Mandible-Maxilla
Malignant tumors
Clear cell carcinoma of salivary gland

Author: Anthony Martinez, M.D. (see Authors page)
Editor: Kelly R. Magliocca, M.D.

Revised: 15 February 2016, last major update February 2016

Copyright: (c) 2004-2016, PathologyOutlines.com, Inc.

PubMed Search: Clear cell carcinoma [title] salivary gland
Definition / General
  • Rare, malignant, translocation associated epithelial salivary gland tumor characterized by nests and cords of clear cells surrounded by hyalinizing stroma
  • EWSR1 rearrangements in >80% of cases
Terminology
  • AFIP uses terminology - clear cell adenocarcinoma
  • WHO uses terminology - clear cell carcinoma, not otherwise specified (NOS)
  • Also called hyalinizing clear cell carcinoma (HCCC)
Epidemiology
  • Rare, < 1% of all salivary gland tumors
  • Mean age: 6th decade
  • Slightly more common in females (1.2:1)
Sites
  • More common in minor salivary glands (~80%), particularly base of tongue, palate, floor of mouth, tongue and buccal mucosa in oral cavity/oropharynx (Head Neck 2016;38:426)
  • Less common in major salivary glands; parotid more common than submandibular gland
Etiology
  • As with many translocation tumors, lesion tends to pursue a line of differentiation rather than originate from a particular line of derivation
  • Currently, there is evidence that HCCC pursues a squamous line of differentiation based on:
    • Ultrastructurally, the tumors have tonofilaments, desmosomes and glycogen
    • Frequent connection to the surface mucosal epithelium
    • Electron microscopy findings including some basal lamina reduplication
Clinical Features
  • Clinically, patients present with swelling and mass lesion
Diagnosis
  • Diagnosis dependent on clinical, radiologic and pathologic correlation
Prognostic Factors
  • Generally, has an indolent clinical course with a good prognosis
  • Recurrence rate ~11%
  • The presence of necrosis, local/regional disease or positive margins is associated with recurrence
  • Some sources say ~25% have regional nodal metastases at presentation (Cancer 2009;115:75), but recent studies have challenged that (Genes Chromosomes Cancer 2011;50:559)
Case Reports
Treatment
  • Primary resection with negative margins
Clinical Images

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Echo, CT, MRI

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Local findings

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Mass

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Operative findings

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Post operative

Micro Description
  • Nests and cords of clear cells with distinct borders and round to oval nuclei
  • As with many translocation tumors, many areas of the lesion have a monotonous appearance
  • A minority of the cells can contain eosinophilic as opposed to clear cytoplasm
  • The cells are surrounded by variably hyalinized stroma
Micro Images

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Stratified squamous epithelium

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Mitotic figures

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Islands of of epithelial cells

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Hyalinized areas

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Carmine stain

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PAS

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p63. CD10, PAS

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P63+

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Pancytokeratin+

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AE1/AE3, S100, SMA

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Mucicarmine-

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SMA-

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Calponin-

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S100-

Positive Stains
Negative Stains
Molecular / Cytogenetics Description
  • > 80% show EWSR1 rearrangement by FISH
Differential Diagnosis
  • Clear cell odontogenic carcinoma (CCOC)
    • Malignant epithelial odontogenic neoplasm also composed primarily of clear cells, which usually occurs in anterior mandible
    • Unlike HCCC, the nests or cords may show focal palisading of basal cells (“ameloblastic”)
    • Both tumors have EWSR1 rearrangements
    • May represent "odontogenic analogue"

  • Clear cell variant of calcifying epithelial odontogenic tumor (CEOT)
    • Benign epithelial odontogenic neoplasm, clear cell variant may be composed primarily of clear cells
    • Occurs in posterior mandible, intra-osseous location
    • Variably sized polyhedral eosinophilic epithelial cells with distinct cell borders are arranged in small clusters, trabeculae, islands or a sheet-like pattern
    • Nuclear pleomorphism is expected, but without appreciable mitotic activity
    • Eosinophilic amyloid-like matrix material is haphazardly deposited in association with the tumor islands and calcified concentric profiles (Liesegang rings) are often identified.
    • Ancillary studies show the epithelial cells of CEOT highlight with cytokeratin AE1/3, CK5/6 and p63, and amyloid-like material exhibits apple green birefringence when stained with Congo red and viewed with polarized light

  • Clear cell renal cell carcinoma (CCRCC)
    • Usually a known history of renal cell carcinoma
    • CCRCCs are positive for PAX8

  • Epithelial-myoepithelial carcinoma
    • Malignant bisphasic tumor with an inner duct-like epithelial component and an S100+ outer myoepithelial component
    • Occurs more commonly in the major salivary glands
    • Hyalinizing clear cell carcinoma has only the clear cell epithelial component, and is S100-

  • Mucoepidermoid carcinoma, clear cell variant
    • Malignant epithelial tumor with variable amounts of mucous, epidermoid and intermediate cells
    • Parotid gland most common location
    • Mucicarmine will be positive in mucocytes
    • Can be associatied with MAML2 rearrangement and NOT EWSR1 like HCCC

  • Sinonasal renal cell-like adenocarcinoma (SRCLA)
    • May be difficult to differentiate, but clear cell tumors involving the maxillary or palatal structures require consideration of a sinonasal neoplasm with secondary involvement of the oral region (Int J Clin Exp Med 2014;7:5469)
    • Rare tumor characterized by a clear cell glandular proliferation, most often involving the nasal cavity, associated with a favorable clinical course
    • Has round cells with clear cytoplasm and a prominent nucleolus arranged in a follicular pattern
    • A tubular arrangement and papillary architecture of the clear cell proliferation have also been described
    • No mucinous or myoepithelial differentiation, no necrosis, no hyalinization of stroma
    • SRCLA vs. HCCC: no stromal hyalinization, no stromal vascularity; often has larger clear cells than HCCC and CCOC; has robust CA-IX immunostaining vs. focal positive in HCCC; negative for EWSR1 rearrangement