Primary Pulmonary Mucoepidermoid Carcinoma: Histopathological and Moleculargenetic Studies of 26 Cases

Abstract

Introduction: Pulmonary mucoepidermoid carcinoma (PMEC) is an uncommon neoplasm of the lung and the main salivary gland-type lung carcinoma. The aims of this study were to review the clinicopathological and immunohistochemical features of PMEC and characterize the genetic events in PMEC.

Methods: We reviewed the pathology cases in our hospital and found 34 initially diagnosed PMEC cases, 26 of which were confirmed as PMEC after excluding 8 cases of MEC-like pulmonary carcinoma. The clinicopathological characteristics of the 26 PMEC cases and the 8 cases of MEC-like pulmonary carcinoma were retrospectively reviewed. MAML2 rearrangement was detected by fluorescence In Situ Hybridization (FISH). Immunostains of ALK, calponin, collagen IV, CK7, EGFR, HER2, Ki-67, Muc5Ac, p63, p40, and TTF-1 were performed. DNA was extracted from 23 cases of PMEC. Mutation profiling of the EGFR, KRAS, BRAF, ALK, PIK3CA, PDGFRA, and DDR2 genes were carried out using next-generation sequencing (NGS), Sanger sequencing, and quantitative polymerase chain reaction (QPCR) in 9 successfully amplified cases.

Results: Twenty-six cases of PMEC (18 low-grade, 8 high-grade) included 13 men and 13 women aged 12-79 years. Twenty-two cases had a central/endobronchial growth pattern, and 4 cases had a peribronchial growth pattern. Immunohistochemically, CK7, Muc5Ac, p40, and p63 were positive in all cases (26/26);EGFR was positive in 11 cases (11/26); TTF-1, Calponin, HER2 and ALK were negative in all cases (0/26). MAML2 rearrangement was identified in 12 of 18 PMEC cases. No mutations were detected in any of the 7 genes in the 9 cases that qualified for mutation analysis. Twenty-three PMEC patients had follow-up information with a median interval of 32.6 months. Both the 5- and 10-year overall survival rates (OS) were 72.1%, and a high-grade tumor was an adverse prognostic factor in PMEC. There were 8 cases of MEC-like pulmonary carcinoma aged 36-78 years: 2 cases were located in the bronchus, and 6 cases were located in the lung. p63 and TTF-1 were positive in all cases (8/8), p40 was positive in 5 cases (5/8), and ALK was positive in 5 cases (5/8). No cases of MAML2 rearrangement were detected, but there were 5 cases of ALK rearrangement.

Conclusions: PMEC is a primary malignant pulmonary tumor with a relatively good prognosis that is historically characterized by the presence of mucous cells and a lack of keratinization. There are distinct differences between PMEC and MEC-like pulmonary carcinoma in tumor location preference, immunophenotype, and molecular genetics, and the differential diagnosis is critical due to the therapeutic and prognostic considerations.

Fig 1. Microscopic images of primary pulmonary mucoepidermoid carcinoma.

(A) Cross-section of the lobe bronchus demonstrating primary pulmonary mucoepidermoid carcinoma with an endobronchial growth pattern (H&E, lower power). (B) The same case with solid nests and a cystic component that comprises the tumor with hyalinization stroma, foci of calcification, and mucus in the cystic component (H&E, x75). (C) The tumor was composed of mucous, intermediate, and epidermoid cells without keratinization (H&E, x150). (D) Another primary pulmonary mucoepidermoid carcinoma case showing dedifferentiation with severe nuclear atypia, necrosis, and salient mitotic figures (right side) and the upper left corner showing the typical mucoepidermoid carcinoma area (H&E, x150).

Fig 2. Microscopic images of MEC-like pulmonary carcinoma.

(A) Case 1 showing solid nests in the left upper corner and mucin-filled cysts and mucous cells on the right side (H&E, x75). (B) Case 2 showing many mucous cells in the solid nests (H&E, x150). (C) Case 3 showing a cribriform-like structure with mucous cells (H&E, x150). (D) Case 4 was a mucoepidermoid carcinoma-like adenosquamous carcinoma (H&E, x150) (the illustration in the lower right corner clearly shows keratinization).

Fig 3. Immunostains of PMEC.

(A) Muc5AC highlighted the partial mucous cells within the tumors (x150). (B) p63 was positive in both intermediate and epidermoid cells (x150). (C) TTF-1 was negative in all three cells (x150). (D) ALK was negative (x150). (E) Ki-67 was positive in the nucleus in a low-grade tumor, and the labeling index is 2% (x150). (F) Ki-67 was positive in the nucleus in the dedifferentiation area, and the labeling index is about80% (x150).

Fig 4. Immunostains of MEC-like pulmonary carcinoma.

(A) P63 was positive in some cells in the same case in 2A (x150). (B) TTF-1 was positive in some cells in the same case in 2A (x150). (C) p63 was positive in some cells in the same case in 2B (x150). (D) TTF-1 was positive in some cells in the same case in 2B (x150). (E) p63 was positive in some cells in the same case in 2C (x150). (F) TTF-1 was positive in some cells in the same case in 2C (x150). (G) ALK was positive in tumor cells as the same case in 2C (x150). (H) ALK was positive in some tumor cells as the same case in 2D (x150).

Fig 5. FISH analysis.

(A) The MAML2 gene is rearranged in PMEC and shows a disruption of the red and green signals (x1000, oil immersion). (B) The MAML2 gene is not rearranged in MEC-like pulmonary carcinoma and only shows overlapping yellow or green/red fusion signals (x1000, oil immersion). (C) TheALK gene is rearranged in MEC-like pulmonary carcinoma and shows a disruption of the red and green signals (x1000, oil immersion).

Fig 6. Overall survival of the 23 PMEC patients with follow-up.

(A) OS according to age. (B) OS according to growth pattern. (C) OS according to tumor diameter. (D) OS according to tumor grade. (E) OS according to Ki-67 labeling index. (F) OS according to surgical resection.