TERT Promoter Mutations Are Frequent in Atypical Fibroxanthomas and Pleomorphic Dermal Sarcomas

Klaus G Griewank; Bastian Schilling; Rajmohan Murali; Nicola Bielefeld; Marion Schwamborn; Antje Sucker; Lisa Zimmer; Uwe Hillen; Jörg Schaller; Thomas Brenn; Dirk Schadendorf; Thomas Mentzel


Mod Pathol. 2014;27(4):502-508. 

In This Article

Abstract and Introduction


Activating mutations in the TERT promoter leading to increased telomerase expression were recently identified in cutaneous melanoma and subsequently in many other types of cancer. These mutations lead to increased telomerase expression, allowing cells to proliferate continuously without entering apoptosis or senescence. Atypical fibroxanthomas and pleomorphic dermal sarcomas are genetically poorly understood tumors developing in the skin of older patients. Known genetic events in these tumors are mutations in TP53 (atypical fibroxanthoma and pleomorphic dermal sarcoma) and RAS (pleomorphic dermal sarcoma) genes, often having a UV signature. We analyzed a cohort of 27 atypical fibroxanthomas and 34 pleomorphic dermal sarcomas for the presence of TERT promoter mutations by conventional Sanger sequencing. TERT promoter mutations were identified in 25 (93%) atypical fibroxanthomas and in 26 (76%) pleomorphic dermal sarcomas. Mutations were found to have a UV signature (C>T or CC>TT) and were largely identical to those detected in cutaneous melanoma. Our data show that TERT promoter mutations are the most frequent mutations in atypical fibroxanthomas and pleomorphic dermal sarcomas reported to date. The identified mutations confirm the pathogenetic role of UV exposure in both atypical fibroxanthomas and pleomorphic dermal sarcomas and suggest that telomere maintenance through increased expression of telomerase plays an important role in the pathogenesis of these tumors.


Atypical fibroxanthomas and pleomorphic dermal sarcomas of the skin are rare mesenchymal tumors that typically arise in the skin of older patients and are genetically poorly characterized.

Atypical fibroxanthomas are rapidly growing exophytic tumors that occur in sun-damaged skin, primarily in the head and neck region of elderly patients.[1–3] They are well-circumscribed tumors occurring more frequently in males. Risk factors include UV exposure, irradiation, xeroderma pigmentosum, and organ transplantation.[4] Histologically, they are usually composed of atypical spindled and pleomorphic tumor cells including tumor giant cells, and are centered within the dermis with limited extension into the subcutis. They show high mitotic activity including atypical mitotic figures.[2] However, they do not invade into the deep soft tissues, and despite increased proliferative activity, areas of tumor necrosis and lymphovascular and/or perineural invasion are not present. A diagnosis of atypical fibroxanthoma requires exclusion of other neoplasms, in particular, melanoma, squamous cell carcinoma, and leiomyosacroma. Atypical fibroxanthomas generally have a good prognosis, and usually complete excision and regular follow-up are recommended.[1]

The term 'pleomorphic dermal sarcoma' was introduced by Fletcher[5] and describes tumors presenting with a similar morphology to atypical fibroxanthomas, but which in addition show extensive involvement of subcutis and/or invasion into deeper structures, areas of tumor necrosis, lymphovascular invasion, and perineural invasion. Pleomorphic dermal sarcomas exhibit more aggressive clinical behavior than atypical fibroxanthomas, and have the potential for local recurrence and metastasis.[6] They are therefore categorized as tumors with low-grade malignant potential.[6] The tumors now defined as pleomorphic dermal sarcomas have also been referred to as cutaneous undifferentiated pleomorphic sarcomas, and in the past as superficial malignant fibrous histiocytomas.[7–9] There are currently no effective therapies for metastasized pleomorphic dermal sarcomas.

Distinguishing atypical fibroxanthoma from pleomorphic dermal sarcoma is not possible based on cell morphology alone, as they may show similar cyotologic features. The criteria allowing the distinction of pleomorphic dermal sarcoma from atypical fibroxanthoma are: extensive infiltration of subcutis, or invasion into fascia or muscle; necrosis; and vascular or perineural invasion.[2,5] Making the distinction between these tumors based solely on biopsy specimens should be avoided, as biopsies can be superficial or not show the deepest extent of tumor involvement. Although attempts have been made to identify immunohistochemical markers facilitating the distinction of atypical fibroxanthoma from pleomorphic dermal sarcoma (eg CD99 and LN-2 (refs.[10,11])), none have proven reliable in routine practice.[1–3]

Little is known of the genetic events leading to the development of atypical fibroxanthomas and pleomorphic dermal sarcomas. Previous small studies identified UV-signature mutations in TP53 in atypical fibroxanthomas (7/10 (ref. 12) and 4/6 (ref. 13) cases) and pleomorphic dermal sarcomas (1/4 cases, diagnosed as 'malignant fibrous histiocytomas'[13]), as well as one HRAS mutation and one KRAS mutation in eight pleomorphic dermal sarcomas (diagnosed as 'malignant fibrous histiocytomas') analyzed.[14] In another study, pleomorphic dermal sarcomas (diagnosed as 'undifferentiated pleomorphic sarcomas') were found to harbor more frequent DNA copy number alterations than atypical fibroxanthomas.[15]

Two recent studies in cutaneous melanomas identified novel recurrent mutations in the promoter region of TERT, coding for the catalytic subunit of the telomerase holoenzyme, in up to 71% of tumors.[16,17] The mutations showed a characteristic UV signature (C>T and CC>TT).[18] Functional studies found that these mutations lead to increased gene expression, most likely by creating ETS transcription factor binding sites.[16,17] A follow-up study screening a panel of different neoplasms identified TERT promoter mutations in a number of other common cancers, that is, in high frequencies in hepatocellular cancer, bladder cancer, and gliomas.[19]

In view of (a) the common occurrence of TERT promoter mutations with a UV signature in melanomas, (b) the strong association of atypical fibroxanthomas with UV exposure, and (c) the histologic similarities between atypical fibroxanthomas and pleomorphic dermal sarcomas, we investigated the presence of TERT promoter mutations in these tumors.