Cutaneous lymphoma.pptx, ppt for pathology pgs

Cutaneous lymphomas

1. Cutaneous lymphoma

2. Lymphoproliferative disorders of the skin fall into two major categories Primary cutaneous lymphoma :Non Hodgkin lymphomas presenting in the skin with no evidence of extra cutaneous disease at the time of diagnosis Secondary cutaneous lymphoma : Systemic lymphomas that secondarily involve the skin

3. T- and B-Cell Infiltration Patterns

4. Primary cutaneous lymphoma Mature B-cell lineage : Extra nodal marginal zone lymphoma of mucosa associated lymphoid tissues(MALT lymphoma ) Primary cutaneous follicle centre lymphoma Primary cutaneous diffuse large B-cell lymphoma , leg type

5. Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissues ( MALTLymphoma ) >50 yrs Male predominance Usually Arms and trunk Papules/Plaques/Nodules Multifocal Results of chronic antigenic stimulation by antigen inserted intradermally Eg : tattoo, vaccines ,tick –borne bacteria( Borrelia sp.)

6. Two subtypes Class-switched -  90% Monotypic plasma cells  IgG and, to a lesser extent, IgA or IgE expression It lacks CXCR3, shows a predominant type 2 helper T cell environment and lacks reactive germinal centre colonization Indolent course 2) Non-class-switched   - 10%  Diffuse proliferation of large nodules of neoplastic B cells CXCR3 and IgM expression  

7. Nodular or diffuse dermal infiltrate, sparing the overlying epidermis - Grenz zone

8. Cells resembles centrocyte ( i rregular / angulated nuclear contours with inconspicuous nucleoli) Cells with less cytoplasm - small lymphocyte Neoplastic cells

9. Cells with ample cytoplasm - monocytoid appearance Extends into underlying subcutaneous tissue Reactive Plasma cell located at periphery of infiltrate and in the sub epidermal compartment

10. Plasmacytic differentiation : Intranuclear ( Dutcher bodies ) or intracytoplasmic ( Russell bodies) immunoglobulin inclusions Russell bodies

11. The cell of origin is -post–germinal center marginal zone B cell Positive marker : Kappa / lamda , CD 19, CD20,CD79a,BCL2 Negative : CD5,CD10,BCL6,Cyclin D1 Germinal centre : BCL6+,BCL2- and CD21 +(follicular dendritic cells ) Extracutaneous spread rare 5 year disease specific survival rate 0f 90%-favourable prognosis

12. Differential diagnosis Chronic lymphocytic leukemia  /  small lymphocytic lymphoma :  CD5 + /  CD23 + Cutaneous lymphoid hyperplasia : clinical correlation helpful Does not usually have a bottom heavy infiltrate Preservation of germinal center follicles Primary cutaneous follicle center lymphoma : Expression of BCL6 and CD10 outside of follicles would favor the neoplastic cells of PCFCL

13. Primary cutaneous follicle centre lymphoma PCFCL is a neoplasm derived from follicular center B cells including centrocytes (cleaved follicular center cells) and centroblasts ( noncleaved follicular center cells). Approximately 10% of cases of cutaneous lymphoma Scalp , forehead and trunk M:F -1.5:1 Middle aged adults Solitary or multiple firm erythematous to violaceous non ulcerating plaques /nodules

14. Clustered plum-colored nodules covered by thinned, glistening epidermal layer.

15. Histopathology Follicular / diffuse/ combination of both Sparing epidermis , Intact grenz zone Perivascular and per adnexal infiltration Follicles are ill defined; lack tingible body macrophages and mantle zone

16. Mixture of centrocytes and centroblasts Predominance of large centrocytes T cells are abundant

17. Positive : B cell markers ( ,  CD19 ,  CD22 ,  CD79a  or  PAX5 ) Germinal center markers:  BCL6 Negative CD10 positive in < 25% of cases Positive in follicular pattern and usually negative in diffuse pattern BCL2  ( negative or show faint staining) Combination of positive staining for both  BCL2  and  CD10  highly suggests secondary skin involvement by follicular lymphoma IRF4 / MUM1 CD 5 and CD43

18. Primary cutaneous diffuse large B cell lymphoma , leg type Primary cutaneous large B cell lymphoma (PCLBCL) composed exclusively of centroblasts and immunoblasts , typically arising in the leg 20% of all primary cutaneous B cell lymphomas Elderly patients, median age is seventh decade of life F:M =3:1 Presents as solitary or multiple localized reddish-brown tumors

19. Superficial and deep dermal involvement Epidermis spared (may be ulcerated) obliterating the adnexa, and often extends into the underlying subcutaneous tissue.

20. Large, monotonous, diffuse sheets of centroblasts and immunoblast Brisk mitotic activity frequently seen Small B cells and follicular dendritic cell meshworks are often absent

21. POSITIVE IRF4/MUM1 BCL2 BCL6 Fox P1 Ki67 index high (~70%) CD30 CIgM CD20 NRGATIVE CD10 CD5 CD30 Molecular : Translocation of  IGH  genes with  MYC  or  BCL6

22. PCL-Mature T/NK- cell lineage Mycosis fungoides including variants /subtypes Sezary syndrome Primary cutaneous CD30+ T cell lymphoproliferative disorder Lymphomatoid papulosis Primary cutaneous anaplastic large cell lymphoma Subcutaneous panniculitis –like T cell lymphoma Primary cutaneous γδ T cell lymphoma Primary cutaneous CD8+aggressive epidermotropic cytotoxic Tcell lymphoma Primary cutaneous CD4+small/medium T cell lymphoma Hydroa vacciniform –like lymphoma

23. Mycosis fungoides Epidermotropic primary cutaneous T cell lymphoma of small to medium sized T lymphocytes with cerebriform nuclei. m/c type of cutaneous T cell lymphoma (50%of all PCL) M:F=2:1 Median age at diagnosis in 50s Typical lesions initially present as large, erythematous scaling patches and plaques Generally resistant to anti-inflammatory therapy

24. Erythematous scaling patches and plaques of early disease. Plaques and nodules of advanced disease.

25. Early lesions of MF -patchy bandlike lymphocytic infiltrate within the papillary dermis, often associated with coarse fibrosis Neoplastic T cells are small- to medium-sized lymphocytes that characteristically contain nuclei with dense heterochromatin and elaborately indented ( cerebriform ) nuclear contours and perinuclear halos

26. Linear aggregation of neoplastic lymphocytes along the dermal–epidermal junction. Section stained for CD4 emphasizing this linear pattern of early epidermotropism

27. Plaque-stage disease characterized by prominent clusters of atypical lymphocytes within the epidermis ( Pautrier microabscesses ).

28. In more advanced stages, there is loss of epidermotropism . The dermal infiltrate is nodular to diffuse and may extend into the subcutaneous tissues May show transformation to large, highly atypical cells ( large-cell transformation or LCT )

29. LCT is defined as large-sized cells (4X size of small lymphocytes) with prominent nucleoli Composing ≥ 25% of the infiltrate or forming microscopic nodules Seen in greater than 50% of tumor-stage lesions A/W aggressive behavior

30. Positive : Mature T cell phenotype:   CD3,CD4,CD5,TCR β CD30 (Partially positive ) Negative : Cytotoxic phenotype : CD8 and TCR γ T-cell intracellular antigen [TIA-1] Perforin granzyme B

31. CD4 CD8 MF: CD3/CD4 (Helper) immunophenotype CD4:CD8 ratio increased in epidermis

32. Pattern of epidermal infiltration MF : Linear alignment along dermo-epidermal junction Pautrier’s microabscess Pagetoid spread Eczema/ ACD: Marked spongiosis Langerhans cell collections

33. Pattern of dermal  infiltration MF Band -like, sparing vascular plexus No disruption of basal cells Stuffing dermal papilla Eczema/ ACD/PL/lichenoid dermatitis: Lymphocytes involve vascular plexus

34. Prognosis Poor prognosis : Clinical stage IV disease Age older than 60 years Large cell transformation and Elevated lactate dehydrogenase (LDH) Median survival for stage IA is ≥ 20 years Median survival beyond stage III is approximately 5 years

35. Variants of Mycosis Fungoides 1.Folliculotropic mycosis fungoides Characterized by infiltration of hair follicles by atypical T cells Minimal to absent epidermotropism Often a/w follicular mucinosis secondary to intracellular mucin production by keratinocytes- “ alopecia mucinosa ” Follicular papules and plaques or comedones , and intense pruritus skin of the face and the scalp as well as sun-exposed extremities Poor survival and increased risk of disease progression compared to typical MF

36. Infiltration of hair follicle Reactive lymphoid infiltrates, granulomatous reaction, abundant eosinophils or plasma cells, or cyst formation Follicular mucinosis characterized by pools of pale blue–staining mucin

37. 2.Localized pagetoid reticulosis ( Woringer – Kolopp disease ) Rare form of MF Solitary acral lesion Epidermal infiltration of medium- to large-sized neoplastic T cells (abundant pale cytoplasm) A/W epidermal acanthosis and hyperkeratosis so clinically resembles to squamous proliferation such as a verruca or eczema. The pagetoid growth pattern of the neoplastic T cells –By strong expression of adhesion molecules , CLA and αEβ7

38. Neoplastic T cells are either CD4 + or CD8 + and CD30 positive Because of the pronounced epidermotropism , pagetoid reticulosis may mimic Superficial spreading melanoma Pagetoid squamous carcinoma in situ, or Extramammary Paget disease.

39. 3.Granulomatous slack skin (GSS ) Clinical features: Initially, indurated plaques axilla/inguinal folds Plaques become atrophic, wrinkled, pendulous Patients younger Other classic features of MF absent a/w systemic lymphoma

40. Skin with increased folding (intertriginous sites) Atypical T-cell infiltrates are A/W non-caseating dermal granulomas formed by histiocytes and multinucleated giant cells( Elastolytic granulomas ) Which may contain ingested elastic fibers ( elastophagocytosis ) or engulfed lymphocytes ( lymphophagocytosis ) Dense and extends deep into the subcutis Gradual loss of elastic fibres

41. Large, multinucleated giant cells are admixed among the lymphocytes and histiocytes

42. 4.Acanthosis nigricans –like (vegetating/ papillomatous ) mycosis fungoides . Flexural sites (axillae and groin), neck, nipple, and areolae Clinically and microscopically resembles acanthosis nigricans or seborrheic keratosis Microscopy A bandlike atypical lymphoid infiltrate with epidermotropism Elongated interconnected rete ridges Pseudo–horn cysts

43. 5.Bullous (vesicular) mycosis fungoides Present as blisters that may develop on normal skin or within typical plaques and tumors of MF Features of classical MF + clefting at different planes Subcorneal , intraepidermal - result from confluence of Pautrier microabscesses , Subepidermal - secondary to reduced keratinocyte adherence to the basement membrane due to cytokines produced by the lymphoma cells Immunofluorescence studies are negative in bullous MF.

44. 6.Granulomatous mycosis fungoides papules, plaques, and tumors Comparing to GSS clinically , bulky skin lesions are absent here Typical MF + variable granulomatous inflammation( In the form of interstitial, tuberculoid / sarcoidal , or palisading granuloma) Multinucleated giant cells, usually of the foreign-body type (Langerhans and Touton giant cells also seen ) Lymphophagocytosis and elastophagocytosis are less common than in GSS

45. 7.Hyperpigmented mycosis fungoides Rare variant , diffuse macular hyperpigmentation Classical MF + Marked elongation of the rete ridges Basal hyperpigmentation Dermal melanophages Ultrastructural studies - giant melanin granules in the tumor cells, keratinocytes, Langerhans cells, and macrophages

46. 8.Hypopigmented mycosis fungoides In young patients with dark skin Asymptomatic or slightly pruritic, hypopigmented patches Degenerative changes in melanocytes secondary to nonspecific cellular injuries, Impaired melanosome transfer to keratinocytes indistinguishable from classical MF histopathologically . Frequent CD8 + phenotype expression Dermal pigment incontinence as well as the presence of an atypical T-cell infiltrate

47. 9.Ichthyosiform mycosis fungoides Rare variant of MF, Pruritic and ichthyosiform , often with excoriations. A/W comedo -like areas and/or follicular keratotic papules. Microscopy Ichthyosiform areas : Typical features of MF + compact orthohyperkeratosis and hypergranulosis Follicular papules :cystic dilatation of hair follicles with keratotic plugs and folliculotropic atypical lymphocytes

48. 10.Mycosis fungoides palmaris / plantaris MF lesions are limited to palms and/or soles Annular hyperpigmented patches and plaques / vesicles/ pustules /hyperkeratotic/verrucous plaques / psoriasiform plaques, ulceration and nail dystrophy. Presence of histopathologic findings of classical MF and clonal rearrangement of the TCR genes will help in reaching the correct diagnosis.

49. 11.Poikiloderma vasculare atrophicans Early lesions -either large plaques or small papules arranged in a netlike configuration. Lesions show erythema, mild scaling, epidermal thinning, mottled hypo- and hyperpigmentation, and telangiectasia-resemble changes of radiodermatitis .

50. Microscopy : epidermal atrophy epidermal infiltration by atypical lymphocytes Band of lymphocytes, histiocytes , and melanophages in the papillary dermis Ectasia of superficial dermal vessels

51. 12.Pustular mycosis fungoides Pustular eruptions that may be limited to the palmoplantar areas / may be generalized. Intraepidermal collections of atypical lymphocytes with neutrophils and eosinophils . High levels of interleukin-8 by the lymphoma cells results in the formation of pustular lesions 13.Verrucous (hyperkeratotic) mycosis fungoides Hyperkeratotic/verrucous and occur on lower extremities, face, and trunk . Classic features of MF in a background of epidermal hyperplasia with hyperkeratotic scale

52. Sézary Syndrome Cell of origin is central memory T cell Triad of: Generalized redness and scaling of the skin (erythroderma) Lymphadenopathy Presence of clonally related neoplastic T cells in the skin, lymph nodes, and peripheral blood.

53. The recent international consensus statement for MF and SS updated criteria for SS Excluding the requirement of lymphadenopathy, Specifically (a) erythema covering 80% body surface (b) a T-cell clone within the peripheral blood (c) a high blood tumor burden, meaning to 1,000/ μL Sézary cells CD4:CD8 ratio 10:1 or Atypical CD4 + cells in the blood(≥ 40% of CD4+ / CD7- and ≥ 30% of CD4+ / CD26- T cells )  

54. Bandlike papillary dermal lymphoid infiltrate with minimal epidermotropism Neoplastic T cells are generally CD4 + T cells that frequently show loss of CD7 loss of T-cell markers such as CD2, CD3, and CD5

55. Atypical lymphocytes with cerebriform nuclear contours, called Lutzner cells and larger Sézary cells

56. TNM STAGING OF MF AND SEZARY SYNDROME T category is based on the percentage of skin surface involvement and the lesional morphology (patchy, plaque, tumor or erythroderma) N category is based on the presence of dermatopathic lymphadenopathy, lymphoma cells and evidence of clonality M category is based on the presence or absence of visceral involvement Peripheral blood staging is based on the quantity of abnormal lymphocytes (blood tumor burden) and presence or absence of clonality

57. STAGING FOR CL OTHER THAN MF/SS

58. Primary Cutaneous CD30-Positive T-Cell Lymphoproliferative Disorders Spectrum of diseases characterized by indolent clinical behavior and expression of CD30 Includes Lymphomatoid Papulosis Primary cutaneous anaplastic large cell lymphoma

59. Lymphomatoid Papulosis( LyP ) Generalized juicy red papules and nodules Trunk and extremities Regress within weeks to several months & resulting in mild scarring Frequently in middle-aged adults M:F 2–3:1 5 to 10% of cases may involve regional (draining) lymph nodes Cell of origin is skin-homing T cell

60. Subclassification of lymphomatoid papulosis   PATTERN COMPONENT IHC MIMICS Type A Wedge shaped Lymphoid infiltrates + neutrophils, eosinophils and histiocytes CD30+ Scattered classic Hodgkin lymphoma Type B epidermotropism and band-like small to medium atypical lymphocytes with cerebriform nuclei CD30 - mycosis fungoides , patch stage Type C sheets Large atypical lymphocytes CD30+ uniform primary cutaneous anaplastic large cell lymphoma Type D epidermotropism small to medium lymphoid infiltrate CD30+ pagetoid reticulosis Type E angiocentric and angiodestructive   small to medium size lymphocytes CD30+ scattered large cells extranodal T/NK cell lymphoma, nasal type

61. localized infiltrate in superficial and mid-dermis, forming a wedge-shaped angiocentric architecture.

62. Positive stains Activate T helper phenotype CD3 CD4 CD30 CD45RO HLA-DR CD25 TIA1  and  granzyme B Negative stains Usually CD8 Negative Variable loss of pan T cell antigens CD2 CD5 CD7

63. Primary Cutaneous Anaplastic Large-Cell Lymphoma Composed of large cells with an anaplastic, pleomorphic or immunoblastic cytomorphology with > 75% malignant cells positive for CD30 one or more localized, rapidly growing, frequently ulcerated reddish-brown nodules or papules Partial regression of untreated lesions may occur Excellent prognosis with an estimated 5-year survival of greater than 90% Extracutaneous dissemination occurs in approximately 10% of patients

64. Nodular or diffuse infiltrates of large, anaplastic cells that involve the dermis and occasionally the subcutis epidermal invasion by atypical cells Necrosis and/or angioinvasion may be seen Marked epidermal hyperplasia

65. Large,pleomorphic atypical cells account for the majority of the infiltrate Background of secondary inflammatory elements may be observed and occasionally eosinophilia is marked .

66. POSITIVE CD 30  in more than 75% of neoplastic cells CD4 cytotoxic granule proteins : granzyme B, TIA-1 NEGATIVE Aberrant T-cell phenotypes : CD2 CD3 CD5 EMA and ALK1 are negative

67. Subcutaneous Panniculitis-Like T-Cell Lymphoma T ypically involves subcutaneous adipose tissue  Median age: ~25 - 35 years F:M ~2:1 Solitary or multiple erythematous subcutaneous tender and deep nodules or plaques Lower / upper extremities, trunk, head and neck B symptoms in ~70% of patients

68. Cellular infiltrate involving both septa and lobules within the sub cutis Relative sparing of the overlying dermis and epidermis composed of small- to medium-sized lymphocytes with visible cytoplasm admixed with fewer large transformed cells with hyperchromatic nuclei.

69. TIA-1 –IHC showing characteristic rimming around individual adipocytes. Malignant cells express a mature CD3 + , CD4 − , and CD8 + T-cell phenotype. CD30 and CD56 staining are consistently negative.

70. Primary Cutaneous Gamma-Delta T-Cell Lymphoma Originating from a clonal proliferation of mature, activated γδ T cells with a cytotoxic phenotype Disseminated indurated plaques and ulcerated/necrotic nodules/tumors Scaly patches are infrequent Extremities and trunk A hemophagocytic syndrome occurs in 50% of patients Epidermotropism , diffusely dermal, panniculitic or combination pattern

71. Variably sized cells with irregular to pleomorphic nuclei and coarsely clumped chromatin Angioinvasion is common Phagocytosis of blood cells by histiocytes is observed Subcutaneous involvement with rimming of adipocytes

72. Neoplastic cells commonly demonstrate a CD3 + , CD2 + , CD4 − , CD5 − , CD7 +/− , CD8 − , and CD56 + phenotype Origin from a mature and activated cytotoxic γδ T cell, there is strong expression of cytotoxic proteins (TIA-1, granzyme B, and perforin )

73. CD3 CD56 TIA 1 Beta F1

74. Primary Cutaneous CD8-Positive Aggressive Epidermotropic Cytotoxic T-cell Lymphoma ( PCCD8AC-TCL) Proliferation of epidermotropic CD8 + cytotoxic T cells Aggressive clinical course Middle-aged to elderly (median age = 53 years ) M:F = 1.4:1 Localized / disseminated eruptive papules, nodules, or tumors with central ulceration and necrosis or hyperkeratotic patches and plaques Spread to other visceral sites(lung, testis, central nervous system, and oral mucosa), but nodal involvement is unusual

75. Heterogeneous patterns including lichenoid, nodular, or diffuse infiltrates Variably sized, pleomorphic T lymphocytes Commonly with marked epidermotropism

76. Epidermis may be acanthotic or atrophic with variable numbers of apoptotic keratinocytes and spongiosis Adnexal invasion/destruction is frequently present, while angioinvasion is less common

77. The neoplastic cells display a CD3 + , CD4 − , CD8 + , CD7 −/+ , CD45RA + , CD45RO − , granzyme B + , perforin + , and TIA-1 + p Ki67 proliferation index is high. CD2 ,CD5, CD56 and CD30 are negative No reactivity in tumor cells for EBER in situ hybridization

78. Primary Cutaneous CD4-Positive Small/Medium T-Cell Lymphoma( PCSM-TCL) Cutaneous infiltrate of small- to medium-sized, CD4 + , pleomorphic T cells Patients are adult or elderly. Range from multiple reddish papules to solitary plaque/nodules Upper half of the body (especially head and neck) The prognosis is excellent, particularly in cases with a solitary lesion

79. Dense, diffuse, or nodular infiltrate of small- to medium-sized pleomorphic T cells filling the dermis and often extending into the upper subcutis Infiltration of adnexal structures (sweat glands, pilar units) is common

80. POSITIVE CD3 CD4 The atypical CD4 + T cells express follicular T-cell markers PD-1 BCL6 CXCL13 NEGATIVE CD8 TIA-1 granzyme B CD30 CD10

81. Hydroa Vacciniforme –Like Lymphoma EBV + cutaneous lymphoproliferative disorder of childhood Papulovesicular eruption, systemic symptoms Predominantly affects children Lesions will arise on both sun-exposed and sun-protected areas Patients often develop systemic symptoms such as fever, weight loss, hepatosplenomegaly, and lymphadenopathy

82. Dense infiltrate of atypical αβ or γδ T which fill the dermis and into the subcutis . Overlying ulceration, necrosis, angiocentricity , and involvement of adnexal structures are common Positive for CD2, CD3, and CD8 +/− CD56 + ve in cases with NK-cell infiltrate. In situ hybridization for EBER is positive.

83. Indolent subtypes of CL Mycosis fungoides MF subtypes Early Folliculocentric MF Granulomatous slack skin Pagetoid reticulosis CD30 lymphoproliferative disorders (LPD) Anaplastic large cell lymphoma(ALCL), Lymphomatoid papulosis ( LyP ) Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) Cutaneous acral CD8+ T cell lymphoma CD4+small/medium T-cell lymphoproliferative disorder (SMPTCLPD) B-cell lymphomas: marginal zone lymphoma, follicle center lymphoma

84. Aggressive subtypes of CL Folliculocentric MF (“Advanced FMF”) Sezary Syndrome Adult T-cell leukemia /lymphoma Aggressive CD8+ epidermotropic cytotoxic TCL ( Berti’s ) Cutaneous gamma delta TCL (GDTCL) Extra nodal NK/T-cell lymphoma nasal type Chronic Active EBV Peripheral T-cell lymphoma, NOS Diffuse large B-cell lymphoma, leg type and intravascular B-cell lymphoma

85. T cell B cell Mostly epidermotropic Absent Has a lichenoid pattern Nodular and diffuse patterns Lacks Grenz zone Grenz zone present Top heavy Bottom heavy Usual patterns……………..

86. Epidermotropic infiltrates Neoplastic Non neoplastic MF Lymphocytic contact dermatitis Pagetoid reticulosis Lymphoid drug reactions Lymphomatoid papulosis Actinic reticuloid PCACE-TCL CD 8 + pseudolymphoma CGD-TCL Papuloerythroderma of Ofuji Extranodal NK/T cell Lymphoma ATLL

87. Dermal infiltrate High clinical index of lymphoma after ruling out drugs,IBR, infections, tattoos etc CD 3 predominant CD 20 predominant MF  PCS/MCD4+TLPD  PCACD8+TLPD  PCAEC8+TCL  PCGDTCL  CD 30 + Lyp /ALCL PCMZL PCFCL LG DLBCL IVBCL

88. S/c infiltrate SPTCL-Subcutaneous panniculitis like T cell Lymphoma PCGDTCL-Primary cutaneous gamma delta T cell lymphoma NK/TCL- Natural killer/T cell lymphoma CBL-Cutaneous B cell Lymphoma

89. Angiocentricity Gamma delta lymphoma TCR gamma delta (+) Rapid onset necrotic plaques/ tumors Extranodal NK/TCL, nasal type EBV+, CD56+, often mid-face/Asian Nodules/ tumors / plaques Lymphomatoid papulosis “E” CD30 (+), self-resolving papules

90. CUTANEOUS INVOLVEMENT BY SYSTEMIC LEUKEMIAS/LYMPHOMAS

91. Myeloid Lineage 1.Myeloid Sarcoma: Tumor mass consisting of myeloblasts occurring at an anatomical site other than the bone marrow and distorts the normal tissue architecture The most common extramedullary site in adults is the skin- cutaneous myeloid sarcoma (CMS) Higher incidence with AML with monocytic differentiation f/b AML with or without maturation

92. Multiple erythematous to hemorrhagic plaques and nodules

93. Mixed angiocentric and interstitial infiltration within dermis. Interstitial infiltrate of leukemic cells between dermal collagen bundles including “ single-file” pattern .

94. Perivascular infiltrate of cytologically monotonous and homogeneous myeloblasts . Immature chromatin and distinct nucleoli of blast forms.

95. Positivity may depend on the patterns of differentiation CD68 / KP1 ,  lysozyme ,  CD33 ,  CD43 : positive in high percentage of cases CD45 ,  MPO  and  CD117  are also commonly seen but are not present in all cases (likely in > 50% of cases) CD56 ,  CD34  and  TdT : positive in only subset of cases (likely in < 50% of cases) CD71  and  glycophorin  for lesions with erythroblastic differentiation   CD42b  and  CD61  for lesions with megakaryoblastic differentiation

96. Negative for lymphoid lineage markers, such as  CD20  and  CD3 Usually negative for  CD19  and  PAX5  but association with t(8;21)(q22;q22.1)  RUNX1-RUNX1T1  can show positive expression

97. 2.Chronic Myelomonocytic Leukemia CMML is defined by persistent peripheral blood monocytosis of greater than 1 × 10 9 cells/L, < 20% blasts in peripheral blood or bone marrow, and morphologic evidence of myeloid dysplasia. 4 distinct clinicopathologic groups: Myelomonocytic cell tumors Collections of mature plasmacytoid dendritic cells (PDCs) BPDCN( Blastic plasmacytoid dendritic cell neoplasm ) “ blastic indeterminate dendritic cell tumors ”

98. older adults/elderly with a male predominance. Multiple erythematous papules or nodules in a wide anatomic distribution. Collections of mature PDCs form disseminated erythematous macules and papules that may be pruritic, while BPDCN presents as bruise-colored plaques and nodules

99. The PDCs form multifocal nodules in the dermis. Bland cells with mature chromatin and moderate amounts of eosinophilic cytoplasm Mature PDCs express CD4, CD123, TCL-1, BDCA-2/CD303, and granzyme B Negative for CD56, myeloperoxidase, or lysozyme low Ki67 proliferation index

100. Plasmacytoid Dendritic Cell Lineage Blastic Plasmacytoid Dendritic Cell Neoplasm (previously known as blastic NK-cell lymphoma or CD4 + /CD56 + hematodermic neoplasm) Rare, aggressive neoplasm that is derived from the plasmacytoid dendritic cell precursor Middle-aged and elderly individuals, with a M:F -3:1 localized or multifocal Plum- or bruise-colored plaques or tumors covered by a glistening, attenuated epidermal layer

101. Diffuse interstitial infiltrate Sparing of the epidermis and extension into the subcutis Cells with intermediate size, irregular nuclear contours, slightly dispersed chromatin, and small distinct nucleoli. Extravasation of erythrocyte Positive CD4, CD56, CD123, TCL-1, CD2AP, and BDCA-2/CD303 show variable expression of terminal deoxynucleotidyl transferase ( TdT ), CD7, CD33, and CD68 Negative for CD3, CD20, CD79a, CD34, CD117, myeloperoxidase, and lysozyme

102. B-Cell Lineage 1.B Lymphoblastic Leukemia /Lymphoma High-grade malignancies derived from B lymphoblasts B-LBL has a propensity for bone and cutaneous sites Children and young adults who are younger than 35 years of age M:F- 1:1 Skin lesions-secondarily to or concomitant with B-ALL or nodal B-LBL Cutaneous B-LBL without evidence of disease elsewhere ( aleukemic leukemia cutis, or primary cutaneous B-LBL)

103. In patients with a prior diagnosis of B-ALL, cutaneous involvement may be the first sign of relapse following therapy. The lesions -solitary, less commonly multiple, erythematous papules and nodules. Predilection for head and neck sites

104. Diffuse dermal infiltrate sparing the overlying epidermis by a Grenz zone and extending into subcutis Homogeneous infiltrate of lymphoblasts with round to irregular nuclei containing finely stippled chromatin and small nucleoli . Positive B-lineage markers CD19, CD79a, CD22, and PAX5, CD10,CD20 The most consistent marker of immaturity is TdT Negative surface immunoglobulin and myeloperoxidase

105. 2.Chronic Lymphocytic Leukemia /Small Lymphocytic Lymphoma B-cell lymphoma composed of small lymphocytes that may be present in the bone marrow and peripheral blood (CLL) and/or in tissues, particularly lymph nodes (SLL). CLL/SLL is the most common mature B-cell neoplasm to secondarily involve the skin - leukemia cutis . Patients with CLL/SLL may also demonstrate nonneoplastic cutaneous changes ( leukemid reactions ) Infection, vasculitis, purpura, generalized pruritus, exfoliative erythroderma, and paraneoplastic pemphigus

106. Localized or disseminated erythematous papules, plaques, or nodules Head and neck, trunk, and/or extremities. “ facies leonina ” Transformation to a highgrade large B-cell lymphoma -known as Richter syndrome, Manifest as solitary or multiple rapidly growing subcutaneous nodules or tumors Richter syndrome is characterized by a diffuse infiltrate of large-sized immunoblasts and centroblasts

107. Dense periadnexal /perivascular infiltrate or a nodular/diffuse dermal infiltrate, intact grenz zone , extends into the underlying subcutaneous tissue Uniform populations of small lymphocytes containing rounded, hyperchromatic nuclei with inconspicuous nucleoli Express B-cell markers CD19, CD79a, and PAX5, as well as CD23 ; demonstrate aberrant expression of T-cell markers CD5 and CD4 Negative : CD10 and cyclin D1

108. 3.Mantle Cell Lymphoma B-cell lymphoma composed of small- to medium-sized lymphocytes with irregular nuclear contours Behaves more aggressively than CLL/SLL. The M/C site of involvement is the lymph node Other hematopoietic organs (bone marrow, peripheral blood, spleen) may also be involved. Cutaneous involvement is rare. solitary or multiple macules, nodules, or plaques

109. Diffuse population of small- to medium-sized lymphocytes filling the dermis with sparing of the overlying epidermis Morphologic evidence of the blastoid variant (mitotically active medium-sized cells with dispersed chromatin and distinct nucleoli) Express B-cell markers CD19, CD20, CD79a, and PAX5 ; demonstrate aberrant expression of T-cell marker CD5 and cyclin D1 Negative : CD10 or CD23

110. 4.Follicular Lymphoma B-cell lymphoma composed of admixed centrocytes and centroblasts , and most commonly arises in lymph nodes. Involvement of other hematopoietic sites (bone marrow, spleen, peripheral blood) Infrequently, FL involves extranodal / extramedullary sites such as skin, gastrointestinal tract, ocular adnexa, breast, and testis Head and neck is the most common location Lesions are often solitary. Relapse may occur in both cutaneous and extracutaneous sites.

111. The dermis is replaced by nodules of neoplastic cells that superficially resemble germinal centers but show attenuated mantle zones and lack the “starry-sky” appearance of reactive germinal centers owing to the absence of tingible -body macrophages. Positive B-cell markers (CD19, CD20, CD79a, PAX5) germinal center cell markers (CD10, BCL6), and aberrant expression of BCL2 Negative CD5, cyclin D1, and CD43.

112. 5.Plasma Cell Neoplasm Are a group of disorders characterized by an expansion of clonal plasma cells. Cutaneous involvement as secondary manifestation multiple myeloma Occurs in patients with late-stage disease and high tumor burden Cutaneous disease may also reflect direct extension from an underlying bony lesion. Multiple erythematous or violaceous papules or nodules occurring over a wide anatomic distribution Signal of advanced disease with a poor prognosis

113. Diffuse interstitial infiltration of the dermis associated with surface erosion Cellular infiltrate composed of plasma cells Strong reactivity for CD138 in the plasma cells Kappa and lambda CD20, CD19, and CD45 are characteristically negative

114. 6. Diffuse Large B-Cell Lymphoma Neoplasm of large B cells characterized by diffuse tissue infiltration. Red to purpuric papules, nodules, and infiltrated plaques. Solitary with a predilection for the head and neck region or trunk

115. Dermis is diffusely effaced by a destructive infiltrate . Uniform, monotonous population of large, transformed lymphoid cells resembling centroblasts or immunoblasts B-cell phenotype (expression of CD19, CD20, CD79a, and PAX5) and often a high Ki67 proliferation index Negative for CD15, CD30, CD138

116. 7.Plasmablastic Lymphoma Is an uncommon large B-cell lymphoma that arises in immunocompromised patients, often secondary to HIV infection but also in the post transplant setting Localized, single or multiple, asymptomatic red papules or nodules Composed of diffuse dermal infiltrates of large-sized cells, which may resemble immunoblasts or more plasmacytoid appearance with eccentrically placed nuclei. The overlying epidermis is spared.

117. Admixed mitotic figures, apoptotic bodies, and tingible -body macrophages are commonly observed. IHC is similar to that of plasma cells- CD138 and IRF4/MUM1 The Ki67 proliferation index is typically high. No expression of B-cell markers CD20 and PAX5 or of CD45

118. 8.Intravascular Large B-Cell Lymphoma Aggressive process( angiotropic ) Demonstrates intraluminal aggregation of large malignant B cells within vessels of involved tissues Indurated, red/purple plaques and nodules, preferentially on the trunk or thighs. Telangiectasia and epidermal changes due to ischemia, including scaling and ulceration, also may be observed

119. Superficial dermal vessels are partially occluded by hyperchromatic malignant cells. Malignant-appearing lymphocytes partially adherent to the endothelial surface of involved vessels. CD20 ,IRF4/MUM1 and BCL2 are commonly positive , and there is variable expression of CD5, CD10, and BCL6.

120. 9. Lymphomatoid Granulomatosis Rare and variably aggressive lymphoproliferative disorder Characterized by angiocentric and angiodestructive infiltration of extranodal tissues, including the skin, by EBV + B cells and reactive T cells Skin lesions manifest variably as multiple red papules, plaques, or nodules Commonly on the trunk and extremities .

121. Atypical lymphocytes have infiltrated and partially destroyed the involved vessel walls. The EBV + B cells are reactive for CD20, variably positive for CD30, and negative for CD15

122. T-/NK-Cell Lineage 1.T Lymphoblastic Leukemia/Lymphoma Is a high-risk neoplasm that is derived from precursor T lymphocytes. T-LBL typically arises in the mediastinum or lymph nodes, and cutaneous involvement is rare. Erythematous to hemorrhagic papules and nodules, or subcutaneous masses Cutaneous T-LBL is more commonly seen in the adult population

123. Dermis is preferentially involved by a diffuse interstitial infiltrate, with little or no epidermotropism , morphologically indistinguishable from B-LBL. Tumor cells are uniformly atypical, with scant cytoplasm and nuclei characterized by slightly irregular, sometimes grooved contours and moderately condensed to evenly dispersed chromatin patterns with small nucleoli. The tumor cells are positive for TdT and may express CD1a, CD2, CD3, CD4, CD5, CD7

124. 2. Anaplastic Large-Cell Lymphoma ALCL is a systemic T-cell neoplasm that is characterized by large, pleomorphic cells that strongly express CD30 lesions range from papules to ulcerating tumors. Cutaneous involvement – indicates worse prognosis A wide morphologic spectrum has been described Large cells may predominate (the common variant) Large cells may be admixed with histiocytes ( lymphohistiocytic variant) Smaller atypical lymphocytes (small-cell variant).

125. Diffuse dermal infiltrate by large, anaplastic lymphoid cells Positivity for CD 30 ,cytotoxic-associated markers(TIA-1, granzyme B, and perforin ) Pan-T-cell maturation markers (e.g., CD3, CD5, and CD7 ) are frequently negative

126. 3. Angioimmunoblastic T-Cell Lymphoma AITL is a nodal T-cell lymphoma Nonspecific eruptions of macules and papules over the trunk and extremities resembling a viral exanthem . Pruritus is frequently reported Involved lymph nodes show partial or complete architectural effacement with an interfollicular mixed polymorphous infiltrate of small- to medium-sized atypical lymphocytes

127. Superficial perivascular lymphoid infiltrate with or without atypia Often showing vascular hyperplasia; vasculitis Positive: CD3 coexpresses CD10 , PD-1, CXCL-13)

128. 4 . Adult T-Cell Leukemia /Lymphoma High-grade T-cell neoplasm caused by a retrovirus, human T-cell lymphotrophic virus type 1 (HTLV-1) Multiple local to disseminated erythematous patches, papules, plaques, nodules, and tumors to generalized erythroderma

129. Nodular to diffuse infiltrates of atypical lymphocytes, and may exhibit papillary dermal involvement, epidermotropism , and/or Pautrier microabscess formation, mimicking MF .

130. Neoplastic lymphocytes contain enlarged hyperchromatic nuclei with irregular, often convoluted nuclear contours. Anaplastic cells with clumped nuclear chromatin and prominent nucleoli may also be observed Positive: CD4 ,CD2, CD3, and CD5. CD25 , FoxP3 ,CD30. But generally lack CD7 and CD8

131. The peripheral blood contains atypical cells with hyperlobated nuclear profiles (“ flower cells”)

132. 5. Extranodal NK/T-Cell Lymphoma, Nasal Type Aggressive lymphoma characterized by angiocentric and angiodestructive infiltrates of EBV + malignant cells with an NKcell or, rarely, a cytotoxic T-cell phenotype Cutaneous involvement may be the primary manifestation of the disease (“primary cutaneous NK/T-cell lymphoma, nasal type”), or may occur secondarily. Rapidly growing reddish plaques or tumors, frequently with ulceration

133. Diffuse, focally angiocentric , and angiodestructive dermal/subcutaneous infiltrate with occ. focal epidermotropism . The epidermis may be ulcerated or in some may show florid pseudoepitheliomatous hyperplasia

134. Cells are medium in size with irregular to elongated nuclei, coarse chromatin, inconspicuous nucleoli, and moderate quantities of pale cytoplasm . Infiltration and fibrinoid necrosis of affected vessel walls, zones of coagulative necrosis, and apoptosis

135. 6. Peripheral T-Cell Lymphoma, Not Otherwise Specified Heterogeneous group of nodal and extranodal T-cell neoplasms that do not meet the criteria for the other T-cell malignancies defined by the current classification scheme. Solitary, localized or more commonly generalized eczematous plaques, modules, or erythematous tumors; pruritis Diffuse or nodular dermal and subcutaneous infiltrates with variable numbers of medium- to large-sized pleomorphic or immunoblast -like T cells are typical. Central ulceration may occur.

136. 7. T-Cell Prolymphocytic Leukemia T-PLL is a relatively rare, aggressive neoplasm composed of T cells with a mature, post thymic phenotype In addition to blood and bone marrow, sites of involvement include lymph nodes, liver, spleen, and skin Plaques and nodules that are variably erythematous to hemorrhagic in appearance TCR genes are rearranged

137. Perivascular dermal infiltrate without epidermotropism Circulating cells exhibit round to irregular nuclear contours, distinct nucleoli, and cytoplasmic blebs.

138. Classical Hodgkin Lymphoma Cutaneous involvement by CHL is exceedingly rare, occurs in advanced disease, and is indicative of a poor prognosis Asymptomatic erythematous papules and nodules that frequently demonstrate ulceration. Non neoplastic skin lesions including hyperpigmentation, urticarial, erythroderma, and alopecia. Nodular or diffuse dermal infiltration without epidermotropism

139. Pleomorphic infiltrate and a characteristic Reed–Sternberg cell and that is reactive for the CD30 antigen Positive - CD30 and often CD15 , show weak nuclear expression of PAX5 Negative for CD45 and CD20

140. Immunophenotype: T cells CD2, CD3, CD5, CD7, CD45RO(UCHL-1) : Mature T cells   CD4 : Helper T cells :  CD8 : Suppressor T cells :  CD5/CD43 : may see aberrant expression in B lymphomas  CD7/CD5 : may be lost in MF CD30 : activated lymphocytes CD25 : activated T, induced by HTLV-1 (ATLL)   TIA-1, granzyme B, perforin : cytotoxic T cells  TCR-beta (beta F1): identifies alpha/beta T cells TCR-gamma : identifies gamma delta T cells   PD-1: Follicular helper T-cells (CD4+SMTLPD, AILD)  CD56: ENKTCL-NT EBV: EBER

141. Immunophenotype B cells CD20, CD79a, CD19, CD22, CD23, Pax 5: Mature B cells CD5: T cell marker, expressed in some B cells (mantle cell lymphoma, B-CLL/SLL) CD23, LEF1: B-CLL/SLL Cyclin D-1, SOX11: mantle cell Bcl6, LM02, HGAL, CD10, Bcl2, MUM-1, IgM, EBER : helpful in subtyping B cell lymphoma MYC (and BCL2): for prognosis