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Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Differential diagnosis | Board review question #1 | Board review answer #1 | Board review question #2 | Board review answer #2Cite this page: Chapman E, Ng T. Clear cell carcinoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/salivaryglandsclearcellcarcinoma.html. Accessed March 20th, 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
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
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
Negative stains
Electron microscopy description
- Cytoplasmic glycogen, tonofilaments of keratin, desmosomes (Am J Surg Pathol 1994;18:74)
Electron microscopy images
Images hosted on other servers:
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:
- 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:
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
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
