Syndromic Aspects of Soft Tissue Tumors in the Young Cheryl M. Coffin, M.D., Professor of Pathology, Microbiology, and Immunology, Emerita Vanderbilt University, Nashville, TN

Objectives To summarize syndrome-associated soft tissue neoplasms To emphasize pathologic-syndromic prototypes: rhabdomyosarcoma, Gardner fibroma and desmoid, neurofibroma and MPNST, schwannoma variants, and malignant rhabdoid tumor To review clinicopathologic, genetic, and syndromic aspects

Conditions Associated with RMS I Adenomatous polyposis coli (APC) Beckwith-Wiedemann syndrome (LOH p15.5: IGF2, CDKA1C, H19, LIT1) Bloom syndrome (REQL3) Cardio-facial-cutaneous syndrome Constitutional mismatch repair deficiency (PSM2) Costello syndrome (RAS pathway: HRAS) Familial pleuropulmonary blastoma syndrome (DICER)

Conditions Associated with RMS II Familial rhabdoid predisposition syndrome (SMARCB1) Gorlin- Goltz syndrome (PTCH) Hereditary retinoblastoma (RB1) Hypomelanosis of Ito (various mosaicisms) Li-Fraumeni syndrome (TP53, CHEK2) Mosaic variegated aneuploidy (BUB1B) Miscellaneous congenital anomalies Neurofibromatosis type 1 (NF1)

Conditions Associated with RMS III Neurofibromatosis type 2 (NF2) Nijmejen breakage syndrome (NBS1) Roberts syndrome (ESCO2) Rubinstein-Taybi syndrome (CREBBP) Second malignant neoplasm, various syndromes Tuberous sclerosis (TSC1, TSC2, TSC3) Wardenburg syndrome (PAX3) Werner syndrome (WRN, RECOL2)

Embryonal Rhabdomyosarcoma (ERMS) 1st decade (highest incidence 0-4 yrs) Median age 6.5 years Head/neck, GU tract frequent sites Favorable and intermediate subtypes Anaplasia Trisomies 2q, 8, 20; LOH 11p15.5; tumor-related locus 11q Loss of 9q22 (PTCH), 1p35.36 (PAX7), or 17 TP53 mutation

Alveolar Rhabdomyosarcoma (ARMS) Later childhood and adolescence Extremities most frequent site Unfavorable prognostic subtype PAX3-FOXO1 with t(2;13) or PAX7-FOXO1 with t(1;13) in 25% of cases Syndrome-associated RMS with “alveolar” appearance generally lacks PAX-FOXO1 rearrangement

Anaplastic Rhabdomyosarcoma May be associated with Li-Fraumeni syndrome, TP53 mutation Anaplasia observed in both ERMS and ARMS Close resemblance to undifferentiated sarcoma, especially pleomorphic subtype

Spindle Cell/Sclerosing Rhabdomyosarcoma (SSRMS) Infants, children and adults Paratesticular region, trunk, and head/neck most frequent sites in children Favorable prognosis in children Molecular genetic subtypes: NCOA2 gene rearrangement in infants, MYOD1 mutation in 56% of pediatric cases Syndromic aspects undetermined as yet

Syndromic Rhabdomyosarcomas Most are ERMS PAX-FOXO1 rearrangement absent in rare syndromic “alveolar” RMS Consider the possibility of a syndrome in a very young child with RMS “ERMS” in a small lung biopsy may be part of a larger pleuropulmonary blastoma

Gardner Fibroma and Desmoid-Type Fibromatosis Gardner fibroma is desmoid precursor lesion Gardner fibroma and desmoid-type fibromatosis may be an initial manifestation of APC mutation or familial adenomatous polyposis in a child The family history may not be apparent without thorough history-taking

Gardner Fibroma A benign soft tissue lesion consisting of thick, haphazardly arranged collagen bundles with interspersed bland fibroblasts, a plaque-like growth pattern with infiltration and entrapment of surrounding structures… (WHO 2013) 78% diagnosed in 1st decade Trunk most frequent site (back, paraspinal, chest) 50% associated with desmoid (concurrent, sequential, after surgery) APC in 69%

Gardner Fibroma Diagnostic pitfalls due to nondescript histologic appearance: normal fibroadipose tissue, scar, lipoma Surgical impression is that a lesion is present: listen to the surgeon! Biopsy or surgical excision may promote development of a desmoid-type fibromatosis in the site: a conservative approach is now favored

Desmoid-Type Fibromatosis A fibroblastic neoplasm that arises in deep soft tissues and is characterized by infiltrative growth and a tendency toward local recurrence, but an inability to metastasize (WHO 2013) Peak in 2nd-3rd decades, rare before 5 yrs Abdomen, trunk, shoulder girdle, head/neck, extremities APC mutation new or familial

Familial Adenomatous Polyposis Caused by germline APC mutation: 1/3 sporadic 2/3 familial Average age of onset for intestinal adenomas is 25 years; can occur in 1st decade 100% lifetime risk of intestinal adenocarcinoma; rare before 10 years

APC in Children Congenital hypertrophy of retinal pigment epithelium Epidermoid cysts Osteomas Dental abnormalities Gardner fibroma and desmoid-type fibromatosis Hepatoblastoma Brain tumors Rhabdomyosarcoma Nasopharyngeal angiofibroma

Gardner Fibroma and Desmoid-Type Fibromatosis Consider APC mutation if a child has: Gardner fibroma, desmoid at a young age, multiple desmoids, Gardner fibroma adjacent to desmoid macroscopically or microscopically APC may not have been recognized clinically even when multiple generations are affected Careful follow-up, surveillance, assessment of parents and siblings and genetic counseling may be indicated

Neurofibroma and MPNST Neurofibroma and MPNST in children suggest the possibility of neurofibromatosis type 1 (NF-1) Both tumors are monoclonal , with alterations of he NF1 gene on 17q11.2, including germline mutations and biallelic inactivation

Neurofibroma A benign peripheral nerve sheath tumor composed of differentiated schwann cells, perineurial-like cells, fibroblasts, mast cells, and residual interspersed myelinated and unmyelinated axons embedded in extracellular matrix (WHO, 2013) Plexiform neurofibroma is typical of NF-1 Wide anatomic distribution, superficial or deep, often associated visibly with nerve Early onset in NF-1

Atypical Neurofibroma or MPNST? Atypical neurofibroma: hypercellularity, smudged dark nuclei, mitotic activity controversial, p53 non-reactive MPNST: hypercellularity, enlarged (3-fold) hyperchromatic nuclei, mitoses (may be scarce), p53 reactivity What about transitional forms in NF-1?

Hybrid Nerve Sheath Tumors Hybrid nerve sheath tumors are benign peripheral nerve sheath tumors with combined features of more than one conventional type (neurofibroma, schwannoma, perineurioma; WHO, 2013) Peak in early adulthood, wide age range May be associated with NF-1 Wide anatomic distribution

Other Manifestations of Childhood NF-1 Malignancies; RMS, myelogenous leukemia, osteosarcoma, neuroblastoma, Wilms tumor Tibial bowing Congenital pseudarthrosis Long bone dysplasia Scoliosis Macrocephaly Optic glioma

Childhood Neurofibroma and MPNST Neurofibroma and MPNST in children suggest the possibility of NF-1; hybrid tumors also occur Risk of malignant transformation in neurofibroma Risk of other malignancies in NF-1 Pathologic pitfalls: cellular schwannoma, other spindle cell tumors, epithelioid MPNST

Conventional Schwannoma Conventional schwannoma is a common, benign, usually encapsulated nerve sheath tumor that is composed of well-differentiated schwann cells (WHO 2013) Associated with neurofibromatosis type 2 (NF2) mutation or schwannomatosis (SMARCB1 with mosaic loss of INI1 protein) Rare in childhood Head, neck , extremities, skin, subcutaneous tissue, deep soft tissue

Melanotic Schwannoma Melanotic schwannoma is a rarely metastasizing nerve sheath tumor with a uniform composition of variably melanin-producing schwann cells (WHO 2013) Rare in children Paraspinal, spinal, GI Associated with Carney complex (CNC1, CNC2, PRKAR1A)

Schwannoma Various syndromic associations: neurofibromatosis type 2, schwannomatosis, SMARCB1 mutation, Carney complex Rare in childhood outside the context of phakomatoses Diagnostic pitfall: MPNST and other spindle cell sarcomas, melanoma

Malignant Rhabdoid Tumor Malignant rhabdoid tumor is a highly malignant soft tissue tumor which consists of characteristic rounded or polygonal neoplastic cells with glassy eosinophilic cytoplasm containing variable numbers of hyaline-like inclusion bodies, eccentric nuclei and macronucleoli…alterations of SMARCB1 gene… (WHO 2013) Onset usually before 2 yrs Renal, extrarenal (soft tissue, viscera), CNS, congenital disseminated Sporadic and familial forms

MRT Immunohistochemistry Polyphenotypic Coexpression of vimentin and cytokeratin (CAM 5.2, CK8, CK18), confirmed by EM Membranous EMA expression Loss of expression of INI-1 (SMARCB1, HSNF5) Variable CD99, synaptophysin, Leu7, NSE, muscle specific actin, S100

MRT Genetics 80% have homozygous inactivation of SMARCB1 gene on 22q11.2 98% of extrarenal rhabdoid tumors have genomic alterations of both copies of SMARCB1 60% have germline SMARCB1 mutation Germline mutation or deletion of SMARCB1 “first hit” in patients with familial malignant rhabdoid tumor syndrome Rare cases have loss or mutation of SMARCA4 on 19p13.2

Malignant Rhabdoid Tumor Challenges Morphologic variability Cellular distortion in skin and other sites Overlap with epithelioid sarcoma Family history may not have been recognized Non-specificity of INI-1 protein loss Broad differential diagnosis

Tumors with INI-1 Protein Loss Malignant rhabdoid tumor Epithelioid sarcoma Myoepithelial carcinoma Schwannoma, familial (mosaic pattern) Extraskeletal myxoid chondrosarcoma Epithelioid MPNST Chordoma, poorly differentiated Synovial sarcoma Renal medullary carcinoma

Conclusions A sarcoma at a younger than usual age may be a manifestation of a genetic disorder The pathologist, by calling attention to the possibility of a syndrome-associated soft tissue neoplasm, can improve the present and future care of the patient and the family New pathologic-syndromic associations and molecular pathways will continue to be discovered

References Alaggio R, Coffin CM. Pediatric soft tissue sarcomas: the past 50 years and future challenges. Pediatr Dev Pathol 2015; in press. Coffin CM, Davis JL, Borinstein SC. Syndrome-associated soft tissue tumours. Histopathology 2014; 64: 68-87. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO Classification of Tumours of Soft Tissue and Bone. IARC: Lyon, 2013.