Disclosures I have nothing to disclose. Pleomorphic sarcomas: MFH, - PowerPoint PPT Presentation

Disclosures I have nothing to disclose. Pleomorphic sarcomas: MFH, where did you go? Andrew Horvai, MD, PhD Clinical Professor, Pathology 78 year old man Questions ฀ Where did the diagnosis of MFH come from? Slowly growing 15 cm soft tissue mass in the thigh ฀ ฀ How can we subclassify pleomorphic sarcomas? Deep but does not involve bone ฀ Biopsy at referring hospital read as “MFH” ฀ What are meaningful clinicopathologic categories of ฀ pleomorphic sarcomas? 1

Where did MFH come from? Where did MFH come from? 1960s: Stout et al. multiple reports of “fibrous xanthoma” and 1972: Kempson and Kyriakos ฀ “histiocytoma” Cultured cells from MFH (Ozello, Stout and Murray) ฀ ฀ Initially ameboid movement, phagocytosis  histiocytes ฀ Later, bipolar spindled cells  fibroblasts ฀ “Facultative fibroblasts”: histiocytes capable of fibroblast differentiation Kauffman SL, Stout AP. Cancer 1961 14:469-82. Ozzello et al Cancer 1963 16:331-44. Kempson RL, Kyriakos M. Cancer 1972 961-76. “Histiocytes” MFH Histotype? Theories ฀ ฀ Facultative fibroblasts (facultative histiocytes?) ฀ Mixture of fibroblasts and histiocytes ฀ Stem cell with dual differentiation into fibroblasts and histiocytes Problems ฀ ฀ No histotype supported by ancillary diagnostic and in-vitro methods ฀ Some well-differentiated tumors (liposarcoma, leiomyosarcoma, etc.) contain areas indistinguishable from pleomorphic, storiform or giant- cell MFH ฀ No unifying genetic changes (usually profound genomic instability) 2

Reappraisal of MFH Reappraisal of MFH (2001) Undifferentiated sarcoma Evans tumor Other Myxofibrosarcoma Fibrosarcomatous DFSP Myofibroblastic sarcoma Leiomyosarcoma Osteosarcoma WD liposarcoma Myogenic sarcoma NOS Pleomorphic Rhabdomyosarcoma liposarcoma Fletcher CD. AJSP 1992 16:213-28. Fletcher CD et al J Clin Oncol 2001, 19:3045. Fletcher CD et al J Clin Oncol 2001, 19:3045. Reappraisal of MFH Reappraisal of MFH (2001) (UCSF, 2017) Undifferentiated sarcoma Dedifferentiated liposarcoma Undifferentiated sarcoma Pleomorphic rhabdomyosarcoma MPNST Adult fibrosarcoma Pleomorphic hyalinizing angiectatic tumor Myxoinflammatory fibroblasic sarcoma 3

Pleomorphic tumors are not always sarcoma Reappraisal of MFH Diagnosis Clin-path clues Immunostains Genetics Clinically meaningful classification, what is practical?  Sarcomatoid carcinoma Cohesive cells, clinical history, Diffuse keratin Not sarcoma superficial near epithelium P63+ INI1 intact   Melanoma Melanoma Nesting, in-situ component, SOX10, S100, HMB45, BRAF V600E pigment MelanA  Carcinoma Germ cell tumor Young patient, para-aortic, SALL4, OCT4, Keratin,  Others: Germ cell, hematopoietic mediastinum, history CD30 Hematolymphoid In nodal anatomic sites, LCA, CD4, MPO, CD30 Variable Sarcoma (limited data)  multifocal, round cells, dyshesive  Defined histotype  Dedifferentiated liposarcoma better than “MFH”  Myogenic sarcoma “worse” than non-myogenic  Uncertain histotype  Myxofibrosarcoma  Atypical fibroxanthoma / pleomorphic dermal sarcoma  Myxoinflammatory fibroblastic sarcoma  Undifferentiated pleomorphic sarcoma (UPS) Sarcomatoid carcinoma Sarcomatoid carcinoma 4

Sarcomatoid carcinoma Melanoma Keratin EMA p63 INI1 T2 F/S T2 F/S Melanoma Melanoma 5

Pleomorphic sarcomas with defined Melanoma histotype S100 SOX10 Diagnosis Clin-path clues Stains Genetics Dedifferentiated Well differentiated component, MDM2, CDK4 Amp(12q13-15) liposarcoma retroperitoneum, scrotum Rhabdomyosarcoma Strap cells Myogenin, MyoD1, desmin Leiomyosarcoma Abundant dense cytoplasm Caldesmon, SMA, desmin (2 of 3) Myofibrosarcoma Loose, fasciitis-like SMA (tram-track) MelanA Pleomorphic Pleomorphic lipoblasts Oil red O liposarcoma Extraskeletal Produces osteoid or bone SATB2 (sensitive, not osteosarcoma specific) Malignant peripheral NF1, pre-existing benign nerve SOX10, S100 (sens. ~ nerve sheath tumor sheath tumor 50%) H3K27Me3 loss Pleomorphic sarcomas with Dedifferentiated liposarcoma defined histotype McCormick et al Am J Surg Pathol 1994, 18:1213-23. 6

Dedifferentiated liposarcoma Dedifferentiated Liposarcoma: Pleomorphic sarcomas with 12q13-15 amplification defined histotype Leiomyosarcoma ฀ Rhabdomyosarcoma ฀ Myofibroblastic ฀ MDM2, CDK4 sarcoma “Myogenic NOS” ฀ Horvai et al. 2009 Mod Pathol 22(S1): 14A Fletcher CD et al J Clin Oncol 2001, 19:3045. 7

Pleomorphic leiomyosarcoma Pleomorphic leiomyosarcoma SMA Desmin Caldesmon Caldesmon Pleomorphic rhabdomyosarcoma Pleomorphic rhabdomyosarcoma 8

Pleomorphic rhabdomyosarcoma (myogenin) Myofibroblastic sarcoma Myofibroblastic sarcoma Myofibroblastic sarcoma Desmin SMA Caldesmon Caldesmon 9

Pleomorphic sarcomas with uncertain Pleomorphic sarcomas with histotype defined histotype - clinical Diagnosis Recurrence Metastasis Mortality Diagnosis Clin-path clues Stains Genetics Dedifferentiated 51% 15% 26% @ 5 yrs. Myxofibrosarcoma Superficial, predominantly Nonspecific, most Variable liposarcoma myxoid, branching vessels negative Myogenic sarcomas ?% 56% 39% @ 20 yrs. Atypical fibroxanthoma / Dermal, subcutaneous, sun Nonspecific: Vimentin, NOTCH1/2 Pleomorphic dermal damage CD10; negative for FAT1 sarcoma keratin and melanocytic Undifferentiated 13-42% 31-35% 37% @ 5 yrs. Pleomorphic hyalinizing Foot, middle age, damaged S100 negative TGFBR3-MGEA5 pleomorphic sarcoma angiectatic tumor vessels, 0-1/10 hpf Myxoinflammatory Acral, foot, pseudolipoblasts, Nonspecific BRAF (in pure fibroblastic sarcoma inflammation, <1 mf / 50 hpf MIFS) McCormick et al Am J Surg Pathol 1994, 18:1213-23. Fletcher CD et al J Clin Oncol 2001, 19:3045. Myxofibrosarcoma (myxoid “MFH”) Myxofibrosarcoma 10

Atypical fibroxanthoma, Atypical fibroxanthoma, undifferentiated dermal sarcoma pleomorphic dermal sarcoma McCalmont TH. J Cutan Pathol 2011; 38:853. McCalmont TH. J Cutan Pathol. 2012 39:8. Pleomorphic hyalinizing Myxoinflammatory fibroblastic angiectatic tumor (PHAT) sarcoma (MIFS) 11

Myxoinflammatory fibroblastic Pleomorphic sarcomas with sarcoma (MIFS) uncertain histotype - clinical Diagnosis Recurrence Metastasis Mortality Myxofibrosarcoma 31% 15% 23% @ 3 yrs. (grade 1-3) Atypical fibroxanthoma 8% 0-3% 0-2% @ 20 yrs. Pleomorphic dermal 28% 5-10% 0-2% @ 2 yrs. sarcoma Pleomorphic hyalinizing 33% 0% 0% @ 4 yrs. angiectatic tumor Myxoinflammatory 51% 2% 0% @ 5 yrs. fibroblastic sarcoma Undifferentiated 13-42% 31-35% 37% @ 5 yrs. pleomorphic sarcoma Odei B et al. Am J Clin Oncol 2017 epub. Koch M et al. Anticancer Res 2015 35:5717. Miller K et al. Am J Surg Pathol 2012 36:1317. Folpe AL, Weiss SW. Am J Surg Pathol 2004 11:14-17. Laskin WB et al. Am J Surg Pathol 2014 38:1. Roland CL et al. Ann Surg Oncol 2016 23:2220. How much further should we How much further should we subdivide UPS? subdivide UPS? Lymphoma: DLBCL, Lymphoma: DLBCL, ฀ ฀ Undifferent Undifferenti- anaplastic anaplastic ated iated sarcoma sarcoma Myeloid sarcoma Myeloid sarcoma ฀ ฀ Follicular “dendritic cell” Follicular “dendritic cell” ฀ ฀ Interdigitating “dendritic cell” Interdigitating “dendritic cell” ฀ ฀ True histiocytic sarcoma True histiocytic sarcoma ฀ ฀ Cannatella J and Horvai A. Manuscript in prep Cannatella J and Horvai A. Manuscript in prep 12

Take-home messages What do I do? 1. Avoid the diagnosis of Malignant Fibrous Histiocytoma (MFH). 2. Unclassified Pleomorphic Sarcoma (UPS) is a diagnosis of exclusion. Biopsy: 3. Prior to diagnosing UPS, exclude non-sarcomas, myogenic ฀ ฀ Desmin, SOX10, Keratin sarcoma, dedifferentiated liposarcoma. ฀ History of NF1: S100, H3K27Me3 4. Consider AFX/PDS based on dermal location ฀ Looks myoid: SMA, caldesmon ฀ If retroperitoneal, scrotal or imaging to suggest fat: MDM2, CDK4 Excision: ฀ ฀ H&E: lipoblasts, cartilage, bone, benign neurofibroma, mitotic activity ฀ Same stains as above ฀ Make sure mitoses correlate with pleomorphism esp. in feet 13