EXTRAORDINARY CASE REPORT
Granular Cell Basal Cell Carcinoma: Report of a Case and Review of the Literature Stephanie L. Claassen, DO,* Michael C. Royer, MD,*† and Walter L. Rush, MD†
Abstract: Granular cell basal cell carcinoma (BCC), characterized by large cells with abundant eosinophilic cytoplasm and conspicuous granularity, is an extremely rare variant of BCC with only 14 cases reported in the literature to date. A case of an 82-year-old man with clinically suspected BCC of the face is presented. Microscopic examination demonstrated characteristic morphologic and immunophenotypic features of granular cell BCC, as well as novel expression of p16 and lack of bcl-2 expression, both of which are previously undescribed in granular BCCs in the literature to date. Although very rare, this entity is important to include in the differential of any nodular cutaneous neoplasm with granular features. The rarity of this lesion makes immunohistochemistry especially helpful. As in other BCCs, granular cell BCCs typically strongly express Ber-EP4 and cytokeratins. The granular BCCs are characteristically periodic acid–Schiff positive, but show no expression of S100 protein. The rarity of the granular cell BCC and the aggressive biological behavior of the entities that may share similar histologic features make arriving at the correct diagnosis paramount to appropriate clinical management. The fifteenth case of granular cell BCC with subsequent review of the literature is reported, with particular focus on the immunohistochemical characteristics. Key Words: granular cell basal cell carcinoma, p16, bcl2, immunohistochemisty
granularity that may range from a minority of the lesional cells to the entirety of the neoplasm.3–5 We report the 15th case of granular cell BCC with subsequent review of the literature, with particular focus on the immunohistochemical characteristics.
CASE REPORT An 82-year-old man presented with a nodular lesion on his left temple with clinical features of BCC, arising at the site of a previously biopsy-proven BCC. Complete excision of the lesion was performed for histologic evaluation; the specimen was subsequently submitted to the Joint Pathology Center consultation service for further evaluation.
MATERIALS AND METHODS Glass slides and paraffin-embedded tissue were received by our consultation service. Additional sections were initially stained with hematoxylin and eosin followed by additional immunohistochemical and histochemical stains including: CK8/ 18 (DAKO, Glostrup Denmark), CK7 (DAKO), epithelial membrane antigen (EMA) (DAKO), AE1/AE3 (Ventana, Tuscon, Arizona), CK5/6 (DAKO), Ber-EP4 (DAKO), Bcl-2 (Ventana), CD163/DR (Ventana), p16 (Ventana), CD68 (Ventana), p63 (Ventana), D2-40 (DAKO), S100 protein (Ventana), and periodic acid–Schiff (PAS).
(Am J Dermatopathol 2014;36:e121–e124)
INTRODUCTION Basal cell carcinoma (BCC) is the most common cutaneous neoplasm.1 Although typically demonstrating fairly characteristic clinical features, this neoplasm exhibits a wide histological spectrum, reflecting its origin from multipotent follicular germ cells.2 An extremely uncommon variant of BCC is the granular cell BCC, first described by Barr and Graham in 1979, with only 14 cases total reported in the literature to date.3–15 The granular cell BCC is characterized by large cells with abundant eosinophilic cytoplasm with conspicuous From the *Department of Pathology, Walter Reed National Medical Military Center, Bethesda, MD; and †Department of Dermatopathology, Joint Pathology Center, Silver Spring, MD. The authors declare no conflicts of interest. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense. Reprints: Stephanie L. Claassen, DO, Department of Pathology and Laboratory Medicine, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Building 9, Arrowhead, Room #0849, Bethesda, MD 20889 (e-mail: [email protected]). © 2013 Lippincott Williams & Wilkins
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RESULTS Microscopically, the biopsy shows a proliferative neoplastic lesion with a nodular growth pattern and central cystic degeneration located in the superficial dermis. The superficial portion of the neoplasm exhibits more conventional characteristics of BCC, with basaloid cells, peripheral palisading, associated tumor–dermal clefting and abundant extracellular mucin (Fig. 1). Although the majority of neoplastic cells exhibit some degree of granularity, the deeper portion of the tumor transitions into a subpopulation of markedly larger cells with abundant, distinctly granular, eosinophilic cytoplasm that eccentrically displaces the nucleus (Fig. 2). Numerous intracytoplasmic eosinophilic round inclusion bodies are present in the granular cell population; these are reminiscent of the pustulo-ovoid bodies seen in granular cell tumors (Fig. 3). The nuclei of the granular cells are round with condensed chromatin. Minimal mitotic activity and cell turnover with associated karyorrhectic debris are observed in both the conventional and granular cells. The deeper portion of the tumor exhibits an infiltrative border with surrounding dermal fibrosis. Immunohistochemical examination demonstrates strong diffuse positivity for AE1/AE3, CK5/6 (Fig. 4A), CK8/18, www.amjdermatopathology.com |
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FIGURE 1. Granular BCC with nodular growth pattern, central cystic degeneration, abundant extracellular mucin, and tumor–dermal clefting (hematoxylin–eosin, ·4).
and p63 both in the conventional basaloid cells and in the granular variant cells. The granular cells show strong diffuse immunoreactivity with Ber-EP4 (Fig. 4B) while the more conventional appearing BCC cells show focal positivity. The granular cells express CD68 (Fig. 4C) and D2-40 (Fig. 4D) and exhibit PAS reactivity, whereas the more conventional appearing BCC cells do not. The granular cells also express p16 (Fig. 4E), CK7, and EMA (very focally). All neoplastic cells are completely negative for S100 protein, bcl-2 (Fig. 4F), and CD163. Overall, the histologic features, in conjunction with the immunoprofile, are those of granular cell BCC.
DISCUSSION Granular cell BCC is a rare variant of BCC, with only 14 cases described in the literature to date; Table 1 summarizes all reported cases.3–15 This variant shares similar demographics with conventional BCC, with the majority of cases
FIGURE 2. Subpopulation of markedly larger tumor cells with abundant, distinctly granular, eosinophilic cytoplasm that eccentrically displace the nucleus (hematoxylin–eosin, ·20).
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FIGURE 3. Numerous intracytoplasmic eosinophilic round inclusion bodies (pustulo-ovoid bodies) are present in the granular cell population (hematoxylin–eosin, ·60).
of granular cell BCC occurring on the face of men (male to female ratio 3:1) at an average age of approximately 65 years (range: 30–93 years).3–15 Clinically, this variant behaves biologically similarly to conventional BCC and is successfully treated with complete excision.6,7,9,12 All cases of granular cell BCC have exhibited a nodular growth pattern, occasionally with cystic changes.3,4,6–8,11,12 The relative percentage of morphologically granular cells can range from a minor subpopulation to the entirety of the lesion.3–7,9,10,12,15 Ultrastructurally, the cytoplasmic granularity corresponds to cytoplasmic, membrane bound lysosome-like granules containing 0.2- to 0.4-mm electrondense bodies.3–7 The ultrastructural findings of pentalaminate desmosomes, in conjunction with the immunohistochemical expression of cytokeratins and the epithelial antigen Ber-EP4, support an epithelial origin of these cells. The granularity seen in the context of a BCC is hypothesized to result from degenerative intracellular processes. Inclusions similar to the pustuloovoid bodies seen in granular cell tumors may also be present in granular BCCs.3 The mitotic rate is generally low to nearly absent, especially within the variant granular cells.3–7,9 The exceptional case reported by Dundr et al12 described a relatively high proliferative rate (up to 25%–29%) when assessed by MIB1, with no difference appreciated between the conventional and granular variant subpopulations. All cases of granular cell BCC reported in the literature have shown positivity for keratins; some of which are lowmolecular-weight cytokeratin, high-molecular-weight cytokeratin, CK8/18 (CAM 5.2), cytokeratin 1 (MNF-116), and CD15 (leu M1).5–8,10–15 The overwhelming majority of cases also show positive expression of AE1/AE3 except for the case reported by Chang et al.15 Granular cell BCCs also characteristically express Ber-EP4 and are reactive for PAS.4,7,10–13,15 All cases that analyzed p63 expression, including this case, showed strong positivity.13–15 Our case is the first case of granular cell BCC to evaluate for, and show positivity for, p16 and D2-40. The p16INK4a protein, a tumor suppressor gene that inhibits cell cycle progression, is thought to play a key role in tumorigenesis 2013 Lippincott Williams & Wilkins
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FIGURE 4. Tumor cells diffusely express (A) CK5/6, (B) Ber-EP4, and (C) CD68. The granular variant cells are focally positive for (D) D2-40 and (E) p16. All neoplastic cells are completely negative for (F) bcl-2 (hematoxylin–eosin, ·40).
pathways leading to the development of both melanocytic and nonmelanocytic cutaneous neoplasms, including BCC.19–22 Overexpression of p16, assessed by immunohistochemistry, is present in up to 94.2% of BCCs.20–22 The overexpression of p16 strongly correlates to the presence of human papillomavirus that may play an etiological role in this neoplastic process.21,22 Although D2-40 expression is present in approximately 22% of conventional BCCs, this is the first case to demonstrate D2-40 expression in a granular BCC.23 Expression of CD68 may or may not be present, and when positive is typically restricted to the morphologically granular cells, as was in our case.12,13,15 CD68 expression correlates with the lysosomal derivation of the cytoplasmic granularity confirmed by electron microscopy.3–7 Granular cell BCC may or may not possess lysozyme activity when assessed by muramidase.4,6,7,11 Although the bcl-2 immunohistochemical stain decorates the majority (67%–100%) of BCCs, including 2 previous granular BCCs variants tested, our case showed no bcl-2
expression.13,15,17,18 Ramdial et al24 assessed bcl-2 expression in BCCs in the context of biological behavior and suggests low/no bcl-2 expression, defined as expression in less than 50% of neoplastic cells, strongly correlates with more clinically and histologically aggressive tumors evidenced by local infiltration and recurrence. Secondary to these features, increased rates of recurrence in bcl-2–negative BCCs were observed regardless of achievement of complete excision with tumor-free margins.24 Our case, which lacks bcl-2 expression, recurred after approximately 4 years and exhibits a more infiltrative border than characteristically seen in BCCs; these features may concur with the observations of Ramdial et al.24 Although EMA is typically not expressed in granular cell BCCs and in only up to 8% of conventional BCCs, very focal EMA expression is noted for the first time in this case.6,13,25 All cases of granular BCC, including the current case, have been found to be negative for S100 protein, CEA, NSE, and melanocytic markers.5–8,13–15
TABLE 1. Clinicopathologic and Immunohistochemical Features of Granular Cell BCC Case/Ref
Age/Gender
Site
1/3 2/3 3/4 4/5 5/6 6/7 7/8 8/9 9/10 10/11 11/12 12/13 13/14 14/15 Current case
72/M “Elderly”/M 67/M 30/F 67/M 81/M 57/F 50/M 65/M 62/M 69/F 71/M 40/M 93/M 82/M
Nose Face Neck Eyelid Nose Nose Forehead Chest Cheek Chest Nose Face Nose Nose Face
CK NOS
LMW-CK EMA / / / / +
+ + / + + + + / / +
/ / / / 2 / / / / / / 2 / / +(f)
AE1 AE3
HMW-CK, CK5/6 BerEP4
/ / / + +
/ / / / /
/ + + + + + 2 +
/ + / / / + / +
/ / / / / / / / + / + / / + +
D2-40 / / / / / / / / / / / / / / +(g)
p16 CD68 p63 PAS Bcl2 Architecture / / / / / / / / / / / / / / +
/ / / / 2 2 / / / / +(g) +(g) / 2 +(g)
/ / / / / / / / / / / + + + +
/ / + / / + / / / + / + / / +
/ / / / / / / / / / / + / + 2
Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Not given Nodular
Ber-EP4, epithelial antigen; CK NOS, cytokeratin, not otherwise specified; EMA, epithelial membrane antigen; F, female; (f), focal; (g), expression seen in granular variant cells only; HMW-CK, high-molecular-weight cytokeratin; LMW-CK, low-molecular-weight cytokeratin; M, male; (/), not performed; (+), positive; (2): negative.
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BCCs with granular features may present a diagnostic challenge to the surgical pathologist. Features of granular cell differentiation can be seen in a variety of other cutaneous neoplasms including: leiomyosarcoma, angiosarcoma, ameloblastoma, schwannoma, signet ring cell melanoma, granular cell tumor, and primitive polypoid granular cell tumor.5,6 The diagnosis may be further complicated, as in our case, by the absence of demonstrable connection of the tumor to the epidermis in the planes of section examined.10 Another diagnostic challenge may the complete absence of more conventional features of BCC.13,15 Granular cell ameloblastoma may be histologically identical to granular cell BCC; however, location and involvement of a mucosal surface can be reliable differentiators.5,6 Although the granular quality of the cells and the presence of pustulo-ovoid–like bodies may cause confusion with a granular cell tumor, the differentiating characteristic may be the placement of the nuclei, with the nuclei of granular BCCs being more eccentrically displaced while the nuclei of granular cell tumors remain more centrally located. Additional supportive evidence by immunohistochemistry, particularly co-expression of Ber-EP4 and cytokeratins, while lacking S100 protein and melanocytic markers readily identifies the basal cell origin and excludes more worrisome diagnostic entities.5,6 Granular cell BCC is a rare variant of BCC that is not yet fully characterized immunophenotypically. Although typical cases of granular BCC express cytokeratins, BerEP4, p63, PAS, and lysozymal activity, this is the first case of granular cell BCC to identify the presence of p16 expression, which may play a part in the pathogenesis of this variant and more conventional BCCs. This is also the first report of a case of granular cell BCC lacking bcl-2 expression; this finding may be associated with aggressive histologic features and overall worse clinical course. Granular cell BCC requires correlation of clinical, histopathologic, and immunophenotypic features to ensure correct diagnosis. Accurate identification of this rare variant of BCC is essential to exclude other diagnostic entities with similar histomorphologic features to ensure the proper management of conservative, yet complete excision. ACKNOWLEDGMENTS The authors thank the contributors, Drs. Rakhee Saxena and Dawn Ellerson, for referring this challenging and interesting case to their consultation service. Additional special thanks to Ms. Chih Yon Song, RN, Camp Humphreys Clinic, Pyongtaek, South Korea, for her assistance with translation.
3. 4. 5. 6.
7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
24.
REFERENCES 1. Casson P. Basal cell carcinoma. Clin Plast Surg. 1980;7:301–311. 2. Kore-eda S, Horiguchi Y, Ueda M, et al. Basal cell carcinoma cells resemble follicular matrix cells rather than follicular bulge cells: immu-
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25.
nohistochemical and ultrastructural comparative studies. Am J Dermatopathol. 1998;20:362–369. Barr RJ, Graham JH. Granular cell basal cell carcinoma. A distinct histopathologic entity. Arch Dermatol. 1979;115:1064–1067. Mrak RE, Baker GF. Granular cell basal cell carcinoma. J Cutan Pathol. 1987;14:37–42. LeBoit PE, Barr RJ, Burall S, et al. Primitive polypoid granular-cell tumor and other cutaneous granular-cell neoplasms of apparent nonneural origin. Am J Surg Pathol. 1991;15:48–58. García Prats MD, López Carreira M, Martínez-González MA, et al. Granular cell basal cell carcinoma. Light microscopy, immunohistochemical and ultrastructural study. Virchows Arch A Pathol Anat Histopathol. 1993;422:173–177. Boscaino A, Tornillo L, Orabona P, et al. Granular cell basal cell carcinoma of the skin. Report of a case with immunocytochemical positivity for lysozyme. Tumori. 1997;83:712–714. Pahnke TM, Schmidt U, Bug R. Granular cell basal cell carcinoma and granular cell tumor—light microscopic and immunohistochemical comparison [abstract]. Am J Dermatopathol. 1997;19:428. Reichel M. Granular cell basal cell carcinoma. Cutis. 1997;59:88–90. Hayden AA, Shamma HN. Ber-EP4 and MNF-116 in a previously undescribed morphologic pattern of granular basal cell carcinoma. Am J Dermatopathol. 2001;23:530–532. Myung JW, Ha SJ, Park CJ, et al. A case of granular cell basal cell carcinoma [In Korean]. Korean J Dermatol. 2002;40:1128–1131. Dundr P, Stork J, Povýsil C, et al. Granular cell basal cell carcinoma. Australas J Dermatol. 2004;45:70–72. Kanitakes J, Chouvet B. Granular-cell basal cell carcinoma of the skin. Eur J Dermatol. 2005;15:301–303. Ralston J, Kamino H, Liu M. Granular cell basal cell carcinoma: a diagnostically challenging case report and literature review [abstract]. J Cutan Pathol. 2010;37:187. Chang O, Knezevich S. Granular cell basal cell carcinoma. Report of a case [abstract]. J Cutan Pathol. 2012;39:132. Scrivener Y, Grosshans E, Cribier B. Variations of basal cell carcinomas according to gender, age, location and histopathological subtype. Br J Dermatol. 2002;147:41–47. Nakagawa K, Yamamura K, Maeda S, et al. bcl-2 expression in epidermal keratinocytic diseases. Cancer. 1994;74:1720–1724. Cerroni L, Kerl H. Aberrant bcl-2 expression provides a possible mechanism of neoplastic cell growth in cutaneous basal-cell carcinoma. J Cutan Pathol. 1994;21:398–403. Eshkoor SA, Ismail P, Rahman SA, et al. Immunohistochemical expression of CCND1 and p16 genes in tissue microarray. Australas J Cancer. 2009;8:103–108. Cretnik M, Poje G, Musani V, et al. Involvement of p16 and PTCH in pathogenesis of melanoma and basal cell carcinoma. Int J Oncol. 2009; 34:1045–1050. Paolini F, Carbone A, Benevolo M, et al. Human papillomaviruses, p16INK4a and Akt expression in basal cell carcinoma. J Exp Clin Cancer Res. 2011;30:108. Reuschenbach M, Tran T, Faulstich F, et al. High-risk human papillomavirus in non-melanoma skin lesions from renal allograft recipients and immunocompetent patients. Br J Cancer. 2011;104:1334–1341. Plaza JA, Ortega PF, Bengana C, et al. Immunolabeling pattern of podoplanin (d2-40) may distinguish basal cell carcinomas from trichoepitheliomas clinicopathologic and immunohistochemical study of 49 cases. Am J Dermatopathol. 2010;32:683–687. Ramdial PK, Madaree A, Reddy R, et al. bcl-2 protein expression in aggressive and non-aggressive basal cell carcinomas. J Cutan Pathol. 2000;27:283–291. Fan YS, Car RA, Sanders DS, et al. Characteristic Ber-EP4 and EMA expression in sebaceoma is immunohistochemically distinct from basal cell carcinoma. Histopathology. 2007;51:80–86.
2013 Lippincott Williams & Wilkins
Granular Cell Basal Cell Carcinoma: Report of a Case and Review of the Literature Stephanie L. Claassen, DO,* Michael C. Royer, MD,*† and Walter L. Rush, MD†
Abstract: Granular cell basal cell carcinoma (BCC), characterized by large cells with abundant eosinophilic cytoplasm and conspicuous granularity, is an extremely rare variant of BCC with only 14 cases reported in the literature to date. A case of an 82-year-old man with clinically suspected BCC of the face is presented. Microscopic examination demonstrated characteristic morphologic and immunophenotypic features of granular cell BCC, as well as novel expression of p16 and lack of bcl-2 expression, both of which are previously undescribed in granular BCCs in the literature to date. Although very rare, this entity is important to include in the differential of any nodular cutaneous neoplasm with granular features. The rarity of this lesion makes immunohistochemistry especially helpful. As in other BCCs, granular cell BCCs typically strongly express Ber-EP4 and cytokeratins. The granular BCCs are characteristically periodic acid–Schiff positive, but show no expression of S100 protein. The rarity of the granular cell BCC and the aggressive biological behavior of the entities that may share similar histologic features make arriving at the correct diagnosis paramount to appropriate clinical management. The fifteenth case of granular cell BCC with subsequent review of the literature is reported, with particular focus on the immunohistochemical characteristics. Key Words: granular cell basal cell carcinoma, p16, bcl2, immunohistochemisty
granularity that may range from a minority of the lesional cells to the entirety of the neoplasm.3–5 We report the 15th case of granular cell BCC with subsequent review of the literature, with particular focus on the immunohistochemical characteristics.
CASE REPORT An 82-year-old man presented with a nodular lesion on his left temple with clinical features of BCC, arising at the site of a previously biopsy-proven BCC. Complete excision of the lesion was performed for histologic evaluation; the specimen was subsequently submitted to the Joint Pathology Center consultation service for further evaluation.
MATERIALS AND METHODS Glass slides and paraffin-embedded tissue were received by our consultation service. Additional sections were initially stained with hematoxylin and eosin followed by additional immunohistochemical and histochemical stains including: CK8/ 18 (DAKO, Glostrup Denmark), CK7 (DAKO), epithelial membrane antigen (EMA) (DAKO), AE1/AE3 (Ventana, Tuscon, Arizona), CK5/6 (DAKO), Ber-EP4 (DAKO), Bcl-2 (Ventana), CD163/DR (Ventana), p16 (Ventana), CD68 (Ventana), p63 (Ventana), D2-40 (DAKO), S100 protein (Ventana), and periodic acid–Schiff (PAS).
(Am J Dermatopathol 2014;36:e121–e124)
INTRODUCTION Basal cell carcinoma (BCC) is the most common cutaneous neoplasm.1 Although typically demonstrating fairly characteristic clinical features, this neoplasm exhibits a wide histological spectrum, reflecting its origin from multipotent follicular germ cells.2 An extremely uncommon variant of BCC is the granular cell BCC, first described by Barr and Graham in 1979, with only 14 cases total reported in the literature to date.3–15 The granular cell BCC is characterized by large cells with abundant eosinophilic cytoplasm with conspicuous From the *Department of Pathology, Walter Reed National Medical Military Center, Bethesda, MD; and †Department of Dermatopathology, Joint Pathology Center, Silver Spring, MD. The authors declare no conflicts of interest. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense. Reprints: Stephanie L. Claassen, DO, Department of Pathology and Laboratory Medicine, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Building 9, Arrowhead, Room #0849, Bethesda, MD 20889 (e-mail: [email protected]). © 2013 Lippincott Williams & Wilkins
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RESULTS Microscopically, the biopsy shows a proliferative neoplastic lesion with a nodular growth pattern and central cystic degeneration located in the superficial dermis. The superficial portion of the neoplasm exhibits more conventional characteristics of BCC, with basaloid cells, peripheral palisading, associated tumor–dermal clefting and abundant extracellular mucin (Fig. 1). Although the majority of neoplastic cells exhibit some degree of granularity, the deeper portion of the tumor transitions into a subpopulation of markedly larger cells with abundant, distinctly granular, eosinophilic cytoplasm that eccentrically displaces the nucleus (Fig. 2). Numerous intracytoplasmic eosinophilic round inclusion bodies are present in the granular cell population; these are reminiscent of the pustulo-ovoid bodies seen in granular cell tumors (Fig. 3). The nuclei of the granular cells are round with condensed chromatin. Minimal mitotic activity and cell turnover with associated karyorrhectic debris are observed in both the conventional and granular cells. The deeper portion of the tumor exhibits an infiltrative border with surrounding dermal fibrosis. Immunohistochemical examination demonstrates strong diffuse positivity for AE1/AE3, CK5/6 (Fig. 4A), CK8/18, www.amjdermatopathology.com |
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FIGURE 1. Granular BCC with nodular growth pattern, central cystic degeneration, abundant extracellular mucin, and tumor–dermal clefting (hematoxylin–eosin, ·4).
and p63 both in the conventional basaloid cells and in the granular variant cells. The granular cells show strong diffuse immunoreactivity with Ber-EP4 (Fig. 4B) while the more conventional appearing BCC cells show focal positivity. The granular cells express CD68 (Fig. 4C) and D2-40 (Fig. 4D) and exhibit PAS reactivity, whereas the more conventional appearing BCC cells do not. The granular cells also express p16 (Fig. 4E), CK7, and EMA (very focally). All neoplastic cells are completely negative for S100 protein, bcl-2 (Fig. 4F), and CD163. Overall, the histologic features, in conjunction with the immunoprofile, are those of granular cell BCC.
DISCUSSION Granular cell BCC is a rare variant of BCC, with only 14 cases described in the literature to date; Table 1 summarizes all reported cases.3–15 This variant shares similar demographics with conventional BCC, with the majority of cases
FIGURE 2. Subpopulation of markedly larger tumor cells with abundant, distinctly granular, eosinophilic cytoplasm that eccentrically displace the nucleus (hematoxylin–eosin, ·20).
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FIGURE 3. Numerous intracytoplasmic eosinophilic round inclusion bodies (pustulo-ovoid bodies) are present in the granular cell population (hematoxylin–eosin, ·60).
of granular cell BCC occurring on the face of men (male to female ratio 3:1) at an average age of approximately 65 years (range: 30–93 years).3–15 Clinically, this variant behaves biologically similarly to conventional BCC and is successfully treated with complete excision.6,7,9,12 All cases of granular cell BCC have exhibited a nodular growth pattern, occasionally with cystic changes.3,4,6–8,11,12 The relative percentage of morphologically granular cells can range from a minor subpopulation to the entirety of the lesion.3–7,9,10,12,15 Ultrastructurally, the cytoplasmic granularity corresponds to cytoplasmic, membrane bound lysosome-like granules containing 0.2- to 0.4-mm electrondense bodies.3–7 The ultrastructural findings of pentalaminate desmosomes, in conjunction with the immunohistochemical expression of cytokeratins and the epithelial antigen Ber-EP4, support an epithelial origin of these cells. The granularity seen in the context of a BCC is hypothesized to result from degenerative intracellular processes. Inclusions similar to the pustuloovoid bodies seen in granular cell tumors may also be present in granular BCCs.3 The mitotic rate is generally low to nearly absent, especially within the variant granular cells.3–7,9 The exceptional case reported by Dundr et al12 described a relatively high proliferative rate (up to 25%–29%) when assessed by MIB1, with no difference appreciated between the conventional and granular variant subpopulations. All cases of granular cell BCC reported in the literature have shown positivity for keratins; some of which are lowmolecular-weight cytokeratin, high-molecular-weight cytokeratin, CK8/18 (CAM 5.2), cytokeratin 1 (MNF-116), and CD15 (leu M1).5–8,10–15 The overwhelming majority of cases also show positive expression of AE1/AE3 except for the case reported by Chang et al.15 Granular cell BCCs also characteristically express Ber-EP4 and are reactive for PAS.4,7,10–13,15 All cases that analyzed p63 expression, including this case, showed strong positivity.13–15 Our case is the first case of granular cell BCC to evaluate for, and show positivity for, p16 and D2-40. The p16INK4a protein, a tumor suppressor gene that inhibits cell cycle progression, is thought to play a key role in tumorigenesis 2013 Lippincott Williams & Wilkins
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FIGURE 4. Tumor cells diffusely express (A) CK5/6, (B) Ber-EP4, and (C) CD68. The granular variant cells are focally positive for (D) D2-40 and (E) p16. All neoplastic cells are completely negative for (F) bcl-2 (hematoxylin–eosin, ·40).
pathways leading to the development of both melanocytic and nonmelanocytic cutaneous neoplasms, including BCC.19–22 Overexpression of p16, assessed by immunohistochemistry, is present in up to 94.2% of BCCs.20–22 The overexpression of p16 strongly correlates to the presence of human papillomavirus that may play an etiological role in this neoplastic process.21,22 Although D2-40 expression is present in approximately 22% of conventional BCCs, this is the first case to demonstrate D2-40 expression in a granular BCC.23 Expression of CD68 may or may not be present, and when positive is typically restricted to the morphologically granular cells, as was in our case.12,13,15 CD68 expression correlates with the lysosomal derivation of the cytoplasmic granularity confirmed by electron microscopy.3–7 Granular cell BCC may or may not possess lysozyme activity when assessed by muramidase.4,6,7,11 Although the bcl-2 immunohistochemical stain decorates the majority (67%–100%) of BCCs, including 2 previous granular BCCs variants tested, our case showed no bcl-2
expression.13,15,17,18 Ramdial et al24 assessed bcl-2 expression in BCCs in the context of biological behavior and suggests low/no bcl-2 expression, defined as expression in less than 50% of neoplastic cells, strongly correlates with more clinically and histologically aggressive tumors evidenced by local infiltration and recurrence. Secondary to these features, increased rates of recurrence in bcl-2–negative BCCs were observed regardless of achievement of complete excision with tumor-free margins.24 Our case, which lacks bcl-2 expression, recurred after approximately 4 years and exhibits a more infiltrative border than characteristically seen in BCCs; these features may concur with the observations of Ramdial et al.24 Although EMA is typically not expressed in granular cell BCCs and in only up to 8% of conventional BCCs, very focal EMA expression is noted for the first time in this case.6,13,25 All cases of granular BCC, including the current case, have been found to be negative for S100 protein, CEA, NSE, and melanocytic markers.5–8,13–15
TABLE 1. Clinicopathologic and Immunohistochemical Features of Granular Cell BCC Case/Ref
Age/Gender
Site
1/3 2/3 3/4 4/5 5/6 6/7 7/8 8/9 9/10 10/11 11/12 12/13 13/14 14/15 Current case
72/M “Elderly”/M 67/M 30/F 67/M 81/M 57/F 50/M 65/M 62/M 69/F 71/M 40/M 93/M 82/M
Nose Face Neck Eyelid Nose Nose Forehead Chest Cheek Chest Nose Face Nose Nose Face
CK NOS
LMW-CK EMA / / / / +
+ + / + + + + / / +
/ / / / 2 / / / / / / 2 / / +(f)
AE1 AE3
HMW-CK, CK5/6 BerEP4
/ / / + +
/ / / / /
/ + + + + + 2 +
/ + / / / + / +
/ / / / / / / / + / + / / + +
D2-40 / / / / / / / / / / / / / / +(g)
p16 CD68 p63 PAS Bcl2 Architecture / / / / / / / / / / / / / / +
/ / / / 2 2 / / / / +(g) +(g) / 2 +(g)
/ / / / / / / / / / / + + + +
/ / + / / + / / / + / + / / +
/ / / / / / / / / / / + / + 2
Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Nodular Not given Nodular
Ber-EP4, epithelial antigen; CK NOS, cytokeratin, not otherwise specified; EMA, epithelial membrane antigen; F, female; (f), focal; (g), expression seen in granular variant cells only; HMW-CK, high-molecular-weight cytokeratin; LMW-CK, low-molecular-weight cytokeratin; M, male; (/), not performed; (+), positive; (2): negative.
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Am J Dermatopathol Volume 36, Number 7, July 2014
Claassen et al
BCCs with granular features may present a diagnostic challenge to the surgical pathologist. Features of granular cell differentiation can be seen in a variety of other cutaneous neoplasms including: leiomyosarcoma, angiosarcoma, ameloblastoma, schwannoma, signet ring cell melanoma, granular cell tumor, and primitive polypoid granular cell tumor.5,6 The diagnosis may be further complicated, as in our case, by the absence of demonstrable connection of the tumor to the epidermis in the planes of section examined.10 Another diagnostic challenge may the complete absence of more conventional features of BCC.13,15 Granular cell ameloblastoma may be histologically identical to granular cell BCC; however, location and involvement of a mucosal surface can be reliable differentiators.5,6 Although the granular quality of the cells and the presence of pustulo-ovoid–like bodies may cause confusion with a granular cell tumor, the differentiating characteristic may be the placement of the nuclei, with the nuclei of granular BCCs being more eccentrically displaced while the nuclei of granular cell tumors remain more centrally located. Additional supportive evidence by immunohistochemistry, particularly co-expression of Ber-EP4 and cytokeratins, while lacking S100 protein and melanocytic markers readily identifies the basal cell origin and excludes more worrisome diagnostic entities.5,6 Granular cell BCC is a rare variant of BCC that is not yet fully characterized immunophenotypically. Although typical cases of granular BCC express cytokeratins, BerEP4, p63, PAS, and lysozymal activity, this is the first case of granular cell BCC to identify the presence of p16 expression, which may play a part in the pathogenesis of this variant and more conventional BCCs. This is also the first report of a case of granular cell BCC lacking bcl-2 expression; this finding may be associated with aggressive histologic features and overall worse clinical course. Granular cell BCC requires correlation of clinical, histopathologic, and immunophenotypic features to ensure correct diagnosis. Accurate identification of this rare variant of BCC is essential to exclude other diagnostic entities with similar histomorphologic features to ensure the proper management of conservative, yet complete excision. ACKNOWLEDGMENTS The authors thank the contributors, Drs. Rakhee Saxena and Dawn Ellerson, for referring this challenging and interesting case to their consultation service. Additional special thanks to Ms. Chih Yon Song, RN, Camp Humphreys Clinic, Pyongtaek, South Korea, for her assistance with translation.
3. 4. 5. 6.
7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
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