Mucoepidermoid Carcinoma: A Comparison of Histologic Grading Systems and Relationship to MAML2 Rearrangement and Prognosis

Abstract

Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy, but categorization is complicated by variability in grading systems and uncertain prognostic significance of MAML2 rearrangement. The aims of this study were to determine the prognostic significance of MEC grading systems and MAML2 rearrangement status. Fifty-three carcinomas originally diagnosed as MEC (45 primary; 8 recurrent) of major and minor salivary glands were graded according to modified Healey, Brandwein, AFIP, and Katabi systems. Fluorescence in situ hybridization for MAML2 rearrangement was performed. Clinical features and outcomes were recorded. Twenty-five (47%) carcinomas scored the same in all grading systems. The most common histologic feature leading to a diagnosis of intermediate grade was isolated solid growth. Brandwein assigned the highest percentage of high grade (29%) and AFIP the highest percentage of low grade (80%). MAML2 was rearranged in 37/46 (80%) cases. Forty-three (81%) were morphologically compatible with MEC, and these were more likely to be low-intermediate grade and MAML2-rearranged. Of primary carcinomas, 6 (13%) recurred. Statistically significant univariate risk factors for recurrence included non-MEC morphology, stage T4, and high Brandwein grade. Margin status, MAML2 rearrangement, and isolated solid growth were not predictive of recurrence. A binary grading system (Brandwein high vs. low-plus-intermediate) could be considered to better reflect biological behavior in MEC. Our study confirms that MAML2 wildtype tumors more likely represent high grade non-MECs, and prior studies demonstrating worse prognosis in MAML2-nonrearranged MECs may be diluted by high-grade non-MECs.

Figure 1:. Four Mucoepidermoid Carcinoma (MEC) Grading Systems Compared

Forty-five primary carcinomas (of which 40 were morphologically compatible with MEC on contemporary re-review) were graded according to four published grading systems. Brandwein assigned the highest rate of high grade (29%), while AFIP the highest rate of low grade (80%). The distribution was similar after eliminating the 5 non-MEC cases [Supplementary Figure 2].

Figure 2:. Carcinomas with Mucoepidermoid Morphology

Most (81%) carcinomas reviewed were morphologically compatible with MEC. Solid growth was the most common reason for assigning Brandwein intermediate grade, as seen in this well-circumscribed (A) mucoepidermoid carcinoma with intermediate cells, glycogenated cells (B), rare mucinous cells, and MAML2 rearrangement (B, inset). Occasional carcinomas morphologically consistent with MEC (C), showed intermediate cells, squamoid cells, and mucinous cells (D) but lacked MAML2 rearrangement. A true high grade mucoepidermoid carcinoma also showed appropriate cell types and high grade features, including perineural invasion (E, inset), rare mucinous cells (F, top inset), and MAML2 rearrangement (F, bottom inset).

Figure 3:. Carcinomas of Non-Mucoepidermoid Morphology

Some carcinomas (19%) originally diagnosed as MEC by the signout pathologist were not compatible with MEC upon contemporary review. This primary palate carcinoma showed micropapillary architecture (A) with extracellular mucin pools (B) and was negative for MAML2 rearrangement, suggestive of the rare mucinous adenocarcinoma. A buccal carcinoma demonstrated abundant eosinophilic hyalinized stroma (C) and a single cell type with clear cytoplasm and wrinkled nuclei (D), consistent with clear cell carcinoma. Another palate carcinoma also showed a single cell type with single-file infiltration within fibrous stroma (E) and perineural invasion (F). The remaining non-MEC cases were not morphologically specific for other salivary type carcinomas.

Figure 4:. Kaplan-Meier Recurrence Curves Based on Ternary Grading of Primary Cases

Considering all 45 primary cases, Brandwein intermediate grade carcinomas behaved similarly to low grade, with no recurrences in either group. Recurrences only occurred in the high Brandwein grade group (A). A binary Brandwein system could be employed as an improved predictor of recurrence [Supplementary Figure 3A]. In the Katabi (C) and modified Healy (E) systems, low, intermediate, and high grade carcinomas had different recurrence-free survival rates, including no recurrences in the low grade groups. AFIP low and intermediate grade carcinomas had worse recurrence-free survival rates compared to other systems, suggesting that this system undergrades carcinomas (G). Additionally, AFIP intermediate grade carcinomas behaved similarly to high grade [Supplementary Figure 3C]. Considering only the 40 primary carcinomas morphologically compatible with mucoepidermoid, the findings are very similar (B, D, F, H) [Supplementary Figure 3B, 3D].