Hyalinizing clear cell carcinoma was first described as a distinct entity in 1994 by Milchgrub et al. in their series of 11 patients [1
]. Since then, approximately 36 additional cases have been reported in the English literature and are summarized in Table [2
]. Our series adds eight more cases of HCCC with histochemical and immunohistochemical profiles. Characteristics of the tumors in our series are very similar to the previously reported cases. A general review of the now reported 55 cases of HCCC shows a female predominance (72.7%) and an older age at diagnosis (68 years, mean). The vast majority of cases (81.8%) occurred within the oral cavity, most commonly the tongue or hard palate. Less common locations include parotid gland, nasopharynx, hypopharynx, and orbit/lacrimal gland.
Summary features of HCCC reported in literature
Grossly, all 55 cases were described as firm, rubbery, or elastic, with varied color including white, tan, red, and grey. In cases that reported tumor size at excision, the range was from 0.5 cm up to 10 cm, with an average of 2.6 cm. Histologically, all cases demonstrated the features of HCCC with monomorphic glycogen rich clear cells in cords, nests, islands, or trabeculae within a hyalinized stroma. Fifteen cases demonstrated foci of myxoid stromal changes [1
]. A dense inflammatory infiltrate composed of lymphocytes and plasma cells was identified in five cases (9.1%), in which one developed lymphoid follicles with germinal centers [8
]. Mitotic figures were identified in 18 cases (32.7%), [1
]. Necrosis was identified focally in one case associated with increased mitotic activity (O’Regan et al. [15
]), which had an aggressive course. In that case, the patient subsequently developed widespread metastatic disease and died within a year of diagnosis [15
]. Perineural invasion was identified in approximately 20 cases (36.4%), with one case showing both perineural and perivascular invasion [1
Thirty-eight of 39 (97.4%) cases reported cytoplasmic glycogen by PAS stain. Only one report (2.6%) mentioned clear tumor cells to be negative for glycogen [11
]. Although in most cases the tumor cells were negative for mucin, four cases were positive for focal extracellular mucin, and one case showed occasional intracellular mucin [1
]. Tumor cells in the vast majority of cases were positive for epithelial antigens including cytokeratin in 36/36 cases (100%), cytokeratin CAM 5.2 in 15/19 cases (78.9%), and EMA in 17/22 cases (77.3%). Immunohistochemical staining for polyclonal CEA was variable, with 8/20 cases (40%) showing at least focal positivity. In contrast, markers of myoepithelial origin including SMA and S-100 were negative in 43 and 37 cases, (100 and 97.3%) respectively.
No distinct morphologic characteristic such as necrosis or increased mitoses, or immunohistochemical profile, uniformly correlated with recurrence, aggressive behavior, or metastatic disease. Metastases and/or local recurrences were identified in approximately one-third of cases [1
]. Nine cases reported metastases (16.4%), five identified at the time of initial diagnosis [1
], one at 4 months [15
], one at 3 years [8
], one at 5 years [5
], and one at 7 years [8
]. The majority of metastases traveled to local lymph nodes and three cases showed distant metastases to the lung, with two of the three lung metastases identified at the time of diagnosis [7
]. In the nine cases with reported recurrences (16.4%), the time span between initial diagnosis and local recurrence ranged from 11 months [5
] up to 6 years [8
]. It is important to differentiate HCCC from other tumors with clear cell features because of their differences in treatment and clinical outcome. These include clear cell mucoepidermoid carcinoma, epithelial-myoepithelial carcinoma, acinic cell carcinoma, some odontogenic tumors, and metastatic clear cell tumors such as renal cell carcinoma. Because HCCC is an uncommon tumor, only occasionally reported in the literature, the diagnosis can be challenging. HCCC should be considered in the differential diagnosis of tumors with the histology marked by monomorphic clear cells arranged in cords, trabeculae, or clusters surrounded by a hyalinized stroma.
In addition to the morphologic features, immunohistochemical stains may help differentiate HCCC from other tumors composed of clear cells. Review of the HCCC literature indicates that cytoplasmic glycogen is present in the neoplastic cells, as are epithelial antigens. Table summarizes the immunohistochemical staining pattern of clear cell tumors in the HCCC differential diagnosis.
Differential diagnosis and staining patterns of clear cell tumors of the head and neck
Clear cell mucoepidermoid carcinoma (MEC) is one of the more common malignancies of the head and neck to be considered in the differential diagnosis of HCCC (Fig. ). The majority of mucoepidermoid carcinomas arise in the parotid gland, and characteristically have three morphologically distinct cell types: mucin-producing cells that can have the appearance of foam cells and/or goblet cells, epidermoid cells, and intermediate cells that have eosinophilic cytoplasm with round nuclei. Unlike HCCC, mucin can be demonstrated within MEC cells by mucicarmine or Alcian blue histochemistry. Immunohistochemical staining for p63 may be beneficial in differentiating MEC from some clear cell tumors [23
], however, it is also positive in HCCC, and may not be helpful if used alone.
Cytoplasmic clearing, clear cell mucoepidermoid carcinoma of oral cavity (200×, H&E)
Epithelial-myoepithelial carcinoma is rare, and the tumor cells tend to show duct-like growth with a biphasic appearance. The duct-like structures are composed of eosinophilic cuboidal epithelial cells surrounded by round to spindled clear cells. The epithelial cells will stain for cytokeratin and epithelial membrane antigen (EMA). The clear cells in this tumor stain for myoepithelial markers including SMA and S-100 [24
Acinic cell carcinoma is often infiltrative and can show different growth patterns including solid, papillary, microcystic, and follicular, and usually more than one cell type can be identified. Clear cell acinic carcinoma is fairly rare and the cells are PAS positive, but unlike HCCC, are diastase resistant [24
Clear cell odontogenic carcinoma is an aggressive tumor and is morphologically characterized by islands of mostly clear cells surrounded by a fibrous stroma. The tumor cells possess abundant glycogen and show positivity for cytokeratin and EMA. However, unlike HCCC, clear cell odontogenic carcinoma tends to be S-100 positive [24
In addition to differentiating HCCC from other primary clear cell tumors of the head and neck, it is also important to consider metastatic tumors in the differential diagnosis. Renal cell carcinoma is commonly composed of glycogen rich clear cells (Fig. ). However, it is often associated with hemorrhage and necrosis, and often will be positive for renal cell carcinoma antigen, CD10, and cytokeratin. Thyroglobulin and thyroid transcription factor-1 (TTF-1) can be used to identify metastases of clear cell thyroid carcinoma [24
Cytoplasmic clearing, renal cell carcinoma (200×, H&E)
In summary, we report a series of eight cases of HCCC with features similar to previously reported cases. After extensive review of the literature, it is apparent that histochemical and immunohistochemical stains can be extremely helpful in distinguishing HCCC from other tumors with clear cell features. Apart from the presence of a hyalinizing stroma, HCCC is generally PAS, cytokeratin, p63, and EMA positive. Additionally, mucicarmine is useful to perform to rule out MEC, PAS and PAS with diastase to rule out acinic cell carcinoma, and SMA and S-100 to rule out clear cell epithelial myoepithelial carcinoma. If clear cell odontogenic carcinoma is in the differential, S-100 may be useful in differentiating this tumor from HCCC. Optional immunohistochemical stains such as CD10 and renal cell carcinoma antigen for renal cell carcinoma, or thyroglobulin and TTF-1 for clear cell thyroid carcinoma, can be useful if the clinical information warrants investigation of a metastasis.
The behavioral profile of our series of eight HCCC cases conformed to the relatively indolent behavior previously reported in these tumors. In a recent case series by Solar et al. [22
], it was noted that 25% of cases reported in the literature had evidence of metastases. With the addition of our cases to the literature, we observed that only 16.4% of cases reported metastases. Additional cases of HCCC need to be reported to further elucidate the true behavior of this rare tumor. While surgical excision with or without radiotherapy remains the primary treatment for HCCC, we agree with Solar et al. [22
] that careful observation and follow-up of these patients is warranted. It is therefore necessary to distinguish HCCC from more aggressive tumors with clear cell features to ensure proper treatment and management.