Basal cell tumor with apocrine differentiation: Apocrine epithelioma

Basal cell tumor with apocrine differentiation: Apocrine epithelioma Fumiko Sakamoto, M.D., Masaaki Ito, M.D., Shinsuke Sato, M.D., Ph.D., and Yoshio Sato, M.D. Niigata, Japan A locally invasive tumor developed in a 71-year-old woman on the right retroauricular skin, involving cartilage and parotid glands. Histologically, the tumor displayed characteristic features of basal cell epithelioma accompanied by stromal fibrosis. Histochemically, an apocrine pattern in enzyme reactions was detected in tumor cells. Ultrastructurally, the tumor cells showed the features of apocrine-type secretory cells and ductlike structures, and the peripheral cells revealed the characteristics of myoepithelial cells. A large number of myofibroblasts was observed in the connective tissue surrounding the tumor nests. From these findings, the woman's tumor was considered to represent a basal cell tumor with apocrine differentiation. (J AM ACAD DERMAToL 13:355-363, 1985.)

Histologically, basal cell epithelioma is known to show varied differentiations toward the epidermal appendages,1,2 especially hair follicle and sebaceous structures. Recently it has been suggested that there might be a basal cell epithelioma with eccrine gland differentiation (eccrine epithelioma).3 Basal cell epithelioma with apocrine differentiation, however, has not been reported to our best knowledge. We report a case of locally invasive tumor that may be considered apocrine epithelioma because of biologic, histologic, histochemical, and ultrastructural findings. CASE REPORT

A 71-year-old woman noticed a mass on her retroauricular skin in March, 1977. The mass had gradually increased in size for 2 years previously and become painful 2 months prior to her first visit to our clinic in January, 1980. She had no past history of malignant tumor in internal organs. On physical examination the reddish brown, raised From the Department of Dermatology, Niigata University School of Medicine. Reprint requests to: Dr, Fumiko Sakamoto, Department of Dermatology, Niigata University School of Medicine, 1 Asahimachi-Dohri, Niigata 951, Japan/0252-23-6161 (ext. 2584),

mass was 2X 1.5 em in diameter and had a central depression and irregular folds on its surface (Fig. 1). On palpation it was firm and seemed to adhere to the underlying tissue. There was no regional lymphadenopathy. During surgery the deeply situated part of the mass could not be removed, and a skin graft was performed. Two years later, several nodules had appeared on and around the previously grafted area. On palpation, an induration was felt to be fixed to the underlying sternocleidomastoid muscle, extending to the surrounding tissue. The recurrence of the original tumor was histopathologically confirmed by biopsy. The extirpation of the recurrent nodules and a radical neck dissection, including parotidectomy and partial mastoidectomy, were carried out in March, 1982. The tumor involved the parotid glands and the frontal wall of the ear canal. The main trunk of the facial nerve and the ear canal could not be separated from the tumor. 60CO radiation therapy was palliatively given. MATERIALS AND METHODS

The surgical materials were prepared for histologic, histochemical, and electron microscopic studies. For histologic studies, the formalin-fixed materials were embedded in paraffin, and deparaffinized sections were prepared in the usual manner. The sections were stained with hematoxylin-eosin, Aldan blue, azan-

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Clinical appearance of apocrine epithelioma. Raised tumor on right retroauricular area shows irregularly folded surface with central depression. Fig. 1.

Mallory, periodic acid- Schiff (PAS), diastase-digestive PAS, and van Gieson stains. Histochemical examinations were performed for the demonstrations of localizations of the following enzymes: succinodehydrogenase,4 acid phosphatase,S alkaline phosphatase, 6 phosphorylase, 7 and {3-glucuronidase. 8 For electron microscopic study, small pieces of the material were fixed in 2.5% glutaraldehyde in 0.1 M sodium phosphate buffer (pH 7.4), postfixed in 2% osmium tetroxide in the same buffer, dehydrated in graded ethanol series and propylene oxide, and embedded in Epon-epoxy resin. Ultrathin sections were made with the Sorval MT-l ultramicrotome, stained with 1% uranyl acetate and Reynolds' lead citrate,9 and observed under an electron microscope (JEM-T8). RESULTS

Histologic and histochemical findings. Histologic examinations revealed that the tumor was composed of irregularly shaped epithelial nests of basaloid cells and fibrous stroma surrounding the nests, giving an appearance of basal cell epithelioma. Islands of the tumor nests were present from all layers of the dermis through subcutaneous tissue and formed a connection with the epidermis in the specimen obtained at the first operation (Fig. 2). The specimen from the second operation showed the invasions by the tumor into the right

Fig. 2. Basaloid cell nests surrounded by fibrous stroma in dermis. Stroma (*) is in part edematous. (Hematoxylin-eosin stain.)

auricular cartilage, tissue surrounding the trunk of the right facial nerve, and right parotid glands, which were normal in histologic appearance. The tumor cells did not reach the skin of the external ear canal, striated muscle, bone, and regional lymph nodes. The tumor cells uniformly had a large vesicular nucleus and clear cytoplasm (Fig. 3) and in part displayed a resemblance to sweat duct structures with distinct cuticles. Furthermore, the tumor had structures such as columnar cells with decapitation and a luminal surface with small cavities, sometimes showing a wreathlike appearance (Fig. 3). Elongated or flattened cells with deeply basophilic nuclei, which seemed to correspond morphologically to the myoepithelial cells of normal sweat glands, were also present at the periphery of the tumor nests (Fig. 3). These myoepithelium-like cells were also grouped within the tumor nests, with connections to the similar peripheral cells (Fig. 3).

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Fig. 3. Basaloid cell nests showing glandular structures. Notice luminal decapitated epithelium (inset). Elongated, darkly stained cells are seen at periphery of nests (arrowheads), sometimes in a group (*). L, lumen. (Hematoxylin-eosin stain.)

The connective tissue stroma surrounding these tumor cell nests also proliferated and showed similar features to those seen in basal cell epithelioma,1,2 that is, proliferation of young fibroblasts and mucinous change (Fig. 2). In some areas a sclerotic feature similar to that of sclerosing basal cell epithelioma, which is characterized by small, closely packed tumor nests and fibrous stroma,1,2 was observed. In the predominantly sclerotic area the epithelial nests appeared to show various degrees of disintegration-loss of the alveolar pattern, as well as loss of cohesion between cells, irregular stainability, and the cleft formation between the nests and stroma (Fig. 4). The presence of glycogen granules in the tumor cells was shown by PAS stain; PAS-positive and diastase-digestive substance was seen in the luminal space of sweat duct-like structures, in the cuticles of ductlike structures, and at the rims of

the' small cavities. PAS-positive basement membranes were variable but not constantly noticed along the peripheral layer of the tumor cell nests. Aldan blue staining was positive in some parts of the tumor cell nests. The cytoplasm of some fibroblast-like cells occasionally stained red by azan-Mallory stain. These cells were sparsely distributed among bluish collagenous fibers in the stroma. Elastic fiber was seldom found in the stroma by van Gieson stain. Histochemical studies for acid phosphatase and f3 -glucuronidase revealed strong but variable activities within the tumor masses. Phosphorylase reaction could not be demonstrated in the tumor cells, in contrast to the positive reaction within control eccrine glands. Succinodehydrogenase reaction was not found. Alkaline phosphatase reaction was uniformly positive in the entire nests, as well as in the walls of blood capillaries in the stroma. The enzyme reaction pattern described

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,.;

;

•

Fig. 4. Basaloid cell nests embedded in fibrous stroma. Disintegration of tumor cells and cleft formation (arrowheads) between nests and stroma are seen. (Hematoxylin-eosin stain.) .

Fig. s. Electron micrograph of tumor cells. Clear and columnar cells (C) group with tendency to form immature luminal structures (*) among them. Dark cells (D) between clear cells (C) possess developed endoplasmic reticulum in cytoplasm. Nuclei (N) of tumor cells show irregular shapes and have large nucleoli (arrows) and nuclear bodies (arrowheads). (Uranyl acetate-lead citrate stain; original magnification, x4,800.)

here was thought to be compatible with that in apocrine tumors. 10 Electron microscopic findings. The tumor·nest was composed of two types of closely packed cells; one had clear cytoplasm and another had dark cytoplasm (Fig, 5). Their nuclei were itregu-

lady shaped with indentations and had abnormally disttibuted chromatin and large nucleoli and nuclear bodies (Fig. 5). The cytoplasm contained well-developed Golgi apparatus with numerous vesicles, mitochondria, ex and f3 types of glycogen granules, and various amounts of tonofilaments

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Fig. 6. Electron micrographs of immature luminal structure in tumor cell nests. Tumor cells are tightly connected with each other; interdigitation of cellular projections and numerous desmosomes (d) are seen (inset). Cytoplasm of tumor cells contains welldeveloped Golgi apparatus (0), numerous mitochondria(m), and a and f3 types of glycogen granules (gl). *, Immature luminal structure; arrowheads, secretory granules; Tf, tonofilaments. (Uranyl acetate-lead citrate stain; original magnification, x 10,000; inset, ><41,300.)

(Fig. 6). The mitochondria were varied in size and shape and occasionally were gigantic and bizarre. Some of the clear cells became tall and columnar and tended to group to form an immature luminal structure a~ong them (Fig. 5). These cells had basally located nuclei (Fig. 5), apically gathered mitochondria (Fig. 6), and/or secretory granules (Figs. 6 to 8). The secretory granule had a dens.e core in its inside ~nd a less dense zone along tJ:1e inner side of its limiting membrane (Fig. 7). The small-to-mediuni-sized (50-100 nm in diameter) granules were usually round or ellipsoidal, but the large ones (up to 300 nm in diameter) were variable . in shape (Fig. 7). Crystalloid (Fig. 7) ariCi myelin-like figures were sometimes found within the granules. Around the lumina, the cells were tightly conm~cted with each other; the interdigitation of cellular projections and numerous desmosomes was seen (Figs. 6, 8). Along the luminal surface, rriicrovilli, which had an axial bundle of microfilaments, were seen, and some parts of the peripheral cytoplasm were pinched off and released into the lumina, leaving a broken site of cell membrane or a demarcation membrane at the periphery of the cell (Fig. 8). An amorphous sub-

stance was present in the lumina (Fig. 8). These findings are similar to those innotmal apocrine secretion (decapitation secretion). 11 The elongated cells with desmosbmal connections with the tumor cells described above were seen at the periphery of the nests (Fig. 9). Their cytoplasm contained a large number of glycogen granules, tonofilaments , and bundles of microfilaments with focal high densities (Fig. 9). These microfilaments, each of which measured 5-8 nm in width, were thought to be myofilaihents, usually located along the stroma side of cell membrane ~nd sometimes occupying the whole cytoplasm (Fig. 9). These findings of the elongated cells are verysimilar to those of myoepithelial cells, which are normally located at the periphery of sweat glands. 12 In the stromal connective tissue near the tumQr tissue, one to several layers of myofibrobhists were observed (Figs. 9 and 10). These cells were loosely distributed without formation of any cellto-cell contact but sometimes possessed hemidesmosome-like structures at the inner side of the cell membrane accompanied by basal laminalike structure along the cell surface (Fig. 10). Young collagen fibrils with an amorphous sub-

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Fig. 7. Electron micrographs of secretory granules seen in tumor cells. Granules are membrane limited and varied in size, shape, and density. Crystalloid structure (arrow in inset) is also seen. gl, Glycogen granules; d, desmosome. (Uranyl acetate-lead citrate stain; original magnification, X57,500; inset, X50,000.)

Fig. 8. Electron micrographs of large, luminal structures in tumor cell nests. Some cells surrounding the lumina (L) contain a large number of tonofilaments (Tf). At luminal surface, microvilli exist and swollen cytoplasmic protrusions undergoing decapitation (*)

are seen. Short arrows (inset) show residual portion of demarcation membrane by decapitation. d, Desmosome; L, lumen; arrowheads, secretory granules; IOllg arrows, broken sites of cell membrane; stars, amorphous substance. (Uranyl acetate-lead citrate stain; original magnification: right, Xl 0,000; left, x 13,700; inset, X50,000.) stance were sparsely distributed in the stromal space (Fig. 10). DISCUSSION Apocrine tumors are rare; however, several varieties of apocrine tumors have been described:

apocrine cystadenoma,13 hidradenoma papilliferum,1 syringocystadenoma papilliferum,1 adenocarcinoma of apocrine glands,14 and tubular apocrine adenoma. 15 The apocrine differentiation of the tumor in our patient is histochemically and ultrastructurally evident. However, the histologic

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Fig. 9. Electron micrograph of myoepithelium-like cells at periphery of tumor cell nest. Myoepithelium-like cell (ME) possesses both tonofilaments (Tf) and myofilaments with focal high densities (arrowheads), desmosomes (d) with dark cell (D), and other tumor cells. Myofibroblasts (MF), which do not possess any connection with tumor cells or with myoepithelium-like cells, are seen in stroma surrounding tumor nest. (Uranyl acetatelead citrate stain; original magnification, X 17,000.)

findings of this tumor seem to differ from both the benign and malignant types of these apocrine tumors reported,1,13-15 since the tumor in our patient is composed mainly of basaloid cell nests and has a behavior similar to that of basal cell epithelioma. Since this tumor is localized in the retroauricular region, ceruminoma16 ,17 and parotid gland tumors are also important in differential diagnosis. Ceruminoma originates from ceruminous glands, which are modified apocrine glands in the external ear canal and may histologically represent an apocrine feature. 16 ,17 However, both ceruminoma and parotid gland tumors can be excluded from the diagnosis in this case, because both the ceruminous and parotid glands histologically remain intact, and the origin of our patient's tumor is the epidermis of the retroauricular skin. On the basis of biologic behavior, malignant skin tumors have been categorized into two main groupS2: a group with individual cell metastasis and a group with aggressive local invasion but no metastasis. Basal cell epithelioma is one of the latter group. Histologically, basal cell epithelioma has been divided into two groupSl: (1) undifferentiated and (2) differentiated to the epidermal appendages, that is, hair follicle, sebaceous glands, and sweat glands. In 1969, Freeman and Winkel-

mann l8 described a skin tumor with a differentiation to eccrine glands and a behavior similar to that of basal cell epithelioma. Later, Sanchez and Winkelmann 3 performed a retrospective survey of ten cases of skin epithelial tumors with eccrine differentiation. They suggested a new entity of basal cell neoplasm and proposed the term "eccrine epithelioma." Basal cell epithelioma with apocrine differentiation, however, has not been reported so far. Eccrine epithelioma is characterizeci histologically by syringoid or morphea-like features. 3,18 There are some similarities between our patient's tumor and eccrine epithelioma,3,18 for example, the basaloid epithelial nests and fibrous stroma. However, our patient's tumor has different epithelial components from those of eccrine epithelioma; eccrine epithelioma shows a tendency to form syringoid nests,3,18 whereas our patient's tumor reveals a round or alveolar shape of epithelial nests, as well as the presence of luminal cells with decapitation. Therefore the term "basal cell tumor with apocrine differentiation (apocrine epithelioma)" seems to be appropriate. In the normal apocrine glands, Hashimoto et a1 11 observed two types of secretory granules: small granules with a light, uniform. density, be-

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Fig. 10. Electron micrographs of myofibroblasts in stroma. Myofibroblasts (MF) have no connection with each other or with tumor cells (T) . Notice hemidesmosome-like structures (arrowheads in inset) and sparse young collagen fibrils with an amorphous substance in stroma (*). (Uranyl acetate-lead citrate stain; original magnification, X 8,800; inset,

X20,240.)

lieved to be modified mitochondria, and large granules varying in size and density and with some features of lysosomes. Hibbs l9 suggested that the apocrine secretory granules were formed in the Golgi cell area and had characteristics of lysosome, including vesicular content, myelin bodies, and crystals. The secretory granules observed in our patient's tumor seem to be comparable with those in Hibb's report. 19 The elongated cells at the periphery of the epithelial nest in our patient's tumor are similar to the myoepithelial cells seen in normal sweat glands,12 nonnal mammary glands,20 or apocrine cystadenoma. 13 Since they have both myofilaments and tonofilaments, they may be called "indeterminate cells "20 or "intermediate cells, "21 meaning transitional forms between myoepithelial and epithelial cells. The presence of these myoepitheliumlike cells strongly suggests a differentiation to sweat glands, including apocrine glands, of our patient's tumor. In the stroma surrounding epithelial nests of our patient's tumor, we observed the myofibroblasts with the ultrastructural features of both fibroblasts

and smooth muscle cells. The correlation of the myoepithelium-like cells to the stromal myofibroblasts is unclear in this report. However, since the myofibroblasts are also observed in various conditions22 and have no cell-ta-cell contact as shown in our report, the myoepithelial cells might not originate from the stromal myofibroblasts but from epithelial tumor cells. REFERENCES I. Lever WF, Schaumburg-Lever 0: Histopathology of the skin, ed. 6. Philadelphia, 1983, J. B. Lippincott Co., pp. 522-575. 2. Pinkus H, Mehregan AH: A guide to dermatohistopathology, ed. 3. New York, 1981, Appleton-Century-Crofts, pp. 457-468. 3. Sanchez NP, Winkelmann RK: Basal cell tumor with eccrine differentiation (eccrine epithelioma). JAM ACAD DERMAToL 6:514-518, 1982. 4. Nachlas MM, Walker DO, Seligman AM: A histochemical method for the demonstration of diphosphopyridine nucleotide diaphorase. J Biophys Biochem Cyto] 4:2938, 1958. 5. Gomod G: Microscopic histochemistry, principles and practice. Chicago, 1952, The University of Chicago Press, p. 189. 6. Takamatsu H: Histologische und biochemische Studien tiber die Phosphatase (1. Mitteilung). Histochemisch Un-

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7. 8.

9. 10. II. 12. 13.

tersuchungsmethodik der Phosphatase und deren Verteilung in verschiedenen Organen und Geweben. Trans Soc Pathol Jpn 29:492-498, 1939. Takeuchi T, Kuriaki H: Histochemical detection of phosphorylase in animal tissues. J Histochem Cytochem 3:153-160,1955. Seligman AM, Tsou KC, Rutenburg SH, Cohen RB: Histochemical demonstration of ,B-D-glucuronidase with a synthetic substrate. J Histochem Cytochem 2:209-229, 1954. Reynolds ES: The use of lead citrate at high pH as an electronopaque stain in electron microscopy. J Cell BioI 17:208-212,1963. Hashimoto K, Lever WF: Histogenesis of skin appendage tumors. Arch DermatollOO:356-369, 1969. Hashimoto K, Gross BG, Lever WF: Electron microscopic study of apocrine secretion. J Invest Dermatol 46:378-390, 1966. Kurosumi K, Kitamura T, Iijima T: Electron microscope studies on the human axillary apocrine sweat glands. Arch Histol Jpn 16:523-566, 1959. Hassen MO, Khan MA, Kruse TV: Apocrine cystadenoma. Arch Dermatol 115:194-200, 1979.

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14. Warkel RL, Helwig EB: Apocrine gland adenoma and adenocarcinoma of the axilla. Arch Dermatol 114: 198203,1978. 15. Landry M, Winkelmann RK: An unusual tubular apocrine adenoma. Arch Dermatol 105:869-879, 1972. 16. Neldner KH: Ceruminoma. Arch Dermatol 98:344-348, 1968. 17. Cankar V, Crowley H: Tumors of ceruminous glands: A clinicopathological study of 7 cases. Cancer 17:67-75, 1964. 18. Freeman RG, Winkelmann RK: Basal cell tumor with eccrine differentiation (eccrine epithelioma). Arch Dermatoll00:234-242, 1969. 19. Hibbs RG: Electron microscopy of human apocrine sweat glands. J Invest Dermatol 38:77-84, 1962. 20. Ozzello L: Ultrastructure of the human mammary gland. Pathol Annu 6:1-59, 1971. 21. Hibbs RG: The fine structure of human eccrine sweat glands. Am J Anat 103:201-217, 1958. 22. Bhawan J: The myofibroblast. Am J Dermatopathol 3:73"78, 1981.

Metastatic cutaneous carcinoid C. B. Archer, M.R.C.P., R. S. Wells, F.R.C.P., and D. M. MacDonald, F.R.C.P. London, England A case of malignant bronchial carcinoid with multiple cutaneous metastases is reported. Despite the extremely aggressive behavior of the disease and the presence of multiple hepatic metastases, the patient did not exhibit the usual clinical features of the carcinoid syndrome. The relevance of the finding of elevated 24-hour urinary vanillylmandelic acid levels in patients with carcinoid tumors is discussed. (J AM ACAD DERMATOL 13:363-366, 1985.)

The cutaneous manifestations of the carcinoid syndrome, including episodic flushing of the skin, patchy cyanosis, telangiectasia, and pellagra-like skin lesions, often dominate the clinical picture in patients with carcinoid tumors. 1 Although rare, malignant carcinoid tumors may metastasize to the From the Department of Dermatology, Guy's Hospital. Reprint requests to: Dr. D. M. MacDonald, Department of Dermatology, Guy's Hospital, St. Thomas' St., London, SEI 9RT, England.

skin. We report an unusual case of malignant bronchial carcinoid with multiple cutaneous deposits in a patient in whom there were no clinical features of the carcinoid syndrome.

CASE REPORT A 68-year-old man complained of numerous subcutaneous lumps, the first of which had appeared 1 year previously on the anterior aspect of the neck. During the previous 6 months this lesion had become painful, with erosion of the overlying skin, and tender, smaller

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