The tumor in this case consisted of three different components: lower-grade (cribriform subtype) of AdCC, solid-subtype AdCC and HGT. As three components existed separately, we believe that HGT occurs abruptly in typical AdCC. In the present case, HGT component lacked biphasic differentiation. Recently, Costa et al. reported three major criteria of AdCC-HGT ; 1) proliferation of tumor cells at least a focal loss of myoepithelial cells surrounding tumor nests, 2) nuclear size at least 2–3 times the size of tubular/cribriform AdCC nuclei and 3) thickened irregular nuclear membranes and prominent nucleoli in a majority of cells. The present case fulfilled at least the above 3 criteria. On the other hand, as HGT component was composed of atypical clear cells, the differential diagnosis with clear cell carcinoma, not otherwise specified (CCCNOS) or myoepithelial carcinoma is needed. However, CCCNOS is usually a low-grade malignant tumor with mildly nuclear atypia and hyalinized stroma, and is diffusely positive for p63 . Therefore, “the sheet-like area” is not CCCNOS component. Clear cell type of myoepithelial carcinoma showed the positivity for myoepithelial markers, such as ASMA and p63 . Therefore, “the sheet-like area” is not the component of myoepitehlial carcinoma. Moreover, the present case is different from low-grade cribriform cystadenocarcinoma (LGCCC), carcinoma ex pleomorphic adenoma (CXPA) and other rare tumors such as an epithelioid angiosarcoma. Usually, LGCCC shows the intraductal lesions with surrounding by p63-positive myoepithelial cells without atypia . The present case showed cribriform pattern, but the tumor was not intraductal lesion. The criteria of CXPA are the malignant tumor, which usually consist of salivary duct carcinoma component, arising from benign pleomorphic adenoma . The present case never contained the component of pleomorphic adenoma. Epithelioid angiosarcoma rarely occurs in the salivary gland, and tumor cells are infrequently positive for CK and p63 . However, epithelioid angiosarcoma focally shows sinusoid-like spaces and is also positive for vimentin and CD31. The present case was negative for vimentin and CD31 (date not shown), and showed no findings such as sinusoid-like spaces.
HGT is recognized when a lower-grade malignant neoplasm abruptly transforms to a high-grade [9, 10], in which the high-grade component is juxtaposed to the original lesion or the original line of differentiation is lost . This concept should be distinguished from malignancy from arising a benign tumor such as CXPA, hybrid tumors, and transformation within a high-grade carcinoma to another high-grade pattern . However, the gradually successive transition from solid-subtype AdCC to HGT was also reported .
Recently, Seethala et al. indicated that, in the HGT area of AdCC, the Ki-67 labeling index was >50%, and commonly showed the diffuse and strong immunopositivity of p53 protein . Although Chau et al. indicated that, in AdCC-HGT, p53 gene mutation and overexpression of cyclin D1 and Her-2 were related to the dedifferentiation process , the accumulation of p53 gene product and overexpression of cyclin A, cyclin B1, and Her-2 were related to such a phenomenon in the present case. Overall, “the sheet-like area” of this tumor was high-grade carcinoma, which was considered the early phase of AdCC-HGT. The HGT component might have gene mutation of p53 and p16, and moreover, amplification of the Her-2 gene, which suggested that this component had the higher-grade malignancy. Nagao et al. reported 6 cases of HGT-AdCC and suggested that the HGT process was related to p53 gene mutation, overexpression of Her-2 and loss of pRb gene products . In HGT of AdCC, the overexpression of p16 may be related to loss of pRb gene products, not human papilloma virus infection . In the genetic analyses on AdCC with HGT, the increase of c-Myc gene and a low level increase of Her-2 gene in HGT areas were observed, but the role of Her-2 in AdCC-HGT still remains unclear . However, the present case supposed that Her-2 overexpression is related to HGT at least.
Among the salivary gland carcinomas, AdCC frequently showed the HGT. Ide et al. reported that early phase of AdCC-HGT consisted of the scattered foci of anaplastic carcinoma in the co-/pre-existing low-grade AdCC . In series of AdCC-HGT reported by Seethala et al., one case had only a 20% HGT component in typical AdCC and another case contained only a 10% HGT component, who died of disease . As median percentage of HGT component is 70%, which is reported by Seethela et al., we consider that if HGT component is less than 10%, it should be included into the early phase of AdCC-HGT. The present case contained no evidence of scattered high-grade lesions, but one small focus of high-grade carcinoma existed in the central area of the AdCC. Ide et al. do not descript on the proportion of HGT components in the main tumor . Sato et al. reported the gradual progression from low-/intermediate-grade AdCC to high-grade AdCC and moreover to AdCC-HGT . The dedifferentiation or the HGT of the salivary gland carcinomas might occur abruptly within the co-/pre-existing low-grade carcinoma, as seen from the histological and immunohistochemical findings of the present case. In the present case, typical AdCC and HGT components were also clearly demarcated, and no findings of gradual progression were observed.