295S Eccrine Differentiation in Basal Cell Carcinoma Peter J. Heenan and Matthew S. Bogle Eccrine differentiation according to histologic and immuno-histochemical criteria was demonstrated in 16 of 66 basal cell carcinomas. The possibility of origin of these neoplasms from the eccrine duct, including the acrosyringium, is discussed in relation to the differences in site distribution and etiology between basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol 100:295S 299S, 1993 Eccrine differentiation is generally regarded as a rare feature of basal cell carcinoma (BCC) [1,2]. In our experience, however, in a population in which BCC is extremely common [3], these tumors often show features suggestive of eccrine differentiation. This study was undertaken, therefore, as an attempt to assess the frequency of eccrine differentiation in a small series of BCC and to consider its implications. MATERIALS AND METHODS Sixty-six consecutive excision specimens of BCC from one pathology laboratory were examined by routine histologic methods [hematoxylin and eosin, periodic acid Schiff (PAS) with and without diastase digestion] on formalin-fixed, paraffin-embedded material. Immunohistochemical staining was performed by an avidin-biotin technique [4] for carcinoembryonic antigen (CEA) (Dako, titer 1:200) and for cytokeratins detected by the monoclonal antibodies AE1 and AE3 (Hybritech; titer 1:200) and CAM 5.2 (Becton- Dickinson; titer 1:20). The criteria used for eccrine differentiation were the following. 1. (a) Alveolar collections of cells with vacuolated cytoplasm within aggregates of typical BCC, forming tubular structures similar to the intraepidermal portion of embryonic eccrine ducts [2]. (b) the presence in the tumor of simple tubular structures similar in morphology to eccrine ducts and lined by flattened eosinophilic (cuticular) epithelium and surrounded by atypical basaloid cells. 2. CEA positivity in the lining cuticular epithelium, in the vacuolated cells, and in the contents, when present, of the lumina [5,6]. 3. positivity for AE1 and AE3 in ductal structures in the tumors in a pattern similar to that seen in normal eccrine ducts and negative staining for CAM 5.2, also as seen in eccrine ducts [6]. 4. PAS positivity after diastase digestion in the contents of the lumina and in the vacuolated epithelium. The patients consisted of 42 men and 24 women, ranging in age from 27 to 86 years; 35 tumors occurred on the head and neck, 22 on the trunk, and nine on the limbs. RESULTS Sixteen of the 66 neoplasms met criteria, 1, 2, and 3 for eccrine differentiation (Figs 1 4). Staining for CEA was seen mainly in linear patterns on the surfaces of cells in the alveolar structures, with less intense cytoplasmic positivity. The pattern for AE1 and AE3 was very similar to that for CEA, mainly in linear luminal and cell-surface distribution, with more diffuse cytoplasmic staining. PAS positivity after diastase digestion was found in the ductal structures in 15 of the 16 neoplasms, although often in only sparse distribution. The tumors Department of Pathology (PJH), The University of Western Australia; and Department of Pathology (MSB), Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia Reprint requests to: Dr. Peter J. Heenan, Cutaneous Pathology, 26 Leura Street, Nedlands 6009, Australia. Abbreviations: BCC, basal cell carcinoma; CEA, carcinoembryonic antigen; PAS, periodic acid Schiff; SCC, squamous cell carcinoma were all of typical solid and adenocystic patterns with peripheral palisading, the common feature of BCC, which might be an indicator of eccrine or follicular differentiation because palisading is a prominent feature of both follicular and eccrine germs [7]. Eight of these tumors came from the head and neck, six from the trunk, and two from the limbs. DISCUSSION The presence of ductal structures in BCC can be interpreted in several ways. Entrapment of Segments of Normal Eccrine Ducts in the Tumor This is a common occurrence in BCC, but although the walls of entrapped ducts are frequently hyperplastic, the structures are otherwise still identifiable as normal ducts. The ductal structures that we interpreted as being intrinsic parts of the neoplasms were composed of atypical epithelium merging with the surrounding tumor. The structures were far more numerous than could be explained by entrapment of normal ducts, and they were distributed throughout the lobules of tumors. In particular, the alveolar collections of vacuolated cells were easily distinguishable from the more sharply defined normal ductal segments. Ductal Differentiation in BCC Might Be of Apocrine Type Apocrine and eccrine ducts are indistinguishable from one another [2]; these tumors, however, came from anatomic sites in which apocrine glands are usually absent or scarce, and no apocrine glands could be seen in the sections, whereas eccrine glands were plentiful. Apocrine ducts have been reported to show positivity for CAM 5.2 [6], but all BCC showed negative results with this reagent in our study. BCC with Sebaceous Differentiation Might Contain Ductal Structures No evidence of sebaceous differentiation, however, was found in these tumors. The alveolar collections of cells showing positivity for CEA in these tumors had relatively large, often single vacuoles and peripheral, flattened nuclei, unlike sebaceous cells with their multiple smaller vacuoles and central, crenated nuclei. Sebaceous glands in our material were CEA negative except for small foci of interstitial or peripheral positivity. The Presence of These Ductal Structures Might Represent True Eccrine Differentiation Although the features described in these tumors are not specific for eccrine differentiation, the combination of histologic and immunohistochemical features similar to those of normal eccrine ducts and common neoplasms of eccrine ducts, such as syringoma (Fig 5), in both their cytologic detail and pattern seems to provide strong evidence for eccrine differentiation. Squamoid eddies in these tumors, some containing central necrotic foci, also stained positively for AE1, AE3, and CEA. Concentric layers of squamoid cells also surrounded alveolar and ductal structures, but the immunostaining in these tubular foci was sharp and linear, in contrast with the more diffuse positivity of the squamoid cells and the irregular, granular staining of necrotic debris. The association of these squamoid eddies with 0022-202X/93/$06.00 Copyright & 1993 by The Society for Investigative Dermatology, Inc.
296S Heenan and Bogle THE JOURNAL OF INVESTIGATIVE DERMATOLOGY Figure 1. a) Basal cell carcinoma with solid and adenoid components, b) At higher power, the neoplasm contains alveolar clusters of cells with clear cytoplasm (large arrow), small duct-like structures (small arrow), and squamoid eddies (asterisk). Figure 2. a) Immunostaining for CEA on the surface of cells in the alveolar clusters, on the luminal surfaces of duct-like structures, in the surrounding cells, and in the squamoid eddies, b) Immunostaining for CEA in the acrosyringium and superficial dermal eccrine duct. Figure 3. a) Immunostaining for AEl and AE3 in ductal and alveolar structures and in squamoid eddies, b) Immunostaining for AEl and AE3 in the acrosyringium and superficial dermal eccrine duct.
VOL. 100, NO 3, SUPPLEMENT, MARCH 1993 ECCRINE DIFFERENTIATION IN BASAL CELL CARCINOMA 297S Figure 4. Immunostaining for CAM 5.2 in the secretory segments of eccrine glands. The eccrine ducts and the BCC (arrow) show no staining. ductal structures and their immunohistochemical staining suggest therefore that they also might be indicators of eccrine rather than epidermal or follicular differentiation. If the features described in these tumors are accurate indicators of eccrine differentiation, it appears that two main implications should be considered: (1) eccrine differentiation is a manifestation of mixed differentiation in neoplasms of multipotent stem-cell origin [8], derived from either the epidermis or adnexal epithelium; and (2) eccrine differentiation might indicate that the neoplasms originate directly from the eccrine duct, including the acrosyringium. Mehregan [9] has suggested that the origin of cutaneous adnexal tumors from the cells of pre-existing structures should be considered as an alternative to the pluripotent stem-cell theory [8]. The possibility of the origin of BCC, itself an adnexal neoplasm according to some authorities [10,11], from the eccrine duct might also be reviewed on the basis of clinical and histologic observations, as proposed by Mehregan for adnexal tumors [9]. Accordingly, points in favor of origin from eccrine ducts of these BCC showing eccrine differentiation are the following. 1. The presence of ductal structures within the tumors showing evidence of eccrine differentiation, as described above. 2. Frequent continuity of the BCC with eccrine ducts, including the acrosyringia [7] and foci of in situ BCC in the walls of eccrineducts (Fig 6). 3. The sharing of common features by eccrine neoplasms and BCC. Eccrine neoplasms, benign and malignant, show positivity for CEA [12,13] in a pattern similar to that seen in these BCC. Eccrine neoplasms frequently also contain squamous eddies or whorls [14,15] similar to the concentric collections of squamoid cells surrounding the ductal structures seen in BCC in this study (Fig 1). The presence of these squamous eddies, also described in BCC as being CEA positive by Kidd et al [16], might be another manifestation therefore of eccrine differentiation rather than an indicator of follicular differentiation [17]. If this is true, eccrine differentiation in this group of tumors might be more prevalent than indicated only by those 16 BCC containing obvious duct for mation because squamous eddies were common in the 50 other neoplasms that were devoid of ductal structures. Furthermore, typical components of both BCC and eccrine ductal carcinoma coexist in some tumors wherein solid groups of uniform basaloid cells with peripheral palisading, indistinguishable from BCC, are present in the superficial dermis and at the dermoepidermal junction, whereas the more deeply infiltrating component consists of typical syringomatous carcinoma (Fig 7). Figure 5. Immunostaining of syringoma for a) CEA; positive staining of luminal contents and of lining epithelium, b) AE1 and AE3. More diffuse positivity for these antibodies in the cytoplasm of the ductal epithelium, with an accentuated linear pattern on the luminal surface. With regard to the remaining BCC in this series, which showed no obvious adnexal differentiation and were composed mainly of solid groups of atypical basaloid cells, it might be postulated that these tumors are also of eccrine origin, representing the least differentiated of this group of neoplasms. Although the recognition of eccrine differentiation in BCC might be regarded as merely an exercise in morphologic classification, eccrine origin of these tumors would have more important biologic implications. BCC is usually described as occurring predominantly on the exposed skin in similar distribution to squamous cell carcinoma (SCC), arising as an apparently direct result of long-term exposure to UV light [18]. In a recent survey of nonmelanocytic skin cancers in the coastal town of Geraldton in Western Australia, however, very marked differences in anatomic site distribution between BCC and SCC were demonstrated [3]. A much larger proportion of BCC than SCC occurred on the trunk, whereas BCC were uncommon on the dorsum of the hand and forearm, which were common sites of SCC. BCC also does not originate from the mucosal surface of the lip, a common site for SCC.
298S Heenan and Bogle THE JOURNAL OF INVESTIGATIVE DERMATOLOGY Figure 6. a) BCC involving acrosyringium. b) BCC involving superficial dermal eccrine duct producing an in situ carcinoma pattern. These differences in site distribution between BCC and SCC invite the following inferences. 1. Some or all BCC might be causally related more to intermit tent than continuous exposure to UV light [19], as are the commonest forms of cutaneous malignant melanoma [20,21], which share some of the site distribution characteristics of BCC. 2. Some or all BCC might be derived from different cells from those that give rise to SCC, and the response to UV light of these cells might be more complex than that of the progenitors of SCC. The acrosyringium, as a biologic and anatomic unit distinct from the intervening epidermis [22,23], appears to react differently to UV light exposure, as shown frequently by the preservation of intact acrosyringia surrounded by atypical epithelium in solar keratoses and SCC (Fig 8), perhaps due to the marked pigmentation of the peripheral basal cells of the acrosyringium [2]. The origin of some BCC from the acrosyringium and dermal eccrine duct therefore might explain, at least in part, the difference Figure 7. a) Features of BCC (arrow) and eccrine ductal carcinoma (asterisk) in the same tumor, b) Typical BCC in the superficial dermis and at the dermoepidermal junction, c) Infiltrating ductal carcinoma with syringomatous features.
VOL. 100, NO 3, SUPPLEMENT, MARCH 1993 ECCRINE DIFFERENTIATION IN BASAL CELL CARCINOMA 299S Figure 8. Intact acrosyringia surrounded by atypical squamous epithelium in solar keratosis. between the relationship of BCC and SCC to sunlight exposure, as suggested by their anatomic site distributions. We thank Dr. B.K. Armstrong for his helpful comments and Mrs. S.G.Jones for typing the manuscript. REFERENCES 1. Sanchez NP, Winkelmann RK: Basal cell tumor with eccrine differentiation (eccrine epithelioma). J Am Acad Dermatol 6:514 518, 1982 2. Abenoza P, Ackerman AB: Syringomatous carcinomas. In: Neoplasms with Eccrine Differentiation. Lea and Febiger, Philadelphia, 1990, p 400 3. Kricker A, English DR, Randell PL et al Skin cancer in Geraldton, Western Australia: a survey of incidence and prevalence. Med J Aust 152:399 407, 1990 4. Falini B, Taylor CR: New developments in immunoperoxidase techniques and their application. Arch Pathol Lab Med 107:105 117, 1983 5. Maiorana A, Nigricoli E, Papotti M: Immunohistochemical markers of sweat gland tumors. J Cutan Pathol 13:187 196, 1986 6. Zuk JA, West KP, Fletcher A: Immunohistochemical staining patterns of sweat glands and their neoplasms using two monoclonal antibodies to keratins. J Cutan Pathol 15:8 17, 1988 7. Ackerman AB: Basal cell carcinoma with follicular differentiation (letter). AmJ Dermatopathol 11:481 497, 1989 8. Pinkus H: Epithelial and fibroepithelial tumors. Arch Dermatol 91:24 37, 1965 9. Mehregan AH: The origin of the adnexal tumors of the skin. A view point. J Cutan Pathol 12:459 467, 1985 10. Foot NC: Adnexal carcinoma of the skin. Am J Pathol 23:1 27, 1947 11. Lever WF: Pathogenesis of benign tumors of cutaneous appendages and basal cell epithelioma. II. Basal cell epithelioma. Arch Dermatol Syph 57:709 724, 1948 12. Penneys NS, Nadji M, Ziegels-Weissman J, Ketabchi M, Morales AR: Carcinoembryonic antigen in sweat-gland carcinomas. Cancer 50:1608 1611,1982 13. Swanson PE, Cherwitz DL, Neumann MP, Wick MR: Eccrine sweat gland carcinoma: an histologic and immunohistochemical study of 32 cases. J Cutan Pathol 14:65 86, 1987 14. Satoh T, Katsumata M, Tokura Y, Iwatsuki K, Takigawa N: Clear cell hidradenoma with whorl formation of squamoid cells: immunohistochemical and electron microscopic studies. J Am Acad Dermatol 21:271 277,1989 15. Kohda M, Manabe T, Ueki H: Squamous islands in eccrine neoplasms. Am J Dermatopathol 12:7 16, 1990 16. Kidd MK, Tshen JA, Rosen T, Actman AR, Goldberg L: Carcinoembryonic antigen in basal cell neoplasms in black patients: an immunohistochemical study. J Am Acad Dermatol 21:1007 1010, 1989 17. McGibbon DH: Malignant epidermal tumours. J Cutan Pathol 12:224 238, 1985 18. McCarthy WH, Shaw HM: Skin cancer in Australia. Med J Aust 150:469 470, 1989 19. Gallagher RP, Ma B, McLean DI et al Trends in basal cell carcinoma, squamous cell carcinoma, and melanoma of the skin from 1973 through 1987. J Am Acad Dermatol 23:413 421, 1990 20. Fears TR, Scotto J, Schneiderman MA: Mathematical models of age and ultraviolet effects on the incidence of skin cancer among whites in the United States. AmJ Epidemiol 105:420 427, 1977 21. Holman CDJ, Mulroney CD, Armstrong BK: Epidemiology of preinvasive and invasive malignant melanoma in Western Australia. Int J Cancer 25:317 323, 1980 22. Hashimoto K, Gross BG, Lever WF: The ultrastructure of the skin of human embryos. 1. The intraepidermal eccrine sweat duct. J Invest Dermatol 45:139 151, 1965 23. Mishima Y: Epitheliomatous differentiation of the intraepidermal eccrine sweat duct. J Invest Dermatol 52:233 246, 1969