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True Malignant Mixed Tumor (Carcinosarcoma) of Parotid Gland With Unusual Mesenchymal Component: A Case Report and Review of the Literature.

True malignant mixed tumor (carcinosarcoma), which is composed of both malignant epithelial and malignant mesenchymal components, is an exceedingly rare tumor of the salivary gland, comprising 0.04% to 0.16% of all salivary gland tumors and 0.4% of all malignant salivary gland neoplasms.[1] Since it was first described in 1951 by Kirklin et al,[2] there have only been approximately 60 cases reported in the English-language literature.[1-20] The most common malignant epithelial component is squamous cell carcinoma or adenocarcinoma, whereas the most common malignant mesenchymal component is chondrosarcoma, followed by fibrosarcoma, leiomyosarcoma, osteosarcoma, and liposarcoma.[1] We report a case of true malignant mixed tumor of the salivary gland that contained a very unusual type of mesenchymal component, rhabdomyosarcoma, in a 47-year-old man with cytologic, histologic, and immunohistochemical findings. To our knowledge, there was only one case report that documented rhabdomyosarcoma in a true malignant mixed tumor of the salivary gland.[7]

REPORT OF A CASE

A 47-year-old man presented with a mass in the left parotid gland that had been rapidly enlarging for 6 weeks. A fine-needle aspiration biopsy was performed at another hospital. The cytologic specimen contained abundant necrotic debris in the background and many groups and single malignant epithelial cells that have marked nuclear pleomorphism, increased nuclear-cytoplasmic ratio, and coarse chromatin pattern. In addition, there were also clusters of stromal cells that showed moderate-to-marked cytologic atypia. Because of the fine-needle aspiration findings, the patient went to the University of California Irvine Medical Center for surgery. A preoperative magnetic resonance image of the left region of the neck with gadolinium TI-weighted sequence showed a 26 x 18-mm tumor in the left cheek with homogeneous intermediate signal (Figure 1). The patient, thereafter, underwent left total parotidectomy with full preservation of the facial nerve.

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Grossly, the parotidectomy specimen weighed 43 g and measured 8.0 x 5.0 x 3.5 cm. The cut surface revealed a relatively well-defined, tan, heterogenous tumor that measured 3.5 x 3.0 x 2.5 cm with focal necrosis. Microscopically, the tumor was mainly composed of 2 components, carcinoma and sarcoma. The former was that of poorly differentiated adenocarcinoma and squamous cell carcinoma (Figure 2). The latter was mostly composed of rhabdomyosarcoma characterized by clusters and sheets of cells with abundant eosinophilic cytoplasm and eccentric round nuclei (Figure 3). Foci of malignant spindle cells representing fibrosarcoma were also identified. Mitotic figures were readily identified and necrosis was also present. Eleven regional lymph nodes were all negative for tumor. In addition, in the center of the tumor, a focus of coexisting pleomorphic adenoma was present characterized by clusters of benign epithelial and myoepithelial cells entrapped in abundant hyalinized and cartilaginous matrix.

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Immunohistochemical studies (Table 1) showed that the carcinoma cells were positive for cytokeratin AE1/AE3. Rhabdomyosarcoma cells were positive for myoglobin (Figure 4), desmin, and HHF-35, whereas fibrosarcoma cells were negative for these muscle markers and only positive for vimentin. Both carcinoma and sarcoma showed some degree of immunoreactivity for vimentin and S100 protein. Smooth muscle actin was negative for both components, but was positive in the adjacent myoepithelial cells of the pleomorphic adenoma and normal ducts.

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 Table 1. Immunohistochemical Profile of Different
 Components of the Tumor(*)

Antibodies Source and Dilution Carcinoma

AE1/AE3 (monoclonal) Signet, Dedham, Mass, predi- +
 luted
Myoglobin (polyclonal) Dako Corporation, Carpinteria, -
 Calif, 1:200
Desmin (monoclonal) Ventana, Tucson, Ariz, predi- -
 luted
HHF-35 (monoclonal) Enzo, Farmingdale, NY, predi- -
 luted
Vimentin (monoclonal) BioGenex, San Ramon, Calif, +
 prediluted
S100 protein (polyclonal) Ventana, prediluted +
Smooth muscle actin Dako, 1:50 -
 (monoclonal)

 Sarcoma
 Rhabdomyo-
Antibodies sarcoma Spindle Cells

AE1/AE3 (monoclonal) - -
Myoglobin (polyclonal) + -
Desmin (monoclonal) + -
HHF-35 (monoclonal) + -
Vimentin (monoclonal) + +
S100 protein (polyclonal) - -
Smooth muscle actin - -
 (monoclonal)

 Pleomorphic Adenoma
 Epithelium/
Antibodies Myoepithelium Mesenchyme

AE1/AE3 (monoclonal) + -
Myoglobin (polyclonal) - -
Desmin (monoclonal) - -
HHF-35 (monoclonal) - -
Vimentin (monoclonal) + +
S100 protein (polyclonal) + -
Smooth muscle actin
 (monoclonal)

(*) Plus sign indicates positive; minus sign, negative.


COMMENT

There are 3 distinct histologic types of malignant mixed tumor: carcinoma ex pleomorphic adenoma, which comprises most malignant mixed tumors; metastasizing mixed tumors; and carcinosarcomas, which are true malignant mixed tumors.[21] In a clinicopathologic study of 146 cases of malignant mixed tumor of the salivary gland, the authors described occasional examples of clearly malignant spindle cell or mixed spindle cell and giant cell variant tumors, some of which exhibited predominantly diffuse pseudosarcomatous pattern.[16] However, carcinosarcoma was not used in that study, and the authors defined the use of malignant mixed tumor as those tumors containing elements of benign mixed tumor and carcinoma. On the other hand, some authors even questioned the existence of true malignant mixed tumor and suggested that the term cancer in pleomorphic adenoma be used.[15] Based on the classification proposed by the Armed Forces Institute of Pathology,[21] carcinosarcoma of the salivary gland does exist, although it is rare. In fact, it is so rare that according to the World Health Organization's histologic classification of salivary gland tumors, malignant mixed tumor only refers to the carcinoma in pleomorphic adenoma.[22] Mixed carcinoma and sarcoma of the parotid gland was first described in 1951 by Kirklin et al[2] of the Mayo Clinic, and sarcomatous component was thought to be the stroma of the tumor. The term true malignant mixed tumor (carcinosarcoma), which means a tumor consisting of both carcinomatous and sarcomatous elements, was first used by King[12] in 1967. Since this time, there have been approximately 60 cases of carcinosarcoma of the salivary glands reported in the English-language literature.

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Gnepp[1] summarized 43 cases of carcinosarcoma of the salivary glands published in the literature. The mean age at presentation for 34 patients with available data was 58 years (range, 14-87 years). There was no sex predominance. Among 37 patients with available data, 18 were female and 19 male. Twenty-seven tumors were from parotid glands, 8 from submandibular glands, 5 from the palate, 2 from unspecified major salivary glands, and 1 from the tongue. Six tumors had microscopic evidence of arising in a benign mixed tumor. There have been another 17 cases either not included in Gnepp's article or reported afterward (Table 2). Clinical data were available in 14 of these cases (mean age, 70 years; range, 51-86 years; 8 women and 6 men). Among these additional 17 cases, 12 were from parotid glands, 2 from submandibular glands, and 3 from the palate. There were 7 cases that showed clear histologic evidence of a preexisting or coexisting pleomorphic adenoma[3,6-8,10,14,17] and 4 cases that failed to demonstrate such a relationship.[5,9,20] In the other 6 cases, it was not stated in the reports whether the carcinosarcoma was associated with a pleomorphic adenoma or not.[4,6,19] Based on the literature of these 60 reported cases of true malignant mixed tumor of the salivary glands, the most common carcinoma was squamous cell carcinoma or adenocarcinoma, whereas the most common sarcoma was chondrosarcoma. The occurrence of chondrosarcoma is not unexpected, given the chondroid nature of benign counterpart. Other sarcomas that have been reported include fibrosarcoma, leiomyosarcoma, osteosarcoma, and rarely liposarcoma or the combination of these sarcomas.[1,7] To the best of our knowledge, there was only one case report that described a malignant mixed tumor with a rhabdomyosarcoma component.[7]
 Table 2. True Malignant Mixed Tumors (Carcinosarcoma) of Salivary
 Glands: A Literature Review

Source, y No. of Cases Patient Age, y/Sex

Torloledo et al,[19] 1984 3 Not applicable
Granger and Houn,[8] 1991 1 84/M
Bleiweiss et al,[5] 1992 1 64/M
Grenko et al,[9] 1993 1 66/F
Gnepp, 1993 (review) 43 See "Comment" section
Spraggs et al,[17] 1994 1 61/F
Gandour-Edwards et al,[7] 1994 1 63/F
Lopez et al,[14] 1994 1 47/F
De la Torre and Larson,[20] 1 83/F
 1995
Bocklage and Feddersen,[4] 2 77/M
 1995 76/M
Carson et al,[6] 1995 2 51/F
 78/F
Alvarez-Canas and Redilla,[3] 1 86/F
 1996
Kim et al,[11] 1998 1 64/M
Latkovich and Johnson,[13] 1998 1 80/M
Kwon and Gu, 2001 (present 1 47/M
 study)

Source, y Type(s) of Sarcoma

Torloledo et al,[19] 1984 Chondrosarcoma
Granger and Houn,[8] 1991 Chondrosarcoma
Bleiweiss et al,[5] 1992 Osteosarcoma
Grenko et al,[9] 1993 Giant cell tumor
Gnepp, 1993 (review) See "Comment" section
Spraggs et al,[17] 1994 Chondrosarcoma
 Osteosarcoma
Gandour-Edwards et al,[7] 1994 Rhabdomyosarcoma
Lopez et al,[14] 1994 Chondrosarcoma
De la Torre and Larson,[20] Osteosarcoma
 1995 Chondrosarcoma
Bocklage and Feddersen,[4] Fibrosarcoma
 1995 Chondrosarcoma
Carson et al,[6] 1995 Osteosarcoma
 Leiomyosarcoma
Alvarez-Canas and Redilla,[3] Fibrosarcoma with chondrosarcomatous
 1996 differentiation
Kim et al,[11] 1998 Chondrosarcoma
Latkovich and Johnson,[13] 1998 Malignant fibrous histiocytoma
Kwon and Gu, 2001 (present Rhabdomyosarcoma
 study) Fibrosarcoma

Source, y Anatomic Location

Torloledo et al,[19] 1984 Parotid gland
 Submandibular gland
 Soft plate
Granger and Houn,[8] 1991 Parotid gland
Bleiweiss et al,[5] 1992 Submandibular gland
Grenko et al,[9] 1993 Parotid gland
Gnepp, 1993 (review) See "Comment" section
Spraggs et al,[17] 1994 Parotid gland
Gandour-Edwards et al,[7] 1994 Parotid gland
Lopez et al,[14] 1994 Parotid gland
De la Torre and Larson,[20] Parotid gland
 1995
Bocklage and Feddersen,[4] Parotid gland
 1995 Parotid gland
Carson et al,[6] 1995 Parotid gland
 Soft palate
Alvarez-Canas and Redilla,[3] Parotid gland
 1996
Kim et al,[11] 1998 Soft palate
Latkovich and Johnson,[13] 1998 Parotid gland
Kwon and Gu, 2001 (present Parotid gland
 study)


In the current case, the carcinomatous component, well illustrated by the cytology specimen, was poorly differentiated with both glandular and squamous differentiation. The sarcomatous component showed mostly rhabdomyosarcomatous differentiation with focal malignant spindle cell differentiation. The latter, due to the lack of immunoreactivity to all the markers but vimentin, was thought to represent a fibrosarcoma. In addition, multiple sections of the tumor showed residue benign mixed tumor, indicating that this true malignant mixed tumor (carcinosarcoma) may have arisen in a preexisting pleomorphic adenoma. This is not an uncommon phenomenon, since approximately one third of the patients with carcinosarcoma had either clinical or histologic evidence of coexisting pleomorphic adenoma. The appearance of rhabdomyosarcoma, on the other hand, is a very unique finding, considering the fact that no benign skeletal muscle cells could be found in benign mixed tumors. This may indicate the diverse differentiation of the mesenchymal elements, which relates to the histogenesis of these lesions. Therefore, we think the current case is unusual and it contributes to the limited literature of this rare entity with cytologic, histologic, and immunohistochemical studies. Furthermore, cytologic features of this entity have only been stressed in 3 articles,[8,10,20] making this case complementary to the limited cytologic literature as well. However, although a malignant neoplasm can be documented by fine-needle aspiration biopsy, histologic examination still remains the most reliable method of diagnosis due to the fact that the sarcomatous element may be focal or small.

Although it is recognized now that true malignant mixed tumors of the salivary glands do exist, their histogenesis and pathogenesis are still under discussion. Clinical, histologic, and immunohistochemical studies and their relationship to pleomorphic adenomas imply that true malignant mixed tumor (carcinosarcoma) and pleomorphic adenoma of the salivary gland may share a common precursor cell in that the myoepithelial cell is a major component in their development,[5,18] On the other hand, it has been shown that some carcinosarcomas arise de novo.[5,9,13,20] Also it has been demonstrated that certain carcinosarcomas do not show evidence of myoepithelial cell origin or differentiation and that they may arise independently of pleomorphic adenoma.[2] In our case, the carcinomatous elements were strongly immunoreactive with cytokeratin AE1/AE3 and sarcomatous elements were negative for cytokeratin. The rhabdomyosarcoma cells were strongly immunoreactive for desmin, HHF-35, and myoglobin. S100 protein and vimentin stained both carcinomatous and sarcomatous components, whereas the latter was weaker and focal. However, both components did not show any immunoreactivity for smooth muscle actin, a marker for myoepithelial cells. This may indirectly support the theory that myoepithelial cells may not be the sole origin of cell. Therefore, it is hypothesized that the primitive mesenchymal cells, being able to differentiate along diverse directions, may have given rise to the appearance of different kinds of sarcoma, in our case, rhabdomyosarcoma and fibrosarcoma. Finally, although we discussed that carcinosarcoma of the salivary glands may occur de novo or in association with a pleomorphic adenoma, it may also be associated with treatment. There have been several reports demonstrating the occurrence of true malignant mixed tumors 30 years after radiation for pleomorphic adenoma.[11,17]

In summary, we report a case of true malignant mixed tumor (carcinosarcoma) of the parotid gland with rhabdomyosarcoma. With a course of local radiation therapy after the surgery, the patient is currently free of disease 12 months after the initial diagnosis.

References

[1.] Gnepp DR. Malignant mixed tumors of the salivary glands: a review. Pathol Ann. 1993;28:279-328.

[2.] Kirklin JW, McDonald JR, Harrington SW, New GB. Parotid tumors: histopathology, clinical behavior, and end results. Surg Gynecol Obstet. 1951;92:721-733.

[3.] Alvarez-Canas C, Rodilla IG. True malignant mixed tumor (carcinosarcoma) of the parotid gland: report of a case with immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81:454-458.

[4.] Bocklage T, Feddersen R. Unusual mesenchymal and mixed tumors of the salivary gland: an immunohistochemical and flow cytometric analysis of three cases. Arch Pathol Lab Med. 1995;119:69-74.

[5.] Bleiweiss IJ, Huvos AG, Lara J, Strong EW. Carcinosarcoma of the submandibular salivary gland: immunohistochemical findings. Cancer. 1992;69:2031-2035.

[6.] Carson HJ, Tojo DP, Chow JM, Hammadeh R, Raslan WF. Carcinosarcoma of salivary glands with unusual stromal components: report of two cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995; 79:738-746.

[7.] Gandour-Edwards RF, Donald PJ, Vogt PJ, Munn R, Min KW. Carcinosarcoma (malignant mixed tumor) of the parotid: report of a case with a pure rhabdomyosarcoma component. Head Neck. 1994;16:379-382.

[8.] Granger JK, Houn H-Y. Malignant mixed tumor (carcinosarcoma) of parotid gland diagnosed by fine-needle aspiration biopsy. Diagn Cytopathol. 1991;7: 427-432.

[9.] Grenko RT, Tytor M, Boeryd B. Giant-cell tumor of the salivary gland with associated carcinosarcoma. Histopathology. 1993;23:594-595.

[10.] Hellquist H, Michaels L. Malignant mixed tumor: a salivary gland tumour showing both carcinomatous and sarcomatous features. Virchows Arch. 1986; 409:93-103.

[11.] Kim T, Yoon GS, Kim O, Gong GG. Fine needle aspiration diagnosis of malignant mixed tumor (carcinosarcoma) arising in pleomorphic adenoma of the salivary gland: a case report. Acta Cytol. 1998;42:1027-1031.

[12.] King O Jr. Carcinosarcoma of accessory salivary gland: first report of a case. Oral Surg Oral Med Oral Pathol. 1967;23:651-659.

[13.] Latkovich P, Johnson RL. Carcinosarcoma of the parotid gland: report of a case with cytohistologic and immunohistological findings. Arch Pathol Lab Med. 1998;122:743-746.

[14.] Lopez JI, Ballestin C, Garcia-Prats MD, De Agustin P. Carcinosarcoma of the parotid gland: immunohistochemical study of a case. Histopathology. 1994; 25:388-390.

[15.] Moberger JG, Eneroth CM. Malignant mixed tumors of the major salivary glands: special reference to the histologic structure in metastases. Cancer. 1968; 21:1198-1211.

[16.] Spiro RH, Huvos AG, Strong EW. Malignant mixed tumor of salivary origin: a clinicopathologic study of 146 cases. Cancer. 1977;39:388-396.

[17.] Spraggs PDR, Rose DSC, Grant HR, Gallimore AP. Post-irradiation carcinosarcoma of the parotid gland. J Laryngol Otol. 1994;108:443-445.

[18.] Stephen J, Batsakis JG, Luna MA, von der Heyden U, Byers RM. True malignant mixed tumors (carcinosarcoma) of salivary glands. Oral Surg Oral Med Oral Pathol. 1986;61:597-602.

[19.] Tortoledo ME, Luna MA, Batsakis JG. Carcinomas ex pleomorphic adenoma and malignant mixed tumors. Arch Otolaryngol. 1984;110:172-174.

[20.] De la Torre M, Larsson E. Fine-needle aspiration cytology of carcinosarcoma of the parotid gland: cytohistological and immunohistochemical findings. Diagn Cytopathol. 1995;12:350-353.

[21.] Ellis GL, Auclair PL. Tumors of the Salivary Glands. Washington, DC: Armed Forces Institute of Pathology; 1996. Atlas of Tumor Pathology, 3rd series, fascicle 17.

[22.] Seifert G, Sobin LH. Histological typing of salivary gland tumors: the World Health Organization's histological classification of salivary gland tumors. Cancer. 1992;70:379-385.

Accepted for publication December 6, 2000.

From the Department of Pathology, University of California Irvine Medical Center, Orange, Calif.

Reprints: Mai Gu, MD, PhD, Department of Pathology, University of California Irvine Medical Center, 101 The City Drive, Orange, CA 92868 (e-mail: mgu@uci.edu).
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Author:Kwon, Meeae Y.; Gu, Mai
Publication:Archives of Pathology & Laboratory Medicine
Date:Jun 1, 2001
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