Oral Clear Cell Tumors

Introduction:

The oral cavity is a potential site for the development of benign and malignant or metastatic tumors. These tumors can form anywhere within the oral cavity, the salivary glands, or even the jaw bone, but salivary clear cell carcinomas are the most common clear cell tumors. The spread of primary metastasis through oral cancer is always to the lungs in males or the breasts in female patients.

What Are Clear Cells?

Clear cells are polyhedral cells with clear cytoplasm and with distinct nuclei. It was originally called Merkel cells, and it was named after Merkel in 1875. They are also called Helle Zellen cells, and because they cannot be stained by hematoxylin or eosin stains, they came to be known as clear cells. These cells are composed of proliferating lesions or groups of tumors that may result from the accumulation of cytoplasmic water content, cellular organelles, zymogen granules, intermediate filaments, or even glycogen accumulation. These clear cells may often be found incidentally upon histological examination of a lesion, and they occur both in benign and malignant tumors. However, the hematoxylin and eosin stains cannot stain these clear cells, and hence, the tumor cannot be detected by these two stains histologically.

The clear cells may arise out of or are primarily derived from four different components, such as:

• Epithelial.

• Hematopoietic.

• Mesenchymal.

• Melanocytic.

Apart from the clear cell tumors of salivary glands, it is also essential to differentiate or identify the clear cell metastatic cancers that occur due to the proliferation from distant cancers like kidney, liver, thyroid, prostate gland, or bowel and metastasize to the oral cavity. In these cancers, the malignant cells can form clear cell tumors in the maxillofacial region as well. Though some lesions may be benign, there are varying subtypes of tumor groups, and significant cases of patients affected invariably report lesions of a malignant, metastatic, or neoplastic nature.

How Are Clear Cell Tumors Classified?

Clear cell tumors of the oral cavity can be classified into:

1. Clear Cell Odontogenic Lesions - These odontogenic lesions may be either cysts or tumors that arise from the derivative or remnants that form the tooth structure or periodontal apparatus.

1. Odontogenic Cysts:

• Gingival cyst of adults.

• Lateral periodontal cyst.

• Clear cell calcifying odontogenic cyst.

2. Odontogenic Tumors:

• Clear cell odontogenic carcinoma.

• Clear cell odontogenic calcifying epithelial tumor.

• Odontogenic ghost cell tumor.

3. Clear Cell Variant Tumors - These tumors may be benign in origin and need to be crosschecked histologically by the pathologist. These can occur anywhere in the oral cavity and are rarer in incidence.

Clear Cell Salivary Gland Tumors:

• Clear cell myoepithelioma.

• Clear cell mucoepidermoid carcinoma.

• Clear cell oncocytoma.

• Clear cell acinic carcinoma.

• Hyalinizing clear cell carcinoma.

• Epithelial, myoepithelial carcinoma.

• Clear cell myoepithelial carcinoma.

What Is the Histopathology of Oral Clear Cell Tumors?

Clear cell tumors can be differentiated from other primary salivary gland tumors only by this histopathologic examination. In the case of clear cell carcinomas in the salivary gland, which are more common, the pathologist can observe nests of clear cells divided by vascular tissues and thin fibrous septa. The periodic acid Schiff stain (PAS) is one of the important and highly useful diagnostic stains that detects or tests positive for mucin, polysaccharides, and glycogen. Calponin-based immunohistochemical staining or other immunohistochemical staining methods may be needed to assess or differentiate and identify clear cell tumors of the maxillofacial region like those tumors of renal cell carcinomas that usually show a strong focal cytokeratin sensitivity (Ck positivity).

In the case of minor salivary gland clear cell carcinomas, the Ck positivity diffusely differentiates it from renal cell carcinomas. Similarly, the immunohistochemical staining with P63 can distinguish mucoepidermoid carcinoma from clear cell tumors. In a similar analogy, certain myoepithelial markers like actin, apart from epithelium-specific markers and epithelium membrane antigens (EMA's), are used to differentiate clear cell tumors from other benign or malignant oral cavity lesions.

What Are the Etiology and Clinical Features of Oral Clear Cell Tumors?

Patients may complain of slow-growing mass, oral discomfort, glandular swelling, the mass of the affected site, and pain. The mean age of prevalence of these heterogeneous tumors is usually in the sixth decade of life and is a slightly more common predisposition in females with a 2:1 ratio. In the salivary glands affected, 80 percent of these tumors can be found in:

• The base of the tongue.

• Palate.

• The floor of the mouth.

• Buccal mucosa.

• Oropharynx.

Though these lesions are rare and less reported in the major salivary glands, the parotid gland is more affected in comparison to the submandibular salivary glands. When these lesions are seen in the salivary glands, they mostly tend to be malignant, except only for two salivary gland benign lesions or subtypes. They are:

• Oncocytoma.

• Myoepithelium.

The recurrence rate of salivary gland lesions is usually around 11 % as per research, and this cancer's clinical course and prognosis are generally good or fair if treated on time. If left untreated or upon clinical presentation, the lesions usually metastasize to regional lymph nodes. With the distinctive primary metastatic tendency, the lesions may infiltrate, destroy, and invade local or surrounding tissues starting from the oral cavity at the site of occurrence and eventually metastasize.

How to Diagnose Oral Clear Cell Tumors?

The features of oral clear cell tumors are very challenging, and it is difficult to differentiate one from another. Oral clear cell tumors are broadly classified into benign and malignant tumors. Benign tumors are classified into odontogenic and nonodontogenic tumors. Odontogenic tumors are classified into cysts and tumors.

A Diagnostic Approach for Cysts and Tumors:

• Histopathology: When cysts and tumors are subjected to histopathology, the findings are epithelial plaques, ghost cells, dentinoids, and amyloid calcifications.

• Special Stains: When subjected to special stains like PAS, it shows PAS positive. When treated with amyloid stains, it shows positive results.

• Immunohistochemistry: When subjected to immunohistochemistry, it shows positive results for odontogenic markers.

Nonodontogenic tumors are classified into salivary gland tumors, melanocytic tumors, and skin tumors.

A Diagnostic Approach for Nonodontogenic Tumors:

• Histopathology: When subjected to histopathology, these do not confirm the diagnosis but may be useful.

• Special Stains: When these types of tumors are subjected to certain special stains such as periodic acid Schiff (PAS), phosphotungstic acid hematoxylin (PTAH), oil red O, and Masson’s Fontana show positive results. When subjected to mucin stain, it shows negative results.

• Immunohistochemistry: When subjected to immunohistochemistry for some tumors, myoepithelial markers are positive, and some show negative results. CK appears to be positive, and HMB 45, melan A to be positive.

Malignant tumors are classified into odontogenic tumors and nonodontogenic tumors. Nonodontogenic tumors are classified into salivary glands, metastatic, melanocytic, skin, and other tumors.

Diagnostic approaches for odontogenic and nonodontogenic tumors include:

• Histopathology: When subjected to histopathology, these do not confirm the diagnosis but may be useful.

• Special Stains: When subjected to certain stains like PAS, and mucin stains, show both positive and negative results for different tumors. Oil red O and Masson’s Fontana show positive results for some tumors.

• Immunohistochemistry: When subjected to immunohistochemistry, epithelial markers show positive results for many tumors, myoepithelial markers show both positive and negative results for some of the tumors, other markers such as amylase, CD10, vimentin, RCC markers, HMB 45, melon A show positive results in certain tumors.

How Are Oral Clear Cell Tumors Managed?

Four major factors influence the treatment planning of clear cell cancers by the oral and maxillofacial surgeon. They are:

• Positive margins.

• The histological grade.

• The invasion capacity of the extent is either neural or vascular.

• The presence of positive neck nodes or lymph node metastasis.

Surgical excision remains the treatment of choice, although if the metastasis has occurred to primary or distant sites by invasive and locally destructive cell behavior. Then, neck dissection and radiotherapy are performed accordingly to prevent further recurrence of the lesions due to distant metastasis or nodal spread. In distant metastasis, the long-term prognosis may be poor; however, as clear cell carcinomas are generally low-grade malignancies, timely treatment will ensure that the patient has a good long-term prognosis.

Conclusion:

Clear cell tumors are challenging diagnostically. The histopathologic assessment by the pathologist is crucial to differentiate them from other tumors. Also, as it is low-grade cancer, timely management can yield a good prognosis in these patients and prevent distant metastasis and nodal spread.