Clear cell carcinoma

Salivary glands
Primary salivary gland neoplasms - malignant
Clear cell carcinoma

Author: Erin Chapman, M.D.

Senior Author: Tony Ng, M.D., Ph.D.

Editor-in-Chief: Debra Zynger, M.D.

Topic Completed: 17 December 2018

Revised: 30 April 2019

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: Clear cell carcinoma salivary glands[TI]

Page views in 2018: 140

Page views in 2019 to date: 1,612

Table of Contents

Cite this page: Chapman E, Ng T. Clear cell carcinoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/salivaryglandsclearcellcarcinoma.html. Accessed September 22nd, 2019.

Definition / general

Unusual salivary gland tumor arising primarily in minor salivary gland sites
Molecularly defined by expression of EWSR1-ATF1 fusion oncogene or related fusion variants
Clear cell odontogenic carcinoma is its counterpart in gnathic bones and shares morphologic, immunohistochemical and molecular characteristics

Essential features

Unusual salivary gland tumor
Most common sites are minor salivary glands of oropharynx and oral cavity (> 80%)
At least focal clear cell morphology with or without hyalinizing background
Molecularly defined by presence of EWSR1 fusion (ATF1 most common partner)
Usually low grade but high grade transformation with aggressive behavior reported
Important to differentiate from other primary and metastatic tumors

Terminology

Also called hyalinizing clear cell carcinoma
Clear cell carcinoma, not otherwise specified (NOS) in WHO 2005 classification
Clear cell adenocarcinoma in AFIP classification

ICD coding

ICD-10: C00 - C14 - Malignant neoplasm of lip, oral cavity and pharynx
ICD-O: 8010 / 3 - Carcinoma, NOS epithelial tumor, malignant
ICD-O: 8005 / 3 - Malignant tumor, clear cell type

Epidemiology

Rare, 2.5% of salivary gland tumors (Head Neck 2017;39:503)
Typically > 60 years old but broad age range (Head Neck Pathol 2013;7:S20)
F > M

Sites

> 80% arise in intraoral minor salivary glands (most commonly base of tongue and soft palate)
Also reported in major salivary gland (parotid > submandibular) and other sites with salivary / seromucinous glands (e.g. nasopharynx, hypopharynx, larynx, nasal cavity, lacrimal gland, endobronchial)

Etiology

Demonstrates squamoid phenotype (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:399, Ultrastruct Pathol 1996;20:519)
Frequent presence of mucin suggests it may represent an adenosquamous carcinoma variant (Head Neck Pathol 2013;7:28)

Clinical features

Submucosal lump presents with swelling or dysphagia; may ulcerate, may be painful

Radiology description

Fairly well circumscribed, contrast enhancing, endophytic or exophytic lesion most often arising in oropharyngeal minor salivary gland sites
T1 isointense, T2 hyperintense in reported case (AJNR Am J Neuroradiol 2007;28:127)

Radiology images

Images hosted on PathOut server:

Contributed by Tony Ng, M.D., Ph.D.

CT scan

Images hosted on other servers:

Echo, CT, MRI

Prognostic factors

Usually low grade, excellent prognosis with complete excision
Necrosis, positive margins and lymph node status associated with recurrence risk (Head Neck 2016;38:426)
Local nodal metastasis in 17 - 25% of cases and overall recurrence of 17% (Int J Oral Maxillofac Surg 2018;47:692, Cancer 2009;115:75)
Rare death, late recurrences and distant metastases reported

Case reports

37 and 45 year old women with very delayed metastases (Head Neck 2015;37:E19)
48 year old man with metastasis 29 years later identified at autopsy (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:819)
55 year old man with endobronchial mass (Head Neck Pathol 2017;11:575)
61 year old man with recurrent base of tongue tumor with high grade transformation (Head Neck Pathol 2012;6:389)
63 year old woman with epistaxis and sinus mass (Diagn Pathol 2017;12:70)
65 year old woman with spinal metastasis (World Neurosurg 2016;90:699.e7)

Treatment

Complete resection ± lymph node dissection curative in most cases
Should have long term followup
Limited data for radiation or chemotherapy (Crit Rev Oncol Hematol 2016;102:55)

Clinical images

Images hosted on PathOut server:

Contributed by Pallavi Parashar, D.D.S.

Submucosal mass

Images hosted on other servers:

Buccal mass

Gross description

White-tan cut surface, appears relatively circumscribed (Head Neck Pathol 2013;7:S20)

Gross images

Images hosted on PathOut server:

Contributed by Erin Chapman, M.D.

Submucosal mass

Microscopic (histologic) description

Cells arranged in nests, cords, trabeculae and sheets
Clear to eosinophilic cells with distinct borders; all have at least focal clear cells
Monomorphic ovoid nuclei
With or without dense hyalinized stroma; some have myxoid areas
Almost half of cases show at least focal mucinous differentiation but not always visible without special stains (Head Neck Pathol 2013;7:28)
Often connects to surface, possibly with pagetoid pattern
Low mitotic rate
Infiltrative edges with desmoplastic stroma; perineural invasion is common
May have tumor associated lymphoid proliferation and overlying pseudoepitheliomatous hyperplasia
Rarely show ductal differentiation, cyst formation or keratinization / pearls
Not seen: features of myoepithelial differentiation
High grade transformation defined by presence of high grade nuclear atypia with nuclear anaplasia, brisk mitotic activity and tumor necrosis (Head Neck Pathol 2013;7:S37)

Microscopic (histologic) images

Images hosted on PathOut server:

Contributed by Tony Ng, M.D., Ph.D.

Soft palate mass

Clear cell proliferation

p40

Base of tongue mass

Clear cell and columnar phenotype

PASD

Buccal mass

Nests and cords of clear cells

Submucosal tissue

Contributed by Erin Chapman, M.D.

Posterior maxilla submucosal tumor

Islands and cords of tumor cells

Images hosted on other servers:

Hyalinizing clear cell carcinoma

Cytology description

Clear cells that have monomorphic nuclei with grooves and inclusions, naked nuclei and a tigroid background with metachromatic matrix described from a scrape preparation (Diagn Cytopathol 2016;44:338)

Positive stains

p63 / p40, high molecular weight keratins (including CK5), EMA, PAS
Mucin ~50%, mostly dot-like intracellular but some diffuse
p16 partial to strong / diffuse

Negative stains

S100, calponin, smooth muscle myosin, actin, GFAP, SOX10, DOG1, PAX8, CK20
HPV (Am J Surg Pathol 2018;42:367)

Electron microscopy description

Cytoplasmic glycogen, tonofilaments of keratin, desmosomes (Am J Surg Pathol 1994;18:74)

Electron microscopy images

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Filopodia and desmosomes

Molecular / cytogenetics description

> 80% of cases have EWSR1-ATF1 fusion (Genes Chromosomes Cancer 2011;50:559, Am J Surg Pathol 2013;37:571)
EWSR1(exon11)-ATF1(exon3) variant most common (versus EWSR1[exon8]-ATF1[exon4] in clear cell sarcoma of soft tissue)
Variant fusion described, EWSR1-CREM (Am J Surg Pathol 2018;42:1182)

Differential diagnosis

Metastatic clear cell renal cell carcinoma:
- History of malignancy
- Vascular pattern
- PAX8 and CAIX positive, p63 negative
Mucoepidermoid carcinoma (Hum Pathol 2017;61:9):
- Admixture epidermoid / squamoid, intermediate, mucinous cells / goblet cells
- Presence of intracytoplasmic mucin is common and does not differentiate but goblet cells and macrocysts with mucin are not expected in clear cell carcinoma
- Presence of MAML2 fusion and absence of EWSR1 rearrangement
- Differentiation is important, as a tumor may be considered intermediate / high grade mucoepidermoid carcinoma
Squamous cell carcinoma:
- Keratinization
- No mucin
- More pleomorphism, mitoses
Myoepithelial carcinoma:
- Morphologic and immunohistochemical evidence of myoepithelial differentiation (e.g. S100, SOX10, SMA positivity)
- Can also demonstrate EWSR1 fusions, although ATF1 not an expected fusion partner (Am J Surg Pathol 2015;39:338, Am J Surg Pathol 2013;37:571)
Clear cell odontogenic carcinoma:
- Identical morphology, immunoprofile and molecular findings
- Arises in gnathic bone
Epithelial myoepithelial carcinoma:
- Biphasic with myoepithelial differentiation
Nonintestinal sinonasal adenocarcinoma:
- Tends to have tubulopapillary pattern
- CAIX+ in renal cell-like sinonasal adenocarcinoma
Other clear cell primary or metastatic tumors:
- Sebaceous carcinoma, acinic cell carcinoma, oncocytoma, melanoma

Board review question #1

The differential diagnosis for clear cell carcinoma of minor salivary gland (pictured) does not include

Metastatic renal cell carcinoma
Mucoepidermoid carcinoma
Myoepithelial carcinoma
Salivary duct carcinoma
Squamous cell carcinoma

Board review answer #1

D. Salivary duct carcinoma

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Board review question #2

80% of cases of clear cell carcinoma of minor salivary gland have rearrangement of which gene, also seen in clear cell sarcoma of soft tissue?

ETV6
EWSR1
FLI1
FUS
MAML2

Board review answer #2

B. EWSR1

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