Hyalinizing clear cell carcinoma of salivary gland: a review and update

Abstract

Hyalinizing clear cell carcinoma (HCCC) is a rare minor salivary gland tumor made up of clear cells and forming cords and nests in a hyalinized stroma. The overall outcome is excellent with only occasional metastatic spread. HCCC has a wide differential diagnosis including other clear cell-containing tumors, such as epithelial-myoepithelial carcinoma, mucoepidermoid carcinoma, and myoepithelial carcinoma. HCCC is currently classified as a "clear cell adenocarcinoma" by the AFIP and as "clear cell carcinoma, not otherwise specified (NOS)" by the World Health Organization (WHO). It is considered by the WHO to be a diagnosis of exclusion. Since the original description in 1994, there have been few new insights into HCCC, until recently. Dardick re-examined the features of HCCC, including the original electron microscopic images, and concluded that HCCC is a squamous lesion, at odds with the above nomenclature. Bilodeau et al. recently showed that this tumor essentially cannot be separated reliably from clear cell odontogenic carcinoma (CCOC) except by location. Antonescu et al. recently identified a consistent EWSR1-ATF1 fusion in HCCC. Bilodeau et al. subsequently argued a link between these two entities, with evidence of similar EWSR1 and ATF1 rearrangements in CCOC. This molecular signature is not present in other clear cell mimics. Cases with recurrence, metastasis, high-grade features and other alternative morphologies or presentations have also been seen and proven by molecular analysis to be HCCC. In the molecular era, HCCC can no longer be seen as a diagnosis of exclusion. It is neither an adenocarcinoma nor a "not otherwise specified" tumor, as the AFIP and WHO currently classify it. This review provides an in-depth look at the current state of knowledge of HCCC from morphology to molecular features. New developments and personal insights are provided that help identify and properly classify this lesion.

Fig. 1

a–d Typical example of hyalinizing clear cell carcinoma (HCCC) showing a combination of cords and nests of clear and eosinophilic cells in a hyalinized background (a). Some HCCC show areas with no striking clearing but show a similar growth pattern. This case shows prominent perineural invasion as well (b). The presence of a fibrocellular stroma juxtaposed to hyalinized stroma is a common finding (c). The hyalinization may mimic cribriform growth (d)

Fig. 2

a–d Skeletal muscle infiltration is common and sometimes subtle (a) Almost half of oral cavity examples of HCCC show connection to the surface epithelium (b). Occasional squamous differentiation can be seen (c). True ductal differentiation is rare. More commonly, entrapped ducts can be seen particularly in parotid examples (d)

Fig. 3

a–d Most HCCC cases show minimal atypia with small bland nuclei (a). Mucinous differentiation is seen in almost half of all cases, usually focally but sometimes diffusely (b). Occasional small cystic spaces can be seen but are not lined by mucinous cells (c). Virtually all cases are positive for one or both of p63 and HMWK (p63 shown here) (d)

Fig. 4

a–d Clear cell myoepithelial carcinoma shows a great degree of morphologic overlap with HCCC. It has common cribriform, solid and nested growth, hyalinization and clear cells (a). However, unlike HCCC it shows strong myoepithelial marker expression with S100 and actins (SMA shown here) (b). Another common mimic includes clear cell calcifying epithelial odontogenic tumor (CEOT). This tumor can show a similar cordlike growth pattern and hyalinized background (c). However the background is made up of amyloid rather than collagen which can also be seen within tumor cells (d). Polarization microscopy showing typical apple-green birefringence (inset). This slide is courtesy of Dr. R. Seethala, University of Pittsburgh Medical Center

Fig. 5

FISH for EWSR1 is becoming a very useful marker for salivary gland tumors with focal or diffuse clear cell differentiation, especially for small biopsies. This positive case shows one normal fused yellow signal and one break-apart signal per cell denoting rearrangement of the EWSR1 gene. The break-apart probe shows one separate green and red signal per cell