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 Table of Contents  
Year : 2018  |  Volume : 8  |  Issue : 2  |  Page : 136-139

Clear-cell squamous cell carcinoma: An uncommon variant of very common malignancy in the head and neck

Department of Pathology, Dr. B. Borooah Cancer Institute (Regional Institute for Treatment and Research), Guwahati, Assam, India

Date of Web Publication18-Dec-2018

Correspondence Address:
Lopa Mudra Kakoti
Department of Pathology, Dr. B. Borooah Cancer Institute (Regional Institute for Treatment and Research), Gopinath Nagar, Guwahati - 781 016, Assam
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijohs.ijohs_23_18

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Clear-cell squamous cell carcinoma (SCC) is an extremely rare and incompletely understood entity. Clear-cell change occurs due to cytoplasmic accumulation of glycogen, water, intermediate filaments, immature zymogen granules, or a paucity of cellular organelles. Clear-cell change can be seen in any of the neoplasms, but as pure form variant, it is difficult to find in head-and-neck SCC. The World Health Organization has recognized clear-cell SCC as separate entity at other few sites such as penis but not in the head-and-neck SCC, and these are known to aggressive variant. We, hereby, present a case of clear-cell variant of squamous carcinoma in lower gingivobuccal mucosa in a 59-year-old male patient. Histopathology showed sheets of clear cell separated by fibrous septa and foci showing squamous cells with malignant features. Periodic acid–Schiff and immunohistochemistry (IHC) were done to rule out differentials of clear-cell variants of different sites such as salivary gland, odontogenic origin, and cutaneous adnexal origin. To establish the prevalence, biological nature, significance, and clinical course of clear-cell SCC in the head-and-neck region, more number of case reports are expected to be published in future. We concluded by emphasizing on the need of further analysis of all clear-cell tumors in the head and neck with histochemistry and IHC investigations to arrive at the proper diagnosis.

Keywords: Clear cells, histochemistry, oral cavity, squamous cell carcinoma

How to cite this article:
Kakoti LM, Mahanta D, Sharma JD, Chowdhury Z. Clear-cell squamous cell carcinoma: An uncommon variant of very common malignancy in the head and neck. Int J Oral Health Sci 2018;8:136-9

How to cite this URL:
Kakoti LM, Mahanta D, Sharma JD, Chowdhury Z. Clear-cell squamous cell carcinoma: An uncommon variant of very common malignancy in the head and neck. Int J Oral Health Sci [serial online] 2018 [cited 2021 Jun 22];8:136-9. Available from: https://www.ijohsjournal.org/text.asp?2018/8/2/136/247800

  Introduction Top

Clear cells, as the name suggests, are microscopic clearance of cytoplasm due to lack of staining with hematoxylin and eosin in the cytoplasm. It occurs due to various reasons such as cytoplasmic accumulation of glycogen, water, intermediate filaments, immature zymogen granules, or a paucity of cellular organelles. Clear-cell change in malignancy is not an uncommon phenomenon, but when a tumor is designated as clear-cell tumor or a variant of some primary tumor, it is limited in numbers. The World Health Organization (WHO) has recognized clear-cell squamous cell carcinoma (SCC) as separate entity at other sites such as penis and skin but not in the head-and-neck region, and these variants at other sites are known to behave in an aggressive manner. Although the WHO has not categorized clear-cell variant in SCC of the head and neck, there are available literature mentioning their occurrence and nature and predicting their behavior. After literature search, we could analyze seven such cases involving the skin and two cases of oral cavity SCC to compare with our case.

  Case Report Top

A 59-year-old male came to the head-and-neck outpatient department with a swelling in the right upper jaw for the past 4 months and complained of pain which was insidious in onset. His intraoral examination revealed an exophytic growth in the right upper jaw and extraoral examination revealed multiple bilateral cervical lymph nodes, largest measuring 3.5 cm × 3.0 cm. Computed tomography scan showed a heterogeneously enhancing lobulated soft-tissue density lesion measuring 50 mm × 38 mm × 35 mm in the right upper alveolus, upper lip, and right nasolabial fold. Incisional biopsy report was given as moderately differentiated SCC. The patient has undergone maxillectomy along with extended radical neck dissection.

On gross examination, a large ulceroproliferative growth measuring 5 cm × 4 cm was seen in the upper jaw extending up to the upper lip and right nasolabial fold. Cut section of the growth was grayish white, and lobulation was noted. Microscopy showed sheets of predominantly clear cells invading into underlying connective tissue stroma. The cells were round to polygonal with clear cytoplasm having nuclear hyperchromasia and atypia [Figure 1]. Underlying maxillary bone was involved by the tumor cells. Foci of tumor cells showed squamoid differentiation with the presence of keratin pearls [Figure 2]. Periodic acid–Schiff (PAS) stain was done to know the nature of clearing artifact and it was negative [Figure 3]. To rule out the other differentials of clear cells in head-and-neck site, immunohistochemistry (IHC) of cytokeratin (CK), S100, and epithelial membrane antigen (EMA) was done. Except CK, all other markers were negative [Figure 4].
Figure 1: Clear cells with foci of squamous differentiation (H and E, ×20)

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Figure 2: Intercellular bridges with individual keratinization indicating squamous differentiation (H and E, ×40)

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Figure 3: Negative staining in clear cells (periodic acid–Schiff, ×20)

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Figure 4: Clear cells showing cytokeratin positivity (immunohistochemistry, ×20)

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A diagnosis of SCC–clear-cell variant has been reported with a pathologic staging of pT4aN2b M0. There were no perineural invasion and lymphovascular invasion. Cut margins were free of tumor infiltration. The patient was not given adjuvant radio or chemotherapy, and followed up period was uneventful for 3 months.

  Discussion Top

There are very few case reports of clear-cell variant of SCC. Kuo[1] was the first one to report the clear-cell subtype of cutaneous SCC in 1980, and Kumar et al.[2] was the first one to mention the same in the oral cavity. Since maximum number of the cases were mentioned from the cutaneous part, we could observe few of the valuable findings to compare our case with them [Table 1]. Although most of the cases were reported in the head-and-neck region, there were two cases reported in axilla and torso too.[8],[9]
Table 1: Clinicopathologic features of a few reported cases of clear-cell squamous cell carcinoma in the English medical literature

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The possible differentials for clear-cell neoplasms in oral cavity region include salivary gland origin (mucoepidermoid carcinoma, acinic cell carcinoma, epithelial-myoepithelial carcinoma, clear- cell myoepithelial carcinoma, and hyalinizing clear-cell carcinoma) and odontogenic origin (clear-cell odontogenic carcinoma and clear odontogenic ghost-cell tumor) and concomitant rare occurrence of SCC and melanoma with clear-cell changes.[7],[9] In case of appearance of clear cells in cutaneous malignancies, the differentials to be ruled out include the various adnexal tumors (clear-cell hidradenoma, eccrine spiradenoma, clear-cell hidradenocarcinoma, tricholemmoma, tricholemmal carcinoma, and pilar tumor), melanocytic lesions (balloon cell nevus, balloon cell melanoma, and amelanotic melanoma), clear-cell acanthoma, and metastatic carcinoma from the renal cell, lung, liver, large bowel, prostate, and thyroid and very rarely clear-cell chondrosarcoma, liposarcoma, clear-cell sarcoma, etc.[5],[7] Therefore, special stains such as PAS with or without diastase to rule out adnexal, salivary gland origin, Sudan black (lipid), mucicarmine, and alcian blue (mucin) along with various IHC markers such as CK (epithelial origin), SMA (myoepithelial), S100 (melanocytic), EMA, and carcinoembryonic antigen (adnexal) are required to arrive at the proper diagnosis. Originally, Kuo described three types of clear-cell SCC, namely, keratinizing (Type I), nonkeratinizing (Type II), and pleomorphic (Type III). Type I tumors are described as neoplasms formed by sheets or islands of clear cells with empty appearing or “bubbled” cytoplasm with foci of keratinization and keratin pearl formation. Type II tumors are described as predominantly dermal neoplasms with parallel and anastomosing cords of cells with central nuclei and finely reticulated clear cytoplasm, without keratinization and ductal or glandular differentiation. Type III demonstrates marked pleomorphism with extensive vascular and perineural invasion.[1],[10] A study from Spain by Corbalán-Vélez et al. had highlighted few of the facts after studying 249 cases of cutaneous SCC that suggested clear cells were common in SCCs, though only some SCCs present a large number of clear cells. The invasive SCCs derived from Bowen's disease presented a larger proportion of clear cells which showed the presence of glycogen and explained as clearing because of adnexal involvement. In their study, observation of the histologic pattern of clear cells around keratin pearls practically ruled out adnexal differentiation where actinic keratosis was the prior lesion and showed p16 positivity. Hence, they suggested that the presence of HPV may be an essential factor for the development of this histologic pattern, whereas actinic keratosis or chronic solar damage would be additional factors.[3] The other possible various attributable factors include arsenic exposure, radiation, chronic ulceration, and immune suppression.[1],[7]

Most of the cases were seen in an elderly female while our case was a middle-aged male. Like all other reported cases, the present case also showed rapidly growing large ulceroproliferative growth and showed aggressive behavior. Except one case report, all other cases of clear-cell SCC were glycogen negative. Corbalán-Vélez et al. had suggested that the development of clear cells in SCC is a progressive process that requires time and occurs only in advanced SCC.[8] Hence, we too support the theory of degenerative changes rather than intracellular accumulation. So, with the presence of any clear cells, the basic PAS stain should be done to predict the cause of clearing and also to rule out the possibility of adnexal and salivary gland origin neoplasms. Further IHC will help to confirm the diagnosis. Al-Arashi and Byers had studied cases of clear-cell SCC in situ (SCCIS) and found that clear-cell change in SCCIS was part of a spectrum which displayed outer root sheath differentiation.[11]

Our case also presented as an aggressive ulceroproliferative growth involving upper alveolus, upper gingivobuccal sulcus as well as small cutaneous part of the upper lip. Jain A, shetty DC et all suggests tumour progression can lead to extensive clear cell changes, perhaps as a secondary phenomenon or as a result of clonal evolution.[12]

  Conclusion Top

Clear-cell change in any tumor may not be very uncommon, but pure clear-cell variant still might be rare incidence. Whenever evidence of primary neoplasm is missing, special stain and IHC help to arrive at the diagnosis. The biological nature and clinical course of clear-cell SCC in the head and neck need to be established because clinical prognosis of these carcinomas may differ from the usual type of SCC. For that, further case studies are required to consider it as a separate variant or just a usual phenotypic phenomenon.

Informed consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


The authors would like to acknowledge the cooperation of technical staff of the department of pathology to carry out the various ancillary tests.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Kuo T. Clear cell carcinoma of the skin. A variant of the squamous cell carcinoma that simulates sebaceous carcinoma. Am J Surg Pathol 1980;4:573-83.  Back to cited text no. 1
Kumar K, Shetty DC, Wadhwan V, Gupta P. Synchronous oral squamous cell carcinomas with unusual histopathological feature. J Oral Maxillofac Pathol 2012;16:420-4.  Back to cited text no. 2
[PUBMED]  [Full text]  
Corbalán-Vélez R, Ruiz-Macia JA, Brufau C, López-Lozano JM, Martínez-Barba E, Carapeto FJ, et al. Clear cells in cutaneous squamous cell carcinoma. Actas Dermosifiliogr 2009;100:307-16.  Back to cited text no. 3
Frazier JJ, Sacks H, Freedman PD. Primary glycogen-rich clear cell squamous cell carcinoma of the mandibular gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e47-51.  Back to cited text no. 4
Lawal AO, Adisa AO, Olajide MA, Olusanya AA. Clear cell variant of squamous cell carcinoma of skin: A report of a case. J Oral Maxillofac Pathol 2013;17:110-2.  Back to cited text no. 5
Nainani P, Singh HP, Paliwal A, Nagpal N. A rare case report of clear cell variant of oral squamous cell carcinoma. J Clin Diagn Res 2014;8:QD07-9.  Back to cited text no. 6
Kaliamoorthy S, Sethuraman V, Ramalingam SM, Arunkumar S. A rare case of clear cell variant of oral squamous cell carcinoma. J Nat Sci Biol Med 2015;6:245-7.  Back to cited text no. 7
Cohen PR, Schulze KE, Rady PL, Tyring SK, He Q, Martinelli PT, et al. Detection of human papillomavirus in cutaneous clear cell squamous cell carcinoma in situ: Viral-associated oncogenesis may contribute to the development of this pathologic variant of skin cancer. J Cutan Pathol 2008;35:513-4.   Back to cited text no. 8
Premalatha BR, Rao RS, Patil S, Neethi H. Clear cell tumours of the head and neck: An overview. World J Dent 2012;3:344-9.  Back to cited text no. 9
Rinker MH, Fenske NA, Scalf LA, Glass LF. Histologic variants of squamous cell carcinoma of the skin. Cancer Control 2001;8:354-63.  Back to cited text no. 10
Al-Arashi MY, Byers HR. Cutaneous clear cell squamous cell carcinoma in situ: Clinical, histological and immunohistochemical characterization. J Cutan Pathol 2007;34:226-33.  Back to cited text no. 11
Jain A, Shetty DC, Juneja S, Narwal N. Molecular characterization of clear cell lesions of head and neck. J Clin Diagn Res 2016;10:ZE18-23.  Back to cited text no. 12


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1]

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