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Atypical Fibroxanthoma.

Atypical fibroxanthoma (AFX) has been a topic for debate since the 1960s, when Helwig (1) coined its present name. He later published in 1973 a study (2) of 140 cases describing its pathologic features. Since then, advancements in immunohistochemistry have made it possible to exclude other similar neoplasms and emphasize its close relationship with undifferentiated pleomorphic sarcoma (UPS). In this article, we review its clinical behavior, pathologic and radiologic features, relevant differential diagnosis, related molecular studies, prognosis, and treatment.

PATHOGENESIS

The pathogenesis of AFX is still unclear, but most publications agree that ultraviolet-induced damage is an important factor in its development. (3,4) For example, most lesions are found in the head and neck region, where exposure to sunlight is the highest. Ultraviolet p53 mutations at dipyrimidine sites, often encountered in other skin tumors, have also been found in AFX, further supporting this theory. (3,4) On the other hand, electron microscopy studies have confirmed a mesenchymal cell origin, most likely a myofibroblast or fibroblast analogous to UPS. (5,6)

CLINICAL FEATURES

Macroscopically, AFX presents on sun-damaged skin as a reddish pink plaque or nodule with central ulceration, crusting, or scales, often confused with squamous cell carcinoma (SCC) or basal cell carcinoma. In a study of 171 cases, 91% occurred on the face, scalp, ears, and neck, with the remaining 9% presenting on the extremities and trunk. (7) Affected individuals were predominantly elderly men, with a mean age of 74 years. (7) The tumor enlarges quite rapidly up to 1 to 2 cm. In rare cases, when lesions exceed 2 cm, subcutaneous involvement should be carefully examined microscopically. (7,8) Dermoscopically, the lesion shows polymorphic vessels radiating toward the center interspersed around white areas. (9)

RADIOLOGIC IMAGING

Radiologic studies are used when the tumor has metastasized or is not easily accessible, such as when it is subungual. Lee et al (10) reported nonspecific sonographic features of a subungual AFX consisting of a heterogeneous, hypoechoic lesion with partial posterior acoustic enhancement and increased central and peripheral vascularity. Magnetic resonance imaging of the same lesion showed intermediate signal intensity on T1- and T2-weighted images, as opposed to SCC and melanoma, which present with high signal intensity. (10)

PATHOLOGIC FINDINGS

Atypical fibroxanthoma presents as a dermally based, circumscribed lesion with overlying epidermal collarette, central ulceration, and parakeratosis (Figure 1, A and B). Mild to severe solar elastosis is regularly encountered adjacent to the tumor. Cells have moderate to severe pleomorphism with spindle, epithelioid, or multinucleated forms (Figure 1, C and D) and atypical mitotic figures. The mesenchymal nature of this tumor provides the groundwork for different histologic variants (clear cell, spindle cell, granular cell, pigmented, keloidal, sclerosing, myxoid, pseudoangiomatous, and variants with osteoclast-giant cell, osteoid, or chondroid formation), making it harder for the pathologist to reach a diagnosis based on histology. Features against a diagnosis of AFX are evident infiltration beyond the dermis, prominent necrosis, and presence of lymphovascular and/or perineural invasion. Small superficial biopsies should contain a comment explaining the importance of excluding subcutaneous invasion, as this favors a diagnosis of UPS.

IMMUNOHISTOCHEMISTRY

The exclusion of other neoplasms by the use of an immunohistochemistry cocktail is required for the diagnosis of AFX. Markers such as CD68 (Figure 2, A), CD10 (Figure 2, B), vimentin, and smooth muscle actin are not specific but are positive in the majority of tumoral cells. S-100, HMB-45, Melan-A, cytokeratins, desmin, caldesmon, and CD31 are negative; however, beware of S-100 staining dermal dendritic cells within the tumor. The Ki67 proliferation index is moderate to high (Figure 2, C). In addition, the use of LN-2 to distinguish UPS from AFX has been debated recently. (11)

MOLECULAR PATHOLOGY

Mihic-Probst et al (12) reported several chromosomal alterations shared by AFX and UPS in a comparative genomic hybridization study. Among those present in both tumors, only -1q, -3p, -5q, -11p, -11q and +7q, +5p, +11q, +12q were considered significant, with UPS being the most frequent tumor with these alterations. (12) Both tumors also disclosed similar frequencies in 9p and 13q deletions, favoring a common histogenesis. Nevertheless, UPS had considerably more genetic alterations than AFX, which can correlate with its more aggressive behavior. (12) H-ras and K-ras mutations were not present in AFX, compared with UPS in one study, which could be used to differentiate UPS from AFX in difficult cases. (13) DNA content quantification studies noted diploid content in AFX versus aneuploidy content in UPS. In some cases, large pleomorphic atypical cells in AFX were found to be aneuploid. (14,15)

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of AFX is focused primarily on poorly differentiated variants of SCC, melanoma, cutaneous leiomyosarcoma, and atypical fibrous histiocytoma. Metastatic tumors and angiosarcomas could be considered in some cases.

Squamous cell carcinoma, specifically spindle cell or desmoplastic variants, can share features with AFX. Careful inspection for carcinoma in situ, tumor connection with the epidermis, intercellular bridges, or signs of keratinization should be done in all cases. Also, SCC frequently invades subcutaneous tissue and shows presence of lymphovascular and perineural invasion. (16) Positive immunoreactivity for pankeratin (AE1/AE3), epithelial membrane antigen, or high-molecular-weight keratins (34PE12, cytokeratin 5/6) are often useful markers for SCC. (17) More recently, p40 antibody was proven to be more specific than p63 in differentiating SCC from AFX. (18) In this study, performed by Henderson et al, (18) all AFX tumors analyzed (27 cases) were negative for p40 and 8 of 27 were positive for p63. In contrast, SCC showed 51 of 53 cases positive for p40 and 53 of 53 cases positive for p63. (18)

Melanoma can be identified by the presence of pigmented cells with vesicular nuclei and eosinophilic nucleoli. Other microscopic findings such as melanoma in situ or the presence of a dysplastic nevus would support this diagnosis. Reactivity to melanocytic markers can be lost with spindle cell or desmoplastic melanoma, although S-100 maintains positivity.

Leiomyosarcoma is often confused with AFX because of its spindle cell nature, atypical mitoses, and pleomorphism. Yet it is mostly encountered in the trunk and extremities of males. Histologically, the tumor is ill defined with plump or spindle cells arranged in fascicles. Nucleoli are elongated with blunt ends. Most tumors show immunoreactivity for smooth muscle actin, caldesmon, desmin, and vimentin.

Histologically, cutaneous angiosarcoma presents anastomosing vascular spaces with pleomorphic, hyperchromatic endothelial cells showing piling up of the endothelium, infiltrative borders, and evident mitotic activity. Although vascular markers such as CD31 may be expressed in AFX, 2 additional markers, D2-40 and Fli-1, were proposed by Cuda et al (19) to differentiate between the tumors. Angiosarcomas displayed a stronger staining whereas AFX showed weaker reactivity for both markers. (19)

Atypical fibrous histiocytoma is the atypical variant of dermatofibroma (fibrous histiocytoma). Atypical fibrous histiocytoma presents in the trunk and extremities of younger individuals. Fascicles of spindle and polygonal cells with increased mitotic activity and multinucleated and atypical forms are seen. Distinguishing features such as epidermal hyperplasia, a grenz zone, and collagen trapping could assist in identifying this lesion. Unfortunately, immunohistochemistry is similar to that of AFX in many cases.

PROGNOSIS AND TREATMENT

Long-term prognosis associated with AFX is excellent, with low risk of metastasis and recurrences. The treatment of choice is wide local excision, though recently Mohs micrographic surgery has proved to be an alternative. (20) Positive margins in the first surgical procedure, deeper invasion, and older age were associated with recurrences and metastasis in one study. (21) Follow-up during the first 2 years is therefore recommended. (21)

CONCLUSIONS

Although AFX typically has a good clinical course, thorough inspection of larger lesions (>2 cm) for necrosis, lymphovascular invasion, and subcutaneous extension is essential to exclude UPS, which carries a higher risk of recurrence and metastasis. Further research in molecular pathology is needed to clarify the relationship between the two entities. A broad immunohistochemical panel, complete surgical excision, and proper follow-up are still considered the standard approach and management of this entity.

Please Note: Illustration(s) are not available due to copyright restrictions.

References

(1.) Helwig EB. Atypical fibroxanthoma: proceedings of the 18th Annual Tumor Seminar San Antonio Society of Pathologists, 1961. Tex State J Med. 1963;59: 664-667.

(2.) Fretzin DF, Helwig EB. Atypical fibroxanthoma of the skin: aclinicopathologic study of 140 cases. Cancer. 1973;31(6):1541-1552.

(3.) De Tos AP, Maestro R, Doglioni C, et al. Ultraviolet-induced p53 mutations in atypical fibroxanthoma. Am J Pathol. 1994;145(1):11-17.

(4.) Sakamoto A, Oda Y, Itakura E, et al. Immunoexpression of ultraviolet photoproducts and p53 mutation analysis in atypical fibroxanthoma and superficial malignant fibrous histiocytoma. Mod Pathol. 2001;14(6):581-588.

(5.) Barr RJ, Wuerker RB, Graham JH. Ultrastructure of atypical fibroxanthoma. Cancer. 1977;40(2):736-743.

(6.) Weedon D, Kerr JF. Atypical fibroxanthoma of skin: an electron microscope study. Pathology. 1975;7(3):173-177.

(7.) Beer TW. Atypical fibroxanthoma: a histological and immunohistochemical review of 171 cases. Am J Dermatopathol. 2010;32(6):533-540.

(8.) Iorizzo LJ 3rd, Brown MD. Atypical fibroxanthoma: a review of the literature. Dermatol Surg. 2011;37(2):146-157.

(9.) Pitarch G. Dermoscopic rainbow pattern in atypical fibroxanthoma. Actas Dermosifiliogr. 2014;105(1):97-99.

(10.) Lee S, Joo KB, Park C, Kim T, Bae T. A case of atypical fibroxanthoma of subungual type: ultrasound and magnetic resonance imaging findings. Clin imaging. 2013;37(1):155-158.

(11.) Hollmig ST, Rieger KE, Henderson MT, West RB, Sundram UN. Reconsidering the diagnostic and prognostic utility of LN-2 for undifferentiated pleomorphic sarcoma and atypical fibroxanthoma. Am J Dermatopathol. 2013; 35(2):176-179.

(12.) Mihic-Probst D, Zhao J, Saremaslani P, et al. CGH analysis shows genetic similarities and differences in atypical fibroxanthoma and undifferentiated high grade pleomorphic sarcoma. Anticancer Res. 2004;24(1):19-26.

(13.) Sakamoto A, Oda Y, Itakura E, et al. H-, K-, and N-ras gene mutation in atypical fibroxanthoma and malignant fibrous histiocytoma. Hum Pathol. 2001; 32(11):1225-1231.

(14.) Michie BA, Reid RP, Fallowfield ME. Aneuploidy in atypical fibroxanthoma: DNA content quantification of 10 cases by image analysis. J Cutan Pathol. 1994;21(5):404-407.

(15.) Worrell JT, Ansari MQ, Ansari SJ, Cockerell CJ. Atypical fibroxanthoma: DNA ploidy analysis of 14 cases with possible histogenetic implications. J Cutan Pathol. 1993;20(3):211-215.

(16.) Brenn, T. Pleomorphic dermal neoplasms: a review. Adv Anat Pathol. 2014;21(2):108-130.

(17.) Gray Y, Robidoux HJ, Farrel DS, et al. Squamous cell carcinoma detected by high-molecular-weight cytokeratin immunostaining mimicking atypical fibroxanthoma. Arch Pathol Lab Med. 2001;175(6):799-802.

(18.) Henderson SA, Torres-Cabala CA, Curry JL, et al. p40 is more specific than p63 for the distincton of atypical fibroxanthoma from other cutaneous spindle cell malignancies. Am J Surg Pathol. 2014;38(8):1102-1110.

(19.) Cuda J, Mirzamani N, Kantipudi R, Robbins J, Welsch MJ, Sundram UN. Diagnostic utility of Fli-1 and D2-40 in distinguishing atypical fibroxanthoma from angiosarcoma. Am J Dermatopathol. 2013;35(3):316-318.

(20.) Leibovitch I, Huilgol SC, Richards S, Paver R, Selva D. Scalp tumors treated with Mohs micrographic surgery: clinical features and surgical outcome. Dermatol Surg. 2006;32(11):1369-1374.

(21.) Davidson JS, Demsey D. Atypical fibroxanthoma: clinicopathologic determinants for recurrence and implications for surgical management. J Surg Oncol. 2012;105(6):559-562.

Liurka Lopez, MD; Roman Velez, MD

Accepted for publication March 3, 2015.

From the Department of Pathology, University of Puerto Rico, San Juan.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Liurka Lopez, MD, Department of Pathology, University of Puerto Rico, Att: Glendalyz Casanova, PO Box 365067, San Juan, PR 00936-5067 (email: liurka.lopez@upr.edu).

Caption: Figure 1. Atypical fibroxanthoma with adjacent solar elastosis (A) and ulceration (B). The tumor shows epithelioid to spindle cell morphology (C) with severe pleomorphism and prominent nucleoli (D) (hematoxylin-eosin, original magnifications X40 [A], X100 [B], X200 [C], and X400 [D]).

Caption: Figure 2. Immunohistochemistry shows positivity for CD68 (A) and CD10 (B) and a high Ki67 proliferation index (C) (hematoxylin-eosin, original magnification X200 [A through C]).
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Author:Lopez, Liurka; Velez, Roman
Publication:Archives of Pathology & Laboratory Medicine
Date:Apr 1, 2016
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