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This tumor of the salivary glands is also known as a benign mixed tumor and presents as a painless mass, typically in adults from the 3rd to 5th decades. The tumor has a circumscribed appearance when it is cut (see gross pictures). The majority of these tumors arise within the parotid gland (75-85%). When occurring in minor salivary glands, the palate is the most common site (60-65%). Complete surgical removal is curative but if the initial surgical procedure does not completely remove the tumor, there is a low recurrence rate of less than 2%.

Rarely, a malignant tumor may arise within this tumor, a phenomenon known as carcinoma ex pleomorphic adenoma. This has been reported to occur in 2-7% of cases. The most reliable features to determine malignancy include an infiltrative growth pattern, vascular permeation, perineural invasion, and marked cytologic atypia with abnormal mitotic figures. There is a second class of tumors which are called metastasizing benign mixed tumors. This seeming oxymoron occurs with tumors that have a histologically benign appearance but usually have a history of multiple local recurrences. Metastases occur several years after the initial diagnosis and may occur to the lungs, regional lymph nodes, skin, and bone. The usual clinical course is good but there are cases which have an aggressive clinical course leading to death in 22% of cases. Fortunately this last category of tumors is very rare.


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Molecular analysis of chromosome 16q regions in dermal analogue tumors of salivary glands: a genetic link to dermal cylindroma?

Choi HR, Batsakis JG, Callender DL, Prieto VG, Luna MA, El-Naggar AK.

Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

Am J Surg Pathol 2002 Jun;26(6):778-83 Abstract quote

Dermal analogue tumor, an uncommon subtype of basal cell monomorphic adenoma of the parotid gland, has a remarkable clinical and histologic resemblance to dermal cylindroma. Molecular studies of familial and sporadic cylindromas have shown frequent alterations at chromosome 16q12-13 that have recently been found to house the cylindromatosis gene (CYLD).

To determine the involvement of the chromosome 16q12-13 region in dermal analogue tumors, we performed loss of heterozygosity analysis using microsatellite markers flanking the cylindromatosis gene locus in 21 sporadic dermal analogue salivary tumors and 12 salivary and dermal lesions from two sisters. Loss of heterozygosity was identified in 17 (80.9%) of the 21 sporadic tumors and in nine of the 12 dermal and salivary gland dermal analogue tumors from the two sisters; a parathyroid adenoma from one sister and two lymphoepithelial lesions from the second sister showed no microsatellite alterations. Microsatellite instability was only identified in three sporadic tumors at marker D16S308. Markers D16S409 (centromeric), D16S541, and D16S308 (telomeric) to the CYLD gene showed the highest incidence of loss of heterozygosity (>65%). The minimally deleted region was flanked proximally by marker D16S389 and distally by marker D16S419 and spanned the 771.5-megabase fragment that included the CYLD locus.

We conclude that dermal analogue tumor and cylindroma share similar incidence of alterations at the 16q12-13 region, supporting a common molecular origin.

PLAG1 gene alterations in salivary gland pleomorphic adenoma and carcinoma ex-pleomorphic adenoma: a combined study using chromosome banding, in situ hybridization and immunocytochemistry.

Martins C, Fonseca I, Roque L, Pereira T, Ribeiro C, Bullerdiek J, Soares J.

1Centro de Investigacao de Patobiologia Molecular (CIPM), Instituto Portugues de Oncologia de Francisco Gentil, Lisboa, Portugal.
Mod Pathol. 2005 Aug;18(8):1048-55. Abstract quote  

Pleomorphic adenoma is the most common benign tumor of the salivary glands. It has marked histological diversity with epithelial, myoepithelial and mesenchymal-type cells arranged in a variety of architectural and differentiation patterns.

Pleomorphic adenoma gene 1 (PLAG1), shown to be consistently rearranged in pleomorphic adenomas, is activated by chromosomal translocations involving 8q12, the chromosome region that is most frequently affected in these tumors.

In this study, we evaluated PLAG1 involvement in salivary gland tumorigenesis by determining the frequency of its alterations in a selected group of 20 salivary gland tumors: 16 pleomorphic adenomas and four carcinomas ex-pleomorphic adenoma, having in common the presence of karyotypic chromosome 8 deviations, either structural, with 8q12 rearrangements, or numerical, with gain of chromosome 8. PLAG1 status was analyzed using in situ hybridization techniques, on metaphase cells, by fluorescence detection and/or interphase cells in paraffin sections, by chromogenic detection. Except for one pleomorphic adenoma case (5%) that lacked PLAG1 involvement, 17 tumors (85%), (14 pleomorphic adenomas and three carcinomas ex-pleomorphic adenoma) showed intragenic rearrangements of PLAG1 and the remaining two cases (10%), (one pleomorphic adenoma and one carcinoma ex-pleomorphic adenoma), had chromosome trisomy 8 only.

To further investigate the role of PLAG1 on pleomorphic adenomas tumorigenesis, as well as the putative morphogenesis mechanism, we attempted to identify the cell types (epithelial vs myoepithelial) carrying 8q12/PLAG1 abnormalities by a combined phenotypic/genotypic analysis in four cases (three pleomorphic adenoma and one carcinoma ex-pleomorphic adenoma) characterized by 8q12 translocations and PLAG1 rearrangement. In these cases, both cells populations carried PLAG1 rearrangements.

This finding further supports the pluripotent single-cell theory, which postulates that the tumor-initiated, modified myoepithelial cell, evolves into the varied somatic cell phenotypes present in pleomorphic adenoma, and reinforces the role of PLAG1 on the tumorigenesis of benign and malignant pleomorphic adenoma.
Histologic localization of PLAG1 (pleomorphic adenoma gene 1) in pleomorphic adenoma of the salivary gland: cytogenetic evidence of common origin of phenotypically diverse cells.

Debiec-Rychter M, Van Valckenborgh I, Van den Broeck C, Hagemeijer A, Van de Ven WJ, Kas K, Van Damme B, Voz ML.

Laboratory for Cytogenetics and Molecular Genetics of Human Malignancies, Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
Lab Invest. 2001 Sep;81(9):1289-97. Abstract quote  

Pleomorphic adenoma gene 1 (PLAG1), a zinc finger transcription factor gene, is consistently rearranged and overexpressed in human pleomorphic adenomas of the salivary glands with 8q12 translocations.

In this report, we describe the immunohistochemical localization of PLAG1 protein in pleomorphic adenomas of the salivary gland and corresponding normal tissue, in relation to cytokeratin, vimentin, and BCL-2 expression. Normal salivary gland tissue was not immunoreactive for PLAG1.

In primary pleomorphic adenomas, cells strongly immunoreactive for PLAG1 were detected in the outer layer of tubulo-ductal structures, which are thought to be the origin of cells with bi-directional, epithelial, and mesenchymal phenotypes.

In contrast, epithelial cells with abundant cytokeratin in the inner tubulo-ductal structures only sporadically expressed PLAG1. BCL-2 immunoreactivity was found mainly in the cells surrounding the tubulo-ductal structures and in the solid undifferentiated cellular masses, within the areas that had moderate PLAG1 immunoreactivity. The variability of PLAG1 expression in neoplastic cells seemed to reflect the morphologic heterogeneity that correlated with the stage of differentiation of the tumor cells.

Immunohistochemical/cytogenetic evaluation of two pleomorphic adenomas with t(3;8)(p21;q12) or t(5;8)(p13;q12) translocations demonstrated the clonal nature of immunophenotypically diverse cells. This finding confirms the theory that pleomorphic adenoma cells share a common single-cell origin, most likely from the epithelial progenitor basal duct cells.


GENERAL Mixture of histologic patterns which gives rise to its name. The epithelial component is made up of trabeculae, tubules, or cysts. The mesenchymal component has a myxoid stroma with elements such as chondroid or bone.
Pleomorphic Adenoma With Extensive Lipometaplasia: Report of Three Cases.

Haskell HD, Butt KM, Woo SB.

From the *Department of Pathology, Brigham and Women's Hospital, Boston, MA; daggerDepartment of Pathology, North Shore Medical Center, Lynnfield, MA; double daggerPathology Services Incorporated, Cambridge, MA; and section signDepartment of Oral Medicine, Immunity and Infection, Harvard School of Dental Medicine, Boston, MA.

Am J Surg Pathol. 2005 Oct;29(10):1389-1393. Abstract quote  

We report a series of three cases of pleomorphic adenoma with extensive lipometaplasia, a recently described subtype of pleomorphic adenoma of salivary gland origin.

Two patients were female and one male, ranging in age from 30 to 45 years. Two occurred in the minor salivary glands of the lip and palate, respectively, and one in the parotid. Typical histologic findings are presented. In addition, one case consists of a proliferation of spindle cells with an interesting combination of mature adipose tissue, hyaline cartilage, and bone in the absence of ductal structures.

The differential diagnosis, as it pertains to other fat-containing tumors (such as lipoadenoma, spindle cell lipoma, interstitial lipomatosis, and benign mesenchymoma), is discussed. It is likely that the ability of myoepithelial cells to undergo various metaplasias is the cause of the unusual histologic appearances of this tumor.
Malignant mixed tumors of the salivary gland: a study of loss of heterozygosity in tumor suppressor genes.

Fowler MH, Fowler J, Ducatman B, Barnes L, Hunt JL.

1Department of Pathology and Laboratory Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Mod Pathol. 2006 Mar;19(3):350-5. Abstract quote  

Carcinosarcomas and carcinoma ex pleomorphic adenoma of the salivary glands are rare tumors that fit into the broader category of malignant mixed tumors. Although most evidence has suggested that the different morphologic components arise from a common clonal origin, there are very few studies that have provided molecular evidence for this clonality.

In this study, we examined a set of seven carcinosarcomas and four carcinomas ex pleomorphic adenoma for tumor suppressor gene loss of heterozygosity, in order to assess the clonal patterns in the varying components. Microdissection was performed to obtain each morphological component and tumor suppressor gene loci on 3p, 5q, 9p, 17p, 17q, and 18q were analyzed. The fractional allelic loss (FAL) was calculated for each area, and the different targets were compared for their molecular profile. The overall mean FAL of the malignant targets was 42%. In carcinosarcomas, the sarcomatous targets had a higher mean FAL than the carcinomatous targets (68 vs 46%, respectively) and in carcinomas ex pleomorphic adenoma, the mean FAL in the benign component was 11 vs 46% seen in the carcinomatous component.

The most frequently lost genetic loci were p53 (17p13, 73%), nm23-H1 (17q21, 55%), and DCC (18q21, 50%). Loss of heterozygosity of 17q21 and 9p21 only occurred in carcinosarcomas and not in carcinomas ex pleomorphic adenoma. Within the carcinosarcomas, the mutational profiles were conserved between epithelial and sarcomatous areas. In carcinomas ex pleomorphic adenoma, loss of heterozygosity was uncommon in the benign component, but the mutations were conserved in the corresponding malignant areas.

These results support the hypothesis that the carcinomatous and sarcomatous components of carcinosarcomas are clonally related. Furthermore, these data support prior studies that suggest a common clonal origin for the benign and malignant components of carcinomas ex pleomorphic adenoma.
Sebaceous carcinoma ex-pleomorphic adenoma: A rare phenotypic occurrence.

Cohn ML, Callender DL, El-Naggar AK.
Ann Diagn Pathol. 2004 Aug;8(4):224-6. Abstract quote  

Primary sebaceous carcinoma of salivary glands is a rare entity with approximately 22 de novo documented cases. Similar tumor arising in a benign mixed tumor has only been reported once.

We report a second case of sebaceous carcinoma in a pleomorphic adenoma and discuss the clinicopathologic features, histogenesis, and the differential diagnosis of this unusual tumor.

Carcinoma ex pleomorphic adenoma: Pathologic analysis of 73 cases

Jean E. Lewis, MD, Kerry D. Olsen, MD and Thomas J. Sebo, MD, PhD

Hum Pathol 2001;32:596-604. Abstract quote

Pathologic factors of predictive value for carcinoma ex pleomorphic adenoma (CXPA), an aggressive salivary gland malignancy, are poorly defined. Because residual mixed tumor may be relatively inconspicuous and various carcinoma subtypes are encountered, misdiagnosis is common. To describe the pathologic features and identify potential prognostic factors, we retrospectively examined 73 cases of CXPA of the major salivary glands treated at Mayo Clinic.

Paraffin section immunostaining for keratins (AE1/AE3, CK7, CK20), epithelial membrane antigen, carcinoembryonic antigen, vimentin, actin, S-100 protein, glial fibrillary acidic protein, and p53 and c-erbB-2 oncoproteins was performed in 69 cases. DNA content and proliferation indices were determined by digital image analysis of Feulgen- and MIB-I-stained sections, retrospectively. Survival was calculated by the Kaplan-Meier method, and prognostic variables were analyzed with the log-rank test. The carcinoma component was predominant in 82% of tumors. Adenocarcinoma not otherwise specified (31 cases) and salivary duct carcinoma (24 cases) were the most frequent histologic subtypes. Sixty-two tumors were high grade (Broders 3 or 4). Residual mixed tumor was extensively hyalinized in 54 cases.

Pathologic features significantly associated with overall survival included pathologic stage (P = .009), tumor size (P = .012), grade (P = .005), proportion of carcinoma (P = .004), extent of invasion (P = .002), and proliferation index of carcinoma (P = .03). Of 4 patients with intracapsular (noninvasive) carcinoma, none had an adverse outcome. The immunohistochemical profile of CXPA included positive staining reactions in the malignant component for AE1/AE3 in 97% of cases, CK7 in 94%, epithelial membrane antigen in 86%, carcinoembryonic antigen in 75%, vimentin in 52%, and S-100 protein in 29%. Expression of p53 and c-erbB-2 oncoproteins was detected in 41% and 30% of the carcinomas, respectively, but neither was associated with decreased survival.

High-grade salivary adenocarcinoma that is difficult to classify should raise the suspicion of possible CXPA. Intracapsular carcinoma has a benign clinical course. Significant prognostic factors in CXPA include tumor stage, grade, proportion of carcinoma, extent of invasion, and proliferation index.



Metastasizing Mixed Tumor of the Parotid Initial Presentation as a Solitary Kidney Tumor and Ultimate Carcinomatous Transformation at the Primary Site

Magdalena Czader, M.D., Ph.D.; Charles G. Eberhart, M.D., Ph.D.; Nasir Bhatti, M.D.; Charles Cummings, M.D.; William H. Westra, M.D.

From the Departments of Pathology (M.C., C.G.E., W.H.W.) and Otolaryngology/Head Neck Surgery (N.B., C.C., W.H.W.), The Johns Hopkins Medical Institutions, Baltimore, Maryland, U.S.A.

Am J Surg Pathol 2000;24:1159-1164 Abstract quote

Benign mixed tumors of the salivary glands are generally regarded as indolent and harmless neoplasms. A subset of benign mixed tumors, however, can undergo carcinomatous transformation (that is, carcinoma ex-mixed tumor). Even more rarely, a mixed tumor that is seemingly benign at the microscopic level will metastasize like a true carcinoma (that is, metastasizing mixed tumor [MZMT]). Despite the benign appearance of the metastatic implants, there is usually little doubt regarding their true nature and origin. Patients invariably have had a mixed tumor removed from the parotid or some other salivary gland, and metastatic spread is usually preceded by multiple episodes of local tumor recurrence.

We report a case of MZMT that presented as a solitary kidney mass.

In the absence of a previous or concurrent salivary gland tumor, its metastatic nature was not appreciated and it was regarded as an unusual but benign kidney adenoma. One year after removal of the kidney mass, the patient presented with signs and symptoms of an aggressive parotid tumor. Pathologic examination of the tumor in the parotid demonstrated a high-grade carcinoma arising from a mixed tumor.

This case underscores the importance of considering MZMT when a seemingly benign mixed tumor is encountered at a nonsalivary site, even in patients without a supportive history. Failure to do so may cause an unnecessary delay in primary tumor diagnosis and management, allow the primary tumor to progress toward a more malignant phenotype, and deny the patient a high expectation for a complete cure.

Prognostic factors in malignant mixed tumors of the salivary gland: Correlation of immunohistochemical markers with histologic classification.

Xin W, Paulino AF.

Department of Pathology, The University of Michigan Hospitals, Ann Arbor, MI.


Ann Diagn Pathol 2002 Aug;6(4):205-10 Abstract quote

Malignant mixed tumor of salivary glands is a rare tumor whose variable behavior and prognosis are related for the most part to the clinical stage and histologic grade of the carcinomatous component.

The purpose of this study is to predict prognosis by comparing the histologic grading and subclassification of the carcinomatous component with the immunohistochemical reactivity for E-cadherin, P53 mutation protein, and cellular proliferation (Ki67). Stains were performed on formalin-fixed paraffin-embedded tissue sections from 18 cases of malignant mixed tumor. Clinical follow-up was obtained for each patient. Regional lymph node and distant organ metastases were the criteria for poor prognosis. Of seven cases with lymph nodes metastasis, five were high-grade tumors (with one subsequent death from brain metastasis) and two were low-grade. Of the eight high-grade tumors, positivity for Ki67, p53, and E-cadherin were noted in six, four, and two cases, respectively. In contrast, of the 10 low-grade tumors, two stained with Ki67, five with p53, and none with E-cadherin. Most notably, all seven metastatic cases (as opposed to only one of 11 nonmetastatic tumors) had Ki67 reactivity of more than 10%.

We conclude that malignant mixed tumor represents a spectrum of malignancies in which the clinical behavior is closely related to the carcinomatous element. In addition to histologic grading, Ki67 is a useful prognostic marker in the evaluation of malignant mixed tumor while p53 and E-cadherin appear to be of limited value.

Am J Surg Pathol 2000;24:1159-1164
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Last Updated March 7, 2006

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