Granular-cell basal cell carcinoma of the skin

ARTICLE

Auteur(s) :, Jean Kanitakis^*, Brigitte Chouvet

Laboratory of Dermatopathology, Edouard Herriot Hospital, 69437 Lyon cedex 03, France

accepté le 22 Octobre 2004

Case report

An immunohistochemical study was performed with the Ventana ES automated AEC immunohistochemistry system (Ventana Medical Systems Inc., Tucson, USA), using antibodies to a panel of antigens related to epithelial and histiomonocytic differentiation and/or proliferation (table 1)( Table 1 ). Most granular cells expressed cytoplasmic reactivity with the AE3 antibody recognizing type II (basic) keratins, but this was reduced as compared with adjacent normal epidermal keratinocytes, often being confined to the periphery of the cytoplasm ( (figure 3) ). Fewer tumor cells also expressed weak reactivity with the AE1 antibody, recognizing keratins 10, 14-K16 and 19. A small percentage (about 15%) of granular BCC cells expressed immunoreactivity for the lysosome-related CD68 antigen, revealed with the KP1 and PGM1 antibodies, and for the CD15 antigen (figures 4A-B). Remarkably, strong CD68 expression was observed in tumor cells floating into pseudo-cystic cavities observed in the center of some tumor masses. The majority of tumor cells (over 80%) showed diffuse, granular cytoplasmic immunoreactivity for the bcl-2 oncoprotein and nuclear immunoreactivity for the p63 protein (figures 5A-B). Rare granular cells (less than 5% of the total) expressed cytoplasmic reactivity for vimentin, occasionally forming a peripheral cytoplasmic rim; vimentin was also expressed by a subset of intratumor dendritic cells (possibly melanocytes or Langerhans cells). 10% of tumor cells (namely among those located close to the epidermis) expressed nuclear reactivity for the p53 oncoprotein. Tumor cells did not express the following antigens: keratins 7, 8, 15, 18, 19, 20, Epithelial Membrane Antigen, Carcinoembryonic Antigen, S100 protein.
Table 1 Antibodies used in this study

Discussion

The majority of GBCC cases are seen in men (sex ratio 2.7:1) with a mean age of 63 years. The lesion develops in 64% of cases on the face, and on the remaining cases on the chest. These epidemiological features do not seem to differ from ordinary BCC. Clinically, GBCC has no specific features; whenever mentioned, the suspected clinical diagnosis was BCC [6, 7, 9]. GBCC have been reported in patients with previous history of ordinary BCC [1].

Histologically, GBCC usually presents the general architecture of a nodular BCC, being composed of well-demarcated tumor masses that usually, although not invariably [7], come in contact with the basal cell layer of the epidermis and/or hair follicles and invade the dermis. The characteristic feature is the presence, within tumor masses, of a variable number of tumor cells with a granular eosinophilic cytoplasm. These cells usually lie towards the center of tumor nodules, being surrounded by more typical BCC cells with a peripheral palissadic arrangement. The relative proportion of each type of cell is variable; occasionally, GBCC consist almost exclusively of granular cells ([2], this case). The cytoplasmic granules are usually PAS-positive ([5, 9], this case), although PAS-positivity may be slight [2] or absent [8]. Electronmicroscopic examinations have shown that the cytoplasmic granules correspond to 0.1-0.5 micron lamellar, lysosome-like structures [1, 2, 4], similar to those seen in other granular-cell tumors. Immunohistochemically, GBCC cells (similar to their ordinary BCC counterparts) do not express S100 protein, Epithelial Membrane Antigen or Carcinoembryonic Antigen ([3-5], this case); however, they express most epithelial antigens present in ordinary BCC, such as keratins ([3-5], [7-9], this case), the Ber-P4 antigen [7, 9] and the bcl-2 and p63 proteins (this case). Some authors reported reactivity for lysozyme [5] and for the lysosome-associated CD68 antigen ([9], this case), but others found no expression of CD68 [4, 5] or lysozyme [4, 8]. These results are consistent with a lysosomal nature of the cytoplasmic granules. However, the mechanism whereby BCC cells acquire a granular cytoplasm is not known; the view has been expressed that cytoplasmic granules develop as a result of degenerative processes. Our finding of CD68-positive tumor cells floating into pseudocystic cavities is in keeping with this hypothesis, since such spaces are thought to result from cell degeneration [12]. However, this finding does not seem specific to GBCC, since we have observed CD68-positive cells within such pseudocystic spaces in other BCC subtypes (unpublished data). Cytoplasmic CD68+ granules could correspond to autophagosomes, developing as a result of cell autolysis. Whatever the explanation, it seems that granular cells belong to the same lineage as ordinary BCC cells, as suggested by the location of granular cells among otherwise typical BCC cells, and by the expression of antigens characteristic of other epithelial and BCC cells.

The etiology of GBCC is unknown. A granular cell tumor (immuno)histologically similar to human GBCC was reported in a Wistar rat that had received intravenous administration of the carcinogenic compound amsacrine [11]. In the human cases reported so far no drug administration was mentioned. The fact that most human GBCC develop in sun-exposed sites (head) suggests that, similar to ordinary BCC, UV radiation is an important factor.

The course of GBCC is uneventful, and prognosis seems similar to that of ordinary BCC; surgical excision is adequate, and no relapses have been reported after several months [3, 4]. In at least two cases ([2], this one), GBCC developed as a recurrence of a previously-excised tumor, and it can be speculated that the primary excision triggered the granular degeneration of the residual tumor; unfortunately the primary tumors were unavailable for study, and this hypothesis cannot be further substantiated.

GBCC must be histologically differentiated from other granular cell tumors, such as granular cell schwannoma (Abrikosof), dermatofibroma, leiomyosarcoma, primitive polypoid granular cell tumor and angiosarcoma, to name but the least rare [3]. The diagnosis usually does not pose substantial difficulty, since GBCC usually comprise typical areas of ordinary BCC that are readily recognized. In case of doubt, namely when the lesion is composed exclusively of granular cells, ultrastuctural examination can be useful by showing cells with epithelial features, such as desmosomes and tonofilaments [2], recognizable even after processing of tissue specimens cut from paraffin blocks [1, 4]. Immunohistochemistry can also help in establishing the correct diagnosis by showing expression of epithelial antigens but not of S100 protein, endothelial markers or desmin (expressed respectively by granular cell schwannoma-Abrikosof, angiosarcoma and leiomyosarcoma). Granular cell ameloblastoma looks histologically very similar to GCBCC, but the different location (oral cavity) readily separates the two tumors.
Table 2 Cases of GBCC reported in the literature

Acknowledgments

References

2 Mrak RE, Baker GF. Granular cell basal cell carcinoma. J Cutan Pathol 1987; 14: 37-42.

3 LeBoit PE, Barr RJ, Burall S, Metcalf JS, Yen TS, Wick MR. Primitive polypoid granular-cell tumor and other cutaneous granular-cell neoplasms of apparent nonneural origin. Am J Surg Pathol 1991; 15: 48-58.

4 Garcia Prats MD, Lopez Carreira M, Martinez-Gonzalez MA, Ballestin C, Gil R, De Prada I. Granular cell basal cell carcinoma. Light microscopy, immunohistochemical and ultrastructural study. Virchows Arch A Pathol Anat Histopathol 1993; 422: 173-7.

5 Boscaino A, Tornillo L, Orabona P, Staibano S, Gentile R, De Rosa G. Granular cell basal cell carcinoma of the skin. Report of a case with immunocytochemical positivity for lysozyme. Tumori 1997; 83: 712-4.

6 Reichel M. Granular cell basal cell carcinoma. Cutis 1997; 59: 88-90.

7 Hayden AA, Shamma HN. Ber-EP4 and MNF-116 in a previously undescribed morphologic pattern of granular basal cell carcinoma. Am J Dermatopathol 2001; 23: 530-2.

8 Myung J, Ha S, Park C, Kang S, Kim S. A case of granular basal cell carcinoma. Korean J Dermatol 2002; 40: 1128-31.

9 Dundr P, Stork J, Povysil C, Vosmik F. Granular cell basal cell carcinoma. Australas J Dermatol 2004; 45: 70-2.

10 Seiler RJ. Granular basal cell tumors in the skin of three dogs: a distinct histopathologic entity. Vet Pathol 1982; 19: 23-9.

11 Courtney CL, Hawkins KL, Graziano MJ. Granular basal cell tumor in a Wistar rat. Toxicol Pathol 1992; 20: 122-4.

12 Weedon D. Skin Pathology. Churchill Livingstone, 2002.