Case Reports

82 7

0 1990 The Japanese Society of Pathology

Ca rcinosa rcoma of the Su bma ndi bular Gland An Autopsy Case

Junko Suzuki’, Minoru Takagi’, Norihiko Okada2, Shigeru Hatakeyama3, and Hajime Yamamoto’

We present a rare case of submandibular gland carcinosar- coma occurring in a 45-year-old male patient. His clinical history revealed that the carcinosarcoma had developed from a carcinoma ex mixed tumor in three years. In spite of repeated resection, intensive chemotherapy and irradia- tion, the tumor recurred and grew rapidly, and the patient died of hemothorax caused by rupture of a pulmonary metastatic tumor. The fourth recurrent tumor and autopsy specimens showed features of carcinosarcoma consisting of three tumor components, i.e., undifferentiated carcinoma, and chondrosarcomatous and osteosar- comatous growth. The metastatic nodules in both lungs and pulmonary hilar lymph nodes showed the same pattern. lmmunohistochemically, the chondrosarcomatous cells were positive for vimentin and S-100 protein, and for epithelial markers such as epithelial membrane antigen (EMA) and cytokeratin (MA-902). Undifferentiated car- cinoma cells, on the other hand, were partially positive for muscle actin other than cytokeratin (KL-1). Ultrastructur- ally, desmosome-like structures were seen in the chon- drosarcomatous cells. These findings suggest that the sarcomatous lesions might have originated from epithelial cells. Acta Pathol Jpn 40: 827-831, 1990.

Key words : Carcinosarcoma, Malignant mixed tumor, Su bmandi bular gland

INTRODUCTION

Malignant mixed tumor of the salivary gland has been classified into three groups by Gnepp (l), a) carcinoma ex mixed tumor, b) carcinosarcoma, c) metastatic mixed

Received March 9, 1990. Accepted for publication September 4, 1990. ‘Department of Oral Pathology, and *Division of Laboratory Medicine, Faculty of Dentistry. 3Department of Pathology, Faculty of Medicine, Tokyo Medical and Dental University, Tokyo. Mailing address: Junko Suzuki, D.D.S. ($$*JlDF), Depart- ment of Clinical Pathology, Tokyo Metropolitan Tama Geri- atric Hospital, 7-1, Aoba-cho I-chome, Higashimurayama, Tokyo 189, Japan.

tumor with a benign appearance. In carcinoma ex mixed tumor, the malignant component is composed of only epithelial elements, both in the primary and/or metastatic foci. Carcinosarcoma contains both car- cinomatous and sarcomatous elements. Metastasizing mixed tumor has the histological appearance of a benign tumor in both the primary and metastatic lesions. The tumors classified as b) and c) are referred to as true malignant mixed tumors (2). However, these two types are not in the WHO classification(3). In terms of fre- quency, most malignant mixed tumors are carcinoma ex mixed tumor. Carcinosarcoma is very rare and only a few case reports have appeared in the literature (4-10).

We present a case of carcinosarcoma of the subman- dibular gland which developed from a pre-existing car- cinoma ex mixed tumor after a long-term course of repeated surgery, chemotherapy and irradiation.

CLINICAL SUMMARY

A 29-year-old Japanese male patient first visited Tokyu Hospital because of a right submandibular tumor in 1971, and underwent tumor resection. The histopath- ological diagnosis was not available, but he was told it was “a chunk of fat ty tissue”. Recurrence in the same region was noted in 1983, and the patient was admitted to the San’iku-kai Hospital for resection of the recurrent tumor and postoperative radiotherapy with a total dose of 60 Gy. In 1984, a second recurrence occurred, and resection of the tumor and postoperative radiotherapy with a total dose of 50Gy was performed. In 1986, there was a third recurrence, and this was treated by resection in August at the same hospital. However, one month later, the patient was transferred to the First Department of Oral Surgery, Tokyo Medical and Dental University Hospital, for treatment of a fourth recurrent tumor.

In October 1986, after chemotherapy and hyperther-

828 Carcinosarcoma of Submandibular Gland (Suzuki et a/.)

Table 1. lmmunohistochemical Study

__ Component

chondro osteo sarcoma Anti bodies u nd iff erent ia td

carcinoma sarcoma Monoclonal antibodies

EMA (E29) Cytokeratin (54 kDa, MA 902) Keratin (56 kDa, KL-1) Muscle actin (42 kDa, MA 931)

Polyclonal antibodies S 100 protein Vimentin Lactoferrin Lvsozvme

+ t -

+ i

I

~

mia for the fourth recurrence, resection of the oral floor, right half of the tongue and mandible, and bilateral radical neck dissection were performed. A subsequent recurrent tumor in the right fauces-pharyngeal region was also resected in December. Soon after, recurrence again developed rapidly in the left fauces-pharyngeal region. This was resected in January 1987, followed by postoperative radiotherapy with a total dose of 14 Gy. The patient died of hemothorax due to rupture of lung metastases in March. 1987.

PATHOLOGICAL FINDINGS The first recurrent tumor in 1983 consisted of two

components, i.e., multiple micronodules revealing the features of a benign mixed tumor with prominent myxomatous lesions showing slight atypia (Fig. la) , and keratinizing squamous cell carcinoma (Fig. 1 b). The second recurrent tumor resected in 1984 was diagnosed

as carcinoma ex mixed tumor. The third recurrent tumor resected in 1986 was composed mainly of undifferentiated carcinoma (Fig. 2). Some squamous cell carcinoma and myxomatous stroma with atypia were recognized. We considered these three specimens to be carcinoma ex mixed tumor.

A t the fifth operation, a tumor measuring 6 x 7 ~ 8 cm with hemorrhage and necrosis was found in the floor of the mouth invading the right subcutaneous mental region and mandibular bone. Histologically, the chief component was undifferentiated carcinoma. There were also squamous cell carcinoma, and chondrosarcomatous and osteosarcomatous lesions (Fig. 3) without a benign appearance. We therefore made a pathological diagno- sis of carcinosarcoma. The sixth and seventh speci- mens showed only undifferentiated carcinoma.

At autopsy, a large tumor occupied the lower half of the face with several subcutaneous tumor nodules. The tumor filled the oral cavity extending to the sphenoid

Figure 1. Material from the first recurrence a Some micronodules showing features of benign mixed tumor with slightly atypical myxomatous components in adipose tissue of the submandibular region. HE. b Malig nant elements showing keratinizing squa- rnous cell carcinoma. HE

Acta Pathologica Japonica 40 (1 1) : 1990 829

Figure 2. Material from the third recurrence. Malignant ele- ments showing undifferentiated carcinoma with multiple mitotic figures. HE.

bone, inferior orbital fissure and dura at the base of the skull. Each tumor was hemorrhagic, necrotic and mark- edly calcified. Histologically, the tumor exhibited undifferentiated carcinoma, chondrosa rcoma tous lesions with chondroid formation (Fig. 4) and osteosarcomatous lesions with osteoid formation. The sarcomatous lesions were continuous with the undifferentiated car- cinoma. The tumor cells in all the histological patterns revealed extensive mitosis and vasal invasion.

Multiple metastases to the lungs and pulmonary hilar

lymph nodes were seen bilaterally. The metastatic foci also revealed undifferentiated carcinoma, chondro- and osteosarcomatous variants. No continuity among them was seen.

For our immunohistochemical studies, we examined formol-fixed and pa raff i n-embedded sections obtained at the fifth operation and autopsy, using the avidin-biotin complex method (1 1). The antibodies used for staining were monoclonal antibodies against epithelial membrane antigen (EMA) (E29; Dakopatts, Glostrup, Denmark), cytokeratin (54 kDa) (MA-902 ; Enzo Diagnostics Inc., New York, NY), keratin (56k Da) (KL-1 ; Immunotech, Marseille, France) and muscle actin (42 kDa) (MA-931 ; Enzo Diagnostics Inc., New York, NY), and polyclonal antibodies against S-100 protein (Dakopatts, Glostrup, Denmark), vimentin (Medac, West Germany), lactoferrin (Dakopatts, Glostrup, Denmark) and lysozyme (Da- kopatts, Glostrup, Denmark). The results are shown in the Table 1. Epithelial markers (EMA E29 and cyto- keratin MA - 902) were positive not only in the undifferentiated carcinoma, but also in the chondrosar- comatous cells in the chondroid lacunae (Fig. 4).

Specimens for ultrastructural examination were obtained from the formol-fixed material from the fifth operation. Ultrast ructurally, their membrane structure was almost completely destroyed, but several des- mosome-like structures were observed in the chondrosar- comato us lesion and hemidesmosome-li ke structures were also apparent between the tumor cell membrane and pericellular collagenous stroma.

Figure 3. Material from the fourth recurrence. Malignant Figure 4. Autopsy material. Recurrent tumor showing transi- tumor cells showing osteoid formation. HE. tion among chondrosarcomatous and osteosarcomatous lesions,

and undifferentiated carcinoma. HE. Inset: Scattered cytokeratin (MA-902)-positive chondrosar- comatous cells within lacunae.

830 Carcinosarcoma of Submandibular Gland (Suzuki et a/ . )

DISCUSSION

The present case was diagnosed as carcinosarcoma of the submandibular gland, one of the categories of true malignant mixed tumor (2), because of its admixture of carcinomatous and sarcomatous lesions. The former consisted mainly of undifferentiated carcinoma and the latter was composed of both chondro- and osteosar- comatous elements. In the pulmonary metastases, both sarcomatous and carcinomatous areas were seen, thus confirming the diagnosis.

Carcinosarcoma of the salivary glands is rather rare. Detailed case reports have been published by King (4), Jacobson et a/. (5), Chen et a/. (6), Tortoledo et a/. (7), Huntington and Dardick (8), Stephen et a/. (9) and Yamashita et a/. (10). In the cases reported previously, carcinosarcoma appeared more frequently in female than in male patients, and occurred most often in the parotid gland. Our present case in a male patient appeared to originate in the submandibular gland, and the tumor appears to be one of the largest ever reported.

Carcinosarcoma of the salivary gland is extremely aggressive and invariably fatal. In the present case, proliferation of the tumor accelerated rapidly after the fourth operation and radiation therapy (total 110 Gy), apparently being corn pat i ble with sarcoma tous t ra nsfor- ma tion.

The origin of carcinosarcoma is unknown, but in this case, an epithelial origin was likely, because of the follow- ing three findings: a) Presence of an apparent transition from a carcinomatous to a sarcomatous pattern. b) Staining of the tumor cells in the chondroid lacunae for epithelial markers (EMA and cytokeratin MA-902). c) Presence of desmosome-like structures in the chon- drosa rcoma tous lesion.

In the present case, S-100 protein, vimentin and muscle actin were observed in the sarcomatous and/or undifferentiated carcinoma. The original cells of un- differentiated carcinoma and carcinosarcoma are difficult to determine. There has been some conjecture as to the origin of undifferentiated carcinoma, especially the role of myoepithelial cells. Batsakis (1 2) considered ana- plastic carcinomas to arise from uncommitted cells anal- ogous to the embryonic primordium before the first regulatory event of cytodifferentiation, and also de- scribed the unreliability of light and even electron micro- scopic observation for correct identification of myoepithelial cells. Nagao et a/. (13), on the other hand, believed that undifferentiated carcinomas could develop subsequent to malignant transformation of myoepithelial cells growing in benign pleomorphic adenomas, and that these malignant cells would be capable of differentiating into various other cell types.

Positive staining of muscle actin and S-100 protein might support a myoepithelial origin of undifferentiated carcinoma, but the possibility of origin from reserve or stem cells in the benign mixed tumor cannot be excluded.

Carcinomatous transformation of benign mixed tumors after radiation therapy has been reported by Nagao et a/. (13) and Saksela et a/. (14). In the pres- ent case, the second, third and fourth surgical specimens were diagnosed as carcinoma ex mixed tumor, in which squamous cell carcinoma and undifferentiated carcinoma were present as malignant components. Carcinosar- coma became unequivocal in the fifth surgical specimen. The doses of radiation therapy employed were 60 Gy in 1983 and 50 Gy in 1984. According to a report by Tountas et a/ . (15), over 70 Gy irradiation to bone can give rise to radiation-induced sarcoma with an incidence of 0.2% or more. We consider that the radiation treat- ment in this case may have played some role in its sarcoma tous transformation.

Acknowledgements : The authors are grateful to the surgery and pathology staff of San’iku-kai Hospital for preparing operation materials, and the pathology staff of Tokyo Metro- politan Tama Geriatric Hospital for their helpful advice and technical support.

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Acta Pathologica Japonica 40 (1 1): 1990 831

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