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18 September 2019 - Case of the Month #483

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Thanks to Dr. Pooja Navale, Icahn School of Medicine at Mount Sinai, New York, New York (USA), for contributing this case and Dr. Kelly Magliocca, Emory University, Atlanta, Georgia (USA), for writing the discussion.


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Case of the Month #483

Clinical history:
A 60 year old man presented with a swelling in the base of the tongue. A mass was excised.

Gross images:

Histopathology images:

What is your diagnosis?

Click here for diagnosis, test question and discussion:

Diagnosis: Hyalinizing clear cell carcinoma of tongue

Test question (answer at the end):
Clear cell carcinoma of salivary gland is most commonly associated with the following gene fusion:



Clear cell carcinoma (CCC, synonym: hyalinizing clear cell carcinoma) is a rare, low grade salivary gland malignant neoplasm most commonly affecting minor salivary glands. The most commonly affected sites are the palate and tongue base. CCC tends to present in the fifth through seventh decades, more often in women (Am J Surg Pathol 1994;18:74, Head Neck Pathol 2013;7:Suppl1:S20).

Macroscopically, CCC exhibits a solid, grey or white-yellow cut surface and may be poorly circumscribed. It is composed of cords, trabeculae and nests of uniform, cytologically bland epithelial cells with clear cytoplasm that may be admixed with smaller polygonal epithelial cells exhibiting eosinophilic cytoplasm. Mitoses are rare. The stroma often shows areas of hyalinization, but this may not be seen in all tumors. Interestingly, this carcinoma may demonstrate a connection to the overlying surface mucosa. Rarely, ducts or gland-like spaces can be seen but distinguishing these areas from entrapped regional tissues may be challenging (Head Neck Pathol 2013;7:Suppl1:S20, El-Naggar et al:WHO Classification of Head and Neck Tumours, 4th Edition, 2017, Head Neck 2017;39:503). Ancillary testing demonstrates that tumor cells of CCC are positive for cytokeratin AE1/AE3, epithelial membrane antigen (EMA), p63 and p40 but they are negative for SOX10, S100, calponin and smooth muscle actin (SMA). CCC most commonly shows the EWSR1-ATF1 gene fusion (Head Neck Pathol 2013;7:Suppl1:S20, El-Naggar et al:WHO Classification of Head and Neck Tumours, 4th Edition, 2017, Head Neck 2017;39:503) although a subset may show the EWSR1-CREM fusion (Am J Surg Pathol 2018;42:1182).

The histologic differential diagnosis for CCC includes clear cell odontogenic carcinoma, mucoepidermoid carcinoma (MEC), renal clear cell carcinoma (RCC), epithelial-myoepithelial carcinoma, and in some cases, squamous cell carcinoma.

Clear cell odontogenic carcinoma is a rare odontogenic malignancy occurring within an intraosseous location of the maxilla or mandible. It exhibits perfect morphologic, immunohistochemical and molecular overlap with CCC, making anatomic site the main distinguishing feature between these two entities.

Mucoepidermoid carcinoma mimics clear cell caricnoma, particularly when occurring in a minor salivary gland location such as the base of tongue or palate with a clear cell component. CCC generally lacks epidermoid cells with abundant eosinophilic cytoplasm and, although occasional mucous cells have been described in CCC, the presence of numerous mucous cells lining cystic spaces or forming discrete clusters would be unusual in CCC. On a molecular level, CRTC1-MAML2 or CRTC3-MAML2 fusion genes are seen in most cases of MEC, but EWSR1-ATF1 gene fusion most commonly characterizes CCC.

Among metastases to the head and neck region, renal clear cell carcinoma (RCC) is not uncommon. Metastatic RCC is most frequently identified in the nasal cavity/paranasal sinus and oral cavity, although involvement of the oropharynx has also been reported (Head Neck Pathol 2009;3:217). Deposits of metastatic RCC exhibit prominent sinusoids, lack hyalinization of the stroma and highlight with vimentin, PAX8 and CD10, in contrast to CCC.

More common in major salivary glands, epithelial-myoepithelial carcinoma (EMCA) can be distinguished by the presence of an abluminal population of myoepithelial cells with clear cytoplasm surrounding the epithelial (ductal) population. The multinodular pattern of growth described in EMCA would be unusual in CCC. The myoepithelial elements of EMCA exhibit reactivity to S100, SMA, calponin, SOX10 and GFAP, markers that would be absent in CCC.

On a small biopsy sample, distinguishing CCC from squamous cell carcinoma with clear cell features or adenosquamous carcinoma can be difficult in view of the possibility of morphologic and immunophenotypic overlap (p63+, p40+). Interestingly, both CCC and squamous cell carcinoma may exhibit reactivity with p16. In an oropharyngeal location such as the tongue base, distinguishing between CCC and HPV related squamous cell carcinoma location may be problematic. HPV-SCC would be more likely to exhibit prominent mitotic activity and increased nuclear pleomorphism, in contrast to the uniformity of CCC. High risk HPV 16/18 detected by RNA in situ hybridization or other means would be expected to be positive only in HPV related squamous cell carcinoma (Head Neck Pathol 2013;7:Suppl1:S20, El-Naggar et al:WHO Classification of Head and Neck Tumours, 4th Edition, 2017, Head Neck 2017;39:503, Am J Surg Pathol 2018;42:367).

CCC is generally regarded as a low grade malignancy, although nodal metastasis may occur in 25%. Distant metastasis and reports of high grade transformation (with EWSR1 rearrangement) have been reported (Cancer 2009;115:75).

Test question answer:

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