SOFT TISSUE TUMOR PATHOLOGY: AN UPDATE

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1 SOFT TISSUE TUMOR PATHOLOGY: AN UPDATE Jason L. Hornick, MD, PhD July 18, 2013 Department of Pathology Brigham and Women s Hospital Harvard Medical School Boston, MA, USA

2 I have no disclosures.

3 New Soft Tissue Tumors Not really new tumors! Uncommon lesions that previously went unrecognized, or Were confused with more common tumor types Collected over years of observation and finally formally described

4 Value in Describing New Soft Tissue Tumors Provide guidelines for separating histologically similar lesions Significant differences in clinical behavior and/or prognosis Facilitate appropriate clinical management and patient follow-up

5 Discovery of New Molecular Genetic Findings in Soft Tissue Tumors Provides insights into pathogenesis Often validates histology-based classification Results in new tools for reproducible diagnosis: Antibodies for immunohistochemistry Probes for FISH / primers for RT-PCR

6 OUTLINE 1. Hemosiderotic fibrolipomatous tumor and myxoinflammatory fibroblastic sarcoma 2. Pseudomyogenic hemangioendothelioma 3. Atypical intradermal smooth muscle neoplasm and cutaneous leiomyosarcoma 4. Hybrid schwannoma/perineurioma 5. Myoepithelioma/myoepithelial carcinoma 6. Post-radiation atypical vascular lesions and cutaneous angiosarcoma

7 HEMOSIDEROTIC FIBROLIPOMATOUS TUMOR AND MYXOINFLAMMATORY FIBROBLASTIC SARCOMA

8 Hemosiderotic Fibrolipomatous Tumor First described as hemosiderotic fibrohistiocytic lipomatous lesion Believed to be a reactive process Now known to be neoplastic Uncommon subcutaneous tumor Ankle and foot of adults Ill-defined margins May recur locally (non-destructive)

9 Hemosiderotic Fibrolipomatous Tumor: Histology Variable admixture of mature adipose tissue and bland fibroblasts Short fascicles and whorls Honeycomb infiltration of fat Prominent hemosiderin deposition May show focal nuclear atypia and pleomorphism Some cases with focally prominent myxoid stroma

10 Hemosiderotic Fibrolipomatous Tumor

11 Hemosiderotic Fibrolipomatous Tumor

12 Myxoinflammatory Fibroblastic Sarcoma Originally also described as: Inflammatory myxohyaline tumor of distal extremities with virocyte or Reed-Sternberglike cells Inflammatory myxoid tumor of soft parts with bizarre giant cells Low grade sarcoma Hands/fingers/wrists >> ankles/feet Significant recurrent potential Rarely metastasize

13 Myxoinflammatory Fibroblastic Sarcoma: Histology Multinodular, infiltrative Hypocellular, myxoid stroma-rich areas with pseudolipoblasts Cellular areas with fibroblastic spindle cells and prominent chronic inflammation Highly variable proportions Large atypical mononuclear/multinucleate cells with inclusion-like nucleoli ( Reed- Sternberg-like or virocyte-like )

14 Myxoinflammatory Fibroblastic Sarcoma

15 Myxoinflammatory Fibroblastic Sarcoma

16 Myxoinflammatory Fibroblastic Sarcoma

17 Myxoinflammatory Fibroblastic Sarcoma

18 Myxoinflammatory Fibroblastic Sarcoma

19 Myxoinflammatory Fibroblastic Sarcoma

20 Myxoinflammatory Fibroblastic Sarcoma

21 Myxoinflammatory Fibroblastic Sarcoma

22 Myxoinflammatory Fibroblastic Sarcoma

23 Myxoinflammatory Fibroblastic Sarcoma Reed-Sternberg-like cells

24 Relationship between these tumor types? MIFS may contain focal areas indistinguishable from HFLT HFLT may contain focal areas with myxoid stroma and occasional atypical or pleomorphic cells HFLT may recur as MIFS

25 Hybrid HFLT/MIFS

26 Hybrid HFLT/MIFS

27 Shared Molecular Genetics! t(1;10)(p22;q24) TGFBR3-MGEA5 Ring chromosomes with 3p12 amplification Same findings in HFLT, MIFS, and hybrid tumors

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29 Elco CP et al. Am J Surg Pathol 2011

30 HFLT karyotype & FISH TGFBR3 45,XX, t(1;10)(p13;q24),del(3)(p11), 15[6] MGEA5 Centromeric Telomeric Courtesy of Paola Dal Cin, Ph.D. Genes Chromosomes Cancer 2011

31 HFLT MIFS MIFS

32 PSEUDOMYOGENIC HEMANGIOENDOTHELIOMA

33 Pseudomyogenic Hemangioendothelioma Originally reported as fibroma-like variant of epithelioid sarcoma Also known as epithelioid sarcoma-like hemangioendothelioma Distinctive rarely metastasizing endothelial neoplasm Often presents with multiple discontiguous nodules in different tissue planes of a limb Histologically mimics a myoid tumor

34 Pseudomyogenic Hemangioendothelioma: Clinical Features Striking male predominance (5:1) Young adults (peak in 2 nd and 3 rd decades) Most patients (75%) present with cutaneous nodules 50% intramuscular; 20% intraosseous lesions 50% local recurrences or develop additional nodules in same anatomic area Usually within 1-2 years of first excision Despite ominous clinical presentation, distant metastasis rare

35 Pseudomyogenic Hemangioendothelioma: Histology Infiltrative margins Sheets, loose fascicles Relatively uniform plump spindle cells with abundant brightly eosinophilic cytoplasm May mimic rhabdomyoblasts 50% with prominent stromal neutrophils Cutaneous tumors often show overlying epidermal hyperplasia Often infiltrate into subcutaneous tissue

36 Pseudomyogenic Hemangioendothelioma

37 Pseudomyogenic Hemangioendothelioma

38 Pseudomyogenic Hemangioendothelioma

39 Pseudomyogenic Hemangioendothelioma

40 Pseudomyogenic Hemangioendothelioma

41 Pseudomyogenic Hemangioendothelioma

42 Pseudomyogenic Hemangioendothelioma

43 Pseudomyogenic Hemangioendothelioma

44 Pseudomyogenic Hemangioendothelioma

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46 Pseudomyogenic Hemangioendothelioma

47 Pseudomyogenic Hemangioendothelioma

48 Pseudomyogenic Hemangioendothelioma

49 Pseudomyogenic Hemangioendothelioma: Immunohistochemistry Diffusely positive for keratin AE1/AE3 Nuclear staining for FLI1 and ERG 50% positive for CD31 Negative for EMA, keratin MNF116, CD34 Expression of INI1 retained

50 Pseudomyogenic Hemangioendothelioma AE1/AE3 ERG

51 der(7)t(7;19) in 1 of 9 additional cases by FISH

52 ATYPICAL INTRADERMAL SMOOTH MUSCLE NEOPLASM AND CUTANEOUS LEIOMYOSARCOMA

53 Cutaneous Leiomyosarcoma Nomenclature widely used for cutaneous smooth muscle tumors with nuclear atypia and/or mitotic activity Predilection for middle-aged and elderly adult male patients Usually arise on trunk and lower extremities Older studies did not distinguish between purely dermal and subcutaneous tumors When confined to the dermis, no metastatic potential Sarcoma designation inappropriate!

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55 Atypical Cutaneous Smooth Muscle Tumors: Outcome Massi et al. 36 cases Follow-up on 27 cases (16 limited to dermis; 11 minimal subcutaneous extension) 3 local recurrence 1 distant metastasis at 15 yrs (primary tumor with minimal subcutaneous extension) Kraft and Fletcher 84 cases Follow-up on 52 cases 18 local recurrence None metastasized

56 Atypical Intradermal Smooth Muscle Neoplasm: Histology Predominantly infiltrative growth pattern Nodular areas Fascicles ramifying through dermal collagen bundles Limited extension into superficial subcutaneous tissue with pushing border Spindle cells with broad nuclei, brightly eosinophilic cytoplasm Degree of nuclear atypia, pleomorphism, mitotic activity irrelevant

57 Atypical Intradermal Smooth Muscle Neoplasm: Immunohistochemistry Similar to smooth muscle tumors of other sites: SMA, desmin, caldesmon nearly always positive Broad-spectrum keratins expressed in 50%

58 Pilar Leiomyoma desmin

59 Pilar Leiomyoma

60 Atypical Intradermal Smooth Muscle Neoplasm desmin

61 Atypical Intradermal Smooth Muscle Neoplasm

62 Atypical Intradermal Smooth Muscle Neoplasm

63 Cutaneous Leiomyosarcoma

64 Classification of Smooth Muscle Tumors of the Superficial Soft Tissues Confined to the dermis: Pilar leiomyoma Atypical intradermal smooth muscle neoplasm Involve dermis and infiltrate subcutis: Cutaneous leiomyosarcoma Involve subcutis: Angioleiomyoma Subcutaneous leiomyosarcoma

65 HYBRID SCHWANNOMA/PERINEURIOMA

66 THE NERVE SHEATH

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68 Hybrid Nerve Sheath Tumors Benign nerve sheath tumors: Schwannoma Neurofibroma Perineurioma In recent years, tumors containing elements of >1 type of nerve sheath tumor recognized First: hybrid neurofibroma/schwannoma (schwannomatous nodules within otherwise typical neurofibroma) Recently: hybrid schwannoma/perineurioma

69 Soft Tissue Perineurioma: Clinical Features Equal gender distribution Wide age range; uncommon in children Most common in limbs, but can arise at essentially any anatomic site Painless subcutaneous mass ~25% deep soft tissue; 10% skin Benign, rarely recur

70 Soft Tissue Perineurioma: Histology Well circumscribed, unencapsulated Storiform, lamellar, whorled architecture Collagenous >> myxoid stroma Thin, elongated spindle cells with delicate bipolar cytoplasmic processes Some cases with ovoid cells EMA positive (may be weak) CD34 in 65%; claudin-1 in 30%

71 Soft Tissue Perineurioma

72 Soft Tissue Perineurioma

73 Soft Tissue Perineurioma

74 Soft Tissue Perineurioma

75 Soft Tissue Perineurioma

76 Soft Tissue Perineurioma

77 Soft Tissue Perineurioma

78 Cutaneous Perineurioma

79 Cutaneous Perineurioma

80 Soft Tissue Perineurioma

81 Soft Tissue Perineurioma EMA

82 Soft Tissue Perineurioma EMA

83 Soft Tissue Perineurioma CD34

84 Hybrid Schwannoma/Perineurioma: Clinical Features Usually involve skin and subcutaneous tissue More rarely deep soft tissue or visceral sites Wide age range and anatomic distribution No association with neurofibromatosis Rarely recur locally

85 Hybrid Schwannoma/Perineurioma: Histology Architecture like soft tissue perineurioma: Storiform and whorled growth pattern Predominantly Schwannian cytology: Plump spindle cells with tapering nuclei and eosinophilic cytoplasm Less conspicuous perineurial cell component: Slender nuclei and delicate elongated cytoplasmic processes Degenerative atypia relatively common

86 Hybrid Schwannoma/Perineurioma

87 Hybrid Schwannoma/Perineurioma

88 Hybrid Schwannoma/Perineurioma

89 Hybrid Schwannoma/Perineurioma

90 Hybrid Schwannoma/Perineurioma

91 Hybrid Schwannoma/Perineurioma

92 Hybrid Schwannoma/Perineurioma

93 Hybrid Schwannoma/Perineurioma S100

94 Hybrid Schwannoma/Perineurioma EMA

95 Hybrid Schwannoma/Perineurioma EMA (brown) S100 (red)

96 MYOEPITHELIOMA/ MYOEPITHELIAL CARCINOMA

97 Myoepithelial Tumors of Skin and Soft Tissue Histologically similar to salivary gland counterparts Cutaneous myoepithelial tumors lie on a spectrum, ranging from mixed tumor ( chondroid syringoma ) to pure myoepithelioma, to malignant counterparts Malignant myoepithelial tumors known as myoepithelial carcinomas Cutaneous myoepithelioma: predilection for extremities, male predominance Usually present as painless nodule

98 Myoepithelial Tumors of Skin and Soft Tissue: Histology Lobulated architecture Reticular, trabecular, or nested growth pattern Variably prominent myxoid stroma Predominantly epithelioid cells with eosinophilic cytoplasm Wide range in cytology: spindle cell, clear cell, plasmacytoid (hyaline cell) components Intratumoral heterogeneity typical Myoepithelial carcinoma: moderate/severe nuclear atypia

99 Myoepithelioma

100 Myoepithelioma

101 Myoepithelioma

102 Myoepithelial Carcinoma

103 Myoepithelial Carcinoma

104 Myoepithelial Carcinoma

105 Myoepithelial Tumors of Skin and Soft Tissue: Immunohistochemistry Usually positive for keratins, EMA, S100 50% positive for GFAP Variable expression of muscle markers (esp. calponin, SMA) Variable expression of p63 Distinctive syncytial variant: negative for keratins

106 Myoepithelioma EMA S100

107 Cutaneous Syncytial Myoepithelioma Distinctive variant exclusive to the skin Sheets of ovoid to epithelioid cells Palely eosinophilic cytoplasm Indistinct cell borders Irregular tumor margins Benign, rarely recur

108 Cutaneous Syncytial Myoepithelioma

109 Cutaneous Syncytial Myoepithelioma

110 Cutaneous Syncytial Myoepithelioma

111 Cutaneous Syncytial Myoepithelioma

112 Cutaneous Syncytial Myoepithelioma

113 Cutaneous Syncytial Myoepithelioma

114 Myoepithelial Tumors of Skin and Soft Tissue: Molecular Genetics EWSR1 rearrangements in ~50% Novel fusion partners EWSR1-PBX1 EWSR1-POU5F1 EWSR1-ZNF444 These fusion partners only account for 1/3 of myoepithelial tumors with EWSR1 rearrangements Cutaneous syncytial myoepithelioma EWSR1-?

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116 Antonescu et al. Genes Chromosomes Cancer 2010

117 Courtesy of Alex Lazar

118 POST-RADIATION ATYPICAL VASCULAR LESIONS AND CUTANEOUS ANGIOSARCOMA

119 Post-radiation Atypical Vascular Lesions and Cutaneous Angiosarcoma Spectrum of cutaneous vascular proliferations after breast-conserving surgery and radiation therapy Atypical vascular lesions may be multifocal, usually benign course Angiosarcoma locally destructive and significant potential for metastasis Considerable clinical and histologic overlap

120 Atypical Post-radiation Vascular Proliferation: Histology Often relatively well-circumscribed Superficial to mid-dermis Dilated, dissecting vascular channels Endothelial cells with hobnail appearance common No multilayering, mitotic activity, or significant nuclear atypia No infiltration of subcutaneous tissue

121 Atypical Post-radiation Vascular Proliferation

122 Atypical Post-radiation Vascular Proliferation

123 Atypical Post-radiation Vascular Proliferation

124 Atypical Post-radiation Vascular Proliferation

125 Atypical Post-radiation Vascular Proliferation

126 Cutaneous Angiosarcoma

127 Cutaneous Angiosarcoma

128 Cutaneous Angiosarcoma

129 Epithelioid Angiosarcoma

130 Spindle Cell Angiosarcoma

131 Post-radiation Cutaneous Angiosarcoma: Molecular Genetics Consistent high-level amplification of MYC gene (8q24) Not observed in atypical vascular lesions, primary mammary angiosarcoma, or angiosarcoma of sun-damaged skin Subset also shows amplification of FLT4 gene (encoding VEGFR3)

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133 Guo et al. Genes Chromosomes Cancer 2011 Manner et al. Am J Pathol 2010

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135 Cutaneous Angiosarcoma MYC

136 Cutaneous Angiosarcoma MYC

137 Summary Classification of soft tissue tumors continues to evolve as new lesions are described Recognition of distinct clinical behavior helps guide management and follow-up Molecular genetic discoveries provide insights into pathogenesis and classification Lead to development of new tools to improve diagnostic accuracy