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Atypical fibroxanthoma
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Atypical fibroxanthoma (AFX) is an uncommon cutaneous neoplasm arising from mesenchymal or fibrohistiocytic cells. AFX is found predominantly in sun-damaged skin, especially of the head and neck of elderly males, and comprises approximately 0.2% of all skin tumors. Rare cases have also been reported in children with xeroderma pigmentosum. Risk factors include male sex, ultraviolet (UV) exposure, history of radiation therapy, immunosuppression, and trauma. Typically, these lesions appear as rapidly growing, ulcerated, exophytic, dome-shaped nodules, usually <2 cm in diameter. Despite its severe cytologic atypia, it tends to be less aggressive. Care should be taken to distinguish these tumors from pleomorphic dermal sarcoma (PDS) and undifferentiated pleomorphic sarcoma (UPS).
The classification of fibrohistiocytic tumors is ambiguous and controversial. This has been compounded by the evolving nomenclature as understanding of the genetic and molecular basis of these tumors improved. Previously, fibrohistiocytic tumors encompassed the superficial AFX and its deep dermal/subcutaneous version, the malignant fibrous histiocytoma (MFH). However, the term MFH is no longer favored due to the heterogeneity of these tumors, most of which are better aligned under other classifications. In the current nomenclature, AFX is primarily a dermally based tumor that remains a diagnosis of exclusion by use of immunohistochemical stains. If invasion into subcutaneous tissue is observed, it is superficial and focal. The presence of extensive or deep subcutaneous tissue invasion, perineural invasion, lymphovascular invasion, abundant atypical mitoses, or tumor necrosis in a tumor that otherwise resembles an AFX histologically is more appropriately classified as a PDS, which carries a worse prognosis. PDS is a term newly proposed in 2012 by Dr. C.D. Fletcher, and therefore its adoption in the literature is included only in newer publications.
Although AFX and PDS likely represent a disease spectrum, this has not been conclusively proven. PDS is clinically indistinguishable from AFX, although reports suggest these tumors are typically larger on presentation (>2 cm). It similarly predominantly arises on sun-damaged skin of elderly men, especially on the scalp. Unlike AFX, PDS is associated with a recurrence rate of 29%, and estimates of metastasis are as high as 20%.
UPSs are a diagnosis of exclusion for sarcomas that do not fit into other categories, including AFX and PDS. Due to the controversial nomenclature of sarcomas, UPS is still used by some authors to describe what would now be considered PDS or AFX. Since the adoption of PDS in 2012, however, the World Health Organization recommends limiting the use of the term UPS to sarcomas arising from deeper tissues, often involving the extremities or retroperitoneum.
Management Strategy
Proper management relies on an adequate biopsy specimen that includes subcutaneous tissue to help distinguish between AFX and PDS. Because these are typically rapidly growing tumors, first-line management is aimed at complete eradication with surgery. Incomplete removal results in recurrences that usually manifest within a year postoperatively. In instances of incomplete removal of PDS, recurrence can present as satellite lesions that represent in-transit metastases.
Due to the rarity of these tumors, the lack of consensus for an excisional safety margin, and the overlap clinically with PDS, Mohs micrographic surgery (MMS) with complete margin evaluation is preferable over wide local excision (WLE) for primary tumors, especially for tumors with substantial subcutaneous invasion. Recurrent tumors should be treated with MMS.
Although radiation and chemotherapy are often used as adjunctive therapies, local tumor control remains the first-line therapy. Because AFX and PDS are induced by radiation exposure, the utility of radiation therapy is unclear. There is also literature suggesting that radiation-induced sarcomas are less responsive to radiation therapy. Additionally, early reports suggest immunotherapy may have the potential to revolutionize the treatment of recurrent or metastatic AFX/PDS.
Specific Investigation
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Biopsy with adequate subcutaneous tissue
Diagnosis requires an adequate biopsy specimen with appropriate immunohistochemical stains (high-molecular-weight cytokeratins, S100, SMA, MelanA/MART1, EMA, CD34, and CD31) to exclude other spindle cell tumors, particularly squamous cell carcinoma, melanoma, angiosarcoma, and leiomyosarcoma. Biopsy and excision specimens should also be evaluted for the extent of subcutaneous invasion, perineural invasion, lymphovascular invasion, atypical mitoses, and tumor necrosis to distinguish between AFX and PDS.
Atypical fibroxanthoma: systematic review and meta-analysis of treatment with Mohs micrographic surgery or excision
Tolkachjov SN, Kelley BF, Alahdab F, et al. J Am Acad Dermatol 2018; 79: 929–34.
This systematic review and meta-analysis included studies published from 1946 to 20 March 2017 with at least five patients treated surgically for AFX. Twenty-three studies were selected, none of which were randomized controlled trials, two were comparative studies, and 21 were non-comparative studies. The review included 907 patients and 914 tumors with a mean patient age of 74.3 (range 25–99) years. Most tumors were located on the head and neck. The mean length of time to follow-up was 41.6 months.
Mohs micrographic surgery (MMS) was used to treat 175 cases and 732 were treated with WLE. In the MMS treatment group, there were five cases of local recurrence (2.0%, 95% confidence interval [CI] 0–4.1%) and five cases of metastasis (1.9%, 95% CI 0.1–3.8%). Of those treated with WLE, 68 had local recurrence (8.7%, 95% CI 5–12.3%) and 17 had metastases (1.0%, 95% CI 0.2–1.9%). The margins for WLE were inconsistently reported. Eleven patients in the MMS group were immunocompromised, and none of these patients experienced local recurrence or metastasis. Ten patients in the WLE group were immunocompromised; four of them (40%) had local recurrence and one (10%) experienced metastatic disease.
In patients with atypical fibroxanthomas, treatment with MMS is associated with a lower risk of local recurrence compared to those treated with WLE (2.0% vs. 8.7%). Of note, studies that used the terms MFH, UPS, or PDS were excluded from analysis.
Atypical fibroxanthoma: The Washington University Experience
Phelan PS, Rosman IS, Council ML. Dermatol Surg 2019; 45: 1450–8.
This is a retrospective cohort analysis of 75 cases of AFX tumors treated at Washington University Medical Center from January 2000 through July 2016. Treatment information was available for 63 of the cases. Median age at diagnosis was 73 years; 56 cases occurred in men, and 19 in women. All subjects with known race were white. Of those with known immune status, 11 (16.2%) were immunosuppressed (secondary to solid organ transplant, hematologic malignancy, or inflammatory bowel disease). Most cases (90.7%) occurred in the head and neck. Forty-two tumors were removed by MMS, 12 by local excision (LE), four by both MMS and LE, two by staged excision, one by multiple LE, one by LE with adjuvant radiation therapy, and one by shave biopsy.
Although preoperative size did not vary significantly between treatment groups, the size of tissue removed was much greater in LE (2.6 cm, 4.5 cm 2 ) compared with MMS (0.6 cm, 1.2 cm 2 ; p =.002 [linear], p =.093 [area]). Follow-up information was available for 50 cases, including 29 treated by MMS (median follow-up 26 months) and 12 treated by LE (median follow-up 50 months). Of these 50 cases, six experienced recurrence. The observed intention to treat recurrence rates were 3.4% for MMS and 25% for LE (RR 0.14 [95% CI 0.02, 1.2], p =.068). After exclusion of the three cases for which the final diagnosis was not AFX, the recurrence rate for true AFX was 8.5%. Recurrence rate did not vary significantly based on immune status.
Although median follow-up time for LE was double that for MMS, bias is unlikely given both groups’ median follow-up was over 2 years, which is what previous studies have shown to be the time during which most recurrent cases of AFX will present. Despite a small sample size of recurrent cases, this retrospective cohort analysis suggests improved outcomes with MMS with the benefit of significantly less tissue removal.
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