T cell lymphomas - By Dr MULUKALA SWETHA

Non hodgkins lymphomas are of two cell types
T-cells
And B-cells
T-cells constitute only 10% of all Non-hodgkins lymphomas.
T cell lymphomas
Basic introduction of the T -cells-development , maturation and functions.
Cell of origin of various nodal and extranodal lymphomas
WHO classification revised 4th edition
Precursor lymphomas-
T-cell prolymphoblastic leukemia/lymphoma
Nodal lymphomas - Angioimmunoblastic lymphoma
Anaplastic lymphoma (ALK+&ALK-)
Peripheral T cell lymphoma - NOS
Extranodal lymphomas-
EN-Nk T-cell lymphoma nasal type
Intestinal lymphomas
EATL
METL
Hepatosplenic lymphoma
Leukemic lymphomas
Adult T cell leukemia
T-cell prolymphocytic leukemia
T cell large granular lymphocytic leukemia
Cutaneous lymphomas
Mycosis fungoides
Sezary syndrome
Summary:
CD8+/CD4- in Extranodal lymphomas: Hepatosplenic lymphomas, MEITL, T-LGL
CD4+/CD8- with diffuse CD30+ is ALCL .
CD4+/CD8- with TFH and TF dendritic markers + is AITL.
CD4+/CD8- with HTLV exposure is ATLL.
CD4+/CD8- with loss of CD7 with cutaneous manifestations+ epidermotropism+spongiosis is Mycosis fungoides.
Waste basket category is PTCL-NOS
CD4+CD8-CD10-PD1- with lymphocytosis is T-PLL
References

1. T CELL LYMPHOMAS BY: Dr. M.Swetha

2. CONTENTS INTRODUCTION PRECURSOR T-CELL NEOPLASM MATURE T-CELL NEOPLASMS SUMMARY

3. 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.

4. WHO CLASSIFICATION OF PRECURSOR LYMPHOID NEOPLASMS T-Lymphoblastic leukemia/lymphoma Early T-cell Precursor lymphoblastic leukemia Nk -lymphoblastic leukemia/lymphoma

5. 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.

6. 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 TR gene rearrangement

7. Peripheral blood smear and Bone Marrow Anemia Granulocytopenia , Lymphoblasts >25% Thrombocytopenia

8. 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.

9. 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 α δ 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

10. CRITERIA FOR DIAGNOSIS Frequently associated with mediastinal mass Relatively uniform cell population with high mitotic rate Variable number of round - convoluted (deeply indented) nuclei Dense, finely granular chromatin, mostly inconspicuous nucleoli Scanty, pale, fragile cytoplasm. 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.

11. 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 c ell 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

12. FREQUENCY OF T- cell LYMPHOMAS

13. NODAL T- CELL LYMPHOMAS

14. ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA (Lymphogranulomatosis-x) D EFINITION : N eoplasm of M ature 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 individual s . SEX : Males > Females LOCALIZATION : Lymph node ( Primary site), Spleen, liver, skin, and bone marrow . CLINICAL FEATURES : Generalised lymphadenopathy, hepatosplenomegaly and polyclonal hypergammaglobulinemia

15. P ATHOGENESIS EBV Infection

16. MICROSCOPIC Lymph node : Three most common features are Diffuse pattern with Partial or complete architecture effacement . Numerous arborizing blood vessels , lined by hyperplastic endothelial cells. Polymorphous population of cells with a variable number of small and large size with Hyperchromatic nuclei and clear cytoplasm. Numerous reactive cells including plasma cells, eosinophils, immunoblasts , small lymphocytes and follicular dendritic cells.

17. Subdivided into 3 histological patterns

18. IMMUNOPHENOTYPE T cell antigens : ε CD3, 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

19. 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

20. 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.

21. 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 . ALK gene overexpression (2p23)

22. MICROSCOPY S mall-medium-large anaplastic cells Interfollicular T zones and s ubcapsular sinuses infiltration Co hesive 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

23. 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

24. IMMUNOPHENOTYPING Positive stains : ALK1 CD30 CD2 CD4 CD5 TIA1 Granzyme B Perforin Negative stains : PAX5 CD15 CD20 CD79a EBER

25. 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%)

26. DIFFERENTIAL DIAGNOSIS ALK –ve anaplastic large cell lymphoma Hodgkins lymphoma Histiocytic sarcoma

27. 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

28. 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)

29. IMMUNOPHENOTYPING POSITIVE STAINS CD30 CD43 CD45 CD2 NEGATIVE STAINS ALK CD3 CD5 CD15 EBV (EBER & LMP)

30. DIFFERENTIAL DIAGNOSIS ALK + ALCL Classic Hodgkins lymphoma Peripheral T – Cell lymphoma (NOS)

31. PERIPHERAL T-CELL LYMPHOMA ( NOS ) ( lym p hoep ithelioid lymphoma; Lennert lymphoma ) Definition : Mature T cell lymphoma that does not meet WHO classification criteria of other mature T cell lymphoma entities H eterogeneous category of nodal and extra nodal mature T-cell lymphomas . (Wastebasket category) AGE : A dults , 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)

32. LYMPH NODE E ffacement of the normal architecture. Para cortical or diffuse infiltrates P olymorphous to monomorphic . Most cases consist of m edium - large cells with irregular, pleomorphic, hyperchromatic, or vesicular nuclei; prominent nucleoli; and m any 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 .

33. 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

34. 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

35. Extra nodal – Diffuse infiltration with similar cells SKIN : Inf iltrat ion in the dermis and subcu tis , often producing nodules , which may undergo central necrosis. Epidermotropism, angiocentricity , and adnexal involvement are sometimes seen.

36. 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

37. 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

38. EXTRANODAL T-CELL LYMPHOMAS

39. 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 : 5 th to 7 th 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

40. 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 EBV

41. LYMPH NODE Monotonous population of cells Paracortex or medullary infiltration. Moderate cytoplasm, folded nuclei and indistinct nucleoli. Coagulative necrosis Frequent mitosis

42. 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

43. CD56 CD7 cCD3 EBER

44. ENTEROPATHY ASSOCIATED T CELL LYMPHOMAS Definition : Intestinal lymphoma derived f rom intraepithelial T cells which occurs in patients with celiac disease Age : 6 th to 7 th 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.

45. 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.

46. 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.

47. 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

48. 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 TCR δγ Negative : CD4, CD5 , surface TCR αβ Cytogenetics/Molecular diagnosis

49. HEPATOSPLENIC T CELL LYMPHOMA (Erythrophagocytic T γ lymphoma) Definition : Rare, aggressive extra nodal neoplasm that originates from c ytotoxic 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.

50. 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) Unknown(80%) Chronic immunosuppression (20%)

51. MICROSCOPY

52. 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 TCR γδ in 80% of cases CD2+, CD3+, CD7+, CD56+, CD8+/-, CD4-, CD5-, Variable CD16 and CD94 (dim or negative)

53. LEUKEMIC LYMPHOMAS

54. 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

55. PATHOPHYSIOLOGY Cell of origin is peripheral CD4+ T regulatory αβ T cell (CD4+ CD25+ FoxP3+) ATLL patients suffer from profound immunodeficiency HTLV1 Type C

56. 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

57. MICROSCOPY PERIPHERAL BLOOD: Medium to large sized lymphocytes with multilobulated nuclei (flower cells), condensed chromatin , absent or small nucleoli , scant slightly basophilic cytoplasm

58. BONE MARROW Pa ttern 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

59. LYMPH NODE Involves paracortical T cell zones D iffuse 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

60. 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

61. 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

62. 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 10 9 /L) with skin and mucosal lesions.

63. Pathophysiology Overexpression of TCL1 family of proteins (which stimulate AKT / protein kinase B driven proliferation) Functional deficit of ATM Unknown, Ataxia telangiectasia

64. 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%

65. LYMPH NODE Effaced with Monotonous lymphoid aggregates Intermediate sized atypical cells CD3+ TCL1A+

66. 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%

67. 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 - R heumatoid arthritis(most common) As sociated with other hematologic malignancies such as B cell lymphoma, myelodysplastic syndrome and aplastic anemia

68. PATHOPHYSIOLOGY Oligo clonal expansion of cytotoxic large granular T cells in response to antigen stimulation Upregulation of cellular survival signals or downregulation of apoptotic pathway s STAT3 / STAT5b mutation as a secondary event Other secondary events - Resistance to Fas / FasL mediated cell deat h. Auto-immune disorders & HTLV1

69. BONE MARROW CD3+ CD8+ granzyme B+ TIA1+ No abnormal lymphocytic infiltration by H&E IHC demonstrates Intra-sinusoidal pattern

70. PERIPHERAL SMEAR Increased lymphocytes containing small to intermediate sized reticulated nuclei and fine to coarse azurophilic cytoplasmic granules

71. 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+ 

72. CUTANEOUS T –CELL LYMPHOMAS

73. MYCOSIS FUNGOIDES DEFINITION : Peripheral T cell lymphoma derived from M ature, 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

74. 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

75. VARIANTS Folliculotropic MF Granulomatous slack skin Pagetoid reticulosis

76. 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

77. IMMUNOHISTOCHEMISTRY Diagnosis of exclusion Mature T cell phenotype ( CD45RO+, T CR β+,   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.

78. 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)

79. PATHOPHYSIOLOGY Abnormalities in pathways: NF κ B / 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 10 9 /L is defined as pre- Sézary and some patients progress to SS

80. 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.

81. LYMPH NODE

82. IMMUNOPHENOTYPING P ositive for CD3 , CD4 , CD5 and CD45RO N egative for CD2, CD7 and CD30 . DIFFERENTIAL DIAGNOSIS Non-neoplastic Erythroderma Adult T – cell leukemia/lymphoma

83. SUMMARY

84. REFERENCES WHO HEMATOLYMPHOID NEOPLASMS, Revised 4 th edition IAOCHIMS LYMPH NODE PATHOLOGY 4 th edition WASHINGTON MANUAL BOOK OF SURGICAL PATHOLOGY

85. THANK YOU