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 #2 | Board review question #3 | Board review answer #3Cite this page: Chapman E, Ng T. Clear cell carcinoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/salivaryglandsclearcellcarcinoma.html. Accessed December 13th, 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
- See also clear cell carcinoma in the Mandible / Maxilla chapter
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
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)
- 60 year old man with a swelling in the base of the tongue (Case of the Month #483)
- 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
Gross description
- White-tan cut surface, appears relatively circumscribed (Head Neck Pathol 2013;7:S20)
Gross images
Contributed by Pooja Navale, M.D.
Contributed by Erin Chapman, M.D.
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
Contributed by Pooja Navale, M.D.
Contributed by Tony Ng, M.D., Ph.D.
Contributed by Erin Chapman, M.D.
Images hosted on other servers:
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)
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
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
Board review question #3
Clear cell carcinoma of salivary gland is most commonly associated with the following gene
fusion:
A. HTN3-MSANTD3
B. EWSR1-ATF1
C. ETV6-NTRK3
D. MYB-NFIB
A. HTN3-MSANTD3
B. EWSR1-ATF1
C. ETV6-NTRK3
D. MYB-NFIB
Board review answer #3
B. EWSR1-ATF1
Advertisement