Year : 2009 | Volume
: 52 | Issue : 2 | Page : 150--154
Spectrum of malignancy in mixed tumors of salivary gland: A morphological and immunohistochemical review of 23 cases
Asim Qureshi, Abrar Barakzai, Najam Ul Sahar, Rubina Gulzar, Zubair Ahmad, Sheema H Hassan
Section of Histopathology Aga Khan University, Karachi, Pakistan
Section of Histopathology, Department of Pathology and Microbiology, Aga Khan University, Hospital, Stadium Road P. O. Box 3500, Karachi
Malignancy arising in mixed tumors of the salivary gland is a distinct entity that can occur sporadically or in association with a background of pleomorphic adenoma. Carcinoma arising with a background of pleomorphic adenoma is well documented. However, there are rare occurrences of aggressive de novo carcinosarcomas of the parotid that have been reported. Various cell lineages such as the epithelial glandular cells and the stromal spindle cells are involved. We report 23 cases of tumors of the salivary gland comprising 18 cases of carcinoma ex pleomorphic adenoma, four cases of carcinosarcoma of the parotid and one case of benign metastasizing pleomorphic adenoma. The occurrence of various malignancies suggests that this phenomenon is not very uncommon and should be looked for when reporting a mixed tumor.
|How to cite this article:|
Qureshi A, Barakzai A, Ul Sahar N, Gulzar R, Ahmad Z, Hassan SH. Spectrum of malignancy in mixed tumors of salivary gland: A morphological and immunohistochemical review of 23 cases.Indian J Pathol Microbiol 2009;52:150-154
|How to cite this URL:|
Qureshi A, Barakzai A, Ul Sahar N, Gulzar R, Ahmad Z, Hassan SH. Spectrum of malignancy in mixed tumors of salivary gland: A morphological and immunohistochemical review of 23 cases. Indian J Pathol Microbiol [serial online] 2009 [cited 2020 May 31 ];52:150-154
Available from: http://www.ijpmonline.org/text.asp?2009/52/2/150/48904
Malignancy arising in pleomorphic adenoma encompasses three entities - carcinoma ex pleomorphic adenoma, carcinosarcoma and metastasizing pleomorphic adenoma. The latter two are exceedingly rare. 
Malignancy in pleomorphic adenoma is usually restricted to the epithelial elements and metastasis reported is restricted to the carcinomatous elements only. It occurs over a wide range, with the majority of cases in the sixth to eighth decades about 10 years after the uncomplicated pleomorphic adenoma. Most series report a slight female predominance.  Any gland can be involved although the parotid is the most common. The tumor typically presents with a long history of the nodule suddenly increasing in size. 
The main requirement of histologic diagnosis is the presence of pleomorphic adenoma and a carcinoma. The former is often largely hyalinized and extensive sampling may be required to detect typical areas.  Sometimes the origin can only be inferred from history. Most forms of carcinoma have been described, the most common being poorly differentiated carcinoma and undifferentiated carcinoma. There is evidence that the former is salivary duct carcinoma and the latter is myoepithelial carcinoma.  Carcinosarcoma is an exceedingly rare malignant tumor composed of a mixture of carcinomatous and sarcomatous, with either component capable of metastasis.  The mean age at presentation is 58 years (14-87 years) and most cases are seen in the parotid gland. It may arise in pre-existing pleomorphic adenoma or de novo .  The differential diagnosis includes spindle cell squamous carcinoma, primary salivary sarcomas and carcinoma ex pleomorphic adenoma. Some of the lesions involve other salivary glands. The disease follows a very aggressive course. Distant spread is usually blood borne whereas lymph node metastasis is rare. 
The outcome of carcinosarcoma is usually poor, with 60% of the patients dying of the disease. , Metastasizing pleomorphic adenoma is defined as histologically benign pleomorphic adenoma that manifests local or distant metastasis. 
Materials and Methods
Twenty-three cases were received in our center in the histopathology section over a duration of 4 years from 2004 to 2008. Demographics and clinical data were obtained. Hematoxylin and eosin slides of all the cases were reviewed. Immunohistochemical studies using the avidin biotin complex immunoperoxidase technique were performed. The following antibodies were used: Cytokeratin AE1/AE3, Vimentin, p53 S-100 Actin and Desmin [Table 1].
Microscopic features of the 18 cases of carcinoma ex pleomorphic adenoma were similar in all the cases, showing histology reminiscent of pleomorphic adenoma with malignant epithelial elements. The carcinomatous component was generally poorly differentiated adenocarcinoma, squamous cell carcinoma and mucoepidermoid carcinoma [Table 1].
Invasion beyond the capsule was noted in all the cases [Figure 1] and was found in four cases.
The microscopic findings of all four cases of carcinosarcoma were essentially those of a biphasic tumor [Figure 2]. The malignant epithelial cells were arranged in glandular structures and nests. The surrounding stroma showed pleomorphic spindle cells with brisk mitotic activity. Special stain for acid mucin periodic acid-Schiff (PAS) with alcian blue was positive in the glandular areas [Figure 3]. Results of the immunohistochemical stains are summarized in [Table 1].
Only one case of metastasizing mixed tumor was diagnosed [Figure 4]. The histology was typical of benign mixed tumor and there were cervical lymph node metastases. The metastatic focus showed distinct pleomorphic adenoma-like areas.
Lymph nodes were received in 10 of the 23 cases. These included four cases of carcinosarcoma and five cases of carcinoma ex pleomorphic adenoma and one case of benign metastasizing pleomorphic adenoma. The lymph nodes were positive in three of the four cases of carcinosarcoma and in one case of benign metastasizing mixed tumor. All the cases of carcinoma ex pleomorphic adenoma were node negative [Table 1].
Cytokeratin CK AEI/AE3 and Vimentin were performed in all the 23 cases [Table 1].
Desmin, Actin and S 100 were performed in all the four cases of carcinosarcoma [Table 1].
P53 overexpression was seen in all the cases of carcinosarcoma [Table 1].
Cytokeratin AE1/AE3 positivity was seen in the carcinomatous areas whereas Vimentin positivity was observed in the malignant mesenchymal elements [Figure 5]. Desmin and Actin positivity were seen in areas of muscle differentiation whereas S100 was present in the chondroid and neural areas [Figure 6].
The spectrum of malignancy in mixed tumors as already stated comprises three distinct entities. , The categorization of these is important for treatment planning and determination of the prognosis. The aggressive tumors have a high MIB1 index, which results in rapid growth. In most reported instances, histology is the gold standard for diagnosis and immunohistochemical stains are required only for finer categorization and help in establishing the proliferative index. 
The main requirement for diagnosis of carcinoma ex pleomorphic adenoma is the presence of pleomorphic adenoma and a carcinoma. The average size of carcinoma ex pleomorphic adenoma is twice its benign counterpart.  Grossly, carcinoma ex pleomorphic adenoma is usually poorly circumscribed and in many is usually extensively infiltrative. An important feature is whether the carcinoma has breached the capsule. On the basis of capsular breach, the tumor is classified as non-invasive, minimally invasive or invasive. Despite its malignant histology, non-invasive tumors generally behave indolently, with a report of only one patient developing metastasis.  In invasive cancers, the extent of capsular invasion is important. In one study, all patients with widespread invasion beyond the capsule died of the disease.  The main practical difficulty encountered by the pathologist with these cases is the rarity of these entities, determination of the extent of invasion with carcinoma, extent of invasion and adequate sampling of the capsule for this purpose. The differential includes various other forms of salivary gland carcinoma. The treatment is radical surgery and neck dissection. Thus, post-operative radiotherapy may be required. Other forms of recurrence include implantation along surgical tracts and spread to body fluids. 
Analogous to benign mixed tumor, carcinosarcomas are composed of both epithelial and mesenchymal components. Cytologic atypia, including cellular and nuclear pleomorphism, hyperchromatism, mitotic figures and invasive growth, distinguish carcinosarcomas from benign mixed tumor. Both carcinomatous and sarcomatous areas are evident and differentiate these neoplasms from carcinoma ex benign mixed tumors in which only carcinomatous areas are present. In most tumors, the sarcomatous component is characterized as chondrosarcoma, osteosarcoma, fibrosarcoma or rhabdomyosarcoma. In most cases, the sarcomatous component dominates over the carcinomatous component. The most frequent carcinomatous component is ductal carcinoma. Metastatic and recurrent tumors usually manifest both the elements. , In some tumors, the foci of benign mixed tumor have also been identified. Sometimes, the excised sites of benign mixed tumors later develop carcinosarcomas. Differential diagnosis includes benign mixed tumor and primary and metastatic sarcomas. In the intra-oral tumor spindle cell carcinoma is also considered in the differential. Biphasic malignant morphology and immunohistochemical stains, including cytokeratin AE1/AE3, Vimentin, S-100 and anti smooth muscle actin are helpful in differentiating carcinomatous and sarcomatous components. 
Carcinosarcoma is an aggressive, high-grade malignancy and aggressive therapy employing radical surgery with and without adjunctive radiotherapy and chemotherapy is used. Hematogenous metastasis is more common; radical neck dissection is appropriately reserved for patients with lymphadenopathy. 
Metastasis of benign metastasizing pleomorphic adenoma can be found in lymph nodes, bone and lungs. Recommended therapy is resection for both primary and metastasis.
Points for Best Practice
While morphology remains the mainstay in diagnosis of salivary gland tumors, immunohistochemistry is valuable in the diagnosis of malignant tumors. Estimation of the proliferation index by MIB1 and P53 gives prognostic information in the carcinomatous and sarcomatous areas, and the most important prognostic indicator in carcinoma ex pleomorphic adenoma is invasion beyond the capsule.[Figure 7]
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