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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e3182a7d272
Brief Reports

Primary Salivary Gland–Type Lung Cancer: Clinicopathological Analysis of 88 Cases from China

Zhu, Fen MD*; Liu, Zilong MD*; Hou, Yingyong MD, PhD; He, Deming MD; Ge, Xiaoxiao MD; Bai, Chunxue MD, PhD*; Jiang, Liyan MD, PhD; Li, Shanqun MD, PhD*

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Author Information

Departments of *Respiratory Medicine and Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; and Department of Respiratory Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.

Disclosure: The authors declare no conflict of interest.

The first two authors equally contributed to this work.

Address for correspondence: Shanqun Li, MD, PhD, Department of Respiratory Medicine, Zhongshan Hospital, Fudan University, 180 Fenlin Road, Building 8, 4th Floor, Shanghai 200032, China. E-mail: li.shanqun@zs-hospital.sh.cn; and Liyan Jiang, Department of Respiratory Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, 241 Western Huaihai Road, Building 3, 8th Floor, Shanghai 200032, China. E-mail: Jiang_liyan2000@126.com.cn

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Abstract

Introduction:

Salivary gland–type cancers are rare lung neoplasms involving mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC), and epithelial–myoepithelial carcinoma (EMC). Their behavior and prognostic features are not clearly defined because of their low incidence. We retrospectively analyzed the clinicopathologic profiles of these tumors in a large series.

Methods:

Eighty-eight patients confirmed as having primary salivary gland–type lung cancer between May 2001 and January 2013 were included from the archives of two thoracic oncology center institutions in China and retrospectively evaluated.

Results:

Of the total 88 patients, 69 were MEC, 12 ACC, and seven EMC. Overall survival (OS) at 3, 5, and 10 years was 91.3%, 86%, and 80.6% in all cases, respectively, and disease-free survival (DFS) was 90.1%, 78.6%, and 55%, respectively. No significant difference was found among MEC, ACC, and EMC groups regarding OS (p = 0.518) and DFS (p = 0.082). Tumor-node-metastasis 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). Intrathoracic invasion was an independent predictor for OS (hazard ratio [HR], 1.129; p = 0.039) and DFS (HR, 1.071; p = 0.011). For patients with MEC, pathological grade also was an independent predictor of OS (HR, 0.045; p = 0.006) and DFS (HR, 0.067; p = 0.001).

Conclusions:

Salivary gland–type lung cancers are a group of low-aggressive entities with higher tendency to recurrence/metastasis. Intensive clinical, radiological, and pathological examinations are essential to estimation of the risk stratification and management.

Primary salivary gland–type lung cancer is rare and represents less than 1% of all lung tumors.1,2 This group of tumors derives from small salivary glands in the respiratory system3 and mainly include two common histological subtypes of mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC) and a less common subtype of epithelial–myoepithelial carcinoma (EMC).4–6 Previously, salivary gland–type lung cancer was mostly reported in small series5,7,8 or described in case reports9–11 because of its low incidence. Thus, relatively little is known about their precise clinical, radiological, and pathological features. Consequently, no consensus on optimal therapeutic strategy is available. The present study aimed to review salivary gland–type lung cancer, with emphasis on clinical behavior, pathologic features, treatment, and prognostic factors in a large series of Chinese patients.

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MATERIALS AND METHODS

This retrospective study was approved by the Institutional Review Board. Between May 2001 and January 2013, patients with primary salivary gland–type cancer were identified pathologically from two thoracic oncology centers (Zhongshan Hospital and Chest Hospital, Shanghai, China). Diagnosis of MEC, ACC, and EMC was made according to the World Health Organization classification of thoracic tumors.12 MEC was graded in line with the algorithm proposed by Auclair et al.13 The grading of ACC and EMC was not performed. Staging was performed in compliance with the tumor-node-metastasis (TNM) staging system of the American Joint Committee on Cancer (7th edition). Follow-ups were conducted via medical records plus telephone interview.

Survival was calculated using the Kaplan–Meier method, and the survival curves were compared by the log-rank test. Cox’s proportional hazards regression model was used for univariate and multivariate survival analysis. Categorical variables were presented as counts and percentages, and comparisons were conducted using Fisher’s exact tests. Continuous variables were presented as median and range, and comparisons were conducted using one-way analysis of variance. All analyses were performed using IBM SPSS Statistics 20.0 (IBM Corporation, New York, NY).

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RESULTS

Clinical Characteristics

In total, 69 MEC, 12 ACC, and seven EMC patients were identified. Patient characteristics are summarized in Table 1. None of the clinical parameters included in Table 1 were found to significantly correlate with histological subtypes.

TABLE 1.
TABLE 1.
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Radiological Appearance

The findings were obtained of computed tomography (CT) or positron emission tomography/CT before treatment in 30 patients with MEC and eight with ACC. CT images showed lesions in the central (n = 26) or peripheral (n = 12) lung. The contour of the tumors were round to oval (n = 31) or lobulated (n = 7). In 20 central MEC tumors, three revealed lobulated masses and the remaining showed oval nodules projecting into the bronchus (Fig. 1A). Ten peripheral MEC tumors exhibited oval nodules (n = 4) or masses (n = 6) with rough margin (Fig. 1B). CT images exposed peripheral lung lesions in six and central lung lesions in two patients with ACC; five of these showed oval nodules and the other three cases were lobulated masses. One ACC case that underwent positron emission tomography/CT showed slight but obviously increased (18)F-fluoro-2-deoxy-D-glucose (18 F-FDG) uptake within the tumor (Fig. 1C–E). In general, the radiological profile of ACC was similar to that of MEC.

FIGURE 1.
FIGURE 1.
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Histopathological Features

Histopathological examination of MEC showed that 45 tumors were low grade, 11 were intermediate grade, and 13 were high grade. Briefly, the low-grade MEC demonstrated frequent macrocysts and microcysts, mucous cells, bland cytologic features, and few mitoses (Fig. 2A). High-grade MEC was characterized by few cysts, few mucous cells, frequent mitoses, and cellular pleomorphism (Fig. 2C). The intermediate-grade MEC represented an intermediate histology in the spectrum from low grade to high grade (Fig. 2B). One case of MEC variant with oncocytic cells was identified, in which cells with eosinophilic cytoplasm predominated (Fig. 2D). All ACC tumors were in cribriform pattern, demonstrating nests of cells with cylindromatous microcystic spaces that contained hyaline or basophilic mucoid material (Fig. 2E). EMC cases imparted a bilayered duct-like histology. The inner layer was lined by cuboidal cells, with finely granular cytoplasm; the outer layer was composed of myoepithelial cells with clear cytoplasm (Fig. 2F).

FIGURE 2.
FIGURE 2.
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Clinical Follow-Up

The median follow-up duration was 49 months (range, 3–134 months), during which the tumor recurrence/metastasis was identified in 15 patients (Table 2), of whom four had positive resection margin at the time of primary surgery. No significant difference was found among the three groups on recurrence/metastasis (Table 1; p = 0.057).

TABLE 2.
TABLE 2.
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Overall survival (OS) at 3, 5, and 10 years was 91.3%, 86%, and 80.6%, respectively, and disease-free survival (DFS) was 90.1%, 78.6%, and 55%, respectively. There was no significant difference among the MEC, ACC, and EMC groups regarding OS (Fig. 3A; p = 0.518) and DFS (Fig. 3B; p = 0.082). OS and DFS in surgical patients with different histological subtypes are shown in Table 3. TNM stage, lymph node involvement, intrathoracic invasion, and margin status were found to be related with OS and DFS (Table 4). Moreover, there was a higher risk of OS (p < 0.001; Fig. 3C) and DFS (p < 0.001; Fig. 3D) in high-grade MEC cases than low to intermediate ones. Multivariate analysis showed thoracic invasion was a significant determinant of OS (hazard ratio [HR], 1.129; 95% confidence interval [CI], 1.006–1.266; p = 0.039) and DFS (HR, 1.071; 95% CI, 1.016–1.128; p = 0.011) for all cases, and pathological grade was a significant predictor of OS (HR, 0.045; 95% CI, 0.005–0.410; p = 0.006) as well as DFS (HR, 0.067; 95% CI, 0.013–0.337; p = 0.001) for patients with MEC.

TABLE 3.
TABLE 3.
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TABLE 4.
TABLE 4.
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FIGURE 3.
FIGURE 3.
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DISCUSSION

In the present study of a cohort of salivary gland–type lung cancer patients with a long follow-up, we found that MEC was the most common histological subtype of salivary gland–type lung cancers, followed by ACC, and our findings are in general consistent with findings of the previous series.4,6,10 Nevertheless, patient demographic information, clinical presentation, and radiological appearance are diverse and lack characteristic features. Thus, pathological examination tends to be the exclusive means to distinguish salivary gland–type lung cancer from other pulmonary lesions. However, salivary gland–type lung tumors are easily diagnosed as common lung cancers in pathology, such as adenosquamous carcinoma because of lack of specific biological markers to facilitate diagnosis as well as differential diagnosis. For samples obtained from endoscopy or pneumocentesis, diagnosis may be more difficult based on limited biopsied tissue. It can be seen that exploring biological markers specific for MEC, ACC, and EMC is of importance.

TNM stage, intrathoracic invasion, lymph node involvement, and margin status were associated with OS and DFS of salivary gland–type lung cancer patients. Tumor grade may predict the OS and DFS of MEC patients, yet considerations of tumor grade with intrathoracic invasion are of predictive value by multivariate analysis. Even if some parameters are not independent prognostic factors, we propose that all the significant factors described above are worthy of consideration for physicians deciding rational therapeutic strategies. Interestingly, no significant difference was seen on the survival among MEC, ACC, and EMC groups, and this result differed from observations made by Hickman et al.14 regarding salivary carcinomas of head and neck. Besides anatomical difference of tumor sites and variation of series, we attributed this difference to the predominance of surgical management in ACC patients in the study by Hickman et al.

As far as treatment options for salivary gland–type lung cancer are concerned, surgical intervention seems optimal, given that limited disease is predominant, and the surgical plan relies on the clinical status of the patient. Complete surgical resection is associated with a favorable long-term outcome, as demonstrated by the present study that positive resection margin had imposed a negative effect on OS and DFS. This finding suggests that salivary gland–type cancer of the lung should be removed as completely as possible. According to the current analysis, lymphadenectomy and postoperative radiotherapy did not confer survival benefit on nonselective patients. So, it does not seem necessary to perform lymphadenectomy and postoperative radiotherapy on every patient with MEC, ACC, or EMC. Only patients with evidence of lymph node involvement may benefit from lymphadenectomy. Additionally, adjuvant radiotherapy could be performed if the resection margins are proved to be positive. More prospective studies are needed to reveal the optimal therapy. Currently, patients with salivary gland–type lung cancer may be safely managed through multidisciplinary approaches.

As previously reported,15 the clinical behavior of MEC of the head and neck could be predicted by pathological grade. Similar findings have been shown for MEC of the lung in the present study. The present study showed that high-grade MEC tumors had more aggressive clinical behavior and higher incidence of recurrence/metastasis with poor survival. However, to date, grading for ACC and EMC tumor is still not well defined. Thus, more studies remain necessary to propose a reproducible and precise grading system for ACC and EMC.

In conclusion, salivary gland–type lung cancer is a group of complex neoplasms with a wide spectrum of clinical presentation and nonspecific radiographic manifestations. No significant prognostic difference was found among the MEC, ACC, and EMC groups. Pathological grade, TNM stage, and complete tumor resection are important prognostic factors. Further prospective studies are needed to confirm our findings.

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ACKNOWLEDGMENTS

Support was provided by Shanghai Leading Academic Discipline Project (No. B115). We thank Professor Xianyin Wang for the language editing.

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Keywords:

Salivary gland–type lung cancer; Mucoepidermoid carcinoma; Adenoid cystic carcinoma; Epithelial–myoepithelial carcinoma

Copyright © 2013 by the International Association for the Study of Lung Cancer

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