Atypical Fibroxanthoma

Not clinically relevant

TP53 mutation due to UV irradiation is believed to be pathogenetically important. AFX shows abnormal accumulation of p53 and a characteristic TP53 mutation pattern. Many AFXs show deletions but lack HRAS, KRAS, and NRAS gene mutations, in contrast to undifferentiated pleomorphic sarcoma. Otherwise, activating mutations in the promoter region of the TERT gene, frequent NOTCH1 and FAT1 mutations, and a similar DNA methylation profile in AFX and pleomorphic dermal sarcoma suggest a close relationship.

AFXs are well-circumscribed nodular or polypoid tumors of the dermis. Ulceration of the epidermis is a common feature.

The histopathological criteria for the diagnosis of AFX must be used strictly, and the diagnosis of AFX should never be made on a biopsy only, or without the use of a panel of immunohistochemical antibodies. AFX represents an intradermal, usually symmetrical and well-circumscribed cellular neoplasm without involvement of the subcutis. Ulceration and collarette formation of the lateral hyperplastic epidermis are frequent. These cellular neoplasms are composed of sheets and fascicles of most often highly pleomorphic polygonal or histiocytoid cells, enlarged and atypical spindled and epithelioid cells, and variable numbers of atypical multinucleated tumor giant cells. Neoplastic cells contain enlarged atypical, vesicular, or hyperchromatic nuclei, and numerous mitoses (including atypical mitoses) are present. By definition, tumor necrosis, lymphovascular and/or perineural invasion, and subcutaneous invasion are absent. Scattered inflammatory cells, numerous vessels, and areas of hemorrhage may be present.
A number of histological subtypes are described, as follows:

Spindle cell, non-pleomorphic AFX: Shows usual features but composed of relatively monomorphic, eosinophilic, spindled tumor cells.

Clear cell AFX: Composed of pleomorphic tumor cells with foamy or clear cytoplasm; must be distinguished from other clear cell neoplasms.

Pigmented (haemosiderotic) AFX: Characterized by intratumoral hemorrhage and osteoclast-like giant cells.

Myxoid AFX: Rare, with prominent myxoid stromal change; must be distinguished from myxofibrosarcoma.

Osteoclast-like giant cell–rich AFX: Contains numerous bland osteoclast-like giant cells.

Keloidal AFX: Shows thick bundles of hyalinized collagen, mimicking keloid.

Granular cell AFX: Composed of tumor cells with granular cytoplasm; must be distinguished from other granular cell tumors.

No specific immunohistochemical marker for AFX is known, and a broad panel of antibodies must be used to exclude other neoplasms. Tumor cells in AFX usually stain positively for vimentin, CD10, and p53, and often for SMA, but these are nonspecific. AFX is consistently negative for keratins, S100, SOX10, CD34, ERG, and desmin. Cases may show nonspecific expression of other markers.

Not clinically relevant

When strict diagnostic criteria are applied, the vast majority of AFXs show benign behavior after complete surgical excision. Local recurrence is rare and distant metastases exceptional. Cases with tumor necrosis or invasion into subcutis may be considered pleomorphic dermal sarcoma.

Not clinically relevant

Essential: usually pleomorphic (but variable) morphology; strict confinement to the dermis; immunonegativity for keratins, S100, and SOX10.