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Squamous Cell Carcinoma Detected by High-Molecular-Weight Cytokeratin Immunostaining Mimicking Atypical Fibroxanthoma.

Both squamous cell carcinoma and atypical fibroxanthoma arise on sun-damaged skin. Occasionally, similar microscopic appearance of these tumors may lead to difficult diagnostic problems.[1] Atypical fibroxanthoma was first described by Helwig[2] in 1963. It typically occurs on the head and neck of elderly patients as a solitary nodule that is often ulcerated. Most tumors measure less than 2 cm in greatest dimension.[3] Histologically, it is a well-circumscribed but not encapsulated dermal nodule composed of pleomorphic spindle cells with bizarre nuclei. Atypical mitotic figures and multinucleated cells are common.[2] Despite its malignant appearance, atypical fibroxanthoma has been considered a tumor of low malignancy, which almost always behaves in a benign fashion.[4] Histologically, atypical fibroxanthoma is indistinguishable from malignant fibrous histiocytoma.[5] Other lesions that can mimic atypical fibroxanthoma are spindle cell squamous cell carcinoma and desmoplastic or spindle cell melanoma. Atypical fibroxanthoma is negative for keratin, S100, and HMB-45; however, not all spindle cell carcinomas stain positively for keratin, and spindle cell or desmoplastic melanoma may rarely be negative for S100 and HMB-45.[6] We present a case of acantholytic squamous cell carcinoma of the skin that metastasized to a lymph node and mimicked atypical fibroxanthoma both histologically and immunohistochemically.

REPORT OF A CASE

The patient is a 73-year-old man who presented with a skin-colored nodule on the right periauricular area. His medical history was significant for chronic lymphocytic leukemia and a splenectomy performed secondary to hypersplenism and thrombocytopenia. Physical examination revealed a 1.2 x 1.2-cm nodule. The initial biopsy specimen microscopically consisted of spindle-shaped and epithelioid cells with irregular nuclei and atypical mitoses, focally forming slitlike spaces lined by atypical cells. Scattered atypical multinucleated giant cells were present. The lesion was negative for S100, HMB-45, and desmin and strongly positive for vimentin, with rare cytokeratin (AE1/AE3) positive cells. Diagnostic considerations were atypical fibroxanthoma or a vascular neoplasm. The specimen, however, was too small for a definitive diagnosis, and an additional and larger biopsy specimen or excision was recommended. The lesion was completely excised and microscopically was similar to the previous biopsy specimen. A diagnosis of atypical fibroxanthoma was made.

The lesion recurred 3 months later. A biopsy and an excision specimen of the recurrent tumor demonstrated a lesion histologically and immunohistochemically similar to the original, with completely negative staining for cytokeratin. The patient was also noted to have a right supraclavicular adenopathy, and this lymph node was excised. Histologic sections of the lymph node showed effacement of the usual architecture by a diffuse infiltrate of malignant small lymphocytes associated with focal pseudoproliferation centers, consistent with chronic lymphocytic leukemia. Pleomorphic spindle cells were present in the subcapsular sinus and focally infiltrated the capsule of the lymph node. Within 1 week of reexcision, rapid recurrence was noted involving the superior margin of the excision and the healing scar (Figure 1). There was no evidence of other head and neck squamous cell carcinoma that could also account for the metastasis in the lymph node.

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PATHOLOGIC FINDINGS

The specimen consisted of a 4.7 x 2.5 cm of skin excised to the depth of 0.5 cm. The epidermal surface was gray to tan-pink. There was a raised gray-pink lesion that measured 1.0 x 0.7 cm within 0.4 cm of the nearest surgical margin. Cut surface revealed the gray-white and firm lesion to be within 0.3 cm of the nearest margin. Histologically, the tumor showed marked pleomorphism and a moderate mitotic rate. The tumor cells were greatly separated from each other, forming large pseudovascular or glandlike spaces, and often acquired a spindle-shaped morphologic structure that resembled a mesenchymal tumor. There was no evidence of continuity with the overlying epidermis (Figure 2). The margins of resection were free of tumor. Immunohistochemical stains showed a weak and focal staining of the tumor cells with the keratin cocktail but a diffuse and strong staining with the high-molecular-weight cytokeratin stain (34[Beta]12 keratin) (Figure 3). The tumor stained positive for vimentin and negative for S100, factor VIII, pan muscle-specific actin (HHF-35), smooth muscle actin, CD34, CD68, and factor XIIIa. The dermis and subcutaneous tissue showed multifocal accumulations of small lymphocytes diagnostic of chronic lymphocytic leukemic infiltrates.

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Based on the positive staining with 34[Beta]12 keratin, the tumor was diagnosed as acantholytic squamous cell carcinoma. Slides from the excision of the first recurrence were reviewed and compared with the present case. In the present case the cells, although spindle shaped in some areas, had a more epithelioid appearance with focal keratinization and a diminution in the amount of interstitial and giant cell formation. Additional immunohistochemistry was performed on the excision of the first recurrence, including high-molecular-weight cytokeratin (34[Beta]12 keratin), for which the tumor was diffusely and strongly positive. It was negative for CD68 and factor XIIIa. Based on these findings and the rapid recurrence of the tumor, the lesion was classified as a recurrent acantholytic squamous cell carcinoma. Sections from the lymph node were reviewed and high-molecular-weight staining was performed, which also indicated the presence of cytokeratin (Figure 4). Thus, the tumor cells in the lymph node represented acantholytic squamous cell carcinoma metastatic to a cervical lymph node.

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COMMENT

Approximately 7% of atypical fibroxanthomas are known to recur.[4] Several reports indicate that atypical fibroxanthoma is also rarely capable of metastasis. Sites of metastases include parotid and mastoid areas,[4] cervical lymph nodes,[5,7,8] and the lung.[9] Two metastatic atypical fibroxanthomas occurred in patients with chronic lymphocytic leukemia.[4,8] Histiocytic and fibroblastic origin of the lesion in one case[4] was confirmed by electron microscopy. Desmosomes, tonofilaments, and melanosomes were not identified in the tumor It was postulated that such rare aggressive behavior of atypical fibroxanthomas might be due to an altered immune response as a result of chronic lymphocytic leukemia.[4,8] Squamous cell carcinomas occurring on sun-damaged skin have a very low incidence of metastasis (about 0.5%). The incidence of squamous cell carcinoma is increased and its aggressive behavior is greater in immunocompromised patients.[10] The patient in the present case also has chronic lymphocytic leukemia and may have altered immune response, which may explain the rapid recurrence and metastasis of his tumor.

Some investigators concluded that the distinction between spindle cell squamous carcinoma and atypical fibroxanthoma was of little prognostic significance.[11] They found that prognosis depended on the depth of invasion and, possibly, on the type of radiation received by the patients.[11] In the present case, however, the tumor has already metastasized, and correct classification may have prognostic and therapeutic implications. In addition, it differs histologically from spindle cell squamous cell carcinoma. Although the tumor showed a large spindle cell component, it also has significant areas of acantholysis and pseudoglandular and pseudovascular spaces. An epidermal component was not present in any section of the several specimens in the present case; therefore, immunohistochemistry was important in the diagnosis.

Vimentin positivity in a squamous cell carcinoma, also demonstrated in the present case, has been reported.[12] Ikegawa et al[12] described 2 patients with poorly differentiated squamous cell carcinoma composed of round acantholytic cells arising in burn scars. Both tumors coexpressed keratin and vimentin and had aggressive behavior, which resulted in disseminated disease and death of the patients.

Atypical fibroxanthomas were found to stain positively for actin in some cases.[6] Positive staining for actin in a tumor that is negative for cytokeratin may be an additional indicator that the lesion is not a carcinoma.[6] However, negative actin staining would not be helpful in distinguishing the 2 tumors.

The first biopsy specimen in the present case, although too small for diagnosis, showed pseudovascular spaces and was strongly vimentin positive. Indeed, squamous cell carcinoma may also be mistaken for angiosarcoma. Pseudovascular adenoid squamous cell carcinomas of the skin were a subject of a report[13] in which the investigators looked at the immunohistochemical characteristics of these tumors. All carcinomas and no angiosarcomas were positive for cytokeratin and endomysial antibody. All angiosarcomas and no carcinomas were positive for CD34. One angiosarcoma and no carcinomas were positive for factor VIII. All angiosarcomas and 2 carcinomas were positive for Ulex europaeus. All angiosarcomas and 3 carcinomas were vimentin positive.[13] Ohsawa et al[14] suggest that the combination of endothelial cell markers, including factor VIII, UEA-1, and CD31, is useful in the diagnosis of angiosarcoma, particularly with a nonvasoformative or poorly vasoformative pattern. The present case demonstrated rare positivity for endomysial antibody.

The first biopsy specimen in the present case also demonstrated focal weak positivity for cytokeratin; however, subsequent biopsy and excision specimens did not. The recognition of an acantholytic epithelial nature of this lesion on hematoxylin-eosin stain of a later excision led to immunostaining for high-molecular-weight keratin, which showed strong positivity. Recently, in a report on spindle cell malignant neoplasms on sun-damaged skin, the authors advocated the use of high-molecular-weight keratin as a sensitive and specific marker for spindle cell squamous cell carcinoma.[15] The present case demonstrates that the high-molecular-weight keratin is also useful in the diagnosis of acantholytic squamous cell carcinoma of the skin.

The initial biopsy specimen of this tumor showed a spindle cell or pseudovascular morphologic structure. It also demonstrated rare cells positive for cytokeratin (AE1/AE3), which might have been an important clue to the diagnosis of squamous cell carcinoma. Therefore, the importance of comparing the morphologic and immunostaining findings of the original specimen with tumor present in reexcision, recurrence, and metastasis specimens of malignant spindle cell neoplasms of the dermis is emphasized.

References

[1.] Kuwano H, Hashimoto H, Enjoji M. Atypical fibroxanthoma distinguishable from spindle cell carcinoma in sarcoma-like skin lesions: a clinicopathologic and immunohistochemical study of 21 cases. Cancer. 1985;55:172-180.

[2.] Helwig EB. Atypical fibroxanthoma. Tex J Med. 1963;59:664-667.

[3.] Fretzin DF, Helwig EB. Atypical fibroxanthoma of the skin: a clinicopathologic study of 140 cases. Cancer. 1973;31:1541-1552.

[4.] Helwig EB, May D. Atypical fibroxanthoma of the skin with metastasis. Cancer. 1986;57:368-376.

[5.] Grosso M, Lentini M, Carrozza G, Catalano A. Metastatic atypical fibroxanthoma of skin. Pathol Res Pract. 1987;182:443-445.

[6.] Longacre TA, Smoller BR, Rouse RV. Atypical fibroxanthoma: multiple immunohistologic profiles. Am J Surg Pathol. 1993;17:1199-1209.

[7.] Jacobs DS, Edwards WD, Ye RC. Metastatic atypical fibroxanthoma of skin. Cancer. 1975;35:457-463.

[8.] Kemp JD, Stenn KS, Arons M, Fischer J. Metastasizing atypical fibroxanthoma: coexistence with chronic lymphocytic leukemia. Arch Dermatol. 1978;114:1533-1535.

[9.] Glavin FL, Cornwell ML. Atypical fibroxanthoma of the skin metastatic to a lung: report of a case, features by conventional and electron microscopy, and a review of relevant literature. Am J Dermatopathol. 1985;7:57-63.

[10.] Kirkham N. Tumors and cysts of the epidermis. In: Elder D, Elenitsas R, Jaworsky C, Johnson B Jr, eds. Lever's Histopathology of the Skin. New York, NY: Lippincott-Raven Publishers; 1997:685-746.

[11.] Evans HL, Smith JL. Spindle cell squamous carcinomas and sarcoma-like tumors of the skin: a comparative study of 38 cases. Cancer. 1980;45:2687-2697.

[12.] Ikegawa S, Saida T, Takizawa Y, et al. Vimentin-positive squamous cell carcinoma arising in a burn scar: a highly malignant neoplasm composed of acantholytic round keratinocytes. Arch Dermatol. 1989;125:1672-1676.

[13.] Nappi O, Wick MR, Pettinato G, Ghiselli RW, Swanson PE. Pseudovascular adenoid squamous cell carcinoma of the skin: a neoplasm that may be mistaken for angiosarcoma. Am J Surg Pathol. 1992;16:429-438.

[14.] Ohsawa M, Naka N, Tomota Y, Kwamori D, Kanno H, Aozasa K. Use of immunohistochemical procedures in diagnosing angiosarcoma: evaluation of 98 cases. Cancer. 1995;75:2867-2874.

[15.] Heintz PW, White CR. Diagnosis: atypical fibroxanthoma or not? evaluating spindle cell malignancies on sun damaged skin: a practical approach. Semin Cutan Med Surg. 1999;18:78-83.

Accepted for publication January 11, 2001.

From the Departments of Pathology (Drs Gray and Robinson-Bostom), Surgery (Dr Robidoux), and Dermatology (Drs Farrell and Robinson-Bostom), Rhode Island Hospital, Brown University School of Medicine, Providence, RI. Dr Gray is currently with the Department of Pathology, Roger Williams Medical Center, Providence, RI.

Reprints: Leslie Robinson-Bostom, MD, Rhode Island Hospital, Department of Dermatology, 593 Eddy St, Providence, RI 02903.
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Author:Gray, Yulia; Robidoux, Henry J.; Farrell, David S.; Robinson-Bostom, Leslie
Publication:Archives of Pathology & Laboratory Medicine
Date:Jun 1, 2001
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