Atypical fibroxanthoma is a rare, low-grade superficial sarcoma that frequently presents as a red nodule or plaque. It is considered a superficial variant of undifferentiated pleomorphic sarcoma (formerly known as malignant fibrous histiocytoma). Although atypical fibroxanthoma has similar histologic features to undifferentiated pleomorphic sarcoma, it behaves less aggressively.
The etiology of atypical fibroxanthomas is poorly understood. It is believed to arise from myofibroblasts or fibroblast-like cells. Ultraviolet light is believed to play an important role since most lesions appear on the sun-exposed head and neck of Caucasian patients. Genetic factors also contribute to the development of atypical fibroxanthoma, since it shares genetic alterations with undifferentiated pleomorphic sarcomas including chromosome 9p and 13q deletions. However, undifferentiated pleomorphic sarcoma has a statistically significant larger amount of genomic alterations and a more aggressive clinical course. Other possible risk factors for atypical fibroxanthoma include trauma to the skin, radiation therapy, and immunosuppression (e.g., diabetes, HIV, organ transplant).
Atypical fibroxanthomas most commonly are seen on the head and neck of elderly Caucasian patients. Other reported sites of atypical fibroxanthoma include the trunk, shoulders, upper extremities, and dorsum of the hands. Trunk and limb lesions are believed to occur more commonly in younger patients (mean age 39) compared to head and neck lesions in the elderly (mean age 69). A review of 171 cases in Western Australia found a patient age-range of 41 to 97 years old (median age 74) with 76% of the tumors occurring in men. Atypical fibroxanthoma also has been reported in patients as young as 13 with predisposing disorders such as Li Fraumeni Syndrome and Xeroderma Pigmentosum. The incidence is increased in immunosuppressed populations, with an estimated incidence of 78 per 100,000 transplant patients.
The pathophysiology of atypical fibroxanthomas is poorly characterized. Ultra-violet (UV) light is believed to be implicated in its pathogenesis due to atypical fibroxanthoma predilection for sun-exposed areas of the body and the presence of atypical fibroxanthoma in xeroderma pigmentosum patients who have defective repair of UV-induced cyclobutane pyrimidine dimers. These UV-induced pyrimidine dimers have been documented in atypical fibroxanthoma lesions, along with mutations in the tumor suppressor gene p53. A variety of rare genetic disorders have been associated with p53-induced atypical fibroxanthomas, including Li Fraumeni syndrome (with germline p53 mutations) and xeroderma pigmentosum. One study showed that mutations of H-Ras and K-Ras genes were present in malignant fibrous histiocytoma but not in atypical fibroxanthoma lesions; this research may prove helpful in establishing the diagnosis of atypical fibroxanthoma.
Hematoxylin and eosin stains of atypical fibroxanthoma lesions show a dermally-based tumor with pleomorphism, atypical mitotic figures, and a spindly architecture. Atypical fibroxanthoma lesions occasionally extend to the subcutaneous tissue. Note that atypical fibroxanthoma is a dermal-based process while spindle cell squamous cell carcinoma variants (on the differential diagnosis) connect with the epidermis and show signs of keratinization. Multinucleated giant cells and solar elastosis are often present in atypical fibroxanthoma biopsy specimens, while a mixed inflammatory infiltrate may be found at the edge of the tumor. Immunohistochemistry is required to rule out other neoplasms including spindloid squamous cell carcinoma, melanoma, and undifferentiated pleomorphic sarcoma. Since atypical fibroxanthoma stains positive for several non-specific stains, including CD10, p53, S100A6, vimentin, and procollagen-1, it is considered a diagnosis of exclusion histologically. Of note, atypical fibroxanthoma stains negative for HMB-45, p40 (often positive in squamous cell carcinoma), desmin, pan-cytokeratin stains, CD31, and has sparse staining for S100, which may help differentiate it from melanoma. Since poorly differentiated sarcomatoid carcinomas may lose cytokeratin expression, a variety of cytokeratin stains should be used. Severe variants of atypical fibroxanthoma have been described based on various histologic findings, including pigmented atypical fibroxanthoma due to hemosiderin deposit and not actual melanin pigment, granular cell atypical fibroxanthoma, sclerotic atypical fibroxanthoma, spindle cell nonpleomorphic atypical fibroxanthoma, osteoid atypical fibroxanthoma, chondroid atypical fibroxanthoma, myxoid atypical fibroxanthoma, keloidal atypical fibroxanthoma, osteoclast-like giant-cell rich atypical fibroxanthoma, and clear cell atypical fibroxanthoma.
While no direct association has been made, researchers hypothesize that arsenic exposure may predispose patients to atypical fibroxanthoma.
Atypical fibroxanthomas present as well-circumscribed red or pink nodules or plaque that may have ulceration, crust, or scale. Atypical fibroxanthoma lesions are typically small in size, with a median diameter of 1 cm with less than 5% of the lesions being greater than 2 cm in diameter. They often develop rapidly but lack symptoms such as pain or pruritus. More than 90% of atypical fibroxanthoma tumors occur on the head and neck, while the remaining cases typically present on the extremities and trunk. Dermoscopy of lesions reveals polymorphic vessels (linear, dotted, hairpin, arborescent, and/or highly tortuous vessels) radiating to the center of the lesion with intervening white areas. The differential diagnosis includes basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, amelanotic melanoma, leiomyosarcoma, atypical (pseudosarcomatous) dermatofibroma, pleomorphic dermal sarcomas, and metastasis from internal malignancies. Compared to atypical fibroxanthoma, pleomorphic dermal sarcomas are often clinically larger and are more likely to recur locally and metastasize.
A skin biopsy is the gold standard for diagnosis of atypical fibroxanthoma since it is a rare condition that clinically mimics basal and squamous cell carcinomas, Merkel cell carcinomas, and amelanotic melanomas. Immunohistochemistry is commonly performed to make the diagnosis (see "histopathology" above).
When atypical fibroxanthoma lesions have metastasized or are poorly accessible (e.g., subungual lesions), magnetic resonance imaging (MRI) may be helpful, which shows intermediate T1 and T2-weighted signal intensity compared to the high signal intensity of squamous cell carcinoma and melanoma.
Fortunately, atypical fibroxanthoma rarely metastasizes and recurs in only 6% to 10% of cases. Risk factors for metastases include immunocompromised patients, tumor depth, vascular or perineural invasion, and the presence of tumor necrosis. The most commonly reported locations for metastases include the parotid gland, lymph nodes, and subcutaneous tissue. Metastases, when present, are typically evident 12 to 24 months after the initial diagnosis of atypical fibroxanthoma. The treatment of choice for atypical fibroxanthoma is surgical excision. Previously, this was done with 1 cm margins, however Mohs micrographic surgery and regular follow-up have become the standard of care, with recurrence rates reported at 0.0% to 6.9%. In patients who are poor surgical candidates, electronic brachytherapy has successfully treated atypical fibroxanthoma and is even more effective if tumors are debulked before therapy. Another reported treatment modality is electrodesiccation and curettage, which may be appropriate for slow-growing lesions that are less than 1 cm in diameter.
Prevention of atypical fibroxanthoma is centered around UV-protection and yearly full-body skin exams for early detection.