Clinicopathological and Genomic Profiles of Atypical Fibroxanthoma and Pleomorphic Dermal Sarcoma Identify Overlapping Signatures with a High Mutational Burden

Abstract

Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are rare tumors developing in chronically sun-exposed skin. Clinicopathological features are similar, but they differ in prognosis, while PDS has a more aggressive course with a higher risk for local recurrence and metastases. In current clinical practice, they are diagnosed by exclusion using immunohistochemistry. Thus, stringent diagnostic criteria and correct differentiation are critical in management and treatment for optimal outcomes. This retrospective single-center study collected clinicopathological data and tumor samples of 10 AFX and 18 PDS. Extracted genomic DNA from tumor specimens was analyzed by a next-generation sequencing (NGS) platform (FoundationOne-CDx™). Among 65 identified mutations, TP53 inactivating mutations were observed in all tumor specimens. In both AFX and PDS, the known pathogenic gene alterations in CDKN2A, TERT promoter, and NOTCH1 were frequently present, along with high mutational burden and stable Micro-Satellite Instability status. The mutational profiles differed only in ASXL1, which was only present in AFX. Further differences were identified in likely pathogenic and unknown gene alterations. Similarities in their genomic signatures could help to distinguish them from other malignancies, but they are not distinguishable between each other using the FoundationOne-CDx™ NGS panel. Therefore, histological criteria to determine diagnosis remain valid. For further insight, performing deep tumor profiling may be necessary.

Keywords: atypical fibroxanthoma; next-generation sequencing; pleomorphic dermal sarcoma; tumor genomic profiling.

Figure 1

Representative flowchart of inclusion and exclusion of patients and samples. * 2 Patients with longitudinal samples.

Figure 2

Clinical and histological picture of a male patient with AFX (a–c) and a female patient diagnosed with PDS (d–f). (a) AFX located at the vertex, (b) proliferation of pleomorphic spindle cells located under a thinned and ulcerated epidermis, (c) high power representation of atypical mitotic figures and multinucleated giant cells, (d) PDS located at the vertex, (e) neoplastic cells located at the deep dermis and infiltrating subcutaneous tissue, (f) pleomorphic, spindle-shaped neoplastic cells.

Figure 3

Primary tumor sites of AFX and PDS. (a) frontal area, (b) parietal area, (c) vertex, (d) auricular area. One primary PDS tumor was located at the lower leg is not represented in this figure.

Figure 4

Lollipop plots highlighting genomic alterations of known and likely mutations in selected genes: (a) TP53 (tumor protein 53), (b) CDKN2A (cyclin-dependent kinase inhibitor 2A), and (c) NOTCH1 (NOTCH receptor 1) in AFX and PDS. Circles are colored with respect to the corresponding mutation types. Color codes are as follows: blue circles are indicating truncating mutations; red circles missense mutations and orange circles are indicating in-frame mutations. The height of the line represents the number of mutations at the specified position. The grey bar represents the entire protein with the different amino acid positions (aa). The coloured boxes are specific functional domains.

Figure 5

Heatmap of identified known and likely pathogenic gene alterations in atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) tumor samples. The red box marks the presence of a gene alteration. The most frequent driver mutations are TP53, CDKN2A, TERT promoter, and NOTCH1.

Figure 6

Heatmap of all identified gene alterations in the analyzed cohort. The red box marks the presence of a gene alteration.

Figure 7

Lollipop plots highlighting genomic alterations of unknown mutations in selected genes: (a) GATA4A (GATA binding protein 4) and (b) CDH1 (cadherin 1) in AFX and PDS. Blue circles are indicating truncating mutations. The height of the line represents the number of mutations at the specified position. The grey bar represents the entire protein with the different amino acid positions (aa). The coloured boxes are specific functional domains.

Figure 8

Heatmap of variants of unknown significance in atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) tumor samples. The red box marks the presence of a gene alteration.