Syringomas

Context.-Chondroid syringoma (CS) is a benign cutaneous adnexal tumor with epithelial and stromal components. Epithelial components derived from folliculo-sebaceous-apocrine germ are evident in apocrine but not in eccrine CS.

Objectives.-To further characterize pilosebaceous differentiation and to identify the presence of Merkel cells in the areas of follicular differentiation.

Design.-Histologie type, folliculo-sebaceous differentiation, character of stroma, and presence or absence of Merkel cells by cytokeratin (CK) 20 immunoreactivity were evaluated in 25 CSs (22 apocrine and 3 eccrine) from the surgical pathology files of Henry Ford Hospital (Detroit, Mich).

Results.-Most CSs occurred in the head and neck region of patients aged 40 years or older. We found no significant difference in sex, age, or location between apocrine and eccrine types. The stroma varied from myxoid (100%) to chondroid (59%), with various amounts of fat (59%) and ossification identified in 2 cases (9%) of apocrine type, but was homogeneously myxoid in the eccrine type. Follicular and sebaceous differentiation was found in 64% and 32% of apocrine CSs, respectively. Only 2 (14%) apocrine CSs with follicular differentiation were positive for CK20 (a few scattered cells in one case and numerous grouped cells in the other in association with follicular epithelium). No correlation was found between type of stroma and the presence of Merkel cells. Scattered Merkel cells were identified in 83% of normal hair follicles and in 33.3% of normal epidermis.

Conclusion.-A high proportion of apocrine CSs show folliculo-sebaceous differentiation. The presence of Merkel cells in foci of follicular differentiation of CS supports the hypothesis that Merkel cells may be an integral constituent of follicles. To our knowledge, the presence of Merkel cells in CS, particularly in proliferative form, has not been described previously in the literature.

(Arch Pathol Lab Med. 2004;128:986-990)

Mixed tumors of skin are composed of both epithelial and mesenchymal components and are histologically similar to benign mixed tumors of salivary glands.1-3 The first case is believed to have been reported by Nasse in 1892.3,4 In 1961, Hirsch and Helwig5 reported a large series in which they coined the term chondroid syringoma (CS) for these tumors, owing to the presence of a sweat gland-like epithelial component and frequent cartilaginous-like stroma. In the same year, Headington3 recognized 2 types, apocrine and eccrine. The apocrine type demonstrates irregular branching tubules (rubulocystic pattern) lined by at least 2-cell-thick epithelium. The eccrine type is characterized by rather uniform, small, round tubules that are evenly spaced within a myxoid-chondroid matrix.

Clinically, CSs are relatively uncommon tumors.6 Most are benign, but they may recur when not excised completely. Several cases of malignant CS with metastasis have been reported.2,7-10

Histologically, these tumors demonstrate a wide spectrum of changes. In addition to the tubules, the epithelial cells may also form nests, cords, single cells, micropapillae, and keratinous cysts. The stroma is usually fibrous and demonstrates frequent myxochondroid changes. In addition to apocrine and eccrine features, these tumors can have folliculo-sebaceous differentiation, particularly in the apocrine variety. This divergent differentiation in CS has been mentioned briefly in earlier reports by Requena et al11 and Rodriguez-Diaz and Armijo.12 The purpose of this study is to further appraise the morphologic spectrum of CS in a larger series with particular reference to pilosebaceous differentiation and clinicopathologic correlation. Owing to the frequent occurrence of hair follicle differentiation, we have performed immunostaining with cytokeratin (CK) 20 for identification of Merkel cells to examine the possibility that they also represent an integral part of follicular differentiation in CS.

MATERIALS AND METHODS

Twenty-five cases of CS were retrieved from the surgical pathology files at Henry Ford Hospital (Detroit, Mich) during the years 1985-1997. Clinical information obtained from the electronic medical records on all cases included age, sex, location, size, and clinical follow-up. Hematoxylin-eosin-stained sections were available for the study in all 25 cases. Sections mounted on sialinized slides using formalin-fixed, paraffin-embedded tissues were used for anti-CK20 immunostaining (Dako Corporation, Carpinteria, Calif) with a Dako autostainer. After drying and deparaffinization, endogenous peroxidase activity was blocked by treatment with 3% hydrogen peroxide. Proteinase K enzyme digestion was used for 10 minutes. All cases and positive controls were incubated in diluted (1:300) CK20 antibodies for 30 minutes at room temperature. Negative controls were incubated for the same period of time in tris-buffered saline (Dako). Slides were further incubated in labeled streptavidin-biotin plus kit (Dako) followed by a high-sensitivity substrate chromogen system (AEC). All slides were counterstained in Mayer hematoxylin, washed in running tap water for 20 minutes, and cover-slipped with liquefied glycerol-gelatin. The presence and pattern of immunoreactivity was noted.

Presence of 2-cell-thick lining epithelium with decapitation secretions was considered minimal criteria for apocrine differentiation. Follicular differentiation was determined by the presence of hair follicle germ, which was often associated with mesenchymal cells of follicular papillae or other mature follicular structures. Mature sebaceous cells, located in the epithelial tracts, were recognized by a vacuolated cytoplasm and scalloped nuclear border. No reliable histologic criteria for eccrine differentiation were available, but we adopted the criteria for eccrine mixed tumor used by Headington.3

RESULTS

Mean patient age was 55 years (range, 35-88 years), and we found no evidence of sex predilection (14 males, 11 females). Median size was 0.5 cm (range, 0.3-0.9 cm). There was a predilection for the head and neck region (64%). Twenty-two cases were apocrine type (Figure 1, A), characterized by branching tubular lumina (Figure 2, A) lined by at least 2-cell-thick epithelium with apical snouts (Figure 2, B) and cytoplasmic granules (Figure 3, A). Only 3 cases showed eccrine differentiation (Figure 1, B). Apocrine CSs showed follicular and sebaceous differentiation in 64% and 32% of cases, respectively (Figure 3, B and C). Sebaceous differentiation was focal and subtle. Hyaline cells with intracytoplasmic eosinophilic inclusions representing myoepithelial differentiation in association with branching tubular structures were noticed in 8 apocrine CSs (Figure 3, D). Collagenous spherules were identified in 2 apocrine CSs.

Apocrine lesions contained myxoid stroma (100%), chondroid stroma (59%), and ossification in only 2 cases (9%) (Figure 4, A). Twelve apocrine CSs showed focal areas of scattered adipocytes in the stroma, particularly around the myxoid areas, and 1 case had aggregates of adipocytes (Figure 4, B). None of these cases showed replacement of the stroma by adipocytes. All eccrine CSs were negative for adipocytes. None of the 3 eccrine CS cases showed apical snouts, pilosebaceous differentiation, hyaline cells, or chondroid stroma.

Only 1 case, which was from the eyebrow and which had multifocal positive margins in the initial specimen, recurred after 4 years. All other tumors were enucleated and no recurrence was encountered.

Normal overlying epidermis was seen in 12 cases of apocrine CS. Scattered Merkel cells were identified in normal hair follicles of 10 cases (83%) and in the basal layer of epidermis of 4 cases (33%) by CK20 immunostains. Only 2 apocrine CS specimens (14%) with follicular differentiation were positive for CK20, one case with a few scattered positive cells and the other with numerous positive cells, particularly in the areas of follicular differentiation (Figure 5). No correlation was found between types of stroma and the presence of Merkel cells.

COMMENT

Chondroid syringomas or mixed tumors of the skin are relatively rare cutaneous tumors, which usually arise in middle age with a predilection for the head and neck region. Clinically, CSs present as a slow-growing, nontender, firm, dermal or subcutaneous nodule or papule.13 It is usually adherent to the overlying epidermis with no fixation to the underlying fascia, which may be responsible for the common preoperative diagnosis of cyst. Most of the reported series showed a 2-3:1 male-female ratio, but Hirsch and Helwig5 reported a male-female ratio of 5:1. No sex predilection was identified in this series.

The hallmark of these biphasic tumors is the spectrum of histologie changes, which is manifest by both epithelial and mesenchymal components. Myxoid change in the stroma was identified in all tumors, while chondroid change was recognized in 59% of cases. It would appear that the designated name of chondroid syringoma calls attention to an inconsistent histologic feature. Adipocytes are common constituents of the stroma, as seen in 59% of our apocrine CSs, but none of our cases showed extensive adipose contents, as described by Ohata and Hanada.14

The epithelial component of apocrine CS may manifest a spectrum of adnexal differentiation, including apocrine, follicular, and sebaceous types, while eccrine CSs lack other components. In 1952, Lennox et alls suggested that mixed tumors may represent a variant of hydradenoma with mucinous metaplasia. Headington3 later classified these lesions into 2 types, apocrine and eccrine. Subsequent ultrastructural and immunohistochemical studies have favored an eccrine origin for these tumors16; however, after a period of controversy, most authors now agree that most of these tumors show apocrine differentiation. This contention is further supported by the frequent occurrence of folliculo-sebaceous differentiation in apocrine CS. Requena et al11 reported 8 cases of apocrine CS, all with evidence of follicular differentiation. Rodriguez-Diaz and Armijo12 reported 45% of 20 cases with follicular differentiation. In this study, we identified a slightly higher incidence of follicular differentiation (64%) in apocrine CSs. The follicular differentiation ranges from focal to widespread, with easily recognizable areas reminiscent of both infundibular and inferior segment of hair follicle. Sebaceous cells with abundant vacuolated cytoplasm and small nuclei with scalloped borders were focally present in the epithelial cords and tracts in association with follicular differentiation in 7 apocrine CSs (32%). Hyaline cells with pinkish, glassy cytoplasm with intracytoplasmic eosinophilic inclusions were found in 8 cases and represent myoepithelial differentiation in association with a tubuloglandular component.

Merkel cells are found in adult epidermis and in the outer sheath of hair follicles. Cytokeratin 20 is a useful marker for highlighting both normal and neoplastic Merkel cells.17,18 Schultz and Hartschuh19-21 reported Merkel cells in other adnexal tumors, but to the best of our knowledge, this is the first report to study Merkel cells in CS. In our study, overlying epidermis was normal in 12 CSs. Scattered Merkel cells were identified in normal hair follicle and epidermis of 83% and 33% of cases, respectively. Only 2 apocrine CSs with follicular differentiation were positive for CK20, one case with a few immunoreactive cells and the other with numerous positive cells.

The presence of Merkel cells with evidence of Merkel cell proliferation in foci of follicular differentiation of CS supports the hypothesis that Merkel cells may be an integral constituent of follicles, as tumor cells have a divergent phenotypic expression of folliculo-sebaceous-apocrine germ. Presence of Merkel cells is known also in benign tumors with follicular differentiation, but is extremely rare in malignant tumors with possible follicular differentiation, such as basal cell carcinoma.19-22 The lack of consistent expression of Merkel cells in CS with follicular differentiation correlates with distribution of Merkel cells in only certain segments of the hair follicles. None of the eccrine tumors showed hyaline cells, folliculo-sebaceous differentiation, or Merkel cells.

In conclusion, both apocrine and eccrine tumors may be associated with myxochondroid stroma and are designated as apocrine and eccrine CS, respectively. Apocrine CS is more common than eccrine CS and is not restricted to any specific site of origin. Apocrine CS shows folliculo-sebaceous differentiation, sharing the same folliculo-sebaceous-apocrine germ origin. Identification of Merkel cells as a proliferative form in apocrine CS may support the derivation of Merkel cells from folliculo-sebaceous-apocrine germ or their precursor cells, although the origin of Merkel cells (cells with neuroendocrine differentiation) in the skin is not limited to follicular germ. The clinical significance of the presence of Merkel cells in apocrine CS is not known, but one may speculate that CS potentially can give rise to a Merkel cell neoplasm.

References

1. Mills SE. Mixed tumor of the skin: a model of divergent differentiation. J Cutan Pathol. 1984;11:382-386.

2. Harrist TJ, Aretz TH, Mihm MC Jr, Evans GW, Rodriquez FL. Cutaneous malignant mixed tumor. Arch Dermatol. 1981;117:719-724.

3. Headington JT. Mixed tumors of skin: eccrine and apocrine types. Arch Dermatol. 1961;84:989-996.

4. Nasse D. Die Geschwülste der Speicheldrüsen und verwandte Tumoren des Kopfes. Arch Klin Chir. 1892:44:233-302.

5. Hirsch P, Helwig EB. Chondroid syringoma: mixed tumor of skin, salivary gland type. Arch Dermatol. 1961;84:835-847.

6. Yavuzer R, Basterzi Y, Sari A, Bir F, Sezer C. Chondroid syringoma: a diagnosis more frequent than expected. Dermatol Surg. 2003;29:179-181.

7. Redono C, Rocamora A, Villoria F, Garcia M. Malignant mixed tumor of the skin: malignant chondroid syringoma. Cancer. 1982;49:1690-1696.

8. Shvili D, Rothem A. Fulminant metastasizing chondroid syringoma of the skin. Am J Dermatopathol. 1986;8:321-325.

9. Trown K, Heenan PJ. Malignant mixed tumor of the skin (malignant chondroid syringoma). Pathology. 1994;26:237-243.

10. Tsoitis G, Papdimitriou C, Kanitakis J, et al. Malignant cutaneous mixed tumor [abstract]. Am J Dermatopathol. 2000;22:347.

11. Requena L, Sanchez Yus E, Santa Cruz DJ. Apocrine type of cutaneous mixed tumor with follicular and sebaceous differentiation. Am J Dermatopathol. 1992;14:186-194.

12. Rodriguez-Diaz E, Armijo M. Mixed tumors with follicular differentiation: complex neoplasms of the primary epithelial germ. Int J Dermatol. 1995;34:782-785.

13. Chen AH, Moreno EH, Houston B, Funk GF. Chondroid syringoma of the head and neck: clinical management and literature review. Ear Nose Throat J. 1996;75:104-108.

14. Ohata C, Hanada M. Lipomatous apocrine mixed tumor of the skin. Am J Dermatopathol. 2003:25:138-141.

15. Lennox B, Pearse AGE, Richards HC. Mucin-secreting tumors of the skin: with special reference to the so-called mixed-salivary tumor of the skin and its relation to hidradenoma. J Pathol Bacteriol. 1952;64:865-880.

16. Terui T, Obata M, Tagami H. Immunohistochemical studies on epithelial cells in mixed tumor of the skin. J Cutan Pathol. 1986;13:197-206.

17. Moll I, Kuhn C, Moll R. Cytokeratin 20 is a general marker of cutaneous Merkel cells while certain neuronal proteins are absent. J Invest Dermatol. 1995; 104:910-915.

18. Scott MP, Helm KF. Cytokeratin 20: a marker for diagnosing Merkel cell carcinoma. Am J Dermatopathol. 1999;21:16-20.

19. Hartschuh W, Schulz T. Immunohistochemical investigation of the different developmental stages of trichofolliculoma with special reference to the Merkel cell. Am J Dermatopathol. 1999;21:8-15.

20. Schulz T, Hartschuh W. Merkel cells in nevus sebaceus: an immunohistochemical study. Am J Dermatopathol. 1995;17:570-579.

21. Hartschuh W, Schulz T. Merkel cells are integral constituents of desmoplastic trichoepithelioma: an immunohistochemical and electron microscopic study. J Cutan Pathol. 1995;22:413-421.

22. Schulz T, Hartschuh W. Merkel cells are absent in basal cell carcinomas but frequently found in trichoblastomas: an immunohistochemical study. J Cutan Pathol. 1997;24:14-24.

Mohamed E. Salama, MD; Muhammad Azam, MD; Chan K. Ma, MD; Adrian Ormsby, MBChB; Richard J. Zarbo, MD, DMD; Mahul B. Amin, MD; Min W. Lee, MD

Accepted for publication April 30, 2004.

From the Departments of Pathology, Henry Ford Hospital, Detroit, Mich (Drs Salama, Ma, Ormsby, Zarbo, and Lee), North Ottawa Community Hospital, Grand Haven, Mich (Dr Azam), and Emory University, Atlanta, Ca (Dr Amin).

Presented in part at the 35th Annual Meeting ot the American Society of Dermatopathology, Denver, Colo, October 29-November 1, 1998.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Min W. Lee, MD, Department of Pathology, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, Ml 48202 (e-mail: mlee3@ hfhs.org).

Copyright College of American Pathologists Sep 2004
Provided by ProQuest Information and Learning Company. All rights Reserved