Newer soft tissue entities

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1 Newer soft tissue entities Examples among fibroblastic tumors Turku, May 6, 2010 Markku Miettinen, M.D. AFIP, Washington, DC

2 Fibroblastic neoplasms Solitary fibrous tumor /Hemangiopericytoma Low-grade fibromyxoid sarcoma Myxohyaline tumor of distal extremities Inflammatory myofibroblastic tumor Superficial acral fibromyxoma

3 Solitary fibrous tumor Considered closely related if not synonymous with hemangiopericytoma in the 2002 WHO classification Wide variety of locations: besides pleura most common in the Head and neck, Pelvis/Abdomen, Trunk and relatively rare in the extremities Spectrum in biologic behavior (most are benign)

4 Inguinal mass, 63 year man - Solitary fibrous tumor

5 Anatomic location of 1500 non-pleural SFT/hemangiopericytomas (AFIP) Upper extremity 7% Neck 5% Brain 10% Lower extremity 13% Orbit 9% Sinonasal 10% Intra-abdominal 14% Other head 13% Trunk 19%

6 Solitary fibrous tumor Related terms Hemangiopericytoma of soft tissues Deep fibrous histiocytoma of soft tissues Lipomatous hemangiopericytoma Giant cell angiofibroma (Orbit, Soft Tissue) Am J Surg Pathol 1995;19: , Am J Surg Pathol 2000;24:

7 Hemangiopericytoma in the meninges Aggressive neoplasm with almost regular recurrence Relatively common bone metastases Should not be equated with solitary fibrous tumor Solitary fibrous tumors of CNS: Mixed group, benign tumors a majority among reported ones

8 Solitary fibrous tumor Histologic features Alternating cellular and fibrous areas Hemangiopericytoma-like staghorn vessels Diffuse, corded and trabecular patterns Focal myxoid stroma in some cases Mitotic activity varies Focal to more prominent atypia possible Necrosis (larger tumors) Hypercellular foci

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12 Prediction of behavior of solitary fibrous tumor/non-cns hemangiopericytoma Same criteria are applied Largest study of Hemangiopericytoma (Enzinger & Smith, Hum Pathol 1976;7:61-82) Mitotic rate > 4/10 HPFs increases risk of malignant behavior Tumors large > 5 cm, unusual atypia, and tumor necrosis: Uncertain potential, even if mitotic rate is low Late recurrences after 1st surgery Metastases: Lungs, liver, bone

13 Giant cell angiofibroma variant of solitary fibrous tumor

14 Solitary fibrous tumor Special studies CD34 positive SMA occasional Karatin rare cells (occasional) No genetic tests available No recurrent translocations known

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16 Highly cellular focus

17 Sarcomatous transformation

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19 Low-grade fibromyxoid sarcoma (Evans 1987) Predilection to young adults Intramuscular tumor of extemities and trunk, often >10cm Previously classified under benign diagnosis: fibroma, fibromatosis, deep fibrous histiocytoma, neurofibroma Lung metastases may develop in a span of years Also soft tissue metastases, local recurrences Long survival with metastatic disease Metastasis may precede discovery of primary tumor

20 Low-grade fibromyxoid sarcoma

21 Pulmonary metastases of low-grade fibromyxoid sarcoma (10th thoracic surgery)

22 40 Age and sex distribution of 156 patients w low-grade fibromyxoid sarcomas Female Male Age (years)

23 Anatomic distribution of 150 low-grade fibromyxoid sarcomas Lower extremity 36% Head and neck 10% Upper extremity 20% Trunk 34%

24 Low-grade fibromyxoid sarcoma Key histologic features Variable micronodularity Alternating myxoid and collagenous zones Moderate cellularity Fibroblastic atypia mild to none Low mitotic rare (inconspicuous) Prominent capillaries (often) Hyaline rosettes (some cases) Epitheloid cell foci

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29 Hyalinizing spindle cell tumor with giant rosettes Lane et al. Am J Surg Pathol 1997;21: Folpe at al. Am J Surg Pathol 2000;24: Morphologic variant of low-grade fibromyxoid sarcoma Similar demographic profile (young adults) Poorly formed hyaline rosettes common in LGFMS Well-formed rosettes and LGFMS areas in same tumor Same fusion translocation t(7;16)(q34;p11) FUS-CREB3L2 fusion Rarely FUS-CREB3L1 [t(11;16)(p11;p11)]

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34 Low-grade fibromyxoid sarcoma Special studies No specific immunohistochemical markers Negative for Desmin, S100 protein, SMA Variably positive for EMA Genetics Typical fusion translocation t (7;16)(q33;p11) (Karyotyping) FUS-CREB3L2 fusion (PCR, FISH for FUS rearrangement) Alternative fusion FUS-CREB3L1 t(11;16)(p11;p11) [FUS rearrangement also in myxoid liposarcoma]

35 Low grade fibromyxoid sarcoma Abbott Molecular

36 Sclerosing epithelioid fibrosarcoma = Low-grade fibromyxoid sarcoma? Guillou et al. Am J. Surg Pathol 2007;31:

37 Low-grade Fibromyxoid sarcoma vs. Low-grade Myxofibrosarcoma (Myxoid MFH) Low-grade fibromyxoid sarcoma Predilection to young Usually intramuscular Alternating fibrous and myxoid areas Myxofibrosarcoma Predilection to old Often subcutaneous More uniformly myxoid Limited nuclear atypia Inconspicuous mitotic activity Notable nuclear atypia Often atypical mitoses

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40 Acral myxoinflammatory fibroblastic sarcoma Meis-Kindblom & Kindblom 1998 Inflammatory myxohyaline tumor of distal extremities Montgomery & al Hands, fingers and feet/ankle Predilection to young adults Earlier desginations: Myxoid MFH, proliferative synovitis Poorly defined nodule, often dorsal hand/foot Subcutaneous Good prognosis, questionable metastatic potential Local recurrences relatively common

41 40 Age and sex distribution of 126 patient myxohyaline tumors of distal extrem Female Male Age (years

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43 Acral myxoinflammatory fibroblastic sarcoma Inflammatory myxohyaline tumor of distal extremities Histologic features Multinodular Inflammatory appearance of low magnification Variably lymphocytes, eosinophils, plasma cells Vacuolated cells - pseudolipoblasts Epithelioid tumor cells (histiocyte-like) Reed-Sternberg-like cells with macronucleoli Low mitotic activity? Cases with transitional morphology to myxoid MFH

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49 Hodgkin-solua muistuttavia atyppisiä fibroblasteja

50 Acral myxoinflammatory fibroblastic sarcoma Inflammatory myxohyaline tumor of distal extremities Immunohistochemistry Keratin+ cells in 20% of cases, also EMA focally Potential confusion with epithelioid sarcoma Vimentin+ Tumor cells negative for CD34, CD163, Des, SMA, S100

51 Keratin+ tumor cells in acral fibrosarcoma

52 Inflammatory myofibroblastic tumor Previous terminology Inflammatory pseudotumor (GI, lung) Plasma cell granuloma (Lung) Inflammatory fibrosarcoma (Abdomen) Postoperative spindle cell nodule (Bladder) Leiomyosarcoma (Bladder, GI-tract) Pseudosarcomatous fibromyxoid tumor (Bladder) Pseudosarcomatous myofibroblastic tumor (Bladder)

53 Inflammatory myofibroblastic tumor Typically in children and young adults GI-tract, abdomen, lung, urinary bladder Histologically distinctive: spindle cells with abundant amphophilic cytoplasm, lymphocytes and plasma cells Most examples benign, 5% have malignant behavior Malignancy criteria not well-studied

54 Inflammatory myofibroblastic tumors

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60 Inflammatory myofibroblastic tumor Immunohistochemistry ALK (CD246) positive Often (50%), not a defining feature SMA+, variable, Des+ rare Keratins + often (bladder, GI) Negative for KIT, S100, Myogenin (differential diagnosis w rhadbomyosarcoma)

61 Cytoplasmic ALK-positivity in inflammatory myofibroblastic tumor

62 Genetics of inflammatory myofibroblastic tumor ALK gene rearrrangements at 2p23 Typically activating translocations TPM3-ALK, TPM4-ALK Similar translocations in large cell anaplastic lymphoma Resulting in ALK-overactivity FISH diagnosis for ALK-rearrangement (ALK break-apart probe)

63 ALK gene fusions in inflammatory myofibroblastic tumor Table 1. Gene fusions and translocations involving the ALK-gene in inflammatory myofibroblastic tumor. *Translocation has also been observed cytogenetically. FUSION PARTNERSExpected translocation Tumor location Age Sex Ref. TPM3-ALK t(1;2)(q21;p23)* Abdomen 23 y female 62 Lung 30 y female TPM4-ALK t(2;19)(p23;p13)* Abdomen 1 y male 62 CLTC-ALK t(2;17)(p23;q11) Neck 3 y female 63 CARS-ALK t(2;11)(p23;p15) Cervical paraspinal soft tissue 10 y male 64 Pelvis 37 y male ATIC-ALK t(2;2)(p23;q35) Urinary bladder 46 y male 65 RANBP2-ALK t(2;2)(p23;q12) Base of mesentery 7 mos male 66 Abdomen 7 y male SEC31L1-ALK t(2;4)(p23;q21)* Omentum 23 y male 67

64 Superficial acral fibromyxoma Pathology Median age 40 yrs, M:F 2:1 Predilection to distal extemities, 50% involves nail bed Low recurrence rate: 10-15% Uniform spindle cells in myxoid or myxocollagenous matrix Alternating myxoid and collagenous zones Accentuated microvessels Numerous mast cells Low mitotic rate (1-7 per 50 HPFs) Rare focal atypia

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69 Superficial acral fibromyxoma: Immunohistochemical profile Positive for: CD34 (91%), EMA (72%) Negative for: Des, SMA, S100, HMB45, GFAP

70 CD34

71 EMA

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