Case 1. Disclosure. Imaging. Clinical history 5/10/2016. USCAP 2016 Annual Meeting Evening Specialty Conference Bone and Soft tissue Pathology
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1 Disclosure Dr. Agaram has nothing to disclose Case 1 Narsi Agaram, MBBS USCAP 2016 Annual Meeting Evening Specialty Conference Bone and Soft tissue Pathology Clinical history Imaging 1998 A three month old female infant presented with an enlarging mass in the left chest wall. 1
2 Histology 2
3 Differential Diagnosis Infantile Fibrosarcoma Rhabdomyosarcoma 3
4 Immunoprofile Immunoprofile Negative for: SMA HHF35 CD34 S100 EMA BCl2 Keratins DESMIN MYOGENIN Diagnosis Diagnosis Embryonal Rhabdomyosarcoma with spindle cell features. Spindle Cell / Sclerosing Rhabdomyosarcoma. Molecular studies: No evidence of PAX3 FKHR or PAX7 FKHR gene fusions. 4
5 Rhabdomyosarcoma Spindle Cell / Sclerosing RMS update Embryonal Alveolar Pleomorphic Rhabdomyosarcoma Spindle cell RMS Embryonal Alveolar Pleomorphic Spindle cell / Sclerosing 5
6 Spindle cell RMS Spindle Cell RMS morphology 1992 Cavazzana et al. German Italian Cooperative Sarcoma Study. (21 cases) 1993 Leushner et al. Intergroup Rhabdomyosarcoma Study (43 cases) Site: Paratesticular and Head and Neck Pediatric age group favorable behavior Cavazzana AO et al. Am J Surg Pathol 16(3); , 1992 Leuschner I et al. Am J Surg Pathol 17(3); , 1993 Nascimento AF and Fletcher CDM. Am J Surg Pathol 2005;29: Nascimento AF and Fletcher CDM. Am J Surg Pathol 2005;29: Sclerosing RMS Sclerosing RMS Mentzel and Katenkamp (2000) Sclerosing, pseudovascular rhabdomyosarcoma in adults (3 cases) Folpe et al. (2002) Sclerosing rhabdomyosarcoma in adults (4 cases) MentzelT and Katenkamp. Virchows Arch (2000) 436: Folpe AL et al. Am J Surg Pathol 26(9): ,
7 Sclerosing RMS morphology Spindle Cell / Sclerosing RMS Overlapping clinical and morphologic features of Spindle cell and Sclerosing RMS MentzelT and Katenkamp. Virchows Arch (2000) 436: FolpeAL et al. Am J Surg Pathol 26(9): , 2002 Genetics of Sp / Scl RMS Recent developments Genetics of Sp / Scl RMS Recent developments No FOXO1 related gene fusions. Mosquera et al. (2013) 21 RMS (17 spindle cell and 4 sclerosing) NCOA2 rearrangements in 3 congenital / infantile RMS. SRF NCOA2 TEAD1 NCOA2 Mosquera JM et al. Genes, Chromosomes & Cancer 52: (2013) 7
8 Genetics of Sp / Scl RMS Recent developments Genetics of Sp / Scl RMS Recent developments Szuhai et al. (2014) 17 adult spindle cell RMS 7 of 17 (44%) homozygous mutation of MYOD1 p.l122r Kohsaka et al. (2014) MYOD1 mutations in 10% of Embryonal RMS subset of cases with MYOD1 mutations showed PIK3CA mutations. 17 adult spindle cell RMS 7 of 17 (44%) homozygous mutation of MYOD1 p.l122r MYOD1 mutations in 10% of Embryonal RMS subset of cases with MYOD1 mutations showed PIK3CA mutations. Szuhai K et al. J Pathol 2014; 232: Kohsaka S et al. Nature Genetics VOLUME 46 NUMBER 6 JUNE 2014 MYOD1 mutation 8
9 Methodology RNA sequencing Mutation analysis FISH Infantile Spindle cell RMS characterized by gene fusions VGLL2 NCOA2 gene fusion (Case 1) 9
10 VGLL2 CITED2 gene fusion Gene function VGLL2 SRF TEAD1 Function as critical transcription factors (SRF, TEAD1) / co activator (VGLL2) in skeletal muscle development / regulation. MYOD1 Encodes a nuclear protein that belongs to bhlh family of transcription factors. Myogenic factors family MYOD1, MYF5, MYF6, MYOG regulates muscle cell differentiation. p. L122R mutation reduces transcriptional activation and binds to MYC consensus sequences. Morphology of VGLL2 CITED2 fusion positive tumors Morphology of MYOD1 mutated tumors 10
11 MYOD1 / PIK3CA / FGFR4 mutated tumor Follow up Follow up in Case 1 (14 yr) 1998 Chemotherapy and excision 1999 Local recurrence excision 2000 Local recurrence excision, chemo, radiation 2002 Local recurrence excision, radiation Closely followed No evidence of disease at last follow up Summary Infantile Spindle Cell Rhabdomyosarcoma with VGLL2 NCOA2 gene fusion Spindle cell / Sclerosing RMS is one of the 4 subtypes of RMS and can show a spectrum of morphologies If a tumor is negative for SMA and HHF35 and positive for Desmin, consider the possibility of a spindle cell RMS Genetic alterations support the classification of Spindle cell / Sclerosing RMS as a separate subtype 11
12 Summary Summary Pediatric SRMS/ScRMS Spindle cell / Sclerosing RMS Infants (< 1 yr) gene fusion associated MYOD1 mutant +/ PIK3CA mutation Lacking gene fusions / MYOD1 mutations Pediatric Adult Infants (< 1 yr) gene fusion associated MYOD1 mutant +/ PIK3CA mutation Lacking gene fusions / MYOD1 mutations MYOD1 mutant No mutations VGLL2, TEAD1, SRF genes Favorable clinical outcome Aggressive therapy (?) Occurs in 2/3 rd of pediatric SRMS > 1yr Aggressive clinical course with high mortality Seem to follow a favorable course Limited data thank you 12
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