Atypical fibroxanthoma

INTRODUCTION — 

Atypical fibroxanthoma (AFX) is an uncommon, pleomorphic, spindle cell cutaneous malignancy that most commonly presents as a solitary red or pink papule or nodule on the head or neck (picture 1) [1]. Exposure to ultraviolet (UV) light most likely contributes to the development of AFX.

The relationship between AFX, pleomorphic dermal sarcoma, and undifferentiated pleomorphic sarcoma (UPS), a soft tissue neoplasm that shares many histologic features with AFX, is unclear [2]. While some authors consider AFX a less aggressive, superficial variant of pleomorphic dermal sarcoma and UPS, many others view AFX as a distinct malignancy.

The recommended treatment for AFX is surgical removal of the entire tumor with Mohs surgery or wide local excision. AFX generally has a good prognosis. Metastasis is a rare event.

The clinical features, diagnosis, and management of AFX are discussed here. Undifferentiated pleomorphic sarcoma is reviewed separately. (See "Clinical presentation, diagnostic evaluation, and staging of soft tissue sarcoma".)

EPIDEMIOLOGY — 

AFX is an uncommon tumor. A study using data from the Danish National Patient Register estimated an annual incidence of AFX of 8 per 1,000,000 (95% CI 5.8-11) [3].

AFX most commonly occurs in older adults (usually seventh or eighth decade of life) and has a predilection for males. In a series of 945 patients with AFX, the median age at diagnosis was 77.6 years (interquartile range 70 to 84), and 79 percent of patients were male [3].

Although AFX may occur in individuals of all ethnic backgrounds, most reported cases have occurred in non-Hispanic White individuals [4-6]. A personal history of prior basal cell or squamous cell carcinoma is common in patients with AFX [4,7].

RISK FACTORS — 

The mechanisms that lead to the development of AFX are not well understood. Ultraviolet (UV) light exposure has been proposed as a major contributing factor based upon several observations:

●AFX most frequently occurs on sun-exposed skin of the head and neck [3,4,8].

●Similar to nonmelanoma skin cancers promoted by UV light exposure, AFX is most common in older individuals, males, and the non-Hispanic White population [4,5,8,9].

●P53 mutations and cyclobutane pyrimidine dimers (UV photoproducts involved in skin cancer development) have been detected in AFX [10,11].

●Children with xeroderma pigmentosum have developed AFX [12-14].

Additional factors, including radiation therapy, immunosuppression, burns, and trauma have been proposed as contributors to AFX [5,15-17]. However, there are few data to support these theories, and the role of these factors in tumor development remains uncertain.

HISTOGENESIS — 

The origin of tumor cells in AFX has been debated. Immunohistochemical analyses suggest that AFX most likely originates from myofibroblasts or fibroblast-like cells [1,18].

CLINICAL FEATURES — 

AFX usually presents as a solitary, pink or red, firm, papule or nodule that grows over the course of several months and may ulcerate or bleed (picture 1 and picture 2) [1,5,19]. Tumors are usually less than 2 cm in diameter, but occasionally reach several centimeters or more in diameter [5]. A rare pigmented variant of AFX has been reported [20,21].

The head and neck are the most common sites for AFX. Truncal and extremity tumors are less common and may present as larger tumors. Rarely sites such as the eyelid or cornea are affected [22,23].

Most AFX tumors are asymptomatic. Tenderness occurs in a minority. Pruritus is uncommon [5].

HISTOPATHOLOGY — 

Common histopathologic findings of AFX include (picture 3A-B) [24]:

●Well-circumscribed, nonencapsulated dermal tumor that is contiguous with the epidermis or separated from epidermis by narrow zone of collagen (Grenz zone)

●Cellular proliferation of plump spindle cells with prominent nuclei, epithelioid cells, and multinucleated giant cells

●Atypical mitoses and severe cellular pleomorphism

●Variable presence of thin or ulcerated epidermis, or peripheral epidermal collarette

In addition to the classic features listed above, several histologic subtypes of AFX have been described in the literature. Examples include spindle cell predominant, pigmented, clear cell [25,26], osteoclastic, osteoid, chondroid, and granular cell variants [24].

The finding of extensive invasion of subcutaneous fat, high mitotic index, and perineural or lymphovascular invasion suggests the tumor falls into the higher-risk pleomorphic dermal sarcoma/undifferentiated pleomorphic sarcoma category [27].

DIAGNOSIS — 

Because of the rarity of AFX and the tumor's nonspecific clinical features, the correct diagnosis is rarely made clinically. A skin biopsy and immunohistochemical studies are required to confirm the diagnosis. AFX is a diagnosis of exclusion.

Biopsy — An excisional biopsy is the preferred biopsy procedure for AFX. This procedure provides a large tissue sample that allows for visualization of the tumor architecture, which can help to differentiate AFX from undifferentiated pleomorphic sarcoma (UPS), a tumor with a less favorable prognosis, but similar histologic features. However, because clinical suspicion for AFX is often low, a shave biopsy is sometimes the initial diagnostic procedure. The pathologic finding of a tumor composed of spindle cells and epithelioid cells that exhibits marked nuclear pleomorphism raises suspicion for a diagnosis of AFX. (See 'Histopathology' above and "Skin biopsy techniques", section on 'Excisional biopsy' and 'Undifferentiated pleomorphic sarcoma' below.)

Immunohistochemistry — Immunohistochemistry is a valuable tool for differentiating AFX from other spindle cell tumors with similar clinical and histologic findings, including spindle cell squamous cell carcinoma and desmoplastic melanoma. The key immunohistochemical stains employed to distinguish AFX from these tumors include:

●Cytokeratin – Negative in AFX, positive in spindle cell cutaneous squamous cell carcinoma

●S100 – Negative in AFX, positive in desmoplastic melanoma

Depending on the histologic differential, additional stains may aid with diagnosis [1,28-31].

●CD10, actin, and vimentin are often positive in AFX, though these stains are not exclusive to this tumor [6,8,32,33].

●Rarely, melanocyte stains, such as microphthalmia transcription factor (MITF), can be positive in AFX [34].

●The p63 stain is negative in AFX, while it is positive in spindle cell squamous cell carcinoma [30].

●P40 has been shown to be equally sensitive and more specific than p63 for the differentiation of spindle cell squamous cell carcinoma from AFX [35,36].

Dermoscopy — A report of the dermoscopic findings of three AFX tumors led to the identification of white areas and an atypical polymorphous vascular pattern characterized by linear, dotted, hairpin, arborescent, and highly tortuous vessels as dermoscopic features of AFX [37]. These findings are not specific to AFX. (See "Overview of dermoscopy".)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis for AFX includes other benign and malignant cutaneous neoplasms.

Undifferentiated pleomorphic sarcoma — Undifferentiated pleomorphic sarcoma (UPS; formerly known as malignant fibrous histiocytoma [MFH]) (picture 4A-B) is a tumor with a less favorable prognosis that can be difficult to distinguish histologically from AFX [38,39]. UPS is a soft tissue sarcoma that lacks an identifiable line of differentiation.

The term "undifferentiated pleomorphic sarcoma" was replaced with "malignant fibrous histiocytoma" after it was recognized that with more extensive testing, many tumors previously identified as MFH could be classified as other tumors [40]. Because of the pathologic similarities between AFX and UPS, some authors have questioned whether AFX represents a superficial, less aggressive variant of UPS rather than a distinct tumor.

Several histologic characteristics have been proposed as features that may help differentiate AFX and UPS in the clinical setting. Features that may favor a diagnosis of UPS over AFX include involvement of the deep subcutis, penetration of fascia or muscle, necrosis, and vascular invasion [18,40].

A few studies have identified additional findings that suggest a valid distinction between AFX and UPS. In a study of seven AFX tumors and four tumors identified as MFH, the score for cyclobutane pyrimidine dimers (ultraviolet [UV] photoproducts that appear to play an important role in skin cancer development) was significantly greater in AFX than in MFH [10]. In addition, p53 mutations were more commonly detected in AFX (4 of 6 versus 1 of 4). Small studies have also reported genetic differences between AFX and UPS/MFH [41,42].

Other tumors — Disorders that may clinically resemble AFX include basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, amelanotic melanoma, pyogenic granuloma, and adnexal tumors. The rare pigmented form of AFX may be clinically mistaken for pigmented melanoma or pigmented basal cell carcinoma [20,21].

The histologic differential diagnosis for AFX includes other dermal tumors that contain spindle cells. Examples include spindle cell squamous cell carcinoma, desmoplastic melanoma, and leiomyosarcoma. Immunohistochemical studies are useful for distinguishing AFX from these disorders. (See 'Immunohistochemistry' above.)

EVALUATION AND STAGING — 

Patients diagnosed with AFX should receive a full skin examination that includes inspection of the tumor site to estimate the clinical extent of the tumor and palpation of the regional lymph nodes. The skin examination also serves to detect the presence of other cutaneous malignancies.

Radiologic imaging is not necessary for the evaluation of most patients with AFX. When the clinical examination suggests the possibility of extensive tissue invasion (large [eg, ≥2 cm diameter], infiltrative [bound down], or poorly defined tumors), radiologic imaging can be useful for estimating the extent and depth of tumor invasion. Radiologic imaging of distant body sites is not indicated in the absence of signs or symptoms that suggest distant disease. (See 'Prognosis' below.)

TREATMENT — 

Due to the potential for metastatic spread of AFX, treatment of these tumors is recommended (see 'Prognosis' below). Complete surgical removal with Mohs surgery or wide local excision (WLE) is the recommended method of treatment. (See "Mohs surgery".)

Mohs surgery — Although we consider both Mohs surgery and WLE acceptable options for the treatment of AFX, we prefer Mohs surgery for the treatment of AFX on the head and neck because of the tissue-sparing effects of the procedure. The 2 cm margin suggested for WLE of AFX is often difficult to achieve in these areas [43]. Tumors located in other sites in which securing a 2 cm margin is difficult (eg, lower leg) can also benefit from the Mohs surgery procedure. (See 'Wide local excision' below.)

The marked cellular pleomorphism characteristic of AFX makes the identification of tumor cells on frozen tissue sections relatively easy. No high-quality trials have compared the efficacy of Mohs surgery and WLE, leading to uncertainty about the comparative efficacy of these procedures.

The use of Mohs surgery for AFX is supported by several retrospective studies that have identified a low risk for tumor recurrence after this procedure [4,7,44-46]. In a systematic review and meta-analysis of 23 observational studies including 907 patients, of whom 175 were treated with Mohs micrographic surgery (MMS) and 732 with WLE, the local recurrence rate was 2 percent (95% CI 0-4.1) among patients treated with MMS versus 8.7 percent (95% CI 5-12.3) among those treated with WLE after a pooled mean follow-up period of 42 months (range 1 to 315 months) [47]. The metastatic rates were not significantly different in the MMS and WLE groups (1.9 percent [95% CI 0.1-3.8] and 1 percent [95% CI 0.2-1.9], respectively).

Disadvantages of Mohs surgery compared with WLE include the longer duration of the procedure, higher cost, and the lower availability of the procedure. Mohs surgery requires a surgeon specifically trained in the procedure and specialized equipment for tissue examination. (See "Mohs surgery", section on 'Surgical technique'.)

A modification to Mohs surgery, staged excision with circumferential margin assessment ("slow Mohs"), in which formalin-fixed, paraffin-embedded tangential sections are examined to determine circumferential tumor-free margins prior to wound closure has also been used [48]. The efficacy of this procedure for AFX has not been compared to standard Mohs surgery.

Wide local excision — WLE can successfully treat AFX. However, only a small portion of the tumor margin is examined with WLE during pathologic examination. Tumors may recur if the excision margins are inadequate [4,45].

Surgical margins of 2 cm are suggested based on a retrospective study that found that in 59 tumors treated with Mohs surgery, margins of 2 cm or less cleared 97 percent of tumors [4]. A cumulative probability model based on published data on 83 tumors without recurrence indicated that the margin required to clear 95 percent of tumors by WLE was approximately 2 cm [49].

Due to the frequent location of AFX on the head and neck, such margins are often not feasible. Postoperative margin assessment by a pathologist should be performed after all AFX excisions.

Data on the efficacy of WLE for the management of AFX are limited. Reported tumor recurrence rates following WLE typically have ranged between 0 and 20 percent [43]. However, in many reports of AFX treated with WLE, surgical margins have not been specified. Thus, the likelihood of successful treatment with any specific surgical excision marker is unclear.

Radiation — Radiation therapy is an additional option for treatment of AFX that is typically reserved for adjuvant treatment of tumors that cannot be excised with clear surgical margins. Occasionally, radiation therapy is given as the primary mode of treatment for patients who are not candidates for surgery. (See 'Recurrent tumors' below.)

Immunosuppressed patients — Mohs surgery is our preferred method of treatment for AFX in immunosuppressed patients. In a retrospective study of 12 AFX tumors that occurred in solid organ transplant recipients, none of the six tumors initially treated with Mohs surgery recurred or metastasized [50]. In contrast, three of five tumors removed with surgical excision recurred, including one that also metastasized. Of note, the surgical margins for the WLEs were not specified. If WLE is performed, we suggest excising the tumor with 2 cm margins [50].

Recurrent tumors — Guidelines for the management of recurrent tumors are lacking. We typically manage recurrent AFX tumors with Mohs surgery. If WLE is performed, we excise these tumors with 2 cm margins whenever feasible. Adjuvant radiation therapy is administered if complete excision of the recurrent tumor is not possible.

PROGNOSIS — 

Overall, AFX has a good prognosis. Recurrences usually develop within three years after excision [50]. Age>74 years and male sex have been found to be associated with an increased risk of recurrence [51].

Metastasis is rare. In a population-based study, metastasis occurred in 8 of 945 patients (0.8 percent) with AFX [3]. The lymph nodes are often the initial site of metastasis [52]. In a series of 53 patients with AFX treated with Mohs surgery, the relapse-free survival at 12 months was 91 percent; five patients had a relapse within two years and four developed metastases [6].

●In a review of approximately 1500 published cases for which information on outcome was available, the overall recurrence rate was 7.6 percent; among 451 patients for whom complete follow-up data were available, the disease-specific survival was 98 percent at 5, 10, and 20 years [53].

●In a study using data from the Danish National Registries on 945 patients with AFX with a median follow-up of 7.3 years, local recurrence occurred in 10 percent of patients, in most cases within five years after the excision of the primary tumor [3].

Immunosuppressed patients have a less favorable prognosis for this tumor than immunocompetent patients. There is concern that immunosuppressed patients with AFX may also have an increased risk for aggressive tumor behavior based on a small retrospective study of published and unpublished cases that documented three tumor recurrences and one metastasis in 12 solid organ transplant recipients with AFX [50]. Additional studies are necessary to confirm an increase in risk for aggressive tumor behavior in this population.

Involvement of the subcutis portends a worse prognosis and should prompt concern for undifferentiated pleomorphic sarcoma. However, rare cases of metastases and death have been reported with little or no subcutaneous involvement [54]. Some authors have proposed labeling these more aggressive, superficial lesions as dermal pleomorphic sarcomas [55].

FOLLOW-UP — 

There are no standard guidelines for the follow-up regimen for patients with AFX. We perform a full skin examination every six months to check for tumor recurrence and additional cutaneous malignancies. We also palpate regional lymph nodes to evaluate for evidence of metastatic disease.

SUMMARY AND RECOMMENDATIONS

●Epidemiology and risk factors – Atypical fibroxanthoma (AFX) is an uncommon cutaneous tumor that is most likely to occur on sun-damaged skin in older adult males. Ultraviolet (UV) light exposure is theorized to be a major risk factor for the development of AFX. (See 'Epidemiology' above and 'Risk factors' above.)

●Clinical presentation – AFX usually presents as a solitary pink or red nodule. Tumors are often less than 2 cm in diameter but may be larger. The head and neck are the most common sites for tumor development. (See 'Clinical features' above.)

●Pathology – The classic pathologic findings of AFX are a dermal tumor composed of spindle cells, epithelioid cells, and multinucleated giant cells. Cellular pleomorphism is a prominent feature. (See 'Histopathology' above.)

●Diagnosis – AFX is a diagnosis of exclusion. A skin biopsy and immunohistochemical studies are necessary to confirm the diagnosis. Immunohistochemistry is particularly useful for differentiating AFX from other spindle cell tumors that may present with similar clinical and pathologic features, such as spindle cell squamous cell carcinoma and desmoplastic melanoma. (See 'Diagnosis' above.)

●Treatment – We suggest Mohs surgery over wide local excision (WLE) for the treatment of AFX on the head, neck, or other sites in which conservation of healthy tissue is a high priority (Grade 2C). WLE with a 2 cm margin is an alternative to Mohs surgery. Radiation therapy may be an option for patients who are not surgical candidates. (See 'Treatment' above.)

●Prognosis – The prognosis for AFX is usually good. Tumors may recur if surgical margins are inadequate. Metastasis is rare. (See 'Prognosis' above.)