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Salivary glands

Epithelial / myoepithelial tumors

Malignant mixed tumor


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 29 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
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● Usually defined as carcinoma that develops in association with benign primary or recurrent pleomorphic adenoma
● Rare spectrum of carcinomas demonstrating abrupt transition from benign tumor (usually pleomorphic adenoma); often adenocarcinoma NOS, myoepithelial, salivary duct, terminal duct or undifferentiated carcinomas, usually with benign stroma
● Also called carcinoma ex pleomorphic adenoma

Clinical features
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● 4% of salivary neoplasms, 12% of salivary malignancies, but only 1% of intraoral salivary gland or minor salivary gland neoplasms
● 5% of parotid tumors but 18% of malignant parotid tumors
● Median age 55 years, average age 60 years, but also children (9% of salivary gland neoplasms in children), teenagers
● Associated with pleomorphic adenomas: 2% risk of malignant transformation if present < 5 years, 10% risk if 15 years
● Note: prior history of pleomorphic adenoma may be difficult to obtain, but necessary for diagnosis unless benign tumor coexists with malignant tumor
● Note: must rule out malignant mixed tumor if a high grade carcinoma of salivary glands is difficult to classify, by vigorous searching for a benign mixed tumor (may be 5 mm or less)
● Clinically, have sudden increase in growth, pain or facial paralysis, facial tingling, trismus
● 23% have recurrence, 56% regional or nodal metastases, 44% distant metastases (lung, bone/vertebral column, abdominal organs, CNS, kidney), 30-50% survival at 5 years

Prognostic factors (must thoroughly sample tumor)
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● Stage, extent of invasion beyond the capsule (<8 mm is associated with benign behavior)
● Histologic type and grade of carcinoma, proliferation index, proportion of carcinoma
● Extent of invasion, vascular invasion, atypical mitoses
● Pathological stage, tumor size, proliferation index (Arch Pathol Lab Med 2009;133:1763)

Case reports
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● 47 year old man with parotid tumor containing pleomorphic adenoma and rhabdomyosarcoma (Arch Pathol Lab Med 2001;125:812)
● 71 year old man with submandibular tumor with giant cell component (Arch Pathol Lab Med 2000;124:1559)

Treatment
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● Surgery, radiotherapy, chemotherapy
● Possibly WT1 peptide based immunotherapy, trasuzamab/capecitabine

Gross description
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● Widely infiltrative with hemorrhage and necrosis
● Average size 4 cm, mean size 6 cm
● May be encapsulated

Micro description
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● Abrupt transition from benign tumor (usually pleomorphic adenoma); often adenocarcinoma NOS, myoepithelial, salivary duct, terminal duct, undifferentiated, usually with benign stroma (rarely stroma is chondrosarcoma)
● Extensively infiltrative with marked atypia, necrosis, frequent mitotic figures, perineural and vascular invasion
● Occasionally benign pleomorphic adenoma is present with hyalinization and hypocellularity
● Malignant component: adenoid cystic carcinoma, carcinosarcoma (with chondro-, lipo-, rhabdomyo- and spindle cell sarcoma component), clear cell carcinoma, epithelial-myoepithelial carcinoma, giant cell tumor, mucoepidermoid carcinoma, salivary duct carcinoma, sarcomatoid carcinoma, sebaceous carcinoma, small cell carcinoma, squamous cell carcinoma
● May have ossification, increased lymphatic vessels
● Current classification/prognostic subtypes: in situ carcinoma (earliest stage, intracapsular), non-invasive (intracapsular, including in situ carcinoma), minimally invasive (<1.5 mm) and invasive (Hum Pathol 2010;41:927)
● Note: clinical malignant behavior is associated only with cytologically malignant foci beyond the capsule of original tumor

Micro images
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Squamous cell carcinoma, rhabdomyosarcoma and myoglobin+ sarcomatous component


Resembling oncocytic papillary adenocarcinoma with osteoclast-like giant cells


Salivary duct carcinoma arising from pleomorphic adenoma

Cytology description
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● Poorly differentiated carcinoma, macronucleoli, irregular nuclear membranes

Positive stains
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● AE1/AE3 (97%), CK7 (94%), EMA (86%), CEA (75%), vimentin (52%), S100, S100P, p53 (41%), HER2 (30%) (Hum Pathol 2001;32:596, Am J Surg Pathol 2011;35:346)
● Also B72.3, PLAG1 (Mod Pathol 2005;18:1048), CEA, IL6, galectin 1 and 3, peroxiredoxin, PDGFA, PDGFRalpha (Hum Pathol 2009;40:390), E-cadherin, AR, XIAP, p21, topo2alpha, nuclear and cytoplasmic beta catenin, maspin, tenascin and fibronectin, cyclin D1, PCNA/Ki67, cytoplasmic and nuclear p16 (Arch Pathol Lab Med 2011;135:882), EGFR, Mcm2 and TGFbeta
● Also STAT3, p63 (variable), pRb, COX2, GCDFP15 and MUC1, 2, 5AC, 6 (mucin rich salivary duct carcinoma type), FGF2 (in situ carcinoma)

Negative stains
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● Estrogen and progesterone receptors, CK20, desmin, actin, GFAP, EBV ISH, PLUNC, NCAM

Molecular / cytogenetics description
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● Associated with 8q12-13 and 12q13-15 rearrangements
● Diploid or aneuploid
● Abnormal karyotype
● LOH at 3p, 6q, 8p, 8q, 12q, 8q, 9p, 17p
● Amplification of MYC, MDM2, HMGA2, MGC2177, PLAG1, PMSC6P, LYN, WIF1 rearrangement and loss of other allele
● qMSP abnormal methylation, RASSF1 methylation and the epigenotype panel p16/hTERT/RASSF1/WT1 related to malignancy

Differential diagnosis
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Adenoid cystic carcinoma: Mcm2 higher
● Carcinosarcoma: LOH at 17q21 and 9p21 (Mod Pathol 2006;19:350)
● De novo carcinoma: PLAG1+
Pleomorphic adenoma: no malignant component
Polymorphous low grade adenocarcinoma
Schwannoma

End of Salivary glands > Epithelial / myoepithelial tumors > Malignant mixed tumor


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