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5/25/19 Disclosure I have no conflicts of interest to disclose Hematopoietic neoplasms presenting as soft tissue tumors Karthik Ganapathi Associate Clinical Professor Hematopathology, Dept. of Laboratory Medicine University of California,

  1. 5/25/19 Disclosure • I have no conflicts of interest to disclose Hematopoietic neoplasms presenting as soft tissue tumors Karthik Ganapathi Associate Clinical Professor Hematopathology, Dept. of Laboratory Medicine University of California, San Francisco Current Issues in Anatomic Pathology May 23, 2019 Objectives Outline • To recognize morphologic and • Case presentation immunophenotypic features of common and uncommon hematopoietic neoplasms • Morphologic features and immunophenotype presenting as soft tissue tumors • Final diagnosis, ancillary studies and review • To effectively utilize ancillary studies in the workup of these entities 1

  2. 5/25/19 Case 1 • 53-year old man with a PMH of CAD presented with abdominal pain and weight loss • Imaging showed a 5 x 4 x 4 cm retroperitoneal mass • A biopsy was performed CD45 CD20 CD43 CD2 CD3 EMA CD30 ALK1 2

  3. 5/25/19 Anaplastic large cell lymphoma (ALCL) Case 1 - Diagnosis • CD30-positive mature T-cell lymphoma with anaplastic morphology • 2017 WHO Heme classification – ALCL, ALK-positive (ALCL, ALK+); + for ALK rearrangement – ALCL, ALK-negative (ALCL, ALK-) Anaplastic large cell lymphoma, ALK-negative – Breast implant-associated ALCL (BI-ALCL) - for ALK rearrangement – Primary cutaneous ALCL (C-ALCL) • Significant clinicopathologic differences between ALCL subtypes; hence subclassification is important • Accurate diagnosis - immunohistochemistry and FISH studies ALCL, ALK- ALCL, ALK- • Disease predominantly of older adults (40-65 yrs.) • Immunophenotype – CD30 - strong and diffuse (> 80% of tumor cells, membranous and Golgi • Nodal or extranodal (soft tissue, bone) presentation pattern) • Advanced stage with B-symptoms – variable CD30 staining on a subset of cells NOT ACCEPTABLE - a more accepted diagnosis in this situation is peripheral T-cell lymphoma, not • Histology otherwise specified (PTCL, NOS) with CD30 expression – Sheets of cohesive large, anaplastic cells with pleomorphic nuclei – ALK1 is NEGATIVE by definition – Loss of one or more pan T-cell markers (CD3, CD2, CD5, CD7) seen in a – Hallmark cells (indented nuclei with cytoplasmic pseudoinclusions), subset of cases doughnut cells, multi-nucleated tumor cells frequent – Usually positive for CD2, CD4, TIA-1, Granzyme B, Perforin – Foci resembling undifferentiated carcinoma or sarcoma seen in a subset of – Negative for CD8, CD15, CD56, EBV cases – Most cases are more pleomorphic than ALCL, ALK+ Null cell phenotype • – Loss of all pan T-cell antigens and CD45 - not as common as in ALCL, ALK+ but has been reported – CD43 almost always positive (indicates hematopoietic origin) – T-cell receptor gene rearrangement studies can confirm T-cell origin 3

  4. 5/25/19 Genetics of ALCL, ALK- PTCL, NOS with ALCL CD30 expression • Genetically heterogenous with different clinical outcomes • Rearrangements of DUSP22 (6p25.3) seen in ~ 30% • Rearrangements of TP63 secondary to inv(3)(q26q28)( TBL1XR1/TP63 ) seen in ~ 10% • DUSP22- rearranged ALCL have a good prognosis, comparable to ALCL, ALK+ • TP63-rearranged ALCL have dismal prognosis • ALCL cases lacking ALK , DUSP22 and TP63 rearrangements, referred to as triple-negative ALCL • DUSP22 but not TP63 rearrangements described in C-ALCL • To date all BI-ALCL cases are triple negative CD30 CD30 Diagnostic algorithm in ALCL Outcomes in ALCL ALCL diagnosis based on morphology and immunophenotype Positive ALK1 IHC Negative Dx: ALCL, ALK- Dx: ALCL, ALK+ P63 IHC FISH for ALK rearrangement (optional) Positive Negative FISH for DUSP22 and FISH for DUSP22 TP63 rearrangements rearrangement Parrilla Castellar ER, Jaffe ES, et al. Blood. 2014 Aug 28;124(9):1473-80. 4

  5. 5/25/19 Case 2 • 65-year old woman with PMH significant for hypertension presented with lower extremity weakness • Imaging studies showed a T11 paraspinal mass • A biopsy was performed S100 CD1a CD45 CD4 Pan CK HMB45 Other negative immunostains GFAP, CK7, CK20, CD20, CD3, CD30, ALK-1, CD34, CD21, CD35, BRAF, MPO CD68 CD163 5

  6. 5/25/19 Histiocytic sarcoma (HS) Case 2 - Diagnosis • Aggressive neoplasms derived from mature histiocytes/macrophages • No age predilection but more often in adults Histiocytic sarcoma • Predominantly extranodal (soft tissue, GI, brain) • Neoplastic cells are large, pleomorphic with abundant eosinophilic cytoplasm (finely vacuolated) • Features of activated macrophages (hemophagocytosis) can be present • Mitotic figures (incl. atypical forms) and necrosis often seen Diagnostic workup of HS HS - Immunophenotype • A diagnosis of HS requires • Positive – Absence of specific epithelial, mesenchymal, melanocytic, – CD45 (variable), CD68 (KP1 and PGM1), CD163 (most lymphoid markers specific), CD4, CD14, PU.1 (nuclear), Lysozyme – Presence of monocytic/macrophage markers – S100 (weak expression in a subset of cases) – Absence of primitive/immature hematopoietic markers • Differential diagnosis • Negative – Non-hematopoietic neoplasms (high-grade carcinoma, – CD20, CD3, CD30 (B-, T-cell lymphoma) pleomorphic sarcoma, melanoma) – Lymphoma (diffuse large B-cell, anaplastic large cell) – CD1a, Langerin (Langerhans cell sarcoma) – Myeloid sarcoma – CD21, CD23, CD35, Clusterin (Follicular dendritic cell – Other histiocytic/dendritic neoplasms sarcoma) – CD34, CD117, CD13, MPO (Myeloid sarcoma) • Expression of at least 2 histiocytic markers is preferred - no official minimal requirement 6

  7. 5/25/19 HS - Ancillary testing Case 3 • FISH – No specific recurrent cytogenetic aberrations (diagnostic or • 15-year old girl who was previously healthy prognostic) presented with jaw pain, swelling and fevers for 2 • Molecular months – Recurrent mutations in RAS-MAPK pathway (MAP2K1, NRAS, KRAS, BRAF, PTPN11, NF1, CBL) identified in a subset • Imaging studies showed a lytic left mandibular • A subset of cases show clonal relationships with lymphoid mass neoplasms – Mostly B-cell lymphomas (Follicular lymphoma, CLL/SLL, Mantle cell lymphoma) – HS share molecular and cytogenetic aberrations with these lesions • A biopsy was performed – Thought to represent transdifferentiation/ dedifferentiation – No prognostic significance Pan CK Desmin S100 CD56 7

  8. 5/25/19 Case 3 - Diagnosis CD45 CD4 Myeloid sarcoma MPO TdT Other negative immunostains - Myogenin, Myo D1, PAX-5, CD3 Concurrent bone marrow flow cytometry - abnormal monocytic events positive for CD4, CD11c, CD13, CD56, CD64 and negative for CD14, CD34, CD117 Myeloid sarcoma (MS) MS - Morphology • Tumor mass of myeloid blasts occurring outside the bone • Cells - cohesive aggregates of intermediate to large mononuclear marrow - any anatomical site cells - blastoid morphology may not be obvious • Architectural effacement a requirement - otherwise it is • Differential diagnosis leukemic infiltration of tissue (eg: leukemia cutis) – Non-hematopoietic neoplasms (high-grade carcinoma, • MS can occur in different clinical settings pleomorphic sarcoma, melanoma) – De novo (in the absence of an underlying myeloid neoplasm) – Lymphoma (diffuse large B-cell) – Associated with AML (before, during or after a dx of AML) – Histiocytic sarcoma – Blastic transformation of MDS, MPN and MDS/MPN • The differentiation between myeloid sarcoma and histiocytic • MS is treated like AML; studies have shown similar prognostic sarcoma can be difficult findings as in AML – complex karyotype denotes poor prognosis – MS - less pleomorphic, coarse/evenly distributed chromatin – MS arising in the background of other myeloid neoplasms – HS - larger cells, more pleomorphic, vesicular nuclei associated with poor outcome 8

  9. 5/25/19 MS - Immunophenotype MS - Ancillary testing • FISH • A significant subset of MS have myelomonocytic or monocytic/monoblastic features – In non-decalcified specimens, AML FISH can identify recurrent cytogenetic aberrations that can help subclassify and guide therapy • Positive – t(8;21)( RUNX1/RUNX1T1 ) - can often present as MS – Myeloid: CD34, CD117, CD33, Lysozyme, MPO (subset) – Monocytic/Monoblastic: CD14 (subset), CD68, CD163 – Erythroid: CD71, Glycophorin A/C, Hemoglobin • Molecular – Megakaryoblastic: CD61, CD42b, vWF Ag – NPM1 mutations seem to be more prevalent in MS (especially cutaneous lesions) • CD45 and MPO stains can be inconsistent but CD43 is almost – FLT3 mutations have been described always positive – Can be useful for prognosis and management • CD56 is positive in a subset of cases (incl. non-monocytic) • A diagnosis of MS should prompt a bone marrow biopsy with appropriate workup • If clinical history available, flow cytometry can be useful Case 4 • 59-year old man with no significant PMH presented with a left thigh mass • Palpation showed a poorly-circumscribed subcutaneous mass with attached skin, 5 x 4 x 2 cm • A biopsy of the mass including representative overlying normal-appearing skin was performed 9

  10. 5/25/19 S100 S100 Rosai-Dorfman Disease (RDD) Case 4 - Diagnosis • Rare subtype of non-Langerhans cell histiocytosis • Familial, immune-related and neoplasia-associated subtypes recognized Rosai-Dorfman disease • Approximately 50% cases extranodal (any tissue can be (Rosai-Dorfman-Destombes disease) involved), but skin and subcutaneous tissue most common • Mutually exclusive mutations in KRAS and MAP2K1 identified in ~ 1/3 rd of RDD patients - confirms clonal origin • Managed with surgery, radiation and corticosteroids 10

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