Atypical Fibroxanthoma

Abbreviations

R.M. Knudson ¥ R.H. Cook-Norris (*) ¥ J.S. Youse ¥ R.K. Roenigk

Department of Dermatology, Mayo Clinic, Rochester, MN, USA

e-mail: cooknorris.robert@mayo.edu; youse.jeremy@mayo.edu

Summary: History

¥Atypical Þbroxanthoma is a soft-tissue neoplasm.

¥Benign clinical course despite highly atypical cells.

¥Aggressive potential has been controversial.

21.1History

The term atypical fibroxanthoma was Þrst used by Helwig [1] in 1961 to describe a soft-tissue neoplasm that generally followed a benign clinical course despite having highly atypical cells. Since that time, there has been controversy regarding the aggressive potential of this neoplasm. It has been described by some to be a benign entity or ÒpseudomalignancyÓ [2Ð4], by others to have a very low risk of recurrence or metastasis [5], and by others to be highly aggressive with high metastatic potential [6Ð19]. Several different terms, such as pseudosarcoma, paradoxical fibrosarcoma, pseudosarcomatous reticulohistiocytoma, and cutaneous malignant fibrous histiocytoma, have been used to describe the entity now commonly called atypical Þbroxanthoma [1, 20Ð22].

Summary: Pathogenesis

¥Origin is undifferentiated mesenchymal progenitor cell.

¥UV radiation implicated in pathogenesis.

Table 21.1 Location of atypical Þbroxanthoma by age at diagnosis in 93 patients

Adapted from Ang et al. [6]. Used with permission a Values are no. of patients (%)

21.2Pathogenesis

AFX is thought to originate from an undifferentiated mesenchymal progenitor cell that can differentiate into histiocytic, Þbroblastic, or myoÞbroblastic phenotypes [23Ð25]. UV radiation, associated with the development of AFX [26], affects DNA molecules by causing the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone [4] photoproducts [27]. SpeciÞcally, single or double cytosine to thymine transitions are formed at dipyrimidine sites exclusively by UV photoproducts [28, 29]. Additionally, UV-induced p53 gene mutations at dipyrimidine sites have been demonstrated in AFX and have been implicated in its pathogenesis [30, 31].

Summary: Clinical Features

¥Most common location is head and neck.

¥Many different clinical presentations.

21.3Clinical Features

AFX is an uncommon cutaneous tumor and generally occurs on the head or neck (Table 21.1) [6]. The male- to-female ratio has been reported to be 3:1, and older men of European descent are affected most often [5]. AFX tends to occur in patients with a previous history of skin cancer involving the head and neck. This distribution is thought to be a result of its association with UV radiation and sun exposure. Typically, patients initially have a red, often ulcerated, rapidly growing nodule on the ear, face, or scalp [5, 6, 32]. Clinical distinction of AFX from other neoplasms is difÞcult without histopathologic examination because it can resemble basal-cell carcinoma, squamous cell carcinoma, or keratoacanthoma (Fig. 21.1aÐc). The average lesion size at diagnosis is 1.5Ð2.0 cm [6, 33Ð35]. Some reports suggest that patients younger than 65 years are more likely than older patients to have an AFX on a limb or areas other than the head and neck, but the data have been inconsistent [5, 6, 8, 36Ð39]. Involvement in areas of previous trauma and radiation therapy has

c

Fig. 21.1 Examples of atypical Þbroxanthoma. (a) SuperÞcially ulcerated plaque with overlying crust on the forehead. (b) Exophytic friable nodule on the scalp. (c) Red nodule with overlying crust on the forehead

21.4Pathology

Histologically, AFX is composed of a well-demarcated dermal proliferation of highly atypical, pleomorphic epithelioid, spindle, and multinucleated cells, generally within a surrounding background of solar elastosis (Fig. 21.2) [32]. Atypical mitoses are frequently present. Generally, involvement of the subcutaneous or deeper tissues is minimal. If involvement of the subcutaneous tissue is present, it is generally focal and limited. Several morphologic patterns have been described, including pleomorphic spindle and epithelioid cells, predominantly spindle cells, purely spindle cells, and

predominantly epithelioid cells [32]. Various histologic variants also have been described, including keloidal, myxoid, clear cell, granular cell, and osteoclastlike giant cell variants; a spindle cell nonpleomorphic variant; variants with plaquelike changes; and tumors with hemorrhagic and pseudoangiomatous areas [5, 32].

Other entities have a similar histologic morphology to AFX, including spindle cell melanoma, leiomyosarcoma, and spindle cell squamous cell carcinoma. The diagnosis of AFX, therefore, is made by excluding other malignant neoplasms with a similar histologic appearance. The use of immunohistochemical stains

Fig. 21.3 Immunohistochemical staining in atypical Þbroxanthoma. Staining with antibodies to various proteins shows that the tumor cells are negative for S100 (a), are negative for

wide-spectrum keratin (b), are negative for desmin (c), and have focal positivity for CD31 (d). Original magniÞcations, ×4

is therefore essential in the diagnosis of AFX. AFX is negative for S100 protein (excludes spindle cell melanoma), highand low-molecular-weight cytokeratins (generally exclude spindle cell squamous cell carcinoma), and desmin (excludes leiomyosarcoma) (Fig. 21.3). Scattered or grouped S100-positive Langerhans cells can be found in AFX, however; therefore, staining for CD1a can be useful in highlighting Langerhans cells in AFX. Use of stains for several other proteins has been reported in the literature, with variable results. Focal positivity has been reported for CD31 (Fig. 21.3); smooth muscle actin has been either focally positive or frequently positive; epithelial membrane antigen has been either negative or focally positive; and CD68 and vimentin were frequently found to be positive [5]. In some cases of spindle cell squamous cell carcinoma, keratin reactivity can be only focal or

absent. Staining for high-molecular-weight cytokeratin 34bE12 and p63 has been found to be helpful in distinguishing poorly differentiated squamous cell carcinomas from AFX [3, 41Ð43]. Procollagen 1 staining also has been reported to be useful in the diagnosis of AFX but must be interpreted carefully because it can also be positive in desmoplastic malignant melanoma and desmoplastic squamous cell carcinoma [44].

Some have considered AFX to represent a superÞcial variant of malignant Þbrous histiocytoma (MFH), which has recently been given the name pleomorphic sarcoma because the speciÞc line of differentiation is unknown. Some consider these tumors to be on a spectrum, being classiÞed as AFX when based in the dermis, superÞcial MFH when based in the subcutaneous tissue, and deep MFH when based in the deep soft tissue and skeletal muscle [39]. Typically, MFH lesions are larger, invade deeper,