| Objective:1. The present study aimed to analyze the clinicopathologic profiles of salivary gland-type lung cancers involving mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC) and epithelial-myoepithelial carcinoma (EMC) in a large series of Chinese patients.2. To study the prevalence of the rearrangement nature of mammalian mastermind like 2 (MAML2) gene in MEC of the lung, and estimate the prognostic value of MAML2 rearrangement in refining clinicopathological prognostic factors in pulmonary MEC.3. To examine the molecular consequences of MAML2 rearrangement, we also detected the expression of potential downstream targets of the MECT1-MAML2 fusion, including Notch target (HES1) and cAMP/CREB targets (FLT1 and NR4A2).4. To determine the potentiality of MAML2 rearrangement in discriminating pulmonary MEC from morphologic mimics, such as adenosquamous carcinoma (ASC).Methods:1. Between May 2001 and January 2013, patients with primary salivary gland-type lung cancer were identified from the archives of two thoracic oncology centers (Zhongshan Hospital and Shanghai Chest Hospital, Shanghai, China). All medical records were reviewed pertaining the ages, gender, smoking status, presenting symptoms, tumor location and size, stage, computed tomographic (CT) findings, options of treatment and clinical outcome. Follow-ups were conducted via medical records plus telephone interview.2. Tissue samples of formalin-fixed, paraffin-embedded blocks with primary pulmonary MEC were available from Zhongshan Hospital and Shanghai Chest Hospital. Specimens of primary adenosquamous carcimnoma were obtained from Zhongshan Hospital during 2007 and 2011.3. Formalin-fixed, paraffin-embedded tissue sections of MECs and ASCs were tested by Fluorescence in situ Hybridization (FISH) to detect the rearrangement of MAML2 gene.4. The expression of several potential downstream targets of the MECT1-MAML2 fusion, including the Notch target (HES1) and the cAMP/CREB targets (FLT1 and NR4A2) were analyzed using immunohistochemistry on formalin-fixed, paraffin-embedded tissue sections sections of pulmonary MEC with two-step method.Results:1. Clinical CharacterisiticsTotally,47 males and 41 females were included in our study. The median age was 48 years (range 7-75 years).69 MEC,12 ACC and 7 EMC were identified. The most common presenting symptoms were cough (48.9%). Tumors were located in lobe (84.1%), main bronchus (10.2%) and trachea (5.7%). In compliance with the tumor-node-metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC,7th edition),61 cases (69.3%) were disease of stage Ⅰ,16 (18.2%) stage Ⅱ,9 (10.2%) stage Ⅲ and 2 (2.3%) stage Ⅳ. Eighty-four patients of 88 underwent surgical management and 4 were given systemic chemotherapy due to systemic metastasis. The common operative procedures were lobectomy. None of the clinical parameters above were found to significantly correlate with histological subtypes.2. Radiological AppearanceThe findings were obtained of radiological appearance before treatment in 30 patients with MEC and 8 patients with ACC. CT images in cases with MEC showed lesions in the central lung in 20 and in the peripheral lung in 10. The contour of theMEC tumors were round to oval (n=26) or lobulated (n=4). In 20 central MEC tumors,3 revealed lobulated masses and the remaining 17 showed oval nodules project into the bronchus. Three of the 20 central MEC cases had bronchial stenosis or obstruction and two had obstructive pneumonia. Four of the 10 peripheral MEC tumors exhibited oval nodules with smooth margin and 6 with rough margin. CT images exposed peripheral lung lesions in 6 and central lung lesions in 2 patients with ACC, and 5 of them showed oval nodules with smooth margin and the other 3 cases were lobulated masses. One ACC case underwent PET/CT showed slight but obviously increased 18F-FDG uptake within the tumor.3. Histopathologial FeaturesHistopathological examination the low grade MEC demonstrated frequent macrocysts and microcysts, mucous cells, bland cytology and few mitoses. High grade MEC was characterized by few cysts, few mucous cells, frequent mitoses and cellular pleomorphism. The intermediate grade MEC represented an intermediate histology in the spectrum from low grade to high grade.ACC cases were characterized by ductal cells with secretory features and modified myoepithelial cells with hyperchromatic and angular nuclei. All ACC tumors were in cribriform pattern demonstrating nests of cells with cylindromatous microcystic spaces which contained hyaline or basophilic mucoid material.EMC cases imparted a bi-layered duct-like histology. The inner layer lined by cuboidal cells, with finely granular cytoplasm; the outer layer was composed of myoepithelial cells with clear cytoplasm.Histologically, lymph node involvement was detected in 15 cases, in which 12 were in MEC group (low grade tumor:5 cases; intermediate grade tumor:1 case; high grade tumor:6 cases) and 3 in ACC group, and yet involvement of lymph node was not detected in EMC group. Intrathoracic structures including main bronchus, pleura, chest wall, diagram, phrenic nerve and pulmonary vessels were invaded in 16 MEC cases (23.1%) and 5 ACC cases (41.6%).4. Clinical Follow-upApart from one perioperative death, the remaining patients were followed up postoperatively. The median follow-up duration was 49 months (range 3-134 months), during which the tumor recurrence/metastasis was identified in 15 patients, in whom 4 had positive resection margin at the time of primary surgery. However, the recurrence/metastasis occurred more often in ACC group (5 cases,41.7%) than in MEC group (9 cases,13.0%) and EMC group (1 case,14.3%). Eight deaths occurred due to tumor recurrence/metastasis, among which 6 deaths occurred in MEC group (5 high grade tumors versus 1 low grade tumor) and 2 deaths in ACC group.5. Molecular FindingsFISH analysis revealed MAML2 rearrangement in 50% of the PMEC cases, and such property was prominent in considerable younger patients (33 versus 60 years; p =0.001) and restricted to cases of low and intermediate grades. IHC analysis showed that FLT1 and HES1 were expressed at lower level in MAML2 rearranged group than MAML2 non-rearranged group (p<0.001 and p=0.023, respectively).5. Survival AnalysisOverall survival (OS) at 3-,5-,10-year were 91.3%,86% and 80.6% in all cases. Disease-free survival (DFS) at 3-,5-,10-year were 90.1%,78.6% and 55%. No significant difference was found among MEC, ACC and EMC groups on OS (p= 0.518) and DFS (p=0.082). TNM stage, lymph node involvement, intrathoracic invasion and margin status were found to be related with OS (p=0.000,0.029,0.000, 0.004) and DFS (p=0.018,0.042,0.002,0.002). Cox’s proportional hazards analysis suggested that intrathoracic invasion was a significant independent predictor for OS (p=0.039, HR:1.129,95%CI:1.006-1.266) and DFS (p=0.011, HR:1.071,95%CI: 1.016-1.128). For patients with MEC, pathological grade was an independent predictor of OS (p=0.006, HR:0.045,95%CI:0.005-0.410) and DFS (p=0.001, HR: 0.067,95%CI:0.013-0.337).In addition, survival analysis showed significant correlation between MAML2 rearrangement and OS (p=0.023) or DFS (p=0.027).Conclusion:1. Salivary gland-type lung cancers are a group of low aggressive entities with no survival difference among histological subtypes. MEC was the most common histological subtype of salivary gland-type lung cancers, followed by ACC. Intensive clinical, radiological and pathological examinations are essential to estimation of the risk stratification and management.2. As far as treatment options for salivary gland-type lung cancer are concerned, surgical intervention seems optimal, given that limited disease is predominant. TNM stage, intrathoracic invasion, lymph node involvement, tumor grade and margin status were significant predictors for prognosis. Thus the surgical plan shall rely on the clinical status of the patient and prognosis factors.3. MAML2 rearrangement appears frequent in MEC and specific with this tumor. However, this nature did not occur in adenosquamous carcinoma. These findings suggest that molecular detection of MAML2 rearrangement may be of important clinical value in diagnosis as well as differential diagnosis for MEC of the lung. Certain undecided cases can be identified through detecting the MAML2 rearrangement on molecular techniques basis, provided that there be evidential prospective studies conducted to validate this methodology.4. FLT1 and HES1 were expressed at low levels in MAML2 rearranged group and contrarily at high levels in MAML2 non-rearranged group. Both the presence of MAML2 rearrangement and absence of FLT1 tend to confer a favorable clinical outcome. Thus, combined molecular detection of MAML2 rearrangement with FLT1 expression can lead to more reliable predication of the outcomes in patients with such entity. It is worth noting that additional large-scale prospective studies with well-characterized PMECs are needed to further substantiate our findings.5. Considering the high concordance between FISH and RT-PCR and the easy application of FISH method, we believed that FISH analysis of the MAML2 gene split might be more useful screening of a favorable subset of mucoepidermoid carcinoma cases.6. As far as MEC which negative both for MAML2 rearrangement, this subject also remains further study. |
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