most common) • Anaplastic large cell-like • Hodgkin lymphoma-like: seen in early phase of some adult T cell lymphoma
  • 69.
    SKIN LESIONS • Epidermalinfiltration with Pautrier-like micro-abscesses is common. • Hyperparakeratosis is variably present in the overlying epidermis • Dermal infiltration: mainly perivascular but larger tumor nodules with extension to subcutaneous fat may be observed • Papules and nodules: composed of larger cells that replace dermis
  • 70.
    IMMUNOPHENOTYPING • ATLL isneoplasm of mature T cells, CD2+, CD3+, CD5+,TCR αβ+, CD1a-, CD7-, CD10-, PD-1- • ~ 90% of cases are CD4+ CD8- DIFFERENTIAL DIAGNOSIS • Peripheral T cell lymphoma –NOS • Angioimmunoblastic T-cell lymphoma • Anaplastic large cell lymphoma
  • 71.
    T-PROLYMPHOCYTIC LEUKEMIA (T cellchronic lymphocytic leukemia (small cell variant of T cell prolymphocytic leukemia) • Definition : Aggressive, mature T cell leukemia, composed of small to medium sized mature T cells, with high white blood cell (WBC) count and widespread organ involvement • Rare (2% of mature lymphocytic leukemias) • Adults and elderly (> 30 years) Median age: 65 years • Sites : Peripheral blood, bone marrow, lymph nodes, spleen, liver, skin • Clinical picture : Hepatosplenomegaly, lymphadenopathy, Anemia & thrombocytopenia, high leukocyte count (>100 x 109/L) with skin and mucosal lesions.
  • 72.
    Pathophysiology • Overexpression ofTCL1 family of proteins (which stimulate AKT / protein kinase B driven proliferation) • Functional deficit of ATM
  • 73.
    PERIPHERAL SMEAR • Lymphocytosiswith small to medium sized lymphocytes with cytoplasmic blebs, clumped chromatin and variably prominent central nucleolus • Small cell variant in 25% • Cerebriform variant in 5%
  • 74.
    LYMPH NODE Effaced withMonotonous lymphoid aggregates Intermediate sized atypical cells CD3+ TCL1A+
  • 75.
    Cytogenetics/Molecular diagnosis • ClonalT cell receptor gene rearrangements • TCL1A / TCL1B rearrangement: inv(14)(q11;q32) in 80%, t(14;14)(q11;q32) in 10% • Rarely MTCP1 rearrangement t(X;14)(q28;q11) • Complex karyotype in 70 - 80%; • Mutations in ATM gene on 11q23 in 80 - 90% Differential diagnosis • Adult T-cell leukemia/ lymphoma • T-cell large granular lymphocytic leukemia Mature CD3 positive T cells, usually express pan T markers CD2, CD5 and CD7; positive for CD52 CD4+, CD8- in 60%
  • 76.
    T-CELL LARGE GRANULARLYMPHOCYTIC LEUKEMIA • DEFINITION: A chronic T cell lymphoproliferative disorder- clonal proliferation of mature cytotoxic T cells without an identified cause. Presenting with cytopenia. • 2 - 5% of mature lymphocytic leukemias • Gender : M = F • Age : Elderly with a median age of 60 years • SITES : Peripheral blood, bone marrow, spleen, liver • Clinical Features : • Majority have neutropenia or anemia • 30% are asymptomatic but regular complete blood count reveals lymphocytosis and cytopenia • Splenomegaly , autoimmune disorders- Rheumatoid arthritis(most common) • Associated with other hematologic malignancies such as B cell lymphoma, myelodysplastic syndrome and aplastic anemia
  • 77.
    PATHOPHYSIOLOGY • Oligo clonalexpansion of cytotoxic large granular T cells in response to antigen stimulation • Upregulation of cellular survival signals or downregulation of apoptotic pathways • STAT3 / STAT5b mutation as a secondary event • Other secondary events - Resistance to Fas / FasL mediated cell death.
  • 78.
    BONE MARROW CD3+ CD8+ granzymeB+ TIA1+ No abnormal lymphocytic infiltration by H&E IHC demonstrates Intra-sinusoidal pattern
  • 79.
    PERIPHERAL SMEAR • Increasedlymphocytes containing small to intermediate sized reticulated nuclei and fine to coarse azurophilic cytoplasmic granules
  • 80.
    Cytogenetics/Molecular studies • ClonalT cell receptor (TCR) gene rearrangements • STAT3 mutation in 40 - 50% of T cell large granular lymphocytic leukemia • STAT5b mutation in 2% of T cell large granular lymphocytic leukemia Differential diagnosis • Chronic lymphoproliferative disorder of NK cells • Peripheral T cell lymphoma Mature CD3 positive T cells, usually coexpress NK cell associated markers (CD16 and CD57) CD4- CD8+
  • 81.
  • 82.
    MYCOSIS FUNGOIDES • DEFINITION: Peripheral T cell lymphoma derived from Mature, post- thymic T lymphocytes • Presents as cutaneous patches and can progress to plaques, tumors and erythroderma • EPIDEMIOLOGY : M>F ; Median age - 50yrs • SITES: Bathing trunk distribution. • CELL OF ORIGIN: Effector Memory T cells
  • 83.
    MICROSCOPY • Early lesionsare histologically indistinguishable from inflammatory skin diseases • Band-like papillary dermal lymphoid infiltrate • Intraepidermal lymphocytes out of proportion with spongiosis (epidermotropism) ± Pautrier microabscesses • Lymphocytes in the junction and within the epidermis may have haloes & variable nuclear pleomorphism, nuclear contour irregularity (cerebriform cytomorphology can be difficult to appreciate on biopsies) and hyperchromasia
  • 84.
    VARIANTS Folliculotropic MF Granulomatousslack skin Pagetoid reticulosis
  • 85.
    STAGING (ISCL &EORTC) Skin T1 Limited patches, papules or plaques covering < 10% of the skin surface: T1a: patch only T1b: plaque with or without patch T2 Patches, papules or plaques covering ≥ 10% of the skin surface: T2a: patch only T2b: plaque with or without patch T3 One or more tumors (≥ 1cm diameter) T4 Confluence of erythema covering ≥ 80% body surface area Node N0 No clinically abnormal peripheral lymph node N1 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 1 or NCI LN0-2 N1a: clone negative N1b: clone positive N2 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN3 N2a: clone negative N2b: clone positive N3 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 3 - 4 or NCI LN4; clone positive or negative Nx Clinically abnormal peripheral lymph nodes with no histological confirmation Visceral M0 No visceral organ involvement M1 Visceral involvement (must have pathological confirmation) Peripheral Blood (PB) B0 Absence of significant blood involvement: ≤ 5% Sézary cells in PB B0a: clone negative B0b: clone positive B1 Low blood tumor burden: > 5% Sézary cells in PB and does not meet criteria of B2 B1a: clone negative B1b: clone positive B2 High blood tumor burden: ≥ 1000/µL Sézary cells in PB with clone positive
  • 86.
    IMMUNOHISTOCHEMISTRY • Diagnosis ofexclusion • Mature T cell phenotype ( CD45RO+, TCRβ+, CD2+, CD3+, CD4+ [frequent], CD5+, CD7+) is most commonly observed • Loss of CD2 or CD5 favors mycosis fungoides • Partial loss of CD7 is common. • TCR gamma, CD8 & EBER are negative.
  • 87.
    SEZARY SYNDROME • Definition: Leukemic variant of cutaneous T cell lymphoma (CTCL) defined by the presence of erythroderma, generalized lymphadenopathy and clonal T cells with cerebriform nuclei (Sézary cells) • If same clone expressed in skin, lymph node and Peripheral blood – Stronger diagnosis • Cell of origin : Effector memory T cells (CD45RO)
  • 88.
    PATHOPHYSIOLOGY • Abnormalities inpathways: NFκB / JAK STAT activation, cell cycle dysregulation / apoptosis and DNA structural dysregulation affecting gene • Chemokine receptors: CCR4/CCR10 • Overexpression of CD47 CLINICAL FEATURES • Erythroderma • Alopecia • Nail dystrophy • Pruritis Note: Clinical presentation with erythroderma with < 1 x 109/L is defined as pre-Sézary and some patients progress to SS
  • 89.
    MICROSCOPY • SS ishistologically similar to mycosis fungoides but sometimes epidermotropism is not present • May range from limited to superficial perivascular lymphocytic and eosinophilic dermatitis with or without spongiosis (atopic-like lesions) • Pautrier microabscesses are not common • Peripheral blood • Sézary cells: Atypical lymphocytes of intermediate to large size and cerebriform nuclei • Lymph node • Complete effacement of the nodal architecture by monotonous infiltrating population of Sézary cells • Large cell or blastoid morphology may occur in advanced stages.
  • 91.
  • 92.
    IMMUNOPHENOTYPING • Positive forCD3, CD4, CD5 and CD45RO • Negative for CD2, CD7 and CD30. DIFFERENTIAL DIAGNOSIS • Non-neoplastic Erythroderma • Adult T – cell leukemia/lymphoma
  • 93.
  • 94.
    REFERENCES • WHO HEMATOLYMPHOIDNEOPLASMS, Revised 4th edition • IAOCHIMS LYMPH NODE PATHOLOGY 4th edition • WASHINGTON MANUAL BOOK OF SURGICAL PATHOLOGY