Ultrastructural and immunohistochemical characteristics of mucoepidermoid carcinoma of the breast

Ultrastructural and Immunohistochemical Characteristics of Mucoepidermoid Carcinoma of the Breast WEDAD HANNA, MD, FRCP[C], AND HARRIETrEJ, KAHN, MD, FRCP[C) Mucoepidermoid carinoma is a rare subtype o f breast carcinoma. In an attempt t6 elucidate the histogenesis of these tumors, two mucoepidermoid carcinomas were studied electron microscopically and immunohistochemically with antisera to S-100 protein and e p i d e r m a l cytokeratin. Light m i c r o s c o p i c e x a m i n a t i o n showed these tumors to be composed of mixtures of neoplastic mucus-secreting, squamous, and intermediate cells. Ultrastructural examination revealed squamous cells, mucus-secreting luminal cells, and classic myoeplthelial cells. The intermediate cells, which contained focal peripheral myofilaments with dense bodies and plnocytotic vesicles associated with centrally aggregated tonofilaments, were interpreted as modified myoepithelial cells. Classic dendritic myoepithelial and intermediate (modified myoepithelial) ceils stained with antisera to S-IO0 protein and epidermal cytokeratin. Both the ultrastructural and the immunohistochemical features indicate that myoepithelial and duct luminal cells play an important role in the histogenesis of mucoepidermoid tumors of the breast. HuM PATIIOL 16:941--946, 1985.

Two of 18 lymph nodes were positive tbr metastatic carcinoma. Receptor status was 18 finol/mg protein for estrogen receptors and I0 fmol/mg protein for progesterone. The patient received two courses of chemotherapy and was free of metastatic disease 1,t months after surgery.

MATERIALSAND METHODS F o r m a l i n - f i x e d p a r a f f i n - e m b e d d e d tissue sections f r o m both specimens were stained with hemat o x y l i n - e o s i n , mucicarmine, and Alcian blue. Additional sections w e r e stained with antisera to S-100 protein (Dakopatts, C o p e n h a g e n , D e n m a r k ) and epid e r m a l keratin (Dakopatts) by the p e r o x i d a s e - a n t i peroxidase the (PAP) technique. 4 Foi- negative controls normal rabbit s e r u m was substituted f o r the primary antisera. For positive controls n e r v e and skin were used for the S-100 protein and e p i d e r m a l keratin, respectively. Fresh tissue front both t u m o r s was fixed in Universal fixative and processed for routine electron nficroscopy. Sections cut at 1 ~ m were exa m i n e d to select areas r e p r e s e n t i n g squamous, ductal, and intermediate c o m p o n e n t s o f the m i n o r .

M u c o e p i d e r m o i d carcinoma is a rare neoplasm o f the breastA T h e m o r p h o l o g y o f this breast t u m o r is similar to that o f its c o u n t e r p a r t in the salivary gland. T h e role o f the myoepithelial cell in salivary g h m d m u c e o p i d e r m o i d c a r c i n o m a s is c o n t r o v e r sial. 2,5 We u n d e r t o o k an immunohistocllemical and electron microscopic study o f two cases o f mucoepid e r m o i d carcinoma o f the breast in an a t t e m p t to clarify the lfistogenesis o f these tumors.

RESULTS Light and electron microscopic and immunolfistochemical studies showed similar features in the two tumors.

REPORT OF TWO CASES Case I. A 51-year-old woman presented with a mass in the left breast; a mammogram strongly st, ggested ntalignancy. A breast biopsy showed a 2-cm well-circumscribed mass that was considered malignant on the basis of frozen section analysis. The patient underwent modified radical mastectomy. Metastatic carcinoma was not found in the axil[ary lymph nodes. The receptor status of the tumor, as evaluated by a dextran-coated charcoal method, showed estrogen receptor levels of 32 fmolhng protein (positive, >10 finolhng protein) and progesterone of 16 fmol/mg protein (positive, >60 finol/mg protein). Eight months after surgery, the patieat was asymptomatic, witlt no evidence of metastatic disease. She did not receive adjuvant chemotherapy or radiotherapy. Case 2. A 31-year-old woman presented with an illdefined breast lump. Biopsy showed a maligoant tulnor, and the patient underwent modified radical mastectomy.

Light Microscopic Findings In sections stained with l t e m a t o x y l i n - e o s i n tile t u m o r s s h o w e d m i x t u r e s o f neoplastic s q u a m o u s , ductal, and i n t e r m e d i a t e cells in variable p r o p o r t i o n s in d i f f e r e n t areas. T h e intermediate c o m p o n e n t was a r r a n g e d in e i t h e r htrge slteets or small, solid islands i n t e r n f i x e d with s q u a m o u s etfithelium a n d glands (fig.,!). In focal areas the s q u a m o u s cells s h o w e d p r o n u n e n t intercellular bridges (fig. 2). In some portions o f tire t u m o r s t h e cells w e r e p r e d o m i n a n t l y spindle-slmped. T h e t u m o r cells showed little pleomorphism, and occasional mitotic figures were seen. With Hale st~in a positive reaction for mucin was obs e r v e d in ductal s t r u c t u r e s , w h e r e were o f t e n surr o u n d e d by sheets o f squamous elfithelium (fig. 3). T h e lymph n o d e metastases in case 2 had ductal and intermediate c o m p o n e n t s but no squamous areas.

Received from the Department of Pathology, Women's College tlospital and University of Toronto, Toronto. Canada. Revision accepted for publication Fe-'bruary7, 1985. Address corresioondence and reprint requests to Dr. ttanna: Department of l'athology. Women's College ltospital, 76 Grenville Street, Toronto, Ontario M5S 117,2,Canada.

941

Immunohistochemical Findings T i l e s q m u n o u s epitltelium, ductal cells, intermediate cells, and some o f the spindle cells stained

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with keratin antiserum (fig. 4). T h e s u r r o u n d i n g stroma did not stain. T h e antibody to S-100 protein stained some of the spindle cells, emphasizing their dendritic appearance (tig. 5). These cells could also be seen interspersed between the squamous epithelium and around some ductal structures. Some of the i n t e r m e d i a t e cells showed diffuse c),toplasmic staining for S-100 protein, but of less intensity than that of the dendritic cells.

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C o m p l e x g l a n d u l a r structures that had been formed by ductal epithelial cells were surrounded by basal lamina and joined b.y desmosomes. Intracytoplasmic and extracytoplasmic lumina were observed. Some cells in these ductal complexes contained 10nm intermediate filaments that were aggregated into tonofilaments, indicative o f squamous differentia942

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moid carcinoma in tile breast and other sites is based on the presence of a combination of mucus-secreting, SCluamous, and intermediate cells9 Any of these elements can be tile p r e d o m i n a n t c o m p o n e n t o f the tumor, and each can show varying degrees of malignancy. Both of tile patients of the present report were estrogen receptor-positive and p r o g e s t e r o n e receptor-negative. T h e presence of estrogen receptors in these tumors is not unexpected, since they contain ductal components. Normal breast ducts are lined by cluctal cells surrounded by a layer of myoepithelial cells. T h e latter are present in sclerosing aclenosis, fibroaclenoma, nipple adenoma, and ductal hyperplasia, n as well as in in situ and invasive carcinoma. 8 The uhrastructural features of myoepithelial ceils include 6- to 8-nm microtilaments associated with dense bodies and bundles of 8- to 10-nm intermediate tilaments. T h e intermediate filament keratin has been demonstrated in myoepitheli,'d, cells of salivary gland and breast by immunohistochemical techniques. 9,1~Actin filaments have also been localized to the peripheral microfilaments.l~ S- 100 protein is a cellular constituent that was described originally in glial cells of the central nervous system and subsequently in other normal cells, inclucling inyoepithelial cells. ]2,ns In the pleonlorphic a d e n o m a o f tile salivary gland, myoepithelial cells play a prominent role. U1-

tion. Classic myoepithelial cells surroundecl some of these ductal complexes (fig. 6). Islands of well-characterized squamous epithelium were seen9 The cells were joined b)' nunlerous desmosomes. Aggregates of tonofilanlents were seen both around tile nucleus and attached to clesmosomal plaques. In some areas the ductal cells were also attached to squamous ceils by desmosomes. The intermediate ceils showed combinations of squamous and myoid features with perinuclear dense bundles of tonofilaments and peripheral myofilaments with dense bodies (fig. 7). However, these intermediate cells also showetl a spectruna of changes, ranging from predominantly sqtnamous (fig. 8) to predominantly myoid. DISCUSSION

Mucoepidermoid carcinoma of the breast is a rare variant of breast carcinonm. Fisher et al. I reported an incidence of 0.2 per cent, although they suggested that it may actually occur more frequently, masquerading u n d e r different diagnoses, such as squamous metaplasia in infiltrating duct carcinoma or intracystic carcinoma. Both low- and high-grade mucoepidermoid carcinomas of the breast have been reported.LS.6 With tile latter, lymph node and visceral lnetastases have occurred. 6,7 9Tile light microscopic diagnosis of mucoepider943

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FIGURE 6. Complex glandular structure with intracytoplasmic lumina (1.].One adjacent cell contains aggregates of tonofilaments, indicative of squamous differentiation {S]. Classic myoepithelial cells [arrows] are visible at the periphery. { x 7,600.] Inset, higher magnificantion of myoepithelial cells showing dense plaques [arrowheads] and perinuclear aggregation of intermediate filaments.* { x'19,200.)

trastructural studies of this tumor have demonstrated classic and modified myoepithelial cells.m4 Keratin, vimentin, and S-100 protein have been demonstrated in the myoepithelial cells in the pleomorphic adenoma. 10-13 In mucoepidermoid carcinoma of the salivary glands, classic and modified myoel)ithelial cells have been demonstrated both uhrastructurally and imnmnohistochemically with antisera to S-100 prorein, suggesting that these cells play a major role in the histogenesis of this tumor.a, t5 The numbers of myoepithelial cells detected by imhmnostaining wiry considerably from tumor to tumor. 15 O u r findings, both uhrastructural and immunohistochenfical, in the mucoepidermoid carcinoma of the breast are very similar to those reported for mucoepidermoid carcinomas of the salivary glands. Ultrastructurally, squamous cells, ductal cells, and classic myoepithelial cells were present. T h e intermediate cells, which showed a spectrum of myoid and squanlous features on electron microscopic examination, were considered modified myoepithelial cells. The predominance of sqfiamous features in some of these cells indicates that the modified myoepithelial cells could give rise to the squamous component. The intimate ultrastructural relation between ductal and squamous elements suggests that the ductal epithe-

lium can also u n d e r g o squamous metaplasia. Tile dendritic cells in the tumors that stained with the antiS- 100 protein antiserum corresponded to classic myoepithelial cells. T h e intermediate cells that also stained with the anti-S-100 protein antisermn and keratin were interpreted as modified myoepithelial cells. The squamous components, however, were only keratin-positive, indicating that once the lnyoepithelial cells undergo squamous metaplasia they lose the ability to produce S-I00 protein. Our study indicates that'the myoepithelial cells in the tumor can either have the classic dendritic configuration or become modified, forming the intermediate component of the Inucoepidermoid ttmmr. Althou~l the monoclonal theory of tunmr histogenesis is the prevailing hypothesis, m the mtdticellular origins of some tumors have been reported.17,1s O u r findings suggest that mucoepidermoid carcin.oma is of multicellular origin, being derived from both.ductal and myoepithelial cells. Either dt, ctal or myoepithelial cells, in the classic or modified form, can be the predonfinant component of the tumor. The degrees of malignancy in both components can be variable. This indicates that the myocpithelial cells play an important role in the histogenesis of mucoepidermoid carcinomas.

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FIGURE 7. Top, i n t e r m e d i a t e cell with p e r i p h e r a l residual myofilaments a n d d e n s e b o d i e s [arrowheads) in a d d i t i o n to a g g r e g a t e s of t o n o f i l a m e n t s (arrows]. This cell is a t t a c h e d to t w o s q u a m o u s cells (S]. [ x 6,700.] Bottom, higher m a g n i f i c a t i o n p e r i p h e r a l m y o f i l a m e n t s with d e n s e b o d i e s [arrowheads], p i n o c y t o t i c vesicles [PV], a n d a g g r e g a t e s of tonofiTaments [arrows]. [ x 24,000.)

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9. Franke WW, Schmid E, Frendensteln C: Intermediate sized filaments of the prekeratin type in myoepithelial cells. J Cell Biol 8.t:633, 1983 10. Caselitz J, Osborn M, Seifert G, et al: Intermediate sized illament proteins (prekeratin, vimentin, desmin) in the normal parotid gland and parotid gland turnouts: imnumofhmrescence stud)'. Virchows Arch [A] 393:273, 1981 11. Caselitz J, Loning T, Stagnet MJ, et al: lmnmnocytochemical demonstration of filamentous structures in the parotid gland: occurrence of keratin and actin in normal and tumoural parotid gland with special rcspcct to the m)oepithelial cells. J Cancer P,es Clin Oncol 100:59, 1981 12. Kahn IIJ, Marks A, Thorn II, et ah Role of antibody to SI00 protein in diagnostic pathology. Am J Pathol 79:34 !, 1983 13. Nakazato Y, lshiezekiJ, Takahasi K, et ah Localization of Sl00 protein and glial fibrillar)" acidic protein-related antigen in pleomorphic adenoma of tile salivar) glands. Lab Invest 46:621, 1982 14. Dardick 1, Von Nostrand AWP, Pllillips MJ: Histogencsis of salivary gland pleomorphic adenoma (mixed tumor) with an evaluation of the role of myoepithelial cells. HUM PATIIOL 13:62, 19~2 15. Kahn ltJ, Baunml R, Marks A, et ah Myoepithelial cells in salivary gland tumours: an immunobistocbemical study. Arch Patllol Lab Med 109:190, 1985 16. Fialow PJ: Clonal origin of human tt, mours. Annu Rev Med 30:135, 1979 17. Rc/ddy AL, Failkow PJ: Multicelh,lar origin of fibrosarcoma in mice induced b)" the chemical carcinogen 3-methylclloranthrene. J Exp Med 150:878, 1979 18. El-Laban NG, Lee KW, Kramer IR: Duality of the cell population in a calcif)ing epithelial odontogenic tumour, ttistopathology 8:679, 198-t

Acknowledgment. T h e a u t h o r s t h a n k Mario K a n d o for h e r excellent technical assistance. REFERENCES

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