Fibroxanthoma atypical C49; D48.1

Rare, solitary, intermediate malignant fibrohistiocytic tumour of the skin, growing rapidly within a few months, with a relatively benign clinical course, occurring almost exclusively in light-damaged skin of elderly people. Probably it is not an independent clinical picture but a reaction pattern of different, largely undifferentiated neoplasias, but also degenerative processes. Thus, squamous epithelial carcinomas, melanomas, basal cell carcinomas, pseudosarcomatous xanthogranuloma variants, etc. are concealed behind this fine-tissue reaction pattern. Some authors regard the atypical fibroxanthoma as a cutaneous variant of the malignant fibrous histiocytoma (Cooper JZ et al. 2005).

The incidence is 2.5/100,000; m>w;

UV as well as a previous irradiation therapy with X-rays seem to play a decisive pathogenetic role; furthermore, a persistent immunodeficiency (increase of AFX in organ transplant patients) as well as genetic defects such as those e.g. in xeroderma pigmentosum.

Mutations in the tumor suppressor gene p53 have been increasingly found and are thought to have pathogenetic relevance. Furthermore, telomerase reverse transcriptase (TERT) promoter mutations have been detected. These mutaions lead to cell immortalization through activation of telomerases and (Grievank KG et al. 2014).

Histogenesis is still unclear: the likely origin is from poorly differentiated mesenchymal cells of origin, possibly histiocytes or fibroblasts. Proliferations of dedifferentiated keratinocytes are also suspected (in individual cases a focal keratin expression was detected), a myoblastoid proliferation, a proliferation of Langerhans cells and others.

The initial manifestation is particularly frequent during two age peaks, in the 4th and 7th decade respectively, with the latter being significantly larger (in a larger study - Mahalingam S. et al.- the average age was 75.9 years). The first peak refers mainly to non-light-damaged areas (extremities, trunk).

Especially ears, nose, cheeks, neck, capillitium. In younger people also extremities or trunk.

In actinically pre-damaged skin, there is a solitary, up to 3.0 cm large, coarse, indolent, skin-colored, red or brown-red, firm knot with a smooth atrophic surface, which often cannot be displaced on its base (infiltration of the subcutaneous fatty tissue). Often ulcerated and thus encrusted or diffusely bleeding surface.

Usually well-demarcated nodule confined to the dermis and not extending into the subcutaneous fatty tissue (in contrast to pleomorphic dermal sarcoma), consisting of atypical, spindle-shaped or pleomorphic cells with vesicular or bizarre, hyperchromatic nuclei. Bizarrely configured multinucleated giant cells and atypical mitoses are frequently found.

A clear immunohistologic marker for a definitive diagnosis of atypical fibroxanthoma is still lacking. The cells are CD34, S100, desmin, HMB-45 (human melanoma black 45) negative (Koch M et al. 2015) (DD: dermatofibrosarcoma protuberans) and constantly vimentin positive. Furthermore, there is an inconstant reactivity for alpha smooth muscle actin and for CD68. Occasionally, focal keratin expression is observed (so-called keratin-positive AFX). Furthermore, numerous vascular incisions are found. Frequent focal hemorrhages. Cellular variants with pigmentation and granular or clear cell degeneration are possible.

Myxoid sections, which can also dominate the histological picture, are not uncommon. Molecular pathology: the detection of p53 mutations and TERT promoter mutations provide evidence of UV induction of the tumor.

The clinical findings are not very specific. The histological pattern and especially immunohistochemistry is diagnostically important for AFX.

• Clinical:
  • Basal cell carcinoma: Like AFX, also in light-exposed areas; typical pearl-like border accentuation of the BCC is missing.
  • Spinocellular carcinoma: Clinically indistinguishable! Histology is diagnostic.
  • Hyperplastic actinic keratosis: only minimally elevated, clearly increased in consistency by horn deposits. Mostly multitudinous.
  • Keratoakanthoma: Keratoakanthoma-like AFX are described. Growth however slow; no central horn crater!
  • Granuloma teleangiectaticum: Significantly faster growth; typically not preferred in light exposed areas.
  • Malignant melanoma: AFX is unpigmented.
  • Merkel cell carcinoma: Fast growing tumour, clinically difficult to assess. Histology is diagnostic.
  • Dermatofibrosarcoma protuberans: Age peak of DFSP between the ages of 20 and 40 years. No preference for light-exposed skin areas. Rough, almost woody consistency.
  • Skin metastases: Rapid growth is generally expected here; no preference for light-exposed skin areas.
• Histological:
  • Carcinoma, spinocellular, desmoplastic: Fine strands or smaller tumor cell nests with atypical, very polymorphic keratinocytes surrounded by a broad desmoplastic stroma. The tumour tends to infiltrate along autochthonous structures such as nerves or vessels. Tumor cells are cytokeratin - and occasionally vimentin - positive.
  • Melanoma, malignant, desmoplastic: Fascicular or nodular cell trains of atypical, hyperchromatic, spindle cells located between fibrotically dense collagenous fibres. Occasional mitoses. Desmoplastic melanomas show neurotrophy and follow the course of the dermal nerves (desmoplastic-neutral melanoma). Immunohistology: S-100-, (HMB-45-, Melan A- are not always positive) and vimentin positive (!); S-100 is the most reliable marker.
  • Undifferentiated pleomorphic sarcoma (UPS): The AFX is probably the superficial variant of the UPS.
  • Malignant fibrous histiocytoma (MFH): This "controversial" tumor species should not be a true differential diagnosis, because UPS and MFH are probably identical tumors (see note).
  • Leiomyosarcoma: reactivity for smooth muscle actin and (inconstant) desmin. h- caldesmon +; cytokeratin +/-.

Tendency to local recurrence (7-9%). These usually occur within a period of 1-2 years. Very rarely metastasis (0.5-4%) mostly in the regional lymph nodes followed by liver, lung and subcutis.

Excision with a safety margin of at least 0.5 cm. Microscopically controlled surgery is now considered "state of the art".

Radiation therapy can be used as an alternative in cases of unfavourable surgical site. Response only at higher doses (about 60-65 Gy).

Favourable prognosis with complete excision on all sides. A metastasis is rare (note: older statistics show a metastasis rate between 0,5%-10%).

Follow-up should be every six months for the first two years. In the third to the fifth year, annually. Follow-up includes clinical examinations of the patient.

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4. Griewank KG et al (2014) TERT promoter mutations are frequent in atypical fibroxanthomas and pleomorphic dermal sarcomas. Mod Catholic 27:502-508.
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9. Iorizzo LJ et al (2011) Atypical fibroxanthoma: A review of literature. Dermatol Surgery 37: 146-157

10. Mahalingam S et al (2015) Atypical Fibroxanthoma: A case series and review of literature. Auris Nasus Larynx. 42:469-471
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