This tumor is commonly referred to as AFX. Some investigators regard this tumor as a superficial malignant fibrous histiocytoma. Its relatively superficial location within the skin and dermis create leads to an indolent growth pattern and despite its menacing histology, metastases is rare. Other investigators view this tumor as a heterogeneous collection of tumors including a sarcomatoid variant of a cutaneous squamous cell carcinoma.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
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EPIDEMIOLOGY CHARACTERIZATION SYNONYMS AFX
Apoptosis in atypical fibroxanthoma and pleomorphic malignant fibrous histiocytoma.
Westermann FN, Langlois NE, Simpson JG.
Southend Hospital, Essex, UK.
Am J Dermatopathol 1997 Jun;19(3):228-31 Abstract quote
Explanations for the disparate behavior of atypical fibroxanthoma (AFX) as compared with pleomorphic malignant fibrous histiocytoma (MFH) have included the proposition that the former is a pseudosarcoma. Nonetheless, these tumors are now widely regarded as the same process, but with AFX behaving benignly by virtue of its superficial location. However, a neoplasm's metastastatic potential has been proposed to be related to apoptosis.
Therefore, the aim of the present study was to examine apoptotic counts, in conjunction with two important regulators of apoptosis: p53 and bcl-2, to determine if a distinction exists that may account for the different outcomes of these lesions. There was no significant statistical difference between eight AFX and nine pleomorphic MFH in terms of apoptotic behavior, proliferative indexes, p53 protein expression, or presence of bcl-2 product.
Therefore, our results further support the contention that AFX should be regarded as a form of pleomorphic MFH, which demonstrates low malignant potential by virtue of its location in readily accessible sites.
Immunoexpression of Ultraviolet Photoproducts and p53 Mutation Analysis in Atypical Fibroxanthoma and Superficial Malignant Fibrous Histiocytoma
Akio Sakamoto, M.D., Yoshinao Oda, M.D., Eijun Itakura, M.D., Yumi Oshiro, M.D., Osamu Nikaido, M.D., Yukihide Iwamoto, M.D. and Masazumi Tsuneyoshi, M.D.
Department of Anatomic Pathology, Pathological Sciences (AS, YoO, EI, MT), and Department of Orthopaedic Surgery (YI), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Pathology, Matsuyama Red Cross Hospital (YuO), Matsuyama, Japan; and Division of Radiation Biology, Faculty of Pharmaceutical Sciences (ON), Kanazawa University, Ishikawa, Japan
Mod Pathol 2001;14:581-588 Abstract quote
p53 mutation is one of the major results of ultraviolet (UV) radiation. UV photoproducts of cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6–4) photoproducts (64PPs) also play an important role in skin cancer development. Atypical fibroxanthoma (AFX), which mimics malignant fibrous histiocytoma (MFH) histologically, occurs in the sun-exposed skin of the elderly, and therefore, an association with UV has long been suspected.
Eighteen fibrohistiocytic skin lesions comprising AFX (n = 7), storiform-pleomorphic type MFH centered in the subcutis (superficial MFH; S-MFH; n = 4) and benign fibrous histiocytoma (BFH; n = 7) were used for immunohistochemical and molecular analysis. Eight cases of deep MFH (D-MFH) were also analyzed for UV photoproduct expression for the purposes of comparison.
Immunohistochemically, the CPD scores of AFX (3.6 ± 0.4) were significantly higher than those of S-MFH (1.3 ± 0.8), D-MFH (0.8 ± 0.5), or BHF (1.4 ± 0.7); however, the 64PP scores were extremely low in all these tumors (AFX, 0.1 ± 0.1; S-MFH, 0.0 ± 0.0; D-MFH, 0.0 ± 0.0; and BHF, 0.0 ± 0.0). AFX, S-MFH, and BFH showed immunoexpression for p53 (2/7, 2/4, and 0/7), respectively. p53 mutations were detected in AFX (4/6; 67%) and S-MFH (1/4; 25%), but not in BFH (0/5; 0%) using polymerase chain reaction–single-strand conformation polymorphism, and all of the mutations in AFX were either C-T transitions or at dipyrimidine sites.
In conclusion, AFX and S-MFH are both similar fibrohistocytic lesions; however, AFX has high immunoreactivity for CPDs compared with S-MFH, D-MFH, or BFH. These data suggest that CPDs may play an important role in the pathogenesis of AFX.
H-, K-, and N-ras gene mutation in atypical fibroxanthoma and malignant fibrous histiocytoma
Akio Sakamoto, MD
Yoshinao Oda, MD
Eijun Itakura, MD
Yumi Oshiro, MD
Sadafumi Tamiya, MD
Yumi Honda, MD
Akira Ishihara, MD
Yukihide Iwamoto, MD
Masazumi Tsuneyoshi, MD
Hum Pathol 2001;32:1125-1231. Abstract quote
Atypical fibroxanthoma (AFX) which is histologically similar to malignant fibrous histiocytoma (MFH), occurs in the sun-exposed skin.
The presence of mutations at codons 12 and 13 of the H- and K-ras genes and in exons 1 and 2, which include codons 12, 13, and 61, of the N-ras gene was studied in 8 cases of AFX and 8 cases of storiform-pleomorphic–type MFH using polymerase chain reaction (PCR)–restriction fragment length polymorphism and PCR–single-conformation polymorphism. Two of the 8 cases of MFH showed ras mutations in the H-ras gene at codon 12 (GGC-AGC) and in the K-ras gene at codon 13 (GGC-GAC). H- and K-ras gene mutations were not seen in any of the cases of AFX (0 of 8). N-ras gene mutation was not detected in either the AFX (0 of 8) or MFH (0 of 8) cases.
In conclusion, although the number of cases in this study was small, H- and K-ras genes were present in some of the MFH cases and accordingly may play an important role in the pathogenesis of MFH. In addition, the finding that H-, K-, and N-ras gene mutations are not present in AFX may indicate why AFX has a more favorable behavior than MFH.
HISTOPATHOLOGY CHARACTERIZATION GENERAL
Morphological and immunohistochemical characteristics of atypical fibroxanthoma with a special emphasis on potential diagnostic pitfalls: a review.
Luzar B, Calonje E.
Institute of Pathology, Medical Faculty University of Ljubljana, Korytkova 2,1000 Ljubljana, Slovenia. special emphasis on potential diagnostic pitfalls.
J Cutan Pathol. 2009 Oct 6. Abstract quote
The present manuscript gives emphasis on recognizing different morphological variants of atypical fibroxanthoma (AFX), on validation of immunohistochemical markers and on discussing potential diagnostic pitfalls.
Material and methods: Histological features analyzed in 66 AFXs were: ulceration, morphological variants, growth pattern, location in the skin and vascular/perineural invasion. The antibodies used were CK-MNF116, CK-AE1/AE3, S100, smooth muscle actin, desmin, CD31 and EMA.
Results: The study included 59 males, 7 females, aged 55-95 years, mean 77 years. All developed on sun damaged skin. Ulceration was present in 50%. Morphological patterns were pleomorphic spindle and epithelioid cells (60.6%), predominantly spindle cells (19.7%), purely spindle-cells (13.6%), and predominantly epithelioid cells (6.1%). Most were localized in the dermis (57.6%). An expansile (36.4%) rather than infiltrative (6.1%) growth into superficial subcutis was also noted. No vascular/perineural invasion was seen. Additional changes were hemorrhagic and pseudoangiomatous areas (24.2%), granular cell change (22.7%), keloid-like areas (9.1%), myxoid change (7.6%), osteoclast-like giant cells (6.1%) and clear cell change (4.6%). AFXs were consistently negative for S100, CK-MNF116, CK-AE1/AE3 and desmin. Focal positivity for SMA (45.2%), EMA (24.4%) and CD 31 (9.5%) was seen.
Conclusions: A diagnosis of AFX is still made by exclusion of other malignant neoplasms with similar morphology. Immunohistochemistry plays a crucial role in this distinction, but can also be misleading. This study expands the spectrum of non-vascular CD31 positive tumors. Luzar B, Calonje E. Morphological and immunohistochemical characteristics of atypical fibroxanthoma with a special emphasis on potential diagnostic pitfalls.
VARIANTS CLEAR CELL
J Cutan Pathol. 2006 May;33(5):343-8. Abstract quote
Clear cell atypical fibroxanthoma (CCAFX) is a rare variant of atypical fibroxanthoma (AFX), a pleomorphic dermal tumour associated with a good prognosis. A 67-year-old man presented with a rapidly growing nodule on the ear, which had appeared over a 2-week period.
Sections showed an ulcerated nodule composed of pleomorphic spindled and polygonal cells with clear cytoplasm, invested by a delicate vascular stroma, reminiscent of clear cell renal cell carcinoma. Numerous mitotic figures were seen. The tumour cells stained with vimentin, CD68 and CD99 and were cytokeratin-negative. The immunohistochemical and ultrastructural features supported a diagnosis of CCAFX.
The diagnosis of CCAFX requires the exclusion of other pleomorphic clear cell tumours that can occur in the skin by using a combination of morphology, immunohistochemistry and electronmicroscopy.
"Clear cell" atypical fibroxanthoma.
Patterson JW, Konerding H, Kramer WM.
Department of Dermatology, Medical College of Virginia, Richmond.
J Dermatol Surg Oncol 1987 Oct;13(10):1109-14 Abstract quote
An 87-year-old man with extensive solar damage presented with a 2-month history of a dome-shaped, crusted lesion on the dorsum of the left hand. Microscopically, the tumor consisted of fascicles of spindle cells with bizarre nuclei and clear, vacuolated cytoplasm. Histochemical, immunohistochemical, and ultrastructural features supported the diagnosis of atypical fibroxanthoma. There was no evidence of metastatic disease. The lesion was completely excised, and there has been no recurrence in 3 months of observation.
This unusual "clear cell" variant of atypical fibroxanthoma must be distinguished from other clear cell tumors, such as metastatic renal cell carcinoma, clear cell eccrine carcinoma, and clear cell sarcoma (malignant melanoma) of soft parts. Although atypical fibroxanthoma is usually cured by complete surgical excision, metastases have been reported.
Clear-cell atypical fibroxanthoma: an uncommon histopathologic variant of atypical fibroxanthoma.
Requena L, Sangueza OP, Sanchez Yus E, Furio V.
Department of Dermatology, Fundacion Jimenez Diaz, Universidad Autonoma, Madrid, Spain.
J Cutan Pathol 1997 Mar;24(3):176-82 Abstract quote
Atypical fibroxanthoma is a superficial variant of pleomorphic malignant fibrous histiocytoma. Histopathologically, it is characterized by a dermal nodule composed of bizarre cells arranged in a haphazard-to-fascicular pattern. These cells are spindle or rounded, pleomorphic and with numerous atypical mitotic figures. Some cells appear polygonal with ample and foamy cytoplasm.
We recently encountered two elderly patients with atypical fibroxanthoma on their face. Histopathologically, one of the lesions was composed, almost entirely, of clear cells, whereas in the other one aggregations of clear cells constituted a half of the neoplasm. Atypical multinucleated cells with a Touton-like appearance were present.
In addition to clear cells, areas of more conventional atypical spindle cells arranged in fascicles were seen, supporting the diagnosis of atypical fibroxanthoma. PAS staining failed to demonstrate glycogen in neoplastic cells. Immunohistochemistry revealed that neoplastic cells expressed positivity for vimentin, muscle-specific actin, and alpha smooth muscle actin, whereas cytokeratin, S-100 protein, EMA, CEA, and desmin were negative. Ultrastructural studies showed that neoplastic cells contained abundant rough endoplasmic reticulum, mitochondria, and numerous lipid vacuoles within the cytoplasm.
Clear-cell atypical fibroxanthoma is a rare variant of atypical fibroxanthoma that should be differentiated from other clear-cell neoplasms of the skin.
Clear cell atypical fibroxanthoma:a clinicopathologic study.
Crowson AN, Carlson-Sweet K, Macinnis C, Taylor JR, Battaglia T, LaMar WL, Minor D, Sutter S, Hill T.
Department of Dermatology, University of Oklahoma, USA Regional Medical Laboratory, St John Medical Center, Tulsa, OK, USA Regional Dermatology, Bartlesville, OK, USA.
J Cutan Pathol 2002 Jul;29(6):374-81 Abstract quote
INTRODUCTION: The atypical fibroxanthoma (AFX) is considered by most authorities to represent a superficial or minimally invasive variant of malignant fibrous histiocytoma that most often presents as a solitary nodule on the sun-exposed skin of the elderly. Among the rarest variants is the clear cell AFX, a lesion which raises consideration to a differential diagnosis encompassing a variety of neoplastic and non-neoplastic clear cell proliferations.
METHODS: We describe three cases of a distinctive cutaneous neoplasm arising in the sun-exposed skin of elderly patients. In all cases, formalin-fixed, paraffin-embedded tissue was available for analysis. The histology in concert with the immunophenotype was held to be diagnostic of the clear cell variant of AFX.
RESULTS: All tumors comprised sheets of large cells with foamy cytoplasms and hyperchromatic, polyploid nuclei manifesting frequent and atypical mitoses. The critical cells in our cases expressed CD68 but none of CD3, CD20, CD34, S-100 protein, muscle-specific actin, factor XIIIa, Melan-A, carcinoembryonic antigen, or cytokeratin.
CONCLUSION: Although typical examples of AFX provoke diagnostic consideration of spindle cell cancers of the skin (most often spindle cell melanoma, spindle cell squamous cell carcinoma, and leiomyosarcoma), the clear cell variant raises other differential diagnostic considerations instead. These include balloon cell melanoma, sebaceous carcinoma, pleomorphic liposarcoma, chordoma, parachordoma, tricholemmal carcinoma and clear cell squamous cell carcinoma. A diagnosis of AFX is one of exclusion; one must employ immunohistochemical markers to rule out the aforementioned differential diagnostic considerations. By reporting the fifth, sixth and seventh cases of clear cell AFX, we hope to alert dermatopathologists to this distinctive and unusual neoplasm, recognition of which is essential to avoid under- or over-diagnosis and inappropriate therapy.
Atypical fibroxanthoma with osteoclast-like multinucleated giant cells.
Khan ZM, Cockerell CJ.
Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, USA
Am J Dermatopathol 1997 Apr;19(2):174-9 Abstract quote
Atypical fibroxanthoma is a malignant fibrohistiocytic neoplasm that develops most commonly on sun-exposed skin of elderly individuals. A number of different variants have been described, ranging from a purely spindle cell type to a xanthomatous form.
We recently observed an unusual variant of atypical fibroxanthoma in which there were numerous osteoclast-like multinucleated giant cells. Histologically, there was a diffuse spindle cell neoplasm in the dermis exhibiting fibrohistiocytic differentiation associated with inflammatory cells. The neoplastic spindle cells were markedly pleomorphic and many were in mitosis, some being tripolar and tetrapolar. In addition to these features, which are common in atypical fibroxanthoma, there were numerous multinucleated giant cells scattered throughout the lesion with features resembling normal osteoclasts. Epithelioid cells with features of histiocytes were seen in association with these cells. No osteoid was observed, however, that suggested monocyte-macrophage differentiation. The histologic appearance of this lesion was reminiscent of the giant cell variant of malignant fibrous histiocytoma, also termed malignant giant cell tumor of soft parts.
Thus, osteoclast-like giant cells may be seen in atypical fibroxanthoma. These cells probably represent multinucleated histiocytes rather than true osteoclasts. It is important to recognize this variant to avoid confusion with other malignant soft tissue neoplasms.
Granular cell atypical fibroxanthoma: case report and review of the literature.
Wright NA, Thomas CG, Calame A, Cockerell CJ.
University of Texas Health Science, Center at Houston Medical School, Houston, TX.
J Cutan Pathol. 2009 Mar 31.Abstract quote
We present a case of granular cell atypical fibroxanthoma of the scalp. The neoplasm occurred as a tender nodule on the frontal scalp of an 82-year-old Caucasian man.
Histology demonstrated a diffuse proliferation of atypical epithelioid cells with abundant granular cytoplasm. Many of the cells had large irregular nuclei and atypical mitotic figures were present. Immunohistochemical stains were positive for CD68 and procollagen 1 and negative for cytokeratin, HMB-45 and S-100 protein. The granular cell phenotype has been observed in other cutaneous neoplasms including granular cell tumors, dermatofibromas, dermatofibrosarcoma protuberans, fibrous papules, basal cell carcinomas, leiomyosarcomas, angiosarcomas and primitive polypoid granular cell tumors.
We discuss the differential diagnosis and review the previously reported cases of this rare variant of atypical fibroxanthoma.
- Am J Dermatopathol. 2007 Feb;29(1):84-7. Abstract quote
Two cases of an uncommon histopathological variant of atypical fibroxanthoma (AFX) are described.
Even though both lesions presented as clinically conventional atypical fibroxanthoma, histopathology disclosed a neoplasm composed of cells with granular change that was negative for S100 staining, and showed prominent pleomorphism, severe nuclear atypia, and a high mitotic index.
Degenerative change may explain the granular phenotype in these two cases of AFX. The differential diagnosis with primitive nonneural granular cell tumor is discussed.
- Granular cell atypical fibroxanthoma.
Rudisaile SN, Hurt MA, Santa Cruz DJ.
Cutaneous Pathology, WPC Laboratories, Inc., Maryland Heights, MO, USA.
J Cutan Pathol. 2005 Apr;32(4):314-7. Abstract quote
We report on two patients with granular cell atypical fibroxanthoma. Both neoplasms were solitary, light-tan, dome-shaped papules on sun-exposed areas of the head in two elderly white men.
Microscopically, these neoplasms showed a dermal proliferation of pleomorphic granular cells with irregular hyperchromatic nuclei, multinucleated cells, and scattered mitoses. Immunohistochemical stains were positive for CD68 and vimentin and negative for Melan-A or human melanoma black (HMB)-45, S-100 protein, pancytokeratin, and actin, consistent with atypical fibroxanthoma.
The differential diagnosis of granular cells in neoplasms containing cytological pleomorphism is challenging in view of the many different neoplasms that may present with granular cytoplasm. These include the conventional granular cell tumor and its malignant form, leiomyoma, leiomyosarcoma, dermatofibroma, dermatofibrosarcoma protuberans, and angiosarcoma.
KELOIDAL Keloidal atypical fibroxanthoma: a case series
Jinah Kim 1 and Jennifer M. McNiff 1,2
J Cutan Pathol 2009;36:543-547 Abstract quote
Background: Keloidal atypical fibroxanthoma (AFX) is a rare variant of AFX with thick bands of hyalinized collagen. The identification of keloidal collagen associated with fibrohistiocytic cells may erroneously lead to the diagnosis of keloidal dermatofibroma. Although AFX is a pleomorphic cutaneous tumor typically associated with a good prognosis, occasional reports of metastatic AFX highlight the importance of accurate identification.
Methods: A total of nine cases of an unusual variant of AFX with keloidal tumoral sclerosis were collected and examined. The cases were stained with antibodies directed against S100, cytokeratin, CD68 and CD31.
Results: Histopathological examination revealed pleomorphic cells trapped within hyalinized keloidal collagen bands. In several cases, the keloidal collagen also formed ring-shaped structures surrounding CD31-positive vascular structures. Pleomorphic cells were negative for S100 protein and keratin, but consistently labeled with antibodies directed against CD68.
Conclusions: The diagnosis of keloidal AFX requires the exclusion of other malignant and benign lesions with keloidal or sclerotic collagen. Awareness of the rare variant of keloidal AFX may avoid a diagnostic pitfall leading to an erroneous diagnosis, particularly in small biopsies. The finding of sclerotic collagen preferentially deposited around vessels is an interesting and poorly understood phenomenon.
Myxoid atypical fibroxanthoma: a previously undescribed variant.
Patton A, Page R, Googe PB, King R.
Graduate School of Medicine, Knoxville, Tennessee, USA.
J Cutan Pathol. 2009 Nov;36(11):1177-84. Abstract quote
BACKGROUND: Atypical fibroxanthomas (AFX) are dermal-based cutaneous tumors typically found in sun-damaged skin of the elderly. Histologic variants include spindle cell, clear cell, osteoid, osteoclastic, chondroid, pigmented, and granular cell. To date, myxoid change in AFX, has not been described.
METHODS: Four cases were retrieved from the consultation and surgical pathology files of Knoxville Dermatopathology Laboratory, Knoxville, Tennessee during a 4-year period. The clinical and histologic findings were reviewed and Alcian blue/periodic acid-Schiff (PAS) stain and panel of immunohistochemical stains was obtained.
RESULTS: All 4 lesions occurred as solitary lesions in elderly males on the head and neck (2 cases) and upper extremity (2 cases). Histologically all tumors demonstrated a well-circumscribed, cellular lesion centered in the dermis and composed of a mix of atypical pleomorphic and spindle cells in a prominent myxomatous background. A junctional component was absent and the tumors did not arise from the epidermis or adnexal structures. Subcutaneous involvement was absent in all cases. Tumor cells were negative for melanocytic and epithelial markers. Positive staining was noted with CD10 (3/4 cases) and vimentin (4/4 cases).
CONCLUSION: Myxoid change in AFX is rare and previously undescribed in the English literature. Myxoid change may be a prominent finding in benign and malignant cutaneous tumors and awareness of this variant of AFX will avoid misdiagnosis.
Spindle-cell non-pleomorphic atypical fibroxanthoma: analysis of a series and delineation of a distinctive variant.
Calonje E, Wadden C, Wilson-Jones E, Fletcher CD.
Soft Tissue Tumour Unit, St Thomas's Hospital, U.M.D.S., London, UK.
Histopathology 1993 Mar;22(3):247-54 Abstract quote
Atypical fibroxanthoma is a bizarre, cytologically malignant but usually clinically benign, lesion which typically arises in sun-damaged skin of the head and neck region in the elderly. Classically, its morphology is said to represent the dermal counterpart of pleomorphic malignant fibrous histiocytoma.
We have identified 10 cases of a more monomorphic spindle-celled, fascicular variant which, paradoxically, was often mistaken for a clinically malignant lesion because it lacked the pleomorphism of conventional atypical fibroxanthoma. These tumours all arose in the head and neck region as polypoid lesions in the elderly. The tumours were confined to the dermis, often had an epidermal collarette, showed an eosinophilic fascicular morphology and were highly mitotic. All 10 were vimentin positive and five showed very focal actin positivity. Desmin, keratin and S-100 protein were negative in all cases. The clinical course was benign in all cases, justifying their accurate recognition.
The principal differential diagnoses are spindle cell squamous carcinoma, spindle cell melanoma and leiomyosarcoma. Immunohistochemistry plays a key role in this distinction.
Pigmented atypical fibroxanthoma: a tumor that may be easily mistaken for malignant melanoma.
Diaz-Cascajo C, Weyers W, Borghi S.
Am J Dermatopathol 2003 Feb;25(1):1-5 Abstract quote
Nine cases of an unusual presentation of atypical fibroxanthoma that we previously termed pigmented atypical fibroxanthoma are reported.
Pigmented atypical fibroxanthoma can be easily mistaken for malignant melanoma both clinically and histopathologically. The resemblance of pigmented atypical fibroxanthoma to melanoma is secondary to the ability of neoplastic cells to ingest and degrade erythrocytes following intratumoral hemorrhage and to accumulate hemosiderin in their cytoplasm.
The histopathologic diagnosis of pigmented atypical fibroxanthoma can be easily confirmed by immunohistochemistry and iron stain.
The histopathologic spectrum of regression in atypical fibroxanthoma.
Stefanato CM, Robson A, Calonje JE.
Department of Dermatopathology, St John's Institute of Dermatology, St Thomas' Hospital, London, UK.
J Cutan Pathol. 2009 Sep 17. Abstract quote
Background: Atypical fibroxanthoma (AFX) with prominent fibrosis, sclerosis and hyalinization, and near-total tumor regression is rare. Methods: Eight cases of AFX presenting with fibrosis were reviewed as to their tumor architecture, the degree and pattern of fibrosis and the associated inflammatory cell infiltrate.
Results: Seven of eight cases had an exophytic architecture, with ulceration in one case. The degree of fibrosis ranged from 10% to 90%. Early fibrosis (2/8 cases) occurred as thickened sclerotic collagen bundles, either dispersed between the neoplastic cells or as septa imparting a multilobular appearance. Advanced fibrosis (6/8 cases) was associated with lamellar sclerosis, keloidal features, hyalinization and with near-total tumor replacement. Prominent fibrosis rimming the periphery was present in all tumors. An associated lymphoid cell infiltrate with plasma cells and occasionally eosinophils was observed.
Conclusions: Fibrosis with prominent sclerosis and hyalinization replacing the tumor is rare in AFX. Advanced fibrosis, in the absence of a history of prior trauma or surgery, may indicate spontaneous regression. These cases emphasize the importance of recognizing this subset of AFX in order to avoid misinterpretation, particularly in cases with few residual atypical cells.
Atypical fibroxanthoma with prominent sclerosis.
Bruecks AK, Medlicott SA, Trotter MJ.
Calgary Laboratory Services, and Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada.
J Cutan Pathol. 2003 May;30(5):336-9. Abstract quote
BACKGROUND: Malignant cutaneous spindle cell lesions with marked sclerosis are uncommon. Only a few cases of cutaneous leiomyosarcoma and dermatofibrosarcoma protuberans with sclerosis have been published.
METHODS: We report a case of atypical fibroxanthoma (AFX) with prominent sclerosis and hyalinization occurring on the scalp of an 81-year-old male.
RESULTS: Histopathologic examination revealed an exophytic, well-delineated, focally ulcerated tumor arising in sun-damaged skin. The lesion was composed of atypical spindle cells arranged in a fascicled and vaguely storiform pattern. Occasional multinucleated giant cells were present. The tumor cells were strongly positive for CD99 (O13), vimentin, and smooth muscle actin, and focally positive for CD68. There was striking sclerosis with hyalinization throughout the lesion.
CONCLUSIONS: Rarely, AFX may exhibit marked sclerosis with areas of complete replacement of tumor by hyalinized collagen. In a small biopsy, such hyalinization may be a diagnostic pitfall leading to an erroneous diagnosis.
CD10, p63 and CD99 expression in the differential diagnosis of atypical fibroxanthoma, spindle cell squamous cell carcinoma and desmoplastic melanoma.
Kanner WA, Brill LB 2nd, Patterson JW, Wick MR.
Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908-0214, USA.
J Cutan Pathol. 2010 Jul;37(7):744-50. Abstract
BACKGROUND: Atypical fibroxanthoma (AFX) is a pleomorphic spindle cell lesion of the skin; it is considered in the differential diagnosis with spindle cell malignant melanoma (MM) and sarcomatoid carcinoma/spindle cell squamous cell carcinoma (SCC). An optimum approach has yet to fully emerge with respect to the immunohistochemical discrimination of these lesions.
METHODS: Departmental archives from 1978 onwards were searched for clinicopathologically confirmed cases of AFX, MM and SCC. Immunostains for CD10, CD99 and p63 were performed in each case. Scored staining results were analyzed using Fisher's Exact Test.
RESULTS: Twenty-seven of 31 cases of AFX were positive for CD10, as compared with 3 of 22 SCCs and 0 of 20 MMs. CD10 positivity was preferentially associated with the diagnosis of AFX (p < 0.001). p63 reactivity was observed in 15/22 cases of SCCs, 5/31 AFXs and 1/20 MMs. CD99 reactivity was observed in 3/31 cases of AFX, 2/22 SCCs and 3/20 MMs.
CONCLUSION: CD10 positivity is relatively specific in this context for the diagnosis of AFX. Its utility is enhanced when only strong, diffuse membranocytoplasmic staining is considered as a positive result. In contrast to prior reports, p63 was not found to be highly sensitive for SCC. Similarly, CD99 showed no preferential staining of any single diagnostic group of lesions.
Spindle-cell and pleomorphic neoplasms of the skin. A clinicopathologic and immunohistochemical study of 30 cases, with emphasis on "atypical fibroxanthomas".
Silvis NG, Swanson PE, Manivel JC, Kaye VN, Wick MR.
University of Minnesota Medical School, Minneapolis.
Am J Dermatopathol 1988 Feb;10(1):9-19 Abstract quote
Atypical fibroxanthoma belongs to the family of spindle-cell and pleomorphic neoplasms of the skin. The lineage of differentiation of this tumor and the means whereby it can be diagnostically separated from other similar morphologic entities have been controversial.
In order to address these issues, the authors studied 30 spindle-cell and/or pleomorphic cutaneous tumors, including atypical fibroxanthomas (AFXs), superficial malignant fibrous histiocytomas (MFHs), dermatofibrosarcoma protuberans (DFSPs), sarcomatoid squamous-cell carcinomas (SCCs), spindle-cell malignant melanomas (MMs), and leiomyosarcomas, (LMSs). These cases were analyzed using a panel of eight antibodies and the immunoperoxidase technique. AFXs were reactive for vimentin, alpha-1-antichymotrypsin (AACT), alpha-1-antitrypsin (AAT), and cathepsin-B (CB) but failed to display cytokeratin (CK), epithelial membrane antigen (EMA), S-100 protein, and desmin. MFHs and DFSPs exhibited immunophenotypic profiles that were nearly identical to that just described.
In contrast, SCCs were typified by positivity for CK and EMA; MMs exhibited uniform reactivity for S-100 protein; and LMSs contained desmin in four of five cases. A surprising result was the expression of S-100 by LMSs. Also, all tumors displayed at least one of the three proteolytic enzymes assessed in this study (AAT, AACT, and CB), demonstrating the relative diagnostic nonspecificity of these determinants.
It is concluded that AFXs are "fibrohistiocytic" neoplasms, with substantial morphologic and immunohistochemical similarity to MFHs. The immunohistochemical classification of spindle-cell and pleomorphic tumors of the skin necessitates the use of antibody panels to assess the presence of markers that are characteristic of each diagnostic group.
Calponin and h-caldesmon expression in atypical fibroxanthoma and superficial leiomyosarcoma.
Sakamoto A, Oda Y, Yamamoto H, Oshiro Y, Miyajima K, Itakura E, Tamiya S, Honda Y, Ishihara A, Iwamoto Y, Tsuneyoshi M.
Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Virchows Arch 2002 Apr;440(4):404-9 Abstract quote
To evaluate smooth muscle differentiation, myogenic markers [desmin, alpha-smooth muscle actin (SMA), and muscle-specific actin (HHF35)] have been widely used. Calponin and h-caldesmon, which are cytoskeleton-associated actin-binding proteins, have been reported to be more specific myogenic markers, especially since myofibroblasts express a small amount of h-caldesmon. Atypical fibroxanthoma (AFX) occurs in the sun-exposed skin of the elderly and follows a benign clinical course. Histologically, AFX, which is a pleomorphic spindle cell tumor and considered to be a superficial variant of malignant fibrous histiocytoma, also mimics leiomyosarcoma. AFX has been thought to differentiate along pathways with fibrohistiocytic and myofibroblastic phenotypes. AFX ( n=10), superficial leiomyosarcoma (S-LMS) ( n=17) and benign fibrous histiocytoma (BFH) ( n=17) were analyzed for myofibroblastic and smooth muscle differentiation immunohistochemically from the viewpoint of comparison.
AFX and BFH showed immunoreactivities respectively for calponin (3/10, 11/17), desmin (3/10, 1/17), SMA (3/10, 13/17), and HHF35 (1/10, 5/17), but failed to express h-caldesmon (0/10, 0/17). S-LMS had a high immunoreactive rate of calponin (17/17), desmin (13/17), SMA (16/17), and HHF35 (16/17), while also expressing caldesmon (11/17).
The results reveal that AFX and BFH have immunoreactivities for several myogenic markers, with myofibroblastic differentiation (calponin: +/-, h-caldesmon: -), but without the smooth muscle differentiation seen in S-LMS (calponin:+, h-caldesmon: +/-). In addition, calponin and h-caldesmon are considered to be useful markers for distinguishing AFX from S-LMS.
- Evaluation of CD10 and procollagen 1 expression in atypical fibroxanthoma and dermatofibroma.
Department of Pathology, University of California at San Francisco, San Francisco, CA 94115, USA.
- Am J Surg Pathol. 2008 Aug;32(8):1111-22. Abstract quote
Atypical fibroxanthoma (AFX) (dermal pleomorphic sarcoma) remains a somewhat controversial entity. Some authors have averred that AFX is a fiction, suggesting that such lesions merely represent misclassified examples of spindled squamous cell carcinoma. In addition, the immunoperoxidase confirmation of AFX has been less than straightforward and has historically been approached as a diagnosis of exclusion because of the lack of sensitivity and specificity of available "positive" reagents.
Procollagen 1 (PC1) and CD10 represent recently developed immunoperoxidase reagents that have been forwarded as useful in this setting, and we sought to characterize our experience, both to confirm the utility of these antibodies and to compare them.
Our investigation included 3 separate data sets. Group 1 consisted of a retrospective review of 98 consecutive cases in which PC1 was used in the evaluation of dermatopathology specimens in routine practice during a 13-month interval. Group 2 consisted of a direct comparison of 11 AFX, 11 dermatofibroma (DF), and 7 epithelioid dermatofibroma (EDF) using the CD10 reagent on cases identified by database search. Group 3 consisted of a retrospective review of 47 cases in which CD10 was used in routine practice during a 10-month interval. Group 1 included 47 AFX, 13 carcinomas, and 6 melanomas. PC1 expression was observed in 45 of 47 AFX (96%), with a strong reaction in 78% of cases. Among a comparison group of carcinomas, 13 of 13 displayed strong keratin immunopositivity and 11 of 13 (85%) lacked PC1 expression whereas 2 showed focal weak labeling. Six of six melanomas exhibited avid S100 expression and none labeled with PC1. In group 2, strong CD10 immunoreactivity was present in 11 of 11 AFX. Similarly, 11 of 11 DFs were also positive. In contrast, 6 of 7 cases of EDF lacked CD10 expression. Group 3 included 38 AFX and 9 miscellaneous spindle cell proliferations. Of the 38 AFX, 37 (97%) labeled with CD10 and in 34 (92%) the reaction was strong. PC1 immunostaining was also completed in 34 of 38 AFX from group 3 and 27 (79%) cases showed positive labeling. Our results confirm that both PC1 and CD10 can be used as positive markers of AFX.
We believe that CD10 and PC1 immunostaining can be used as a useful adjunct to supplement the diagnosis of AFX, within the context of an immunoperoxidase panel. Not surprisingly, CD10 expression is also common in DF, a benign analog of AFX, with the exception of its epithelioid variant. In direct head-to-head comparison, our experience indicates that the staining of AFX with CD10 is more avid than that observed with PC1. Lastly, out data includes over 80 examples of AFX, <5% of which showed keratin labeling. Given a general lack of keratin expression, it seems unlikely that AFX merely represents poorly differentiated squamous carcinoma.
CD99 Immunoreactivity in Atypical Fibroxanthoma A Common Feature of Diagnostic Value
Carlos Monteagudo, MD
Luis Calduch, MD
Samuel Navarro, MD
Alejandro Joan-Figueroa, MD
and Antonio Llombart-Bosch, MD
Am J Clin Pathol 2002;117:126-131 Abstract quote
Atypical fibroxanthoma (AFX), a pleomorphic superficial cutaneous tumor of low-grade malignancy, shares many morphologic features with malignant melanoma (MM) and squamous cell carcinoma (SCC). Absence of S-100, keratin, and desmin immunoreactivity is the clue for this diagnosis.
In a search for positive markers, we tested 26 cases of AFX with 2 antibodies: O13 (CD99) and protein gene product 9.5 (PGP9.5). We also included 10 cases of poorly differentiated SCC and 10 cases of MM in the study. In AFX, CD99 immunoreactivity was present in 19 cases (73%), whereas focal PGP9.5 immunoreactivity was found in only 9 cases (35%). None of the SCC cases showed CD99 immunostaining. No CD99 immunoreactivity was found in 9 of 10 cases of MM.
To our knowledge, this is the first report of CD99 and PGP9.5 immunostaining in AFX. We believe, based on our results, that CD99 may be a helpful "positive" feature in the histopathologic diagnosis of AFX.
- CD117 immunoreactivity in atypical fibroxanthoma.
Department of Pathology, University of South Florida College of Medicine, Tempa, FL 33612, USA.
- Am J Dermatopathol. 2008 Feb;30(1):34-6. Abstract quote
Atypical fibroxanthoma (AFX) is a spindle cell neoplasm of the skin seen typically on sun-damaged skin of the elderly. Though described as a benign entity, local recurrence and distant metastasis have been reported.
This study aims to investigate the potential pathogenic role of CD117, the c-kit receptor in AFX. CD117 was detected in 15 of the 16 cases (94%). The percentage of positive cells for CD117 expression among all tumors was approximately 30%. CD117 proved to be a very sensitive marker of AFX.
This antibody may be a useful diagnostic adjunct in AFX.
HMB-45 AND MART-1
HMB-45 (gp103) and MART-1 expression within giant cells in an atypical fibroxanthoma: a case report
Megan J. Smith-Zagone, Victor G. Prieto, Ruth A. Hayes, Walter W. Timperman Jr and A. Hafeez Diwan
Journal of Cutaneous Pathology
Volume 31 Issue 3 Page 284 - March 2004 Abstract quote
Background: Atypical fibroxanthoma (AFX) is a cutaneous tumor that primarily occurs in the sun-damaged skin of the head and neck of adults. It is often a rapidly growing, solitary lesion that may clinically resemble squamous cell carcinoma, malignant melanoma, or lobular hemangioma. The histologic differential diagnosis primarily includes spindle cell squamous carcinoma and spindle cell melanoma, and immunohistochemical studies are often needed to establish the diagnosis.
Case report: We report an unusual case of an AFX with aberrant HMB-45 and MART-1 (melanoma antigen recognized by T cells-1) immunohistochemical expression. Clinical information was obtained. Histologic examination and immunohistochemical studies were performed.
Results: A 54-year-old woman presented with a 1.5 cm posterior scalp lesion, which was excised. Microscopic examination revealed a dermal tumor composed of pleomorphic and spindled cells with numerous giant cells. The tumor cells expressed CD68 but did not express either keratin or S-100. In addition, there was focal gp100 (with HMB-45) and MART-1 expression limited to the large, multinucleated cells with vacuolated cytoplasm. A diagnosis of AFX was subsequently made.
Conclusions: This is the first reported case of an AFX with HMB-45 and MART-1 reactivity.
p63 Utility of p63 in the differential diagnosis of atypical fibroxanthoma and spindle cell squamous cell carcinoma
Briana C. Gleason 1 , Kenneth B. Calder 2 , Thomas L. Cibull 1 , Antoinette B. Thomas 3 , Steven D. Billings 3 , Michael B. Morgan 2 , Kim M. Hiatt 1 and Bruce R. Smoller 1
J Cutan Pathol 2009;36:543-547 Abstract quote
Atypical fibroxanthoma (AFX), spindle cell squamous cell carcinoma (SCSCC) and spindle cell melanoma are the primary entities in the differential diagnosis of a cytologically atypical spindle cell tumor arising on sun-damaged skin. AFX is generally regarded as a diagnosis of exclusion in this context: in the absence of S100 or keratin reactivity, a diagnosis of AFX is favored. However, keratin reactivity may be focal or even absent in SCSCC, and although numerous positive markers of AFX have been proposed, none has shown sufficient sensitivity and specificity for routine diagnostic use.
We evaluated 20 AFX and 10 SCSCC with a panel of cytokeratins and p63 to assess the utility of the latter antibody in this differential diagnosis. All 10 SCSCC showed strong expression of p63, whereas all 20 AFX were p63 negative. Two additional cases (excluded from the study) were negative for keratins and S100 on initial shave biopsies, resulting in a favored diagnosis of AFX, but p63 stains performed retrospectively were positive. However, review of the excision specimens in both cases revealed deep subcutaneous extension, excluding AFX.
p63 reactivity argues against the diagnosis of AFX and is therefore a useful addition to the standard immunohistochemical panel for cutaneous spindle cell neoplasms.
Procollagen 1 expression in atypical fibroxanthoma and other tumors.
Jensen K, Wilkinson B, Wines N, Kossard S.
Department of Pathology, Stanford University Medical Centre, and Skin and Cancer Foundation Australia, Darlinghurst, New South Wales, Australia.
J Cutan Pathol. 2004 Jan;31(1):57-61. Abstract quote
BACKGROUND: Procollagen (PC) is secreted by fibroblasts into the extracellular matrix, where it is cleaved to form collagen. The rat anti-human PC-1 monoclonal antibody has been reported to react with atypical fibroxanthoma (AFX), a poorly differentiated but usually benign skin lesion common in elderly patients. We have studied PC-1 staining in 50 tumors with AFX histological features (four of which were subsequently reclassified as non-AFX tumors) to confirm this prior observation. In addition, we have investigated PC-1 in other skin tumors, particularly those with spindled cell or sclerosing/desmoplastic morphologies.
METHOD: Archival material was retrieved and sections were prepared and immunostained with PC-1 as well as a panel of antibodies, including S-100 and MNF-116 (cytokeratins 5, 6, 7, 8, 17, and 19).
RESULTS: PC-1 staining was strongly positive in 40 of 46 (87%) AFXs. Three AFXs displayed weak staining with PC-1 even after repeat staining of 10 tumors that were initially weak. Three additional tumors stained with both PC-1 and MNF-116 and were classified as AFX-like squamous cell carcinoma (SCC). One tumor with AFX-like histology was PC-1 negative and S-100 positive and was classified as an AFX-like melanoma. Positive staining in tumor cells was observed in three of nine (33%) desmoplastic malignant melanomas, three of eight (38%) desmoplastic SCCs, zero of 10 (0%) desmoplastic trichoepitheliomas, zero of 10 (0%) morpheic basal cell carcinomas, and zero of 10 (0%) sclerosing sweat duct carcinomas.
CONCLUSION: PC-1 is a useful antibody in a diagnostic immunohistochemical panel when investigating AFX and AFX-like tumors; however, good technical quality and careful interpretation are necessary when using a panel of antibodies, particularly to keratin and S-100 protein, for optimal accuracy.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES SUPERFICIAL MFH Must distinguish
These tumors have extensive involvement of the subcutaneous fat and have great potential for metastasis
Atypical fibroxanthoma versus benign and malignant fibrous histiocytoma. A comparative study of their proliferative activity using MIB-1, DNA flow cytometry, and p53 immunostaining.
Oshiro Y, Fukuda T, Tsuneyoshi M.
Second Department of Pathology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Cancer 1995 Mar 1;75(5):1128-34 Abstract quote
BACKGROUND. MIB-1 was found to be detectable in formalin fixed, paraffin embedded materials with microwave treatment using Ki-67 monoclonal antibody, and immunostaining has been widely documented as a useful marker of proliferation. Because atypical fibroxanthoma (AFX) is regarded as a fibrohistiocytic tumor with an intermediate potential, the proliferative activity of AFX was compared with that of benign and malignant fibrous histiocytomas.
METHODS. Thirty-eight soft tissue tumors including atypical fibroxanthoma (n = 5), benign fibrous histiocytoma (FH) (n = 17) and malignant fibrous histiocytoma (MFH) (n = 16) were examined using immunohistochemistry to determine MIB-1, DNA flow cytometry, and p53 (PAb 1801) immunostaining.
RESULTS. The mean of the MIB-1 labeling index (MIB-1 LI), defined as the percentage of positive cells for more than 500 cells, was determined in an increasing order as follows: FH, 3.3 +/- 1.8; AFX, 12.2 +/- 6.3; and MFH, 21.5 +/- 10.2. However, the MIB-1 LI of each case in AFX was considerably scattered, and the MIB-1 LI of AFX and MFH overlapped each other. A DNA analysis revealed that the proliferative index (S+G2+M fraction) showed no significant correlation with the MIB-1 LI, and an aneuploid pattern was present in only five (42%) of 12 cases of MFH. p53 positivity was detected in 2 (40%) of 5 cases of AFX and 6 (38%) of 16 cases of MFH.
CONCLUSIONS. Although AFX shows a lower degree in the MIB-1 LI than MFH, the MIB-1 LI shows a limited value in relation to the biologic activity of fibrohistiocytic tumors. Aneuploidy demonstrates a malignant potential in fibrohistiocytic tumors.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS
Atypical fibrous histiocytoma of the skin: clinicopathologic analysis of 59 cases with evidence of infrequent metastasis.
Kaddu S, McMenamin ME, Fletcher CD.
Department of Pathology, Brigham and Women's Hospital, Bosston, MA 02115, USA.
Am J Surg Pathol 2002 Jan;26(1):35-46 Abstract quote
Atypical fibrous histiocytoma is an uncommon, poorly documented variant of cutaneous fibrous histiocytoma.
We studied 59 cases of atypical fibrous histiocytoma to better characterize the clinicopathologic spectrum. There were 33 males and 26 females (median age 38 years; range 5-79 years) with solitary lesions arising on lower (25 cases) and upper (17 cases) extremities, trunk (6 cases), head and neck (4 cases), and vulva (1 case); anatomic location was not stated in six cases. Lesions measured 0.4-8 cm in diameter (median 1.5 cm) and clinically were nodules (40 cases), polypoid tumors (18 cases), or a slightly elevated plaque (1 case).
Histologically, the lesions were primarily dermal with superficial involvement of the subcutis in one third of the cases. Salient features included a proliferation of pleomorphic, plump, spindle, and/or polyhedral cells with mainly large, hyperchromatic, irregular, or bizarre nuclei, set in a background of classic features of fibrous histiocytoma, including spindle cell areas showing a storiform pattern and entrapped thickened, hyaline collagen bundles, especially at the periphery. Multinucleated giant cells, often with bizarre nuclei and foamy, sometimes hemosiderin-rich, cytoplasm were also variably present. The degree of pleomorphism varied from only focal and minimal (14 cases) or moderate (24 cases) to marked (21 cases). Mitotic activity was observed in 55 lesions, and the number of mitotic figures ranged from 1 to 15 per 10 high power fields. Atypical mitoses were noted in 20 lesions. Furthermore, some cases of atypical fibrous histiocytoma displayed other worrisome features less often observed in ordinary FH, including unusually large size (diameter >2 cm, 8 cases), involvement of the superficial subcutis (19 cases), and geographic necrosis (7 cases).
Immunohistochemical studies performed in 42 cases showed only focal smooth muscle actin (10 cases) and CD34 (4 cases) positivity, whereas CD68, S-100 protein, desmin, pan-keratin, and epithelial membrane antigen were negative. Clinical follow-up data available in 21 patients (mean duration of follow-up 50.6 months, median 43 months) revealed local recurrences in three patients (one repeated); two patients developed distant metastases, one of whom died after 96 months. These two cases were not histologically distinct from the group as a whole. We conclude that atypical fibrous histiocytoma has a broader clinicopathologic spectrum than previously realized.
Lesions with floridly atypical features represent potential pitfalls for overinterpretation as pleomorphic sarcoma, which would appear to be inappropriate in most cases. Provided that atypical fibrous histiocytoma is treated by complete excision, a benign outcome is to be expected in most cases. However, similar to the cellular and aneurysmal variants of fibrous histiocytoma, atypical fibrous histiocytoma shows a higher tendency to recur locally than ordinary fibrous histiocytoma and may rarely metastasize.
Recurrence About 7% METASTASIS Am J Dermatopathol 1985;7:57-63
Rare reports to regional lymph nodes and distant mets
- Am J Surg Pathol. 2006 Aug;30(8):1041-6. Abstract quote
Atypical fibroxanthoma (AFX) is a mesenchymal neoplasm usually occurring in sun-exposed skin of elderly patients. The majority have an excellent prognosis, as recurrences are uncommon and metastases are rare.
We present a case of an 81-year-old man who developed widespread peritoneal metastases from an AFX on his scalp, which was completely excised 3 years earlier. Histology of the scalp lesion showed a markedly pleomorphic neoplasm characteristic of AFX. Features associated with increased risk of metastasis, namely lymphovascular space invasion, deep invasion, and substantial necrosis, were not present. An extensive immunohistochemical panel was performed. The tumor cells were negative for melanocytic, epithelial, and smooth muscle immunohistochemical stains, and positive for vimentin, CD10, CD99, and focally for CD68. Histologically, the peritoneal tumor was virtually identical to the original scalp lesion and had an identical immunohistochemical profile. Electron microscopy of the peritoneal tumor revealed pleomorphic undifferentiated cells with abundant lipid vacuoles.
This is the first reported case of AFX with peritoneal metastases. Although AFXs generally have an excellent outcome, pathologists must remain cognizant of the small but real potential for metastasis and this needs to be conveyed in all reports.
TREATMENT Complete surgical removal
Malignant Fibrous Histiocytoma (MFH)
Squamous cell carcinoma of the Skin
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Last Updated July 9, 2010
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