True malignant mixed tumors (carcinosarcoma) of salivary glands James Stephen, M.D.,* John G. Batsakis, M.D.,* Mario A, Luna, M.D.,* Ulla von der aeyden, M.D.,** and Robert i&f. Byers, M.D.,*** Houston, Texas, and Tygerberg, South Africa

UNIVERSITY OF TEXAS SYSTEM CANCER CENTER AND UNIVERSITY OF STELLENBOSCH

True malignant mixed tumors (carcinosarcomas) of salivary glands are of a high grade of malignancy and

are distinguishable from the more frequently occurring carcinomas ex pleomorphic adenoma. Having a

putative origin from a benign pleomorphic adenoma, the true malignant mixed tumor is an aggressive, often

rapidly lethal neoplasm in which the sarcomatous element is most oflen a chondrosarcoma and the epithelial element is most often a ductal carcinoma. The twelve cases in this report represent the largest

recorded series to date.

(ORAL SURG. ORAL MED. ORAL PATHOL. 61597-602, 1986)

N early 20 years ago Moberger and Eneroth,’ after examining 2211 salivary gland tumors, report- ed that their study “gives reason to question the existence of a tumor which merits the denotation of a malignant mixed tumor.” In the telling, these authors were among the first to recognize that the term malignant mixed tumor nearly always means, in a histopathologic sense, a carcinoma arising in a mixed tumor or a pleomorphic adenoma.2

The true malignant mixed tumor of salivary glands, in contrast to the carcinoma ex pleomorphic adenoma, is a rare neoplasm. Manifesting a putative origin in a maternal pleomorphic adenoma, the true malignant mixed tumor is a heterologous neoplasm in which there is a sarcoma and a carcinoma (that is, carcinosarcoma).2 The neoplasm’s rarity is under- scored by its absence in three large series of salivary gland tumors8 that included a total of 7,428 cases.‘*3*4 Tortoledo and co-workers2 indicate that true malignant mixed tumors make up only 0.2% of all malignant lesions of major salivary glands.

In this report, we present clinicopathologic infor-

This study was supported in part by a grant from the Caduceus Foundation, New York, N. Y. *Department of Pathology, University of Texas System Cancer Center, M.D. Anderson Hospital. **Department of Pathology, Faculty of Medicine, University of Stellenbosch. ***Department of Head and Neck Surgery, University of Texas System Cancer Center, M. D. Anderson Hospital.

mation on twelve cases of true malignant mixed tumors (carcinosarcomas) of salivary glands. Eleven are from the surgical pathology files of the Universi- ty of Texas System Cancer Center, M.D. Anderson Hospital, and one case is from the University of Stellenbosch, Tygerberg, South Africa. The eleven M. D. Anderson cases represent the largest number of these tumors ever reported from one institution.

MATERIALS AND METHODS

Case selection for this study required (1) a biphas- ic (carcinosarcoma) malignant lesion in or replacing salivary glands and (2) clinical, gross, and historical exclusion of another possible primary neoplasm capable of presenting a carcinosarcomatous appear- ance in the salivary gland, either by direct extension or by metastasis.

The eleven M. D. Anderson Hospital cases meet- ing these requirements were accessioned over a 32-year period (from 1953 to 1985). The University of Stellenbosch case was accessioned in 1985. Histo- logic sections of the primary malignant lesion were available in all twelve cases, and paraffin blocks were available in eight. Sections from recurrences were available in eight cases and from pulmonary metas- tases in two. All of the neoplasms (primary, recur- rent, and metastases) were studied in multiple sec- tions stained with hematoxylin and eosin.

Follow-up information was available for all patients, and the time period ranged from 17 years to 8 months.

597

598 Stephen et al.

Fig. 1. High-grade ductal carcinoma component in a true malignant mixed tumor of the parotid gland. (Hematoxylin and eosin stain. Magnification, x200.)

Fig. 2. Undifferentiated carcinoma in a true malignant mixed tumor of the parotid gland. (Hematoxylin and eosin stain. Magnification, X200.)

Clinical findings malignant mixed tumor. Two of the four with histo-

The patients were four men and eight women. logically proven pleomorphic adenoma each had Their ages at the time of diagnosis ranged from 25 to three recurrences of their benign tumors over a 85 years (mean, 55 years). Six patients had clinical IT-year period. The preponderant signs and symp- or histologic evidence (four patients) of a pre- toms were either a slowly enlarging, painless mass or existing benign salivary gland tumor at the involved a sudden increase in the size of a prior mass. One site from 10 to 50 years before the diagnosis of true patient had a preoperative paresis of the nerve.

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True malignant mixed tumors of salivary glands 599

Fig. 3. Grade II chondrosarcoma, representing the dominant histologic malignancy in a true malignant mixed tumor of the parotid gland. (Hematoxylin and eosin stain. Magnification, x250.)

Fig. 4. “Dedifferentiated” chondrosarcoma and grade II chondrosarcoma components of a true malignant mixed tumor of the parotid gland. (Hematoxylin and eosin stain. Magnification, X250.)

Pathologic studies neoplasms were grossly infiltrative lesions with Grossjindings. Nine of the neoplasms arose in the extension into the parotid parenchyma.

parotid gland-six in the superficial lobe and three Microscopicjindings. Each of the twelve primary in the deep lobe. Two occurred in the submandibular neoplasms manifested a biphasic, heterologous tissue glands, and one in the palate. composition consisting of a definable carcinoma and

The size of the resected primary neoplasms ranged a histologically malignant sarcoma. The latter was from 2 cm to 6 cm (mean, 3.8 cm). All but one of the the dominant tissue in eleven of the twelve neo-

600 Stephen et al. Oral Surg. June, 1986

Fig. 5. High-grade sarcoma with features of a malignant fibrous histiocytoma in a true malignant mixed tumor of the parotid gland. (Hematoxylin and eosin stain. Magnification, x250.)

Fig. 6. Pulmonary metastasis from a true malignant mixed tumor of the parotid gland showing intermingled sarcoma and undifferentiated carcinoma. (Hematoxylin and eosin stain. Magnification, x80.)

plasms. In two, multiple sections of the neoplasms classifiable as chondrosarcomas, all at least grade II were necessary to find the carcinomatous compo- (Fig. 3); there were areas of dedifferentiated chon- nent. A high-grade ductal carcinoma (Fig. 1) was drosarcoma in two of the tumors (Fig. 4). The present in nine of the neoplasms, undifferentiated remaining two neoplasms were high-grade sarcomas carcinoma in two (Fig. 2), and squamous cell carci- manifesting a preponderantly fibrosarcomatous noma in one. In the latter three, these carcinomas appearance but showing foci of rhabdoid differentia- were the preponderant types but were in company tion and also of malignant fibrous histiocytoma (Fig. with ductal carcinomas. Ten of the sarcomas were 5). In only one of the neoplasms were there histologic

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True malignant mixed tumors of salivary glands 601

remnants of a benign pleomorphic adenoma. Six neoplasms exhibited a prominent stromal hyaliniza- tion, and in five of these diffuse calcification of the hyalinized tissue was prominent. Nonmalignant oste- oid was present in two of the tumors.

Metastatic lung nodules were available for study in two cases. The metastases contained both neoplas- tic elements, either within a given nodule or in separate, uniphasic metastatic nodules (Fig. 6).

Treatment and follow-up results

Four of the twelve patients received all their treatment at M. D. Anderson Hospital or at the University of Stellenbosch. From the records of these patients and others available to us, the following categories of management obtained: (1) surgery only, five patients; (2) surgery and postoperative radiotherapy, four patients; (3) surgery, postopera- tive radiotherapy, and chemotherapy, two patients. The latter two patients had disseminated metastases or advanced local recurrences.

Five patients had local recurrences only (one to three times). Six others manifested metastases with or without local recurrence.

Six of the twelve patients have succumbed to their disease, with a mean survival after treatment of 3.6 years. Two patients are alive with recurrent neo- plasm, both within 1 year of surgery. Two patients died of other causes without recurrences or metasta- ses at 2 and 17 years after treatment. One patient is alive without recurrence 4 years after radical paroti- dectomy and temporal bone resection. In one case the tumor was diagnosed too recently for the patient to be included in this evaluation.

The dominant mode of metastasis was hematoge- nous, with the lungs and bones the preponderant sites of secondary deposits. Only two patients had metas- tases to regional lymph nodes.

DISCUSSION

Table I presents a clinicopathologic summary of the twelve cases of true malignant mixed tumors (carcinosarcomas) of salivary glands outlined in this report. The eleven cases from M. D. Anderson Hospital represent the largest series yet reported from a single institution.

Chen and colleagues,5 in reporting a single exam- ple of carcinosarcoma of the parotid gland, con- firmed the paucity of reports of these lesions in the literature. Furthermore, all of the other cases have been presented in the context of a survey of all malignant salivary gland tumors (for example, four carcinosarcomas in a study of 909 parotid tumors by Kirklin and co-worker#). Of the nine previously

Table I. Clinicopathologic summary of twelve true malignant mixed tumors (carcinosarcomas) of sali- vary glands

Sex of patients Mean age at diagnosis (yr) Site of primary lesion

Size of primary lesion (cm) Patients with local

recurrences Patients with metastases

(local and distant) Patient deaths attributed to

neoplasm

Females, 8; males, 4 55 (range, 25-85) Parotid gland-9 Submandibular gland-2 Palate-l 2-6 (M, 3.8) 8 (66.7%); 5 without

metastases 6 (50%)

6 (50%); mean survival of 3.6 years after primary treatment

recorded cases, follow-up information and a degree of pathologic detail were provided in five. Four of the patients have died-6 months and 1, 2, and 6 years after surgical treatment. The remaining patient was reported alive and well 19 years after surgery.5

The true malignant mixed tumors in our series carry a mortality rate of 50%, with death occurring within 5 years after histologic diagnosis. With singu- lar exceptions, this life-consuming quality of the neoplasms places them in the high-grade category of malignant salivary gland tumors. The degree of lethality shown by true malignant mixed tumors is nearly identical to that found for carcinomas ex pleomorphic adenoma as a groupe2 There is, however, a considerable variation in survival among patients with carcinomas ex pleomorphic adenoma, which is dependent on the histologic type of carcinoma.2 No such relationship exists for the true malignant mixed tumors.

Origin of the carcinosarcoma from a maternal pleomorphic adenoma (mixed tumor) is strongly suggested by the observation of a prior, often recur- rent, pleomorphic adenoma in four of our patients and historical evidence of the event in two others. The finding of a chondrosarcoma and a ductal carcinoma as the two most encountered histologic components of the true malignant mixed tumor also correlates with the often prominent display of their benign counterparts in the pleomorphic adenoma.

Immunohistochemical and ultrastructural studies of pleomorphic adenomas argue strongly in favor of a composition of cells manifesting a continuum of cytoplasmic features from epithelial to mesenchymal cells, rather than two distinct cell populations.7-9

Myoepithelial cells, with their hybrid epithelial and mesenchymal ultrastructure as well as function- al phenotype, certainly qualify as major contributors

602 Stephen et al.

to the continuum seen in pleomorphic adenomas. The observations of a coexpression of the intermediate filaments-vimentin and cytokeratin-in pleomor- phic adenomas further support a phenotypic duality of cells in the tumors.10 Dardick and van Nostrand” have indicated that the myoepithelial cell is also involved in the synthesis, organization, and cytologic modifications of the chondromyxoid regions of pleo- morphic adenomas. The histologic appearance of true malignant mixed tumors of salivary glands and their documented or presumed relationship to pleo- morphic adenomas implicate the myoepithelial cell as a major component in their development.

Unreported findings in our cases confirmed an immunocytochemical coexpression of intermediate filaments in true malignant mixed tumors. The results were predictable in that cells that appeared mesenchymal showed positive vimentin immunoreac- tivity and cells that appeared epithelial were cytoker- atin-positive. S- 100 protein antigen immunoreactivi- ty occurred in all cartilage areas and was found in occasional epithelial cells. Such findings do no more than once again confirm the complexity of pleomor- phic adenomas and their malignant counterparts. The genotypic precursor cell, if there is one, is not clarified.

REFERENCES

1. Moberger JG, Eneroth C-M: Malignant mixed tumors of the major salivary glands: special reference to the histologic structure in metastases. Cancer 21: I 198-l 21 I, 1968.

2. Tortoledo ME, Luna MA, Batsakis JG: Carcinomas ex

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Oral Surg. June, 1986

pleomorphic adenomas and malignant mixed tumors. Arch Otolaryngol 110: 172-l 76, 1984. Eveson JW, Cawson RA: Salivary gland tumours: a review of 2410 cases with particular reference to histologic types, site, age, and sex distribution. J Path01 146: 51-58,-1985: Soiro RH. Strong EW: Tumors of the parotid and subman- dibular glands; astudy of 2200 cases. Proceedings of the fifth joint meeting of the American Society of Head and Neck Surgery and the Society of Head and Neck Surgeons, El Dorado, Puerto Rico, 1985, American Society of Head and Neck Surgery and Society of Head and Neck Surgeons. p. 152. Chen KTK, Weinberg RA, Moseley D: Carcinosarcoma of the salivary gland. Am J Otolaryngol 5: 415-417, 1984. Kirklin JW, McDonald JR, Harrington SW: Parotid tumors: histopathology, clinical behavior and end results. Surg Gyne- col Obstet 92: 721-733, 1951. Krepler R, Denk H, Artieb V, Moll R: Immunocytochemistry of intermediate filament proteins present in pleomorphic adenomas of the human parotid gland: characterization of different cell types in the same tumor. Differentiation 21: 191-199, 1982. Mill SE, Cooper PH: An ultrastructural study of cartilagi- nous zones and surrounding epithelium in mixed tumors of salivary gland and skin. Lab Invest 44: 6-l 2, 1981. Yoshihara T, Kanda T, Kaneko T: A cytochemical study on the salivary gland pleomorphic adenoma (mixed tumor) in the fetal and adult salivary gland. Arch Otorhinolaryngol 240: 231-238, 1984. Caselitz J, Osborn M, Wustrow J, Seifert G, Weber K: The expression of different intermediate-sized filaments in human salivary glands and their tumors. Pathol Res Pratt 175: 266-278, 1982. Dardick I, van Nostrand AWP: Myoepithelial cells in salivary gland tumors-revisited. Head Neck Surg 7: 395-408, 1985.

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Dr. John G. Batsakis Department of Pathology M.D. Anderson Hospital Houston, TX 77030