A 63-year-old man was initially seen with multiple pulmonary nodules 14 years after a left parotidectomy for an epithelialmyoepithelial carcinoma of salivary gland. Eight and 18 months after parotidectomy, the patient had local recurrence of his salivary gland tumor. He remained disease-free before being seen with pulmonary nodules, which were evaluated by open lung biopsy. The pathologic features of the pulmonary nodules were identical to the salivary gland tumor resected 14 years earlier. This is the fourth reported case of epithelial-myoepithelial carcinoma of salivary gland metastasizing to a distant site. 0 1992 John Wiley 8 Sons, Inc. HEAD 81NECK 1992;14:401-406

Epithelial-myoepithelial cell carcinoma of intercalated duct origin is an uncommon clear cell carcinoma of salivary glands, ,which largely arises from the parotid. Tumors with similar histologic features have been described under a variety of names, including glycogen-rich adenoma,1*2 clear cell my~epithelioma,~ tubular solid adenoma,* glycogen-rich-reticulated aden ~ m a cystic ,~ adenoma,6 and clear cell carci-

From the Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska. Address reprint requests to Dr. Brozna at the Department of Pathology, Colorado Permanente Medical Group, 16601 E. Cerntretech Parkway, Aurora, CO 80011 Accepted for publication December 6, 1991 CCC 0148-64031921050401-06 $04.00 0 1992 John Wiley & Sons, Inc

Epithelial- Myoepithelial Carcinoma

n ~ m aDonath .~ and coworkers defined the tumor as epithelial- myoepithelial cell carcinoma of intercalated ducts to reflect its proposed histiogenesis.' Since the report of eight cases by Donath et al., additional cases have been reported clearly demonstrating the malignant potential of this tum01".~-'~ It arises primarily in older patients (seventh and eighth decades) and is slightly more common in women compared to men (approximate female: male 1.6: 1).Focal invasion occurs frequently and single or multiple recurrences complicate the typically protracted postoperative course. Recurrences have been reported to occur from several months to many years after initial resection. Although local recurrences are not uncommon, distant metastases are rare with only three reported cases of metastases involving the kidney,g lung," and All three patients eventually died of their disease at times ranging from 18 months to 28 years following diagnosis. We report a case of a patient who developed pulmonary metatases 14 years after initial resection and two local recurrences of an epithelial-myoepithelial cell carcinoma of the parotid gland. CASE REPORT

A 63-year-old white man underwent a left parotidectomy 14 years earlier in 1975 for removal of a 2.0-cm mass. The tumor was characterized by nests and fasicles of polygonal epithelial cells


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FIGURE 1. Chest CT scan. A large mass with mUltiPle Satellite nodules extends from the hiium into the left lower lobe.

with clear cytoplasm surrounded by areas of myxoid stroma. A diagnosis of benign mixed tumor was made. Approximately 8 months after parotidectomy, a 6-cm subcutaneous nodule appeared at the original site of resection. The re-

current tumor had similar histology to the original tumor and was diagnosed as recurrent malignant mixed tumor. Ten months later the same tumor recurred and was resected from the temporal fossa adjacent to the site of parotidectomy. The patient has since remained free of local disease. Fourteen years after parotidectomy the patient presented with hemoptysis and multiple pulmonary nodules involving both lungs. Chest x-ray showed no pleural effusion. An open lung biopsy of one of the tumor nodules was performed and showed a tumor believed to be a malignant carcinoid tumor. He was then referred to the Denver Veterans Administration Hospital where one of the authors (J. Brozna) reviewed his open lung biopsy material, which was diagnostic for a metastatic epithelial- myoepithelial cell carcinoma of salivary gland. Chest computerized tomographic (CT) study showed multiple bilateral parenchymal nodules. A large mass with multiple satellite nodules extended from the left hilum to the lateral basilar segment of the left lower lobe (Figure 1). A follow-up CT

FIGURE 2. Photomicrograph of the open lung biopsy specimen showing a biphasic tumor with prominent myxoid stroma infiltrated by rnyoepithelial tumor cells with clear cytoplasm and epithelial cells forming ductal structures (hematoxylin & eosin, x200).


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study performed 5 months later showed only minimal tumor growth. For reference, three nodules, measuring 3.3 X 1.2, 1.2 X 1.1, and 1.4 X 1.5 cm at the time of the first CT scans, measured 3.0 x 1.3, 1.3 x 1.2, and 1.7 x 1.3 cm, respectively, 5 months later on a repeat CT scan. The CT findings suggest epithelial-myoepithelial carcinomas are slow-growing tumors. There were no mediastinal nodules. PATHOLOGIC FINDINGS

Formalin-fixed paraffin sections of the open lung biopsy performed at the referring hospital show tumor cells with a multinodular growth pattern and clear cytoplasm surrounded by hyaline and myxoid stroma. Histologically, the tumor is an epithelial-myoepithelial carcinoma of intercalated duct origin. In some areas, a myxoid stroma is the predominant feature (Figure 2), whereas in other areas, ovoid tumor cells with clear cytoplasm and a trabecular growth pattern predominate (Figure 3). Periodic acid- Schiff (PAS) stains confirm the

presence of glycogen in the cytoplasm of the clear tumor cells. In addition to the clear tumor cells, small ducts lined with cuboidal epithelial cells are present. The cuboidal cells have moderate amounts of eosinophilic cytoplasm and centrally or basally located round nuclei. The more well-formed duct structures are surrounded by clear cells overlying the duct epithelial cells. Some ductal lumina contain eosinophilic material which stains strongly with PAS. Intracytoplasmic mucin is not detectable in either the clear cells or the duct epithelial cells. Mitotic figures are rarely seen. The tumor obtained by open lung biopsy has histologic features identical t o the original parotid tumor resected 14 years earlier, which had a thick fibrous capsule surrounding nests of polygonal tumor cells with basophilic nuclei and clear cytoplasm embedded in a myxoid stroma. In contrast, the first local recurrence resected 8 months after parotidectomy had very little myxoid stroma and was composed primarily of proliferating tumor cells with clear cytoplasm (Figure

FIGURE 3. Photomicrographof the open lung biopsy specimen showing areas of tumor composed predominantly of myoepithelial cells with clear cytoplasm and occasional epithelial cells forming ductal structures (hematoxylin & eosin, x400).

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FIGURE 4. Photomicrograph of salivaty gland epithelial-myoepithelial carcinoma exhibiting a biphasic growth pattern with myoepithelial cells with clear cytoplasm and epithelial cells forming ductal structures (hematoxylin & eosin, ~200).

4).A small number of duct structures lined by cuboidal epithelium are intermingled with the proliferating clear cells. The histologic features of the primary parotid tumor, the two recurrent tumors, and the pulmonary metastases were essentially identical and diagnostic for epithelialmyoepithelial cell carcinoma. COMMENT

Donath and coworkers described eight cases of a biphasic clear cell neoplasm of salivary gland, which they called epithelial- myoepithelial carcinoma of intercalated ducts.' Their report demonstrated the low-grade malignant potential of epithelial- myoepithelial carcinoma, since in three of their eight patients recurrent tumors appeared 3 to 5 years after resection. In one patient, regional lymph node metastasis developed after diagnosis, and in another patient, lymph node metastasis was present at the time of initial diagnosis. From histologic descriptions and photomicrographs, it is likely several earlier reports describing glycogen-rich clear cell ade-


Epithelial-Myoepithelial Carcinoma

noma,' tubular solid adenoma: glycogen-richreticulated a d e n ~ m a ,and ~ salivary duct carcinoma' were in fact what is now termed epithelial- myoepithelial carcinoma. Corridan described a glycogen-rich tumor, which he called clear cell adenoma. The tumor was composed of clear swollen cells with dark nuclei and cells with eosinophilic cytoplasm. Small ducts lined by a single layer of cuboidal epithelial cells with eosinophilic cytoplasm were occasionally seen within large areas of clear cells.' The photomicrographs and microscopic description indicate the tumor was an epithelialmyoepithelial cell carcinoma and not a clear cell variant of a pleomorphic adenoma as originally hypothesized by Corridan. Many of the early reports of bimorphic clear cell tumors with histologic features of what is now called epithelial- myoepithelial carcinoma were reported in the German literature. Feyrter described two cases, which he also thought represented a variant of pleomorphic adenoma, having both clear cells and duct-like epithelial


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Table 1. Reported cases of epithelial-myoepithelial carcinoma of salivary gland. No. of cases

Age (yr)

Corridan’ Feyrter4 Kleinsasser et a1.I3

1 2 2

55 -

Donath et al.’



Saksela et aL3 Goldman and Klein‘ Moharned and C h e r r i ~ k ’ ~ Corio et ai.9

1 1

1 16

67 79 50 31 -89

Chen7 Daley et aLno

1 4

Pogrel et al.” Luna et a1.“

1 9

Palmer et a1.14 Littman and Alguacil-Garcia2’



66 78 51 70 72 53 63 54 77 72 72 52 57 63 68 68 83 64

Hamper et aLZ2


27-91 mean 59.3

1 1

78 65


CarriIIo et a1.17 Arora et al.”


Parotid Parotid


‘Three cases are included from a previous study of Donath et a/

Parotid (7) Submaxillary (1) Parotid Parotid Palate Parotid (12) Submaxillary (3) Cheek (1) Parotid Parotid Parotid Parotid Parotid Parotid Parotid Antrum maxilla Parotid Parotid Parotid Parotid Parotid Parotid Parotid Parotid Parotid Submandibular (ex-pleomorphic adenoma) Parotid (15) Submaxillary (2) Minor Salivary (4) Parotid Submandibular

Recurrence (interval) None (1 2 rno) 1 recurrence (2 yr) Lymph node (1 yr) 1 recurrence (2 yr) 3 cases with unknown number of recurrences None (22 rno) 1 recurrence (9 yr) NO follow-up 5 cases with recurrences (9 mo to 28 yr) Metastasis (28 yr) kidney None (7 yr) None None None (8.5 yr) None (12 yr) Metastasis (18 mo) brain 1 recurrence (1 yr) None (6 yr) None (9 yr) 2 recurrences (3 and 4 yr) 2 recurrences (1 and 2 yr) None (9 yr) None (11 yr) 1 recurrence (2 yr) 3 recurrences (6, 7, 8 yr) None NOfOllOW-Up NOfollow-up

4 cases with recurrences (5, 6, 52, 64 mo) 4 cases with lymph nodes involved at diagnosis None (4 mo) 1 recurrence (17 mo)

cells.5 In one patient the tumor recurred 2 years after resection and the patient then remained disease-free for an additional 3 years. In a second patient, there was no recurrence of tumor during a 1 year follow-up period. Kleinsasser described a bimorphic clear cell tumor with histologic features similar to those described by Feyrter, which he called salivary duct car~inoma.’~ In one patient local recurrence and metastasis to a regional lymph node developed 1 year after parotidectomy. A second patient developed local recurrence 2 years after resection but remained disease-free for an additional 5 years after further treatment.

Epithelial- Myoepithelial Carcinoma

Primary site

Combined data from more recent reports indicate epithelial- myoepithelial carcinomas most commonly arise in the parotid gland and can be associated with multiple local recurrences and involve adjacent periglandular and cervical lymph nodes (Table 1).Cytochemical analysis of nuclear DNA of tumor cells from 12 different cases of epithelial- myoepithelial carcinoma showed diploid histograms, which is consistent with the usual biologic behavior of the tumor.22 However, metastases to kidney, brain, and lung which resulted in death of the patients have been reported.”” The metastasis to kidney occurred after six local recurrences and 28 years


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after parotidectomy, whereas the metastases to brain and lung were discovered 1to 2 years after diagnosis. One other report described a clear cell tumor arising in the parotid gland of a 4-year-old girl which recurred four times before the patient died at 43 years of age with metastases to the lung and retroperitoneal lymph nodes. From the original description and photomicrographs, it is possible the tumor represents a epithelial- myoepithelial carcinoma.23 However, the small ductlike structures surrounded by clear cells were reported to be mucin-positive which is not typical of epithelial- myoepithelial carcinomas. Ultrastructural findings of intracytoplasmic tonofilaments and well-formed desmosomes have been noted in the cells lining the central lumina.g Immunohistochemical analysislo714indicates that only the inner layer of cells lining the central lumina have keratin, which supports the idea that these cells arise from the epithelial cells of intercalated ducts. The clear cells surrounding the ductal epithelial cells have ultrastructural features of primitive myoepithelial cells. In addition, the clear cells are positive for smooth muscle myosin which suggests myoepithelial differentiation. It has been proposed that proliferation and differentiation of intercalated duct reserve cells can be bidirectional leading to cells with myoepithelial or epithelial differentiation. l5 Ultrastructural and immunohistochemical analysis substantiate the original conclusions of Donath and coworkers who proposed that the cells of this tumor express both epithelial and myoepithelial differentiation. The data taken together clearly indicate epithelial-myoepithelial cell carcinomas have a low-grade malignant potential that is different from the more aggressive salivary gland duct adenocarcinomas which do not show myoepithelial differentiation. Our report indicates epithelialmyoepithelial carcinomas have a low-grade malignant potential with a propensity for multiple local recurrences. In addition, this report is the fourth example of epithelial-myoepithelial carcinoma of salivary gland metastasizing to a distant site years after parotidectomy.


2. Goldman RI, Klein HZ. Glycogen-rich adenoma of the parotid gland. Cancer 1972;30:749-754. 3. Saksela E, Tarkkanen J, Wartiovaara J. Parotid clearcell adenoma of possible myoepithelial origin. Cancer . 1972;30:742-748.4. Feyrter F. Cher das solide (tubular-solide) adenom de schlerm und speicheldrusen. Frankfurt 2 Pathol 1964;71:300-326, 5. Feyrter F. Uber das glycogenreiche retikulierte adenom der speicheldrusen. Z Krebsforsch 1972;65:446-454. 6. Snellman Z. Ein fall von adenomysticum. Arb Path01 Ins Helsingfors 1933;7:42-50. 7. Chen KTK. Clear cell carcinoma of the salivary gland. Hum Pathol 1983;14:91- 93. 8. Donath K, Seifert G, Schmitz R. Diagnose und ultrastruktur des tubularen speichelgangcarcinom. Virchow Arch [A] 1972;356:16-31. 9. Corio RL, Sciubba JJ, Brannon RB, Batsakis JG. Epithelial-myoepithelial carcinoma of intercalated duct origin. Oral Surg Oral Med Oral Pathol 1982;53:280-287. 10. Luna MA, Ordonez NG, Mackay B, Batsakis JG. Salivary epithelial-myoepithelial carcinomas of intercalated ducts: a clinical, electron microscopic, and immunocytochemical study. Oral Surg 1985;59:482-490. 11. Pogrel MA, Hansen LS. Second primary tumor associated with salivary gland cancer. Oral Surg 1984;59:7175. 12. Pogrel MA. Follow-up report on epithelial-myoepithelial carcinoma of intercalated duct origin. Oral Surg 1985;59172- 173. 13. Kleinsasser 0, Klein HH, Hubner G. Speichelgangcarcinoms: eine den milchgangcarcinomen der brustdruse analoge gruppe von speicheldrusentumoren. Arch Klin Exp Ohren Nasen Kehlkopfieilk 1968;192:100-115. 14. Palmer RM. Epithelial-myoepithelial carcinoma: an immunocytochemical study. Oral Surg Oral Med Oral Path0~1985;59:511-515~ 15. Batsakis JG. Salivary gland neoplasia-an outcome of modified morphogenesis and cytodifferentiation. Oral Surg 1980;49:229-232. 16. Hamper K, Brugmann M, Koppermann R, et al. Epithelial-myoepithelial duct carcinoma of salivary glands: a follow-up cytophotometric study of 21 cases. J Oral Pathol Med 1989:18:299-304. 17. Carrillo R, Poblet E, Rocamora A, Rodriguez-Peralto JL. Epithelial-myoepithelial carcinoma of the salivary gland: fine needle aspiration cytologic findings. Acta Cyto1 1990;34:243- 247. 18. Arora VK, Misra K, Bhatia A. Cytomorphologic features of the rare epithelial- myoepithelial carcinoma of the salivary gland. Acta Cytol 1990;34239-242. 19. Mohamed AH, Cherrick HM. Glycogen-rich adenocarcinoma of minor salivary glands: a light and microscopic study. Cancer 1975;36:1057- 1066. 20. Daley TD, Wisocki GP, Smout MS, Slinger RP. Epithelial-myoepithelial carcinoma of salivary glands. Oral Surg 1984;57:512-519. 21. Littman CD, Alguacil-Garcia A. Clear cell carcinoma arising in pleomorphic adenoma of the salivary gland. Am J Clin Pathol 1987;88:239-243. 22. Hamper K, Brugman M, Kopperman R, et al. Epithelialmyoepithelial duct carcinoma of salivary glands: a follow-up and cytophotometric study of 21 cases. J Oral Pathol Med 1989;18:299- 304. 23. Rawson AJ, Howard JM, Royster HP, Horn RC. Tumors of the salivary glands: a clinicopathologic study of 160 cases. Cancer 1950;3:445-458.

1. Corridan M. Glycogen rich clear cell adenoma of the parotid gland. J Pathol Bacteriol 1956;72:623-626.


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Epithelial-myoepithelial carcinoma of salivary gland with metastasis to lung: report of a case and review of the literature.

A 63-year-old man was initially seen with multiple pulmonary nodules 14 years after a left parotidectomy for an epithelial-myoepithelial carcinoma of ...
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