Are You Confident of the Diagnosis?
What you should be alert for in the history
Atypical fibroxanthoma (AFX) typically presents with the sudden onset of an asymptomatic, solitary, growth of the head and neck. Bleeding and ulceration are common. Patients are commonly elderly and have a history of extensive sun exposure or previous skin cancers. Less common risk factors for AFX include immunosuppression, previous history of radiation therapy in the region of the tumor, and a history of xeroderma pigmentosa. A review of systems is most commonly negative, due to the very small risk for metastasis.
Characteristic findings on physical examination
Atypical fibroxanthoma has a nonspecific clinical appearance on physical examination, characterized by pink or red papules or nodules with a firm texture, located most commonly on the head or neck, and less commonly on the trunk or extremities (Figure 1). Rare locations include the eyelid, cornea, and ocular surface. Most lesions are smaller than 2 cm in diameter, with the average size being 1.1-1.5 cm in diameter (range: 0.3-0 cm). Ulceration (up to 45% of cases) with oozing or bleeding is common.
Expected results of diagnostic studies
The key diagnostic study for AFX is a biopsy. Histopathology of AFX mimics multiple other diseases, so immunostains are necessary to distinguish AFX from tumors with similar histology. Key pathologic features include dermal cellular proliferation of bizarre spindle cells, epithelioid cells, or multinucleated giant cells (Figure 2). The tumor may be contiguous with the epidermis, but there can be a thin zone of collagen separating the tumor from the epidermis.
AFX is located in the dermis and exhibits minimal invasion to the subcutaneous fat. Atypical mitoses with severe pleomorphism and hyperchromatism are common. According to more recent and stricter definitions, AFX will not infiltrate the subcutaneous fat or deeper and will not show lymphovascular invasion, perineural invasion, or necrosis. Tumors that exhibit these characteristics should be classified as pleomorphic dermal sarcoma, which was formerly known as malignant fibrous histiocytoma or undifferentiated pleomorphic sarcoma (see ‘Diagnosis confirmation’ below for further discussion of terminology). Shallow dermal biopsies cannot distinguish between AFX and pleomorphic dermal sarcoma, since the distinguishing features are not captured on a dermal biopsy.
Cellular morphology may include either spindle cells and epithelioid cells or varying percentages of both cell types. Less common histologic transformations include: hemorrhagic areas, pseudoangiomatous areas, granular cell changes, pigmented areas, keloidal areas, myxoid changes, osteoclast-like giant cells, prominent sclerosis, fibrosis, hyalinization, and clear cell changes.
Immunohistochemistry is important to differentiate AFX from its histologic mimickers, and a panel of markers is usually necessary (see ‘Diagnosis confirmation’ below). Diagnosis of AFX remains a diagnosis of exclusion and generally relies on a lack of staining for melanocytic markers, epithelial markers and desmin, with variably positive staining for nonspecific markers, such smooth-muscle actin, CD68, CD10, and vimentin.
AFX has a nonspecific clinical presentation.
The CLINICAL differential diagnosis includes:
-basal cell cancer
-squamous cell cancer
-amelanotic or desmoplastic melanoma
-Merkel cell cancer
Biopsy is necessary to distinguish AFX from these clinical entities.
The PATHOLOGIC differential diagnosis includes:
-spindle cell squamous cell cancer
-desmoplastic or spindle cell melanoma
-pleomorphic derma sarcoma (previously known as malignant fibrous histiocytoma or undifferentiated pleomorphic sarcoma of the skin)
There are no immunohistochemical markers specific for AFX. However, immunostains are necessary to differentiate AFX from spindle cell squamous cell cancer, desmoplastic melanoma, and leiomyosarcoma. AFX will stain negatively for cytokeratin markers, p40, and p63 (distinguishing it from spindle cell squamous cell cancer, which is positive for these markers), negatively for S-100 and SOX-10 (distinguishing it from desmoplastic melanoma, which is positive for these markers), and negatively for desmin (distinguishing it from leiomyosarcoma, which is desmin positive).
There has previously been significant confusion in the literature regarding the relationship between AFX and pleomorphic dermal sarcoma. Reasons for confusion include genetic studies demonstrating that AFX and pleomorphic dermal sarcoma exist on a spectrum, unclear and overlapping terminology, and poorly-defined diagnostic criteria for AFX. Distinguishing between the two entities is important, because pleomorphic dermal sarcoma has metastatic potential. Histopathologic examination of the entire lesion reveals the main distinguishing characteristics. Whereas AFX is limited to the dermis, “pleomorphic dermal sarcoma” demonstrates necrosis, lymphovascular or perineural invasion, or infiltration of the subcutaneous fat or deeper structures such as fascia or muscle. “Pleomorphic dermal sarcoma” is the preferred term for previously described “undifferentiated pleomorphic sarcoma” and “malignant fibrous histiocytoma.”
Who is at Risk for Developing this Disease?
The exact incidence of AFX remains unclear. However, AFX is the most common tumor of the skin other than basal cell cancer, squamous cell cancer, and melanoma seen by Mohs surgeons. Elderly, light-skinned males with a history of extensive sun exposure or skin cancers are at greatest risk for developing AFX.
Risk factors associated with AFX include:
-history of extensive ultraviolet radiation exposure
-history of x-ray radiation exposure
-history of xeroderma pigmentosa
-immunosuppressed status (e.g., organ transplant recipients)
What is the Cause of the Disease?
-The pathogenesis of AFX has been debated and is still unclear. Current evidence suggests that AFX derives from a myofibroblast- or fibroblast-like cell.
Ultraviolet radiation appears to be the most important environmental factor associated with the development of AFX. Evidence supporting the role of ultraviolet radiation in pathophysiology of AFX includes:
-presence of ultraviolet induced signature mutations of p53 in AFX tumors
-presence of cyclobutane pyrimidine dimers, which are induced by ultraviolet radiation, in AFX tumors
-development of AFX in patients with xeroderma pigmentosa, a disease that causes increased sensitivity to ultraviolet radiation.
X-ray radiation and immunosuppression may also contribute to the development of AFX, but the mechanism of their involvement remains poorly understood.
Systemic Implications and Complications
Patients with xeroderma pigmentosa and immunosuppressed patients (e.g., organ transplant recipients) have an increased risk for AFX. These patients have an increased risk for skin cancers other than AFX. Regular skin examinations are necessary to detect and treat skin cancers in these populations. An increased suspicion for AFX may help with the diagnosis in these populations.
Excisional surgical treatment modalities
non-Mohs wide local excision
Destructive surgical modalities
Optimal Therapeutic Approach for this Disease
Complete excision with microscopic confirmation of pathologic margins is the mainstay of therapy. Mohs micrographic surgery is the treatment of choice, due to its optimal cure rate and tissue sparing ability. Local recurrence after Mohs surgery ranges from 0-6.9%, depending on the published case series.
Compared to Mohs surgery, wide local excision results in a higher rate of local recurrence, ranging from 9-16%. AFX is often a poorly defined lesion by clinical inspection; therefore, wide local excision based on clinical examination is more likely to result in positive margins or recurrence. To clear more than 95% of AFX tumors using wide local excision, an excision of 2 cm of clinically normal skin around all clinically visible tumor is recommended. This wide margin is neither practical nor necessary in the majority of AFX cases. While analysis of a large number of cases showed no significant difference in survival rates between the Mohs surgery and wide local excision, this does not take into consideration the increased morbidity resulting from wider margins or local recurrences.
Most AFX tumors are amenable to surgery under local anesthesia, and radiation therapy is rarely necessary. Destructive modalities, such as cryotherapy and electrosurgery, have little evidence to support their use and are not recommended.
After complete surgical excision, patients should be monitored with regular skin and lymph node examinations (every 6 months is appropriate). The primary risk to patients after surgical excision is local recurrence of the AFX. These patients also require regular surveillance to detect de novo skin cancers, for which they are at increased risk. Any local recurrences of AFX or de novo skin cancers should be biopsied and treated promptly.
The true risk for metastasis from AFX is likely very low, although reports in the literature range from 0.5-6%. Higher reported rates of metastasis probably result from misdiagnosis of pleomorphic dermal sarcoma as AFX. Potential sites of metastases for AFX include regional lymph nodes, and the lungs, brain, liver, and skin. Median time to development of metastases ranges from 6.5-13 months. Patients with solitary regional metastases have a better prognosis than patients with multiple distant metastases. Patients should be monitored for any signs or symptoms of metastases to these areas.
Unusual Clinical Scenarios to Consider in Patient Management
Metastases from AFX is extremely rare and complete excision is the only treatment usually required. Radiation therapy and chemotherapy have been used to treat patients with metastatic AFX.
What is the Evidence?
Tardío, JC, Pinedo, F, Aramburu, JA. “Pleomorphic dermal sarcoma: a more aggressive neoplasm than previously estimated”. J Cutan Pathol.. vol. 43. 2016 Feb. pp. 101-12. (A retrospective clinicopathological study of 18 patients with pleomorphic dermal sarcoma.)
Koch, M, Freundl, AJ, Agaimy, A. “Atypical Fibroxanthoma – Histological Diagnosis, Immunohistochemical Markers and Concepts of Therapy”. Anticancer Res.. vol. 35. 2015 Nov. pp. 5717-35. (Comprehensive review of epidemiology, pathogenesis, etiology, clinical presentation, histology, immunohistochemistry, prognosis and follow-up, and treatment of atypical fibroxanthoma.)
Wang, WL, Torres-Cabala, C, Curry, JL. “Metastatic atypical fibroxanthoma: a series of 11 cases including with minimal and no subcutaneous involvement”. Am J Dermatopathol.. vol. 37. 2015 Jun. pp. 455-61. (A retrospective case series reviewing the clinical and histological features of 11 metastatic atypical fibroxanthomas.)
Brenn, T.. “Pleomorphic dermal neoplasms: a review”. Adv Anat Pathol.. vol. 21. 2014 Mar. pp. 108-30. (A comprehensive review article that examines typical characteristics of various pleomorphic dermal neoplasms.)
Iorizzo, LJ, Brown, MD.. “Atypical fibroxanthoma: A review of the literature”. Dermatol Surg. vol. 37. 2011. pp. 146-157. (Comprehensive review of epidemiology, pathogenesis, etiology, clinical presentation, histology, immunohistochemistry, prognosis. and follow-up, and treatment of atypical fibroxanthoma.)
Beer, TW, Drury, P, Heenan, PJ.. “Atypical fibroxanthoma: A histological and immunohistochemical review of 171 cases”. Am J Dermatopathol. 2010. pp. 1-8. (A retrospective case series reviewing the clinical and histologic features of 171 atypical fibroxanthomas from a single institution in Western Australia.)
Wollina, U, Schonlebe, J, Koch, A, Haroske, G.. “Atypical fibroxanthoma: a series of 25 cases”. J Eur Acad Dermatol Venereol. vol. 24. 2010. pp. 943-6. (A retrospective case series of the clinical, pathologic, and treatment characteristics of 25 patients with atypical fibroxanthoma.)
Mihic-Probst, D, Zhao, J, Saremaslani, P. “CGH analysis shows genetic similarities and differences in atypical fibroxanthoma and undifferentiated high grade pleomorphic sarcoma”. Anticancer Res.. vol. 24. 2004 Jan-Feb. pp. 19-26. (A study demonstrating the possible link between atypical fibroxanthoma and undifferentiated pleomorphic fibroxanthoma.)
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