Basal cell (trichoblastic) carcinoma Klaus Sellheyer, MD, Dieter Krahl, MD  Journal of the American Academy of Dermatology  Volume 58, Issue 1, Pages 158-167 (January 2008) DOI: 10.1016/j.jaad.2007.07.008 Copyright © 2008 American Academy of Dermatology, Inc. Terms and Conditions

Fig 1 Expression of epithelial cell adhesion molecule (Ep-CAM) changes during human follicular morphogenesis and is most pronounced in germ stage. Ep-CAM is expressed in the crowded basal cells of pregerm stage (A and B) but increases significantly during the germ stage, in which all epithelial cells show prominent membranous staining (C and D). In the subsequent hair peg stage, only the advancing epithelial component of the developing hair bordering the early follicular papilla is positive for Ber-EP4 (E and F). Some scattered positive cells are also present in the basal cell layer of the primordial follicular infundibulum (F). Most of hair peg follicles, however, do not display immunoreactivity in this anatomic compartment. In the bulbous hair peg stage, immunoreactivity for Ep-CAM is only noted in the most proximal portion of the follicle in close proximity to the lower portion of the follicular papilla (G and H). Note that hair follicles develop synchronously in waves during embryogenesis. Therefore, hair follicles can be present at different stages during the same developmental age. Shown are 13 weeks (A to D), 16 weeks (E and F), and 18 weeks (G and H). (A, C, E, and G, Hematoxylin-eosin stain; original magnifications: A and C, ×400; E, ×200; G, ×100.) (B, D, F, and H, Ber-EP4; original magnifications: B and D, ×400; F, ×200; H, ×100.) Journal of the American Academy of Dermatology 2008 58, 158-167DOI: (10.1016/j.jaad.2007.07.008) Copyright © 2008 American Academy of Dermatology, Inc. Terms and Conditions

Fig 2 Epithelial cell adhesion molecule (Ep-CAM) is expressed in asymmetric fashion during later stages of human follicular morphogenesis. During the hair peg and bulbous hair peg stage, Ep-CAM expression is restricted to the developing proximal outer root sheath opposite to the side of the hair follicle where the hair bulge is located (arrows) (A to C). The hair bulge is seen as a lateral protuberance in the upper part of two hair follicles (A and B) and is located distal to the follicular bulb opposite to the side of the arrow. Other antigens are not expressed asymmetrically during the later stages of embryonic hair follicle development, as shown for apoptotic protein bax (D) and proliferation marker Ki-67 (E), depicted here for comparison. Shown are 13 weeks (A), 18 weeks (B, C, and E), and 19 weeks (D). (A to C, Ber-EP4 stain; original magnifications: A and B, ×100; C, ×400.) (D, Bax; original magnification: ×400.) (E, Ki-67; original magnification: ×400.) Fig D reprinted with permission from Sellheyer K, Krahl D, Ratech H. Distribution of bcl-2 and bax in embryonic and fetal human skin: antiapoptotic and proapoptotic proteins are differentially expressed in developing skin. Am J Dermatopathol 2001;23(1):1-7. Journal of the American Academy of Dermatology 2008 58, 158-167DOI: (10.1016/j.jaad.2007.07.008) Copyright © 2008 American Academy of Dermatology, Inc. Terms and Conditions

Fig 3 The nail matrix is completely negative for epithelial cell adhesion molecule (Ep-CAM). The nail organ was also examined for expression of Ep-CAM, as it is often viewed as a structure with close similarity to the hair follicle. However, in contrast to the hair follicle, the developing nail was completely negative at all stages (A to H). Note that the primordial secretory portions of the eccrine sweat glands, seen within the tip of toe (H) were positive for Ber-EP4, which functioned as internal positive controls. Shown are 11 weeks (A and B), 13 weeks (C and D), 17 weeks (E and F), and 21 weeks (G and H). (A, C, E, and G, Hematoxylin-eosin stain; original magnifications: A, ×100; C, ×50; E and G, ×25.) (B, D, F, and H, Ber-EP4; original magnifications: B, ×100; D, ×50; F and H, ×25.) Journal of the American Academy of Dermatology 2008 58, 158-167DOI: (10.1016/j.jaad.2007.07.008) Copyright © 2008 American Academy of Dermatology, Inc. Terms and Conditions

Fig 4 The sweat glands express epithelial cell adhesion molecule (Ep-CAM) but only during late developmental stages and confined to the secretory portion only. The development of the eccrine glands starts later than hair follicle development. Whereas during gestational week 11, the undersurface of the epidermis is smooth (A and B), soon rete ridges are spaced at regular intervals from each other (C and D). The tips of the rete ridges elongate and sprout the eccrine ducts and glands (E and F). Rete ridges (D) and intradermal eccrine ducts (F) are negative for Ber-EP4. It is only once a lumen develops in the secretory component of the glands that Ep-CAM can be detected (G and H). Note that eccrine glands develop at the tips of the toes first, before they develop in the remaining plantar surface. Therefore, one can see different stages of eccrine gland development within the same foot. Shown are 11 weeks (A and B), 16 weeks (C and D), 17 weeks (E and F), and 23 weeks (G and H). (A, C, E, and G, Hematoxylin-eosin stain; B, D, F, and H, Ber-EP4; original magnifications: ×100.) Journal of the American Academy of Dermatology 2008 58, 158-167DOI: (10.1016/j.jaad.2007.07.008) Copyright © 2008 American Academy of Dermatology, Inc. Terms and Conditions

Fig 5 Superficial basal cell carcinoma (BCC) and embryonic hair germs display an identical expression pattern for epithelial cell adhesion molecule (Ep-CAM). BCCs were strongly positive for Ep-CAM (A) as was the embryonic follicle at the hair germ stage (23 weeks) (B). Vellus hair follicles reacted equally intense with Ber-EP4 (C) with immunoreactivity confined to outer root sheath (D). In adult scalp, only secondary hair germs of telogen phase were positive for Ep-CAM (E) but not follicles in anagen stage (F). (A to F, Ber-EP4; original magnifications: A, C, D, and F, ×200; B, ×400; E, ×50.) Journal of the American Academy of Dermatology 2008 58, 158-167DOI: (10.1016/j.jaad.2007.07.008) Copyright © 2008 American Academy of Dermatology, Inc. Terms and Conditions