Pathology of True Malignant Mixed Tumor (Carcinosarcoma)

Different patterns of malignant change occur in pleomorphic adenoma, of which true malignant mixed tumor (carcinosarcoma) is one form. The other 2 forms are carcinoma ex pleomorphic adenoma and metastasizing benign pleomorphic adenoma.

By definition, carcinosarcoma is a biphasic malignant tumor with a carcinomatous component and a sarcomatous component. Most of these tumors arise in the background of pleomorphic adenoma; however, some arise de novo .

Carcinosarcoma of the salivary glands was first described by Kirklin et al in 1951. ^[1] The term true malignant mixed tumor in the salivary glands was first used by King in 1967 in a study that helped to renew interest in this tumor group. ^[2]

Carcinosarcoma is an extremely rare and aggressive entity. ^[3] It accounts for only 0.04-0.16% of all salivary gland tumors. In the reported cases, patients ranged in age from 15-85 years. There was no predilection with regard to gender. Many of the patients had a history of pleomorphic adenoma, recurrent pleomorphic adenoma, or recurrent carcinoma ex pleomorphic adenoma. ^{[3, 4, 5, 6, 7, 8, 9, 10, 11, 12]} Some cases, however, seem to arise de novo, in the absence of a previous pleomorphic adenoma. ^{[3, 13, 14, 15, 16]}

No clear etiology is known. However, accumulation of genetic mutations could be a factor. A history of exposure to irradiation of pleomorphic adenoma has been reported. ^{[11, 17]} The reported interval between the irradiation and the onset of carcinosarcoma varies from 1 to 36 years.

Two schools of thought exist as to the origin of carcinosarcomas. The convergence hypothesis maintains that multiclonal stem cells of the epithelial and mesenchymal components play a causative role. The divergence hypothesis postulates a monoclonal origin from a single totipotent stem cell with divergent differentiation. ^{[18, 19]} The latter hypothesis is more favored.

Gotte et al hypothesized that the tumor originates from a myoepithelial cell precursor. ^[20] Other investigators have postulated that the tumor originates from inner ductal cells ^[5] or a pluripotent primitive cell. ^[14]

In the major salivary glands, most reported cases of carcinosarcoma (65%) occurred in the parotid gland. ^{[1, 3, 4]} Some cases (19%) have been reported in the submandibular gland. ^{[3, 14, 21]} In the minor salivary glands, the palate is the most common site, ^[6] but other sites, including the cheek, have been reported. ^{[22, 23]}

The tumor presents as a mass that may be rapidly enlarging. ^[24] In some cases, the mass is painful; the pain may be localized, referred, or both. If the parotid gland is involved, signs of facial nerve weakness/paralysis are commonly encountered.

True malignant mixed tumors are poorly circumscribed, with infiltrative borders. They are gray, and focal areas of hemorrhage and necrosis may be present. Some tumors are well circumscribed. Most reported tumors range from 2-13 cm in greatest dimension.

A carcinosarcoma neoplasm is a biphasic tumor in which the carcinomatous component is usually a poorly differentiated adenocarcinoma, an undifferentiated carcinoma, or a squamous cell. ^[25] It may also include adenoid cystic carcinoma, epithelial myoepithelial carcinoma, and salivary duct carcinoma.

The sarcomatous component is usually a chondrosarcoma. Other reported sarcomatous elements include spindle cell sarcoma not otherwise specified (NOS), fibrosarcoma, osteosarcoma, leiomyosarcoma, liposarcoma, follicular dendritic cell sarcoma, undifferentiated sarcoma, myxoid sarcomas, and rhabdomyosarcoma, ^{[26, 16]} among others. The relative proportion of the 2 components is variable, and either component may dominate the histologic picture.

In the images below, the sarcomatous (spindle cell sarcoma) component of the tumor is dominant, with the smaller portion being poorly differentiated adenocarcinoma.

The carcinomatous component of a carcinosarcoma of the parotid gland. In this case, the tumor is a poorly differentiated adenocarcinoma.

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The sarcomatous component of a carcinosarcoma of the parotid gland. In this case, the tumor is a spindle cell sarcoma not otherwise specified (NOS).

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The histologic picture depends on the types of the constituent cells of sarcoma and carcinoma. Extensive infiltration and tissue destruction are common, as are perineural invasion and angioinvasion. Lymphatic spread is less common. ^[27]

Metastases to other sites or lymph nodes may show the carcinomatous or the sarcomatous components alone, or the components may be mixed.

The immunohistochemical panel varies, depending on the observed biphasic components of the tumor. Generally speaking, however, the carcinomatous component is usually positive for cytokeratin and epithelial membrane antigen (EMA). However, it should be noted that in very poorly differentiated tumors, the carcinomatous component may show only focal or weak positive staining for cytokeratins or EMA, a feature that is sometimes encountered in very poorly differentiated cancers of the head and neck. In such cases, electron microscopy may be helpful. The sarcomatous component is vimentin positive.

Few genetic studies have been performed on these tumors, owing to their rarity. However, abnormalities in chromosomes 7, 8, 9, 10, 12, 13, 17, and 18 have been described. ^{[19, 20]} A study showed specific amplifications of mucin 20 (MUC 20) in mesenchymal elements (gene products that are known to be overexpressed in various cancers and that correlate with poor outcome). BMI-1 (a proto-oncogene found to be deregulated in several neoplasms, including salivary gland tumors) was observed in both element loci. ^[19]

Tumor spread may occur by direct extension, hematogenous, lymphatic, or perineural invasion.

Tumor staging in the salivary glands depends on whether the tumor is located in the head or neck area. Tables 1 and 2 define the American Joint Committee on Cancer (AJCC) staging of malignant tumors of the major salivary glands (ie, parotid, submandibular, sublingual). ^[28]

Table 1. TNM Classification (Open Table in a new window)

Table 2. Stage Grouping (Open Table in a new window)

Carcinosarcoma is an aggressive, high-grade tumor. Recurrence, distant metastasis (54%), and angiolymphatic invasion are frequently encountered. The lungs are the most common site of metastasis. Metastasis may also occur to the liver, bones, and brain. Involvement of cervical lymph nodes with metastasis is uncommon.

In a review by Gnepp, ^[3] 58% of patients died as a result of the tumor. A review of 19 cases of de novo carcinosarcomas by Staffeieri et al ^[16] found that 31.6% of patients died of the disease. The median period of survival after diagnosis was 10 months; in 63% of cases, there was no evidence of recurrence after a median period of 22.4 months.

Because of the rarity of the tumor, whether arising de novo or in a pleomorphic adenoma, consensus on therapeutic approaches has been lacking. A combination of surgery followed by radiotherapy seems to be statistically superior to resection alone. ^{[16, 29]} The role of chemotherapy remains unclear.

The results of a retrospective analysis of 15 cases of sinonasal carcinosarcoma suggested that patients with sinonasal carcinosarcoma have disease-specific survival comparable to the case-matched cohort of salivary gland carcinosarcoma patients. The study added that sinonasal carcinosarcoma patients have significantly poor survival outcomes compared to patients from the cohort of carcinosarcoma at all other head and neck sites. ^[30]