A Rare Presentation of Atypical Fibroxanthoma: A Case Report and Discussion Gabriel Guerrero, DO,* Leela Athalye, DO,** Luiza d’Almeida, MD,*** Paul Shitabata, MD,**** Navid Nami, DO*****

*Dermatology resident, PGY2, Northeast Regional Medical Center, Kirksville, MO **Board-certified dermatologist, private practice, Palm Desert, CA ***Board-certified dermatologist, Instituto de Dermatologia Prof. Rubem David Azulay, Rio de Janeiro, Brazil ****Director of dermatopathology, Harbor-UCLA Medical Center, Torrance, CA; Dermatology associate clinical professor of medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA ***** Program director, Dermatology Residency Program, Western University of Health Sciences, Pomona, CA

Disclosures: None Correspondence: Gabriel Guerrero, DO; [email protected]

Abstract Atypical fibroxanthoma (AFX) is a rare, mesenchymal cutaneous neoplasm with low to intermediate malignant potential. AFX typically presents on the sun-exposed areas of elderly white males. We present a less common clinical variant occurring in 38-year-old patient in an area not exposed to the sun. We also review AFX, highlighting differences between the two clinical variants as well as distinguishing it from undifferentiated pleomorphic sarcoma (UPS).

Introduction undifferentiated pleomorphic sarcoma (UPS). keratoacanthoma versus squamous cell carcinoma Atypical fibroxanthoma (AFX) is a rare skin This case report brings awareness to this rare versus pyogenic granuloma. skin cancer, delineates its two clinical subsets and condition, and both its cause and its classification Pathology revealed an ulcerated, atypical spindle are still debated. AFX is currently known as a discusses its controversial histological origins. cell proliferation (Figures 3a, 3b). The atypical rare cutaneous fibrohistiocytic tumor, but the dermal spindle cells were CD68 (Figure 4) term AFX was first used by Helwig in 1961 Case Report and CD163 positive (Figure 5) but negative to describe a dermal tumor of atypical spindle A 38-year-old man presented to the clinic with a for melan-A, S100, factor 13A, and CD34. 1,2 cells. Clinically, two variants of AFX have been 7 mm, erythematous papule with rolled borders Smooth muscle actin (SMA) stained positively described. The more common clinical variant and a central ulcer on the right posterior thigh around blood vessels. The immunohistochemical presents on sun-exposed areas, such as the head (Figures 1 and 2). The lesion was originally findings were consistent with fibro-histiocytic 3 and neck, in older patients (median age 69). The observed by the patient approximately two differentiation and most consistent with less common clinical variant presents in non- months prior to his office visit. The patient AFX. Treatment as a low-grade sarcoma was sun-exposed areas in younger patients (median reported a change in both the size and color recommended. A complete excision was 3 age 39), as it did in our patient. Histologically, of the lesion, as well as episodes of bleeding. performed, and the patient has experienced no this tumor had to be differentiated from other There were no associated symptoms of pain or recurrence of the lesion. malignant skin cancers. In addition, it has been pruritus. Medical history was unremarkable. argued that this tumor may be a superficial A shave biopsy was performed to rule out a Discussion Figure 3a AFX is a rare cutaneous fibrohistiocytic tumor of low to intermediate metastatic potential.1 Due to its rarity, the incidence of AFX is unknown. AFX mainly occurs on sun-exposed skin in elderly white males during the eighth decade

Figure 4

Figure 1

Figure 3b Figure 2 Figure 5

Figure 3. H&E at 10x (a) and 40x (b)

TGUERRERO, ATHALYE, ALMEIDA, HITABATA, NAMI Page 51 of life.3 However, there is a subset of younger of AFX and UPS is identicle, some consider AFX CD10, although non-specific, is strongly positive patients with AFX on non-sun-exposed areas, to be a less aggressive, superficial variant of UPS. in AFX and usually negative in spindle cell SCC such as the trunk and extremities, during the and desmoplastic melanoma.7 CD10 can also 3,4 Histologic differences exist between the two fourth decade of life. AFX usually presents clinical variants (head and neck/sun-exposed stain positive in UPS, which contributes to the as a rapidly growing lesion on sun-damaged areas versus trunk and extremities/non-sun- debate around whether or not AFX is a variant of skin such as the nose, cheeks, ears, neck or scalp. exposed areas) (Table 1). Lesions of the head UPS. Desmin is positive in leiomyosarcoma and The median time between onset and biopsy or and neck (the more common variant’s location negative in AFX, helping distinguish between excision is four months. The lesion is usually a red of presentation) tend to be relatively smaller and the two. Other markers that can be useful in or pink, solitary, asymptomatic papule or dome- better demarcated than lesions on the trunk and differentiating AFX from spindle cell SCC and shaped nodule that is less than 2 cm in diameter desmoplastic melanoma include CD68, CD163, extremities. Lesions on the head and neck only 1 and may be eroded or ulcerated. The non-sun- occasionally extend into the subcutis, whereas procollagen-1 (PC1), p63, and vimentin. exposed clinical variant tends to be slightly larger lesions on the trunk and extremities frequently CD163 is a monocyte-/macrophage-restricted and has a longer duration from onset to biopsy transmembrane glycoprotein. Although CD163 3 extend into the subcutis. The overlying epidermis or excision. Clinically, an AFX lesion may of the lesions on the head and neck are usually is not a highly sensitive or specific marker, it can be resemble SCC, basal cell carcinoma (BCC), or atrophic or ulcerated, and hyperkeratosis and of help as an adjunct stain, as it is usually negative necrotic pyogenic granuloma.3,5 Since AFX has for spindle cell SCC, desmoplastic melanoma, parakeratosis is common. In contrast, the 8 nonspecific clinical features, diagnosis requires a epidermis of lesions of the trunk and extremities and leiomyosarcoma. Finally, LN-2, a protein biopsy. A personal history of skin cancers like expressed in B-cell-rich areas of lymph nodes and 3,4 is often normal or acanthotic. Finally, the BCC or SCC is common in patients with AFX. adjacent skin on the head and neck shows actinic the spleen, is thought to help differentiate AFX The histopathology of AFX generally damage, whereas adjacent skin on the trunk and from UPS.9 It was demonstrated that 90% of demonstrates a dermal circumscribed extremities is usually normal.3 These histological UPS lesions stained strongly for LN-2, whereas 90% of AFX lesions did not stain or stained hypercellular tumor that may extend deep into differences are subtle and usually do not affect 9 the reticular dermis and consists of a mixture the histological diagnosis, although some may weakly for LN-2 (Table 2). of highly pleomorphic spindle cells, epithelioid use these findings to support a diagnosis of UPS. Since AFX is mostly found in sun-exposed areas 6 cells, and multinucleated giant cells. The Currently, no single immunohistochemical of the body, solar radiation very likely plays a proportion of cell types in a lesion varies, and marker is specific for AFX. Therefore, multiple key role in its pathogenesis. However, other the neoplastic cells display a pronounced atypia markers must be used, including those for possible causes are still being considered, such as despite the condition’s relatively benign nature. other similar histologic diseases. Specifically, X-ray radiation, burns, trauma, and a defective Histologically, AFX resembles spindle cell host immune response,4 especially in the non- immunohistochemistry helps differentiate 1 SCC, spindle cell or desmoplastic melanoma, AFX from spindle cell SCC, desmoplastic sun-exposed clinical variant. Evidence that leiomyosarcoma, and undifferentiated melanoma, and leiomyosarcoma.1,6 Due to the ultraviolet (UV) radiation plays a role in the pleomorphic sarcoma (UPS, formerly known cellular origin, cytokeratins are negative for AFX development of AFX has been bolstered in the as pleomorphic malignant fibrous histiocytoma literature. UV radiation may mutate the p53 that 1 and positive for spindle cell SCC. In a similar [MFH]). UPS is a soft tissue sarcoma that occurs fashion, S100 and melan-A are usually negative can be present in AFX.10 Additional evidence primarily in deep soft tissue. Since the histology for AFX, yet positive for desmoplastic melanoma. is also found in xeroderma pigmentosum (XP)

Table 1. Histologic comparison of anatomic variants of AFX (adapted from Fretzin and Helwig3) Histology Head and Neck Trunk and Extremities Location Superficial in dermis Not available

Size Relatively smaller Relatively larger Demarcation Moderate to well Moderate Invasion Occasionally extends into the subcutis but does not Frequently extends into the subcutis invade the deeper soft tissue Overlying epidermis Usually atrophic or ulcerated; hyperkeratosis and Normal; sometimes acanthotic; grenz zone sometimes present patchy parakeratosis common Adjacent skin Usually closely abutted upon the epidermis; adjacent Usually normal skin showed actinic damage

Table 2. Immunohistochemical studies of AFX compared to other cutaneous neoplasms. Spindle Cell Desmoplastic Marker AFX Leiomyosarcoma UPS SCC Melanoma Cytokeratins - + S100 - + Melan-A - + CD10 + - - + Desmin - + CD68 + CD163 + - - - PC1 + LN-2 - +

Page 52 A RARE PRESENTATION OF ATYPICAL FIBROXANTHOMA: A CASE REPORT AND DISCUSSION patients, who have a defect in repair mechanisms of UV-induced DNA lesions. These patients may also have AFX in addition to sun-induced conditions like actinic keratosis, squamous cell carcinomas, and basal cell carcinomas.11-13 The presentation of AFX in a non-sun-exposed region, combined with histology demonstrating no actinic damage, is a reason to look for alternate causes and to consider UPS. Immunosuppression is known to increase the incidence for SCC and BCC. For example, transplant recipients have an increased incidence of cancer presenting in the head and neck, and the vast majority of them are cutaneous in origin.14 This may lead some to assume that immunosuppression may also be a factor that would increase the incidence of AFX. With the true incidence of AFX unknown due to its rarity, establishing an increase in incidence may be difficult. One study mentioned only two AFX cases out of 8,724 (.023%) de novo malignancies in 8,191 solid-organ transplant recipients.15 A second study found one case of AFX out of 642 renal transplant recipients.16 The same study also found two case of MFH (UPS). If AFX and UPS are considered the same, then the incidence may in fact be elevated in immunosuppressed patients. Finally, a third study did not mention AFX out of 484 cutaneous neoplasms in cardiothoracic transplant recipients.14 Although other substantially larger studies of AFX have been conducted, they did not specifically address immunosuppression as a factor.17 AFX is thought to have a very low metastatic potential, with some favoring a diagnosis of superficial UPS for the rare instances of metastasis seen in patients diagnosed with AFX. Since there is a small chance of recurrence and metastasis, treatment of AFX requires surgical techniques such as Mohs micrographic surgery (MMS) or wide local incision (WLE).18,19 MMS seems to have a higher cure rate with fewer recurrences than WLE and allows for tissue sparing, making it the treatment of choice when possible.1,4 Follow-up for two years is recommended, with examination of the surgical site and palpation of the regional lymph nodes.4

Conclusion AFX typically presents in the sun-exposed areas of older white males, although a less common clinical variant presents in non-sun-exposed areas in a younger population. Epidemiology and histology differ between the clinical variants. The immunohistochemistry is important to help rule out other malignant cutaneous neoplasms. Although the prognosis is usually good, MMS is recommended for the small chance of recurrence or metastasis. Finally, the less common clinical variant may provide some insight into the causes of AFX and help with classification of AFX versus UPS.

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