Hematolymphoid lesions of the skin Part II Myeloid neoplastic proliferations Houston Society of Clinical Pathologists Symposium April 14, 2018

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1 Hematolymphoid lesions of the skin Part II Myeloid neoplastic proliferations Houston Society of Clinical Pathologists Symposium April 14, 2018 Carlos A. Torres-Cabala, MD Associate Professor Chief, Dermatopathology Section The University of Texas MD Anderson Cancer Center Houston, Texas

2 No conflicts of interest to disclose

3 Myeloid leukemia cutis Skin involvement in myeloproliferative disorders (CMML) Blastic plasmacytoid dendritic cell neoplasm

4 Myeloid Leukemia Cutis

5 Myeloid Leukemia Cutis Leukemia cutis (LC) by myeloid (granulocytic or monocytic) neoplastic cells occurs in the setting of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative disorders (MPDs) Rare cases of cutaneous involvement without systemic disease are reported as aleukemic LC

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7 Myeloid Leukemia Cutis

8 Myeloid Leukemia Cutis LC occurs in about 10% of patients with AML, less frequently in chronic myeloproliferative disorders The most common types of AML involving skin are AMML and acute monocytic leukemia (50% of patients present with skin involvement) Patients present with a solitary or multiple erythematous, violaceous, or hemorrhagic papules or nodules The prognosis of LC is usually poor

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10 Courtesy of Dr. C. Chian

11 Myeloid Leukemia Cutis LC presents as a perivascular and periadnexal or diffuse infiltrate of mononuclear cells involving dermis and subcutis without extension into the epidermis The term myeloid sarcoma applies when the proliferation of immature myeloid (granulocytic) cells completely effaces the skin architecture (and corresponds to extrahematopoietic myeloid leukemia mostly de novo )

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17 Myeloid Leukemia Cutis The cytologic appearance of the tumor cells vary according to the type of leukemia and therefore the infiltrate may show blastic, monocytoid/histiocytic, or pleomorphic features; in some cases it mimics carcinoma Immature eosinophils may be present

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19 Myeloid Leukemia Cutis Confounding findings: Numerous neutrophils, with or without leukocytoclasia (Sweet syndrome-like) Numerous histiocyte-like cells (Histiocytoid Sweet syndrome-like) Granulomatous changes (and GA-like pattern)

20 Myeloid Leukemia Cutis The AML and MDS cells are commonly positive for CD43 Other markers useful in the diagnosis: lysozyme, myeloperoxidase (at least focally), myeloid nuclear differentiation antigen (MNDA), CD68, and CD45, and may express CD34, CD33, CD4, CD117, CD163, CD56, CD123, HLA-DR In general: lack of expression of T-cell markers, B-cell markers, and CD30

21 Subtil A

22 A B A. CD43 B. CD33 C. Myeloperoxidase C

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24 Myeloid Leukemia Cutis CD34 and CD117 have been reported to have relatively low sensitivity (10-30%) AMML is most likely to be negative for CD34 and CD117 CD34 is often negative in NPM1-mutated cases

25 Myeloid Leukemia Cutis Some AML may express B cell markers: CD19, PAX5, CD79a (AML with t(8;21) Discrepancies between blood/bone marrow and skin phenotypes are not uncommon (CD34)

26 Myeloid Leukemia Cutis Cytogenetics shows normal karyotype in about 40%, complex abnormalities (20%), aneuploidy of chromosome 8 (15%) (Benet et al. 2011) Complex karyotype seems to be most frequent in secondary (39%) than de novo cases (17%) (Claerhout et al. 2018)

27 Myeloid Leukemia Cutis Demonstration of genetic abnormalities is sometimes necessary for a diagnosis of LC or myeloid sarcoma These findings include abnormalities in chromosome 8 copy numbers, monosomy 7, NPM1 mutations, inv (16), and MLL (11q23) gene rearrangement, among others

28 Myeloid Leukemia Cutis In a recent report (Claerhout et al. 2018), de novo MS demonstrated RUNX1-RUNX1T1 (10%), followed by CBFB-MYH11, KMT2A- MLLT3, and JAK2 V617F mutation

29 Eur J Haematol Mar 12

30 Myeloid Leukemia Cutis Molecular tests may aid may confirm and/or establish the diagnosis of LC in aleukemic patients

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32 E. CD68, F. CD163, G. CD33, H. CD43, I. CD34, J. MPO

33 K. Molecular analysis. A01: bone marrow; B01: skin

34 Cutaneous Manifestations of Myeloproliferative Neoplasms (Chronic Myelomonocytic Leukemia)

35 CMML CMML is a chronic hematologic disorder that displays features of both a myeloproliferative and a myelodysplastic syndrome

36 CMML Chronic myelomonocytic leukemia (CMML) cells in the skin have been described to variably display a spectrum of molecules of dendritic cell differentiation in addition to the myeloid markers already described, such as CD123, TCL1, CD1a, and S100

37 CMML Vitte et al. studied a large series of CMML cases involving skin and described four patterns: Myelomonocytic cell tumors Mature plasmacytoid dendritic cell neoplasms Blastic plasmacytoid dendritic cell neoplasms Blastic indeterminate dendritic cell tumors

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45 A clonal relationship between CMML and cutaneous indeterminate dendritic cell neoplasm is supported by the ability of malignant monocytes to differentiate into dendritic cells in vitro IDCN in patients with CMML may be part of the continuum of myeloid, monocytic, and dendritic cell subsets conforming a single hematopoietic neoplasm

46 Blastic Plasmacytoid Dendritic Cell Neoplasm

47 BPDCN Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare tumor thought to derive from precursors of plasmacytoid dendritic cells (pdc, professional type I interferonproducing cells) BPDCN usually affects male adults and presents as asymptomatic nodules or bruiselike lesions, most of the cases without evidence of extracutaneous disease

48 Courtesy of Dr. M. Postigo

49 BPDCN As the disease progresses, it involves peripheral blood and bone marrow At diagnosis most patients present with stage IV disease Cases presenting without skin involvement are extremely rare; most patients eventually develop cutaneous lesions

50 BPDCN Patients develop leukemia in the terminal stage of the disease Median survival is months About a quarter of the cases present with myelodysplasia or other myeloid disorders: 10 to 20% are associated or progress into myeloid processes such as CMML (most frequently), MDS, or AML

51 BPDCN BPDCN is characterized by a dense diffuse infiltrate involving dermis and subcutis, composed by medium-sized cells with blastic appearance Dermal hemorrhage is frequent Less cellular, perivascular infiltrates can be seen in cases undergoing therapy.

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55 BPDCN The tumor cells in BPDCN are classically CD4+/CD56+, but occasional cases with negative or only weak expression of one of the two markers can be encountered 8% of cases are negative for CD4 or CD56

56 BPDCN Other more specific markers of plasmacytoid dendritic cells such as CD123, TCL-1, and TCF4 are generally expressed The tumor cells may express CD43, CD45RA, CD45, CD7, CD2, CD33, CD68 (50-80% as dotlike cytoplasmic pattern), and TdT

57 CD4 CD123 CD56 TdT

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61 CD123/TCF4

62 BPDCN The tumor cells can express other plasmacytoid dendritic cell-associated markers: BDCA-2/CD303 (blood dendritic cell antigen 2, most sensitive marker?), MxA (interferon alpha-dependent) Other hematopoietic precursor-associated antigens (CD38, HLA-DR) are expressed in most of the cases

63 BPDCN 25-30% positive for S100 (more frequently in children) 30% positive for TdT May express BCL2, BCL6, MUM1

64 BPDCN Usually negative for: myeloblastic markers (CD13, MPO, MNDA) monoblastic markers (CD11c, CD14, lysozyme) B and T lymphoblasts (CD19, PAX5, CD3, LAT, CD5, CD20) CD34, CD117, EBER

65 BPDCN Somatic mutations in NRAS, ATM, TET2 and TP53, among others, have been identified in BPDCN ASXL1, IKZF3, ATM, MET, KRAS, IDH2, KIT, APC, RB1, VHL, BRAF, MLH1, RET Some of these mutations are also seen in myeloid leukemias, underscoring the close relationship between BPDCN and myeloid disorders

66 BPDCN Inactivation of tumor suppressor genes (RB1, TP53, ASXL1, PBRM1, CDKN2A/CDKN2B/CDKN1B), activation of oncogenes (NRAS, KRAS), mutations in epigenetic regulators (TET2, TET1, DNMT3A, IDH1, IDH2), frequently mutated in AML and MDS Mutations in IKAROS family genes (IKZF3/IKZF1) and ATM, also found in lymphoid neoplasms Most frequent: TET2 (36%), ASXL1 (32%), NRAS (20%), NPM1 (20%) Same mutations of TET2 and SRSF2 were detected in both CMML and BPDCN

67 BPDCN Genomic losses are frequent Complex aberrations similar to those seen in MDS/AML Losses in 5q21 or 5q34, 12p13, 13q13-q21, 6q23-qter, 15q, chromosome 9 Deleted regions involve 9p21.3 (CDKN2A/CDKN2B), 13q13.1-q14.3 (RB1), 12p13.2-p13.1 (CDKN1B), 13q11-q12 (LATS2), and 7p12.2 (IKZF1) Biallelic loss of 9p21.3 appears to be associated with bad prognosis

68 BPDCN Shorter survival: extensive marrow or peripheral blood blastosis, low TdT, low CD303, low Ki67, CDKN2A/CDKN2B deletions, mutations in DNA methylation pathway genes Boddu et al (MDACC) reported 10-15% of cases showing 8q24/MYC rearrangement and response to ALL therapies

69 Plasmacytoid dendritic cells (pdc) are not present in normal skin Reactive infiltrates rich in pdc can be seen in skin in: Allergic contact hypersensitivity reactions Lupus erythematosus Psoriasis Positive reactions to tuberculin skin test (PPD) Viral infections (herpes simplex, varicella) Hydroa vacciniforme

70 Aggregates of PDCs can be seen in Kikuchi, Castleman hyaline-vascular disease, among others, but these are not extensive nodules

71 Mature plasmacytoid dendritic cell proliferation associated with myeloid neoplasms Most patients with CMML, rarely MDS, AML with monocytic differentiation, NO CML Lymphadenopathy and skin lesions (multiple erythematous macules or papules) Infiltrates of cells similar to normal PDC, with occasional rims of cells phenotypically corresponding to interdigitating dendritic cells (S100+, CD1a+) IHC: similar to normal PDC with occasional aberrant expression of CD2, CD5, CD7, CD10, CD13, CD14, CD15, CD33, low Ki67, negative TdT, CD34

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73 Mature plasmacytoid dendritic cell proliferation associated with myeloid neoplasms There is evidence of clonal relationship between these cells and the myeloid tumor Treatment of the myeloid neoplasm may result in regression of the plasmacytoid dendritic cell infiltrates Prognosis is dismal (evolution of the myeloid process)

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78 Immunology Jan 3

79 Take home messages CD43 is an important marker for the diagnosis of myeloid leukemia cutis Be aware that MPO and lysozyme can be only focally positive in myeloid leukemia cutis CD34 and CD117 may be negative in myeloid leukemia cutis; phenotype discrepancies with bone marrow leukemic cells occur

80 Take home messages Remember that myeloid, monocytoid, and dendritic cells display great plasticity Be aware of histiocytoid or indeterminate dendritic cell proliferations that actually represent involvement by myeloid neoplasms

81 Take home messages Plasmacytoid dendritic cells are not found in normal skin; these cells are usually CD56 negative and Granzyme B positive Tumors derived from plasmacytoid dendritic cells may show a mature phenotype or a blastic phenotype (BPDCN)

82 Acknowledgements Dermatopathology Section Dr. Victor Prieto Dr. Doina Ivan Dr. Jonathan Curry Dr. Michael Tetzlaff Dr. Phyu Aung Dr. Priya Nagarajan

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