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
28
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
45
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!
54
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
67
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-?
115
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)
132
133 Guo et al. Genes Chromosomes Cancer 2011 Manner et al. Am J Pathol 2010
134
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
Myxo-inflammatory Fibroblastic sarcoma
AKA Myxo-inflammatory Fibroblastic sarcoma Acral Myxoinflammatory fibroblastic sarcomaam.j.surg.path1998; 22; 911-924 Inflammatory myxoid tumour of soft parts with bizarre giant cells [Pathol.Res.Pract.
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