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1 Enterprise Interest Nothing to declare

2 Diagnoses one would not like to miss in soft tissue pathology early in your career Marta Sbaraglia, MD Department of Pathology Hospital of Treviso University of Padua

3 Introduction Mistakes can be minimized not abolished Expertise requires time to be developed Challenging cases have greater impact at early stages of career Rarity Exposure to low volume Intrinsic difficulty Lower impact of educational efforts

4 Approach to Diagnosis Clinical presentation Histomorphology Cell shape Pattern of growth Quality of background Type of vascular network Immunophenotype Molecular genetics

5 Case History 10 year-old, boy Subcutaneous nodule of 1,4x1 cm. in the left arm No history of trauma

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7 Differential Diagnosis Dermic Undifferentiated Pleomorphic Sarcoma Low mitotic activity No necrosis

8 Differential Diagnosis Dermic Undifferentiated Pleomorphic Sarcoma Low mitotic activity No necrosis Malignant Melanoma (metastatic) Young age S100 -; Melan A

9 Differential Diagnosis Dermic Undifferentiated Pleomorphic Sarcoma Low mitotic activity No necrosis Malignant Melanoma (metastatic) Young age S100 -; Melan A Sarcomatoid Carcinoma Young age Pan Cytokeratins

10 Differential Diagnosis Dermic Undifferentiated Pleomorphic Sarcoma Low mitotic activity No necrosis Malignant Melanoma (metastatic) Young age S100 -; Melan A Sarcomatoid Carcinoma Young age Pan Cytokeratins Benign (psedosarcomatous) Mesenchymal Tumor

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12 Deep Fibrous Histiocytoma Well-circumscribed Broad age range In brief Storiform or diffuse pattern of growth Nuclear pleomorphism may be observed (6%) Low mitotic activity 20% rate of local recurrence Distant metastasis were reported

13 Take Home Messages Deep FH is a poorly recognized tumor Deep FH can shows striking pleomorphism Pleomorphism per se does not equal malignancy

14 Case History 57 year-old, female Skin lesion of the lombar region One year before an atypical fibrous histiocytoma was diagnosed in the same region Local recurrence Diagnosis changed to sarcomatoid carcinoma TC-PET revealed no other lesions

15 Infiltrative, highly cellular, spindle cell neoplasm Disrupting skin appendages Infiltration of subcutis

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17 CK AE1/AE3

18 SMA Desmin Myf4 MyoD1

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20 Immunohistochemical spectrum of rhabdomyosarcoma and rhabdomyosarcoma-like tumors. Expression of cytokeratin and the 68-kD neurofilament protein. The results show that typical RMS may demonstrate immunohistological pleomorphism with cytokeratin and neurofilament immunoreactivity suggesting the presence of multidirectional differentiation. In addition, there are tumors that by morphology look like RMS and have muscle cell markers but cannot be verified as RMS by electron microscopy; also, these tumors seem to show immunohistological pleomorphism. The presence of non myoid markers in RMS should be considered when making immunohistological diagnosis of soft tissue sarcomas. Miettinen M, rapola J. Am J Surg Pathol Feb;13(2):

21 Rhabdomyosarcoma of the skin Differential Diagnosis Spindle cell carcinoma Cytokeratins +; rhabdomyogenic markers negative Malignant Melanoma S100 +; melanocytic markers +/-; BRAF or NRAS mutation Leiomyosarcoma Rhabdomyogenic markers negative

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23 Adult-type Spindle Cell Rhabdomyosarcoma In Brief 9% of adult RMS Most common in head and neck region Spindle cell (LMS-like) morphology Rhabdomyoblasts quite rare Frequently associated with MYOD1 gene mutation Poor prognosis in adult Am J Surg Pathol 2005;29: J Pathol 2014; 232:

24 Take Home Messages Not all spindle cell, cytokeratin positive, cutaneous malignancies are spindle cell carcinomas Cytokeratins expressed in several non epithelial lesions Leiomyosarcoma Melanoma Epithelioid sarcoma Epithelioid angiosarcoma/epithelioid Emangioendothelioma Rhabdomyosarcoma

25 Case History 8 year-old boy Painless swelling in the distal phalanx of the second finger of the left hand

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27 Differential Diagnosis Benign Necrobiotic Process Conventional-type Epithelioid Sarcoma Epithelioid MPNST

28 CKAE1/AE3 INI1

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30 Classic-type Epithelioid Sarcoma

31 Grannuloma Anulare

32 INI1/SMARCB1 and ES IHC: INI1 lost in ~95% of epithelioid sarcomas Some cases have 22q11 translocations Most tumors show homozygous deletion of INI1 locus Mutations rarely detected Helpful in differential diagnosis Metastatic carcinomas, epithelioid vascular tumors (angiosarcoma, EHE) and melanoma retain INI1

33 SMARCB1-deficent Tumors Malignant Rhabdoid Tumor (100%) Atypical Rhabdoid/Teratoid Tumor of the SNC (100%) E-MPNST and E-schwannoma (50%) Myoepithelial tumors (10-40%) EMCHS (?%) Synovial sarcoma (20-80%) Medullary carcinoma of kidney Collecting duct carcinoma

34 S100 INI1

35 S100 INI1

36 Epithelioid Sarcoma Franz Enzinger Cancer 1970; 26:

37 Epithelioid Sarcoma of Enzinger In Brief Upper distal extremities Adolescents and young adults Epithelioid cells with mild nuclear atypia High recurrence rate with proximal extension To be kept separate from proxymal type Pelvis, perineum and genital tract Adult Epithelioid/Rhabdoid morphology

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39 Often challenging Take Home Messages Young adults May mimic benign processes Frequent cause of medical litigation Immunophenotype Expression of epithelial markes 95% Loss of INI1 expression 40% expression of CD34; ERG Protracted clinical course however deadly

40 Case History 51 year-old, female Recurrent polypoid mass in the nasal cavity Monophasic synovial sarcoma diagnosed 10 years earlier with incomplete surgery

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42

43 SMA S100 desmin myf4

44 Synovial sarcoma Differential Diagnosis EMA/CK +; SYT rearrangements Spindle cells rhabdomyosarcoma Diffusely positive for myogenic markers; S100 most often negative Malignant SFT HPC-like spindle cell neoplasm CD34/STAT6 + MPNST (Malignant Triton Tumor) High grade tumor Frequently NF1 associated Lost of nuclear expression of H3K27

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46

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48 Byphenotipic Sinonasal Sarcoma Middle-aged woman Superior sinonasal tract In Brief Highly cellular uniform spindle cell proliferation Infiltrative growth Concurrent proliferation of surface-type glandular epithelium Prominent HPC-like vascular pattern Associated with PAX3 rearrangements Low risk of recurrence No distant metastases reported

49 Take home massages Low grade malignancy Not to be confused with far more aggressive lesions Synovial sarcoma Spindle cell RMS Malignant SFT MPNST

50 Expertise When your are young everything looks challenging Expertise takes time to be achieved The expert is the one who knows more and more about less and less... In the end he/she knows everything about nothing

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