Genome-wide methylation profiling and copy number analysis in atypical fibroxanthomas and pleomorphic dermal sarcomas indicate a similar molecular phenotype

Abstract

Background Atypical fibroxanthomas (AFX) and pleomorphic dermal sarcomas (PDS) are lesions of the skin with overlapping histologic features and unspecific molecular traits. PDS behaves aggressive compared to AFX. Thus, a precise delineation, although challenging in some instances, is relevant. Methods We examined the value of DNA-methylation profiling and copy number analysis for separating these tumors. DNA-methylation data were generated from 17 AFX and 15 PDS using the Illumina EPIC array. These were compared with DNA-methylation data generated from 196 tumors encompassing potential histologic mimics like cutaneous squamous carcinomas (cSCC; n = 19), basal cell carcinomas (n = 10), melanoma metastases originating from the skin (n = 11), leiomyosarcomas (n = 11), angiosarcomas of the skin and soft tissue (n = 11), malignant peripheral nerve sheath tumors (n = 19), dermatofibrosarcomas protuberans (n = 13), extraskeletal myxoid chondrosarcomas (n = 9), myxoid liposarcomas (n = 14), schwannomas (n = 10), neurofibromas (n = 21), alveolar (n = 19) and embryonal (n = 17) rhabdomyosarcomas as well as undifferentiated pleomorphic sarcomas (n = 12). Results DNA-methylation profiling did not separate AFX from PDS. The DNA-methylation profiles of the other cases, however, were distinct from AFX/PDS. They reliably assigned to subtype-specific DNA-methylation clusters, although overlap occurred between some AFX/PDS and cSCC. Copy number profiling revealed alterations in a similar frequency and distribution between AFX and PDS. They involved losses of 9p (22/32) and 13q (25/32). Gains frequently involved 8q (8/32). Notably, a homozygous deletion of CDKN2A was more frequent in PDS (6/15) than in AFX (2/17), whereas amplifications were non-recurrent and overall rare (5/32). Conclusions Our findings support the concept that AFX and PDS belong to a common tumor spectrum. We could demonstrate the diagnostic value of DNA-methylation profiling to delineating AFX/PDS from potential mimics. However, the assessment of certain histologic features remains crucial for separating PDS from AFX. Electronic supplementary material The online version of this article (10.1186/s13569-019-0113-6) contains supplementary material, which is available to authorized users.

Atypical fibroxanthoma: An analysis of 105 tumors

“…The DNAmethylation profiles of AFX/PDS argue for a common tumor spectrum. 1 Atypical fibroxanthoma often presents as a red nodule or plaque, with or without ulceration. The head-and-neck region is preferred although tumors may occur on other body parts as well.…”

Atypical fibroxanthoma and pleomorphic dermal sarcoma: A reappraisal

“…Molecular studies have failed to demonstrate alterations substantially discriminating AFX from PDS, to date [6][7][8] , inducing some authors to consider AFX as the "not infiltrating precursor of PDS" 8 . From the immunohistochemical point of view, we did not find a different profile among tumors with different cellular types.…”

“…Pleomorphic dermal sarcoma (PDS) is a tumor with overlapping clinical, pathological and immunophenotypical features, but with higher recurrence rate and metastatic potential 4,5 . Recent studies found similar genetic alterations in the two neoplasms 6‐8 . Both AFX and PDS are diagnoses of exclusion, to be made after careful immunohistochemical study, in order to not miss other neoplasms such as squamous cell carcinoma, melanoma, leiomyosarcoma or angiosarcoma 9 …”

“…4,5 Recent studies found similar genetic alterations in the two neoplasms. [6][7][8] Both AFX and PDS are diagnoses of exclusion, to be made after careful immunohistochemical study, in order to not miss other neoplasms such as squamous cell carcinoma, melanoma, leiomyosarcoma or angiosarcoma. 9 Apart from a few histopathologic criteria, 4 it is still unclear what really differentiates these two entities.…”

Dermal Pleomorphic Sarcoma of the Scalp – Report of Two Cases

“…Comparative genomic hybridisation demonstrated similar mutation profiles in genes like FAT1 , NOTCH1 and 2 , CDKN2A , TP53 and TERT promoter, but activating RAS and PIK3CA mutations only in a small number of DPS [7], [8].…”