Histopathology 1990. 17, 3 1 1 - 3 1 7

Chondroid syringoma: a histological and immunohistochemical study of 1 5 cases F.DOMINGUEZ IGLESIAS, F.FRESN0 FORCELLEDO, T.SOLER SANCHEZ, L.FERNANDEZ GARCIA & A.HERRER0 ZAPATERO Department of Pathology, Hospital Nuestra Senora de Covadonga, Oviedo. Spain Date of submission 6 December 1989 Accepted for publication 9 March 1990

D O M I N G U E Z I G L E S I A S F . , F R E S N O FORCELLEDO F . . S O L E R S A N C H E Z T . , F E R N A N D E Z G A R C ~ AL . & H E R R E R O ZAPATERO A .

(1990)Histopathology 17, 3 1 1 - 3 1 7

Chondroid syringoma: a histological and immunohistochemical study of 1 5 cases Fifteen cases of chondroid syringoma have been studied histologically and by immunohistochemical methods in an attempt to establish their phenotypic profile and to elucidate their histogenesis. The epithelial elements were classified as tubuloglandular, solid nests and stromal cells. The inner cell layers of tubuloglandular components had distinct epithelial features, expressing cytokeratin, carcino-embryonic antigen and epithelial membrane antigen. The outer cell layers expressed

vimentin, S- 100 protein, neuron-specific enolase and muscle-specific actin and were negative for epithelial markers. The immunophenotypes of stromal cells and solid nests were similar to those of the outer cell layers. These data suggest that the stromal components may derive from the outer cell of tubuloglandular elements and that myo-epithelial cells have an important role in the histogenesis of these lesions and in their mesenchyma1 matrix production.

Keywords: chondroid syringoma. mixed tumour of skin, immunochemistry, histogenesis

Introduction The chondroid syringoma, or mixed tumour of the skin, is a benign, relatively rare. cutaneous or subcutaneous tumour which presents a characteristic histological appearance, has the ability to form pseudo-adnexal structures similar to sweat glands and produces a chondroid matrix'. Its histological, immunohistological and ultrastructural appearances are comparable to those of mixed salivary gland turn our^^,^. The histogenesis of chondroid syringoma is controversial. Simard proposed that they originated in sweat glands4 and this is now generally accepted. Headington' suggested both an origin which was apocrine and eccrine. However, the most interesting aspects of the tumour lie in its mixed nature, with both epithelial and mesenchymal components present, and in the role played by the myoepithelial cells in the secretory segment of sweat glands in the histogenesis of the mesenchymal components'. The histogenesis of these tumours has recently been studied, not only by light and Address for correspondence: Dr FDominguez Iglesias. Department of Pathology. Hospital Nuestra Seiiora de Covadonga. CICelestino Villamil s/n, Oviedo. 3 3 006 Spain.

electronmicroscopy, but also h i ~ t o c h e m i c a l l y ~ ~ ~ - ~ ~ . However, with the exception of the report of Argenyi and his colleagues"', these studies comprise small numbers, often using only a limited battery of antibodies. In this study of 18 cases of chondroid syringoma, detailed and extensive histochemical investigations were carried out on 15. The immunotypic profiles of the different components were determined in a n attempt to analyse the role of the myoepithelial cell in the histogenesis of the tumour.

Materials and methods The 1 8 cases, subject to biopsy between 1975 and 1988, were selected from the records of the pathologic anatomy department. The formalin-fixed, paraffin-embedded tissues were processed for routine light microscopic examination and stained with hematoxylin and eosin. An imrnunohistochemical study was carried out on 1 5 cases. The tissue blocks were deparaffinized. rehydrated and rinsed in phosphate-buffered saline (PBS) for 5 min and stained by the avidin-biotin complex technique (ABC)" at room temperature as follows: incubation for 3 0 min in 0 . 3 % (w/v) HlOL in methanol was followed by 311

3 12

F.Dominguez lglesias et al.

a 2 0 min rinse in PBS and incubation with 4% (v/v) normal goat serum in PBS (for rabbit polyclonal antibodies) or 4% (v/v) normal horse serum in PBS (for mouse monoclonal antibodies). The sections were then incubated with primary antibodies (Table 1) for 60 min Table 1 . Monoclonal and 'polyclonal antibodies used in the present study

Source Tytokeratin-CK (AEI 1 3 ) Vinicn ti ti-Vim *Glial librillary acidic protein-GFAP I)esmiti-Des Epithelial membrane antigen-EMA 'C'arcino-embryonic antigen-CEA "S- 100 protein Neuron-specific enolase-NSE Muscle-specific actin-MSA

Dako Dako Ortho Biogenix Dako Dako Dako Biogenix Dako

at room temperature, rinsed twice for 5 min with PBS. incubated for 30 min with biotinylated secondary antibody and again rinsed twice in PBS. The avidinbiotin-peroxidase complex was incubated with the sections for 60 min. After rinsing with PBS, sections were incubated with diaminobenzidine (l)AH)-H20? chromogen diluted in Tris buffer. Sections were counterstained with Mayer's hematoxylin. dehydrated and mounted. Trypsinization was performed with 0.57(, w/v solution of type I11 trypsin in Tris buffer for 30 min before reactions using anti-keratin and anti-desmin antibodies. Appropriate negative and positive controls were used.

Results Histologically. all the tuniours were composed of epithelial cells, forming tubuloglandular structures or solid nests in a variable mesenrhymal. myxoid or chondroid background, admixed with other stromal elements (Figure l a ) . The tubuloglandular components in 1 7

Figure 1 a. Typical L.hondroid syringoma with tubuloglandular components embedded in a partially hyalinized fibrous stronia with chondrciid matrix. H & E. h. Darker staining cells (inner row) and 'clear' cells in this ultra-thin section stained with toluidine bluc. a x 44 h x 4.kO.

3 13

Clionrlroid syririgorrirr

cases were lined by two rows of epithelial cells. showing a clear distinction between the inner and outer cell layers (Figure l b ) . In one case ductal structures with small lumens were present, lined only by a single cell layer. In all the cases. nests of polygonal epithelial cells, arranged compactly or loosely, were found. Horn cysts were observed in seven cases. There were two types of mesenchymal matrix: myxoid matrix. seen in all 18 cases; and chondroid matrix, seen in 1 3 . Areas with intermediate features were also noted in all cases. Adipose tissue was observed in three cases and hyaline tissue in two. I M M 11N 0 kI I STOC 13 E M I STR Y

Three cellular components were studied: the tubuloglandular structures with their inner and outer cell layers, the solid nests ofepithelial cells and the stromal cells. The findings are summarized in Table 2. Tubtrlonltrrinulnrstrwturr's The inner cell layer was strongly positive for cytokeratin. epithelial membrane antigen ( E M A ) and carcinoembryonic antigen (CEA) in all cases (Figure 2): in one case this layer reacted positively for vimentin. The outer cell layer was strongly positive for vimentin, S - I 0 0 protein and neuron-specific enolase (NSE) in all cases and for muscle-specific actin in nine cases (Figure 3 ) : in three cases these cells were positive for cytokeratin. Solid nests These were strongly positive for S-1 00 protein in 1 2 of the 1 5 cases. for NSE in six and muscle-specific actin in four. St ror i i d C ~ E S These were strongly positive for vimentin and S-100 protein in all cases. for NSE in 12 and for muscle-specitic actin in four.

Discussion Chondroid syringoma is a rare cutaneous tumour which arises mainly on the face and neck of middle-aged adults. Generally it has a benign behaviour and rarely recurs. However. some cases of malignant tumours have been reported",' 3. Chondroid syringoma was suggested as a specific descriptive term for these tumours. acknowledging that the chondroid matrix originates from the epithelial cells of the tumour'. As the term syringoma denotes. it has been suggested that the tumour is derived from the sweat glands4. However, there is argument as to whether the tumour is derived from eccrine or apocrine glands. Headington proposed two entities, an apocrine type and an eccrine type. The former are generally more common, characterized by tumour and cystic structures covered by two rows of epithelial cells: the eccrine type presents smaller lumens lined by a single row of cells. Recent immunohistochemical studies on gross cystic disease h i d protein seem to endorse the apocrine origin of the majority of c a s e ~ 'Nevertheless, ~. the histogenesis of the tumour continues to be debated, particularly the origin of the mesenchymal component. Most authors suggest a myoepithelial origin for the mesenchymal component, by analogy with mixed tumours of salivary ". Myoepithelial cells are found in numerous human and animal tissues: major and minor salivary glands. the secretory portion of the sweat glands. surrounding ducts in the mammary glands and Bartholin glands and the mucosecretory glands of trachea and oesophagus, as well as in the prostate and lachrymal glands'". These cells appear to be of ectodermal origin and epithelial in nature, suggesting that the tubular terminal epithelial cell could serve as the stem or precursor cell" ". Certain intermediate cytoplasmatic filaments such as cytokeratin and vimentin. muscle-related proteins such as actin and myosin and other proteins such as S-100 protein.

Table 2. Immunohistochemical results in 1 5 cases of chondroid syringoma

Tubu loglandular structures outer cells inner cells

Solid nests Stromal cells

15 1

L(w)

15 lO(Wl

lO(W)

4(w) 41Wl

3

w = weak and variable staining * For abbreviations see 'Table 1.

%wl

15

0

(1 0 2(w) 2(Wl

15

15

0 0

0

15 3(w) 12

0

15

0

I(Wl

15 2(w) 6 12

9

I(w) 4 4

3 14 F . Dominguez lglesias et al.

Figure 2. Tubuloglandular structures: a positive staining for keratin confined to inner cell layer: b positive staining for carcino-embryonic antigen delineating the luminal surface and the intraluminal secretion: c epithelial membrane antigen positivity, also confined to the surface of the inner cell layer.

I

Figure 3 . Tubuloglandular structures: positive staining for a virnentin. b S- 1 0 0 protein. c neuron-specific enolase and d muscle-specific actin confined to the outer cell layer.

3 16 F . Dorninguez lglesias et al.

NSE and al-antitrypsin, have been detected immunohistochemically in the myoepithelial cells of the salivary gland, as well as in pleomorphic adenomas''-22 and in chondroid s y r i n g ~ m a s ~ ~ ~Therefore, -"'. although the localization and type of cell responsible for the mesenchymal component of chondroid syringomas has yet to be established, the myoepithelial cell is a potential candiate-as is the case with mixed tumours of the salivary glands. Such tumours could arise from modified or previously differentiated myoepithelial cells, or possibly from secretory or ductal epithelial cells with the potential to differentiate in various patterns and eventually produce mesenchymal elements by metaplasia'. In this connection a series of interesting conclusions can be drawn from our study. The immunophenotypes of the inner and outer cell layer of the tubuloglandular component are clearly different. The inner cells showed cytokeratin, EMA and CEA reactivity, indicating an epithelial phenotype, whereas the outer cells expressed vimentin, S-100 protein, NSE and muscle-specific actin. These results agree with previous studies on pleomorphic adenomas of the salivary glanddl and are similar to previous reports on chondroid syringoma'-"'. Argenyi and his colleagues"' have suggested that the outer cell layer may contain cytokeratins, although probably of very low molecular weight (40-46 kD) and characteristic of a simple epithelium". This has been corroborated by positive reactions in these cells when a wide spectrum antibody (40-46 kD) was used. The co-expression of cytokeratin and vimentin in the same tumour and even in the same cell has already been documented in pleomorphic adenomas and other neoplasias" 24; positivity for CEA and EMA in the ductal eccrine and apocrine secretory cells is also well-established25~'h.In chondroid syringomas positivity for these antigens is confined to the secretory pole of epithelial cells which form the inner cell layer, while the outer cell layer and the stromal cell were negative. Other workers have also shown the myoepithelial cells of the salivary gland to be negative27. These observations support the theory of a dual differentiation in chondroid syringomas with double cellular components. In our study the immunophenotype of the stromal cells was similar to that of the outer cell layer, with expression of vimentin, $100 protein, NSE and musclespecific actin. The solid nests did not show any uniform staining pattern but the results were, for the most part, similar to those seen in stromal cells, showing variable expression of cytokeratin. Argeyi et al.lo obtained negative results for muscle-specific antigen for all components of the tumour in their 1 2 cases. In contrast, we, and others', clearly demonstrated the expression of muscle-specific actin in the outer cells of the tubulo-

glandular components, as well as in the solid nests and stromal cells in the myxomatous and chondroid areas. We can offer no obvious explanation for this discrepancy, but it requires further study. Other related muscle filaments or proteins such as desmin or myoglobin have been studied in both pleomorphic adenomas and chondroid syringomas'.' 0.20. The simultaneous co-expression of intermediate tilaments and other antigens in the outer cells of the tubuloglandular component and in the stromal cells or solid nests supports the hypothesis that the outer cells may be responsible for the production of the mesenchyma1 component. Finally, it seems to us that the myoepithelial cells, present in the secretory segment of the normal sweat gland, play an important role in the histogenesis of these tumours and could be responsible for the production of the myxoid and chondroid matrix.

References 1. Hirsch P, Helwig EB. Chondroid syringoma. Arch. Dmricitol. 196 1 : 84: 835-847. 2. Yoneda K. Kitajirna Y, Furuta H. Tsuneda Y. Mori S . The distribution of keratin type intermediate lilanients in so-called mixed tumour of the skin. Br. /. Derrnatul. 198 3 ; 109; 393-400. 3. Varela-Duran JV. Diax-Flores LD. Varela-Nunex KV. llltrastructure ofchondroid syringorna. Role of the myoepithelial cells in the development of the mixed tumor of the skin and soft tissues. C m c r r 1979: 44; 148-1 56. 4. Simard LC. Tumour of the palm having the structure of a mixed tumour of the saliviiry gland. Am. /. Cnrnw. 1 9 38: 3 3 : 1 82- 1 95. 5. Headington JT. Mixed tumor of the skin: eccrine and apocrinc type. Arch. Ilr.rtrintoI. 196 1 : 84; 989-996. 6 . Dardick I, Van Nostrand P. Phillips MJ. Histogenesis of salivary gland pleomorphic iidenornir (mixed turnorl with an evaluation of the role of myoepithelial cell. Hum. Patho/. 1982: 1 3 : 62-75, 7. Terui 1'. Obata M. 'ragami H. Imrnunohistochemical studies (111 epithelial cells in mixed turnor of the skin. /. Cutciri. Pntfiol. 1980: 1 3 : 197-206. 8. Kunikane H, Ishikura H, Yamaguchi J, Yoshiki T. [tho 1'.Aizawa M. Chondroid syringoma (mixed tumor of the skin). Acts Patlid. / p i . 1987: 37: 615-625. 9. Ken W. Fuchs A. Subietas A. Immunohistocheniical characterization of chondroid syringoma. Evidence of myoepithelial cell presence in chondroid syringoma. (Abstract ). ilrn. /. Cliri. f'ntfiol. 1988: 90; 497. 10. Argenyi ZB, Balog I

Chondroid syringoma: a histological and immunohistochemical study of 15 cases.

Fifteen cases of chondroid syringoma have been studied histologically and by immunohistochemical methods in an attempt to establish their phenotypic p...
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