1. 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

2. 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

3. 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)

4. 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)

5. 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)

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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%

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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?

21. 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

22. 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

23. 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

24. 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

25. 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)

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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:
Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO Classification of Tumours of Soft Tissue and Bone. IARC: Lyon, 2013.