Mucoepidermoid Carcinoma of the Bronchus: A Review
By Liu, Xiuli Adams, Amy L
* Although mucoepidermoid carcinoma of the salivary gland is relatively common, mucoepidermoid carcinoma arising from the mucous glands of the bronchus is rare. Bronchial mucoepidermoid carcinoma usually presents as an intraluminal mass producing luminal occlusion. Symptoms are airway obstruction and recurrent pneumonia. Macroscopically, mucoepidermoid carcinoma appears as an exophytic intrabronchial mass with intact or ulcerated bronchial mucosa. Microscopically, the tumors are located in the submucosa of the large bronchi. The tumors are usually well differentiated and contain a combination of mucus- secreting, squamous, and intermediate cells. The increased frequency of this tumor in the pediatric population suggests a genetic abnormality. Recent genetic studies have demonstrated reciprocal chromosomal translocations including t(1;11)(p22;q13), t(11;19)(q14-21;p12), and t(11; 19)(q21;p13). Chromosome 11 in the first translocation appears to have been altered resulting in up-regulation of the cyclin D1 gene and overexpression of cyclin D1. The t(11;19)(q21;p13) encodes a novel fusion product capable of disrupting the Notch signaling pathway. (Arch Pathol Lab Med. 2007;131:1400-1404)
Mucoepidermoid carcinoma is defined by the World Health Organization as a tumor characterized by a combination of mucus- secreting, squamous, and intermediate cell types and is not an uncommon tumor in general. 1 It usually arises in the parotid and submandibular salivary glands and in the minor salivary glands of the oral cavity and perimaxillary region. Mucoepidermoid carcinoma of the lung, however, is rare with a reported frequency of 0.1% to 0.2% of primary lung tumors.1 Mucoepidermoid carcinoma of the bronchus is similar to its counterpart arising from the salivary glands but does have some distinct characteristics of its own. Here we present a brief review of this entity, focusing on the salient clinical and pathologic features.
CLINICAL FEATURES
Mucoepidermoid carcinoma of the bronchus occurs in patients with a wide age range from 3 to 78 years.1-5 In the recent literature, it equally affects males and females. 2-11 The majority of cases documented are in the form of case reports or small series. It also appears that most of the cases are generated from the pediatric population. One report has suggested that mucoepidermoid carcinoma accounts for approximately 10% of primary lung tumors in this age group.12 Although coincidence cannot be excluded because of small numbers, the occurrence of mucoepidermoid carcinoma in lungs of patients with congenital abnormalities, including unilateral hypoplastic lung, has been reported.6,11
Because of the typical pattern of involvement of large airways, the clinical symptoms and signs of bronchial mucoepidermoid carcinoma include cough, hemoptysis, bronchitis, wheezing, fever, chest pain, and rarely, clubbing of the fingers.10 The clinical and radiographic differential diagnosis usually includes asthma, pneumonia, atelectasis, middle lobe syndrome, and pleural effusion.3,4,10 Recurrent pneumonia in the same region of the lung should raise clinical suspicion of an endobronchial lesion or mass, such as mucoepidermoid carcinoma.
Although imaging studies generally provide significant information in the evaluation of pulmonary lesions, conventional chest radiography and computed tomography sometimes are not helpful in establishing the diagnosis of mucoepidermoid carcinoma of the bronchus. This may be because of the small size of the neoplasm, especially during the early phase, or because of the endobronchial location combined with interference of associated pneumonia or atelectasis. Increased awareness of the diagnosis may improve the diagnostic yield of imaging studies by intensifying the search for an endobronchial mass proximal to lung lobes with pneumonia and atelectasis. Sometimes an endobronchial mass may only be identified in retrospective review of the chest computed tomography scan images after the diagnosis of mucoepidermoid carcinoma is confirmed in the resected pathologic specimen (Figure 1). To circumvent the problems with imaging studies, flexible fiberoptic bronchoscopy is an excellent diagnostic modality with the capability of visualizing the lesion directly and obtaining tissue for definitive diagnosis.
PATHOLOGIC FINDINGS
Mucoepidermoid carcinoma of the bronchus mainly arises from the large airways, including the trachea and the main or lobar bronchi, but occasionally may involve segmental bronchi or, rarely, the peripheral lung.1,3,10 It usually presents as an exophytic luminal mass, which can be sessile, polypoid with a broad base connected to the bronchial wall, or pedunculated with a well-formed stalk. The cut surface is gray-white-tan with a glistening mucoid texture. Cystic degeneration can be appreciated in some mucoepidermoid carcinomas. The size of the tumor varies considerably within a range from several millimeters to 6 cm in diameter in some studies.3,13,14 The bronchus usually is dilated with abundant mucoid luminal material in the distal portion. The adjacent lung parenchyma generally demonstrates atelectasis or pneumonia.3
Histologically, mucoepidermoid carcinoma consists of 3 components: mucus-secreting, squamous, and intermediate cells. These 3 cell types can be organized into different patterns including glands, tubules, cysts, nests, and solid areas.1 The relative frequency of these 3 cell types in a given case varies considerably and serves as one of the histologic criteria for grading this tumor. In a well-sampled section, the tumor is usually endobronchial and polypoid and displays a close association with the adjacent submucosal salivary-type glands in the bronchus. The mucus- secreting cells are usually large and have light bluegray mucinous cytoplasm. Variants of mucus-secreting cells are reported in the literature, including columnar, goblet, cuboidal, clear, or, occasionally, oncocytic cells. Mucoid substance of similar appearance can also be identified in extracellular spaces or in the lumina formed by the neoplastic cells. The squamous cells may be admixed with the mucus-secreting cells and intermediate cells, or they can form small nests of their own. The squamous cells have intercellular bridges, but keratin whorls and pearls are not seen.14 The intermediate cells usually do not demonstrate specific differentiation and are characterized by a polygonal shape, a centrally or eccentrically located bland nucleus, and relatively abundant amphophilic or slightly eosinophilic cytoplasm. The intermediate cells are usually located at the periphery of the glands or form nests. Other unusual features of mucoepidermoid carcinoma of the bronchus include calcification and prominent lymphoid proliferation (Figure 2, A through C).3,4
Preoperative diagnosis of mucoepidermoid carcinoma can be achieved with small tissue biopsies obtained during bronchoscopic examination. Although most cases of mucoepidermoid carcinoma can be diagnosed confidently, some cases are misdiagnosed with endoscopic biopsy, especially when the tissue is severely fragmented or stroma predominates. Biopsy samples usually demonstrate a fi- brotic stroma, a ”dirty background” composed of extracellular blue-gray mucoid substance, and multiple small cysts lined by mucus-secreting cells and intermediate cells (Figure 3, A and B). The mucus- secreting cells contain the same abundant blue-gray mucinous material present in the dirty background. If the specimen is not crushed, glands, cysts, tubules, and small nests can be appreciated. The coexistence of 3 cell types is very characteristic for a low- grade mucoepidermoid carcinoma.
There still remains some debate regarding the definition of high- grade mucoepidermoid carcinoma in this location. 13,14 High-grade lesions usually demonstrate necrosis, nuclear pleomorphism, active mitosis, and a solid or nested pattern of growth for the intermediate or squamous cells. Low-grade mucoepidermoid carcinoma usually lacks these features. In the literature, most mucoepidermoid carcinomas of the bronchus are categorized as low grade, but high- grade mucoepidermoid carcinomas arising from the bronchus have been reported with a frequency as high as 50% in a few small series.3,10 Low-grade mucoepidermoid carcinoma is usually confined to the bronchus and does not involve adjacent lung parenchyma. However, in highgrade neoplasms, the tumor can infiltrate into the surrounding lung parenchyma.3
CYTOGENETICS
Recent cytogenetic analysis using comparative genomic hybridization and spectral karyotyping of cell lines derived from parotid and bronchial mucoepidermoid carcinomas showed multiple reciprocal translocations.15 These reciprocal translocations involve essentially every chromosome but more frequently involve chromosomes 1, 5, 7, and 11. Several reciprocal translocations were identified: t(11;19), t(1;16), t(6;8), t(1;7), t(3;15), and t(7;15), with the reciprocal t(11;19)(q21;p13) being the major chromosomal abnormality observed in 2 cell lines.15 Although cell lines derived from malignant tumors are notorious for genetic instability, as characterized by the presence of multiple genetic abnormalities of varied nature, including chromosomal translocations, other reports have independently demonstrated t(11;19) in 38.4% of mucoepidermoid carcinomas, and the reported translocations involve the q14-21 region of chromosome 11 and the p12-13 region of chromosome 19.8,16 In 1 mucoepidermoid carcinoma of the lung, t(11;19)(q14-21;p12) was the only karyotypic abnormality identified.8 These results hint that the reciprocal t(11;19)(q14-21;p12) may play a significant role in the tumorigenesis of mucoepidermoid carcinoma. Indeed, recently Tonon and colleagues15 elegantly demonstrated that the t(11;19)(q21;p13) observed in mucoepidermoid carcinoma encodes a novel fusion product, mucoepidermoid carcinoma translocated 1- mastermind-like 2 (MECT1- MAML2), capable of disrupting the Notch signaling pathway. Whether t(11;19)(q14-21;p12) produces an identical fusion protein remains unknown at present. In addition, Barrett et al9 reported a different reciprocal translocation in a mucoepidermoid carcinoma of the bronchus also involving chromosome 11, t(1;11)(p22;q13). Because cyclin D1 is located within the 11q13 locus, the authors suggest that the translocation results in overexpression of cyclin D1 protein and is likely to play a role in the tumorigenesis of this neoplasm. Indeed, immunohistochemical analysis with an anti-cyclin D1 antibody showed diffuse and strong staining in tumor cells. However, a recent report demonstrated that only 20% of mucoepidermoid carcinomas (3/15 cases) had overexpression of cyclin D1 as detected by immunohistochemistry,17 indicating that other factors or genetic aberrations, perhaps the t(11; 19)(q14-21;p12) or t(11;19)(q21;p13), may play a signifi- cant role in the tumorigenesis of mucoepidermoid carcinoma that does not harbor t(1;11)(p22;q13). Larger series of studies are needed to investigate the relative frequency of these translocations, and correlation of the translocation type with cyclin D1 overexpression will determine the significance of cyclin D1 in the development of this tumor and the possible usefulness of cyclin D1 overexpression as a surrogate biomarker.
DIFFERENTIAL DIAGNOSIS
Other primary lung neoplasms, including adenocarcinoma and adenosquamous carcinoma, comprise the major differential diagnoses for mucoepidermoid carcinoma of the bronchus.4 Immunophenotyping of the tumor lesion may be helpful, particularly in the case of a small biopsy sample in which the whole spectrum of the typical histomorphology may not be present in the submitted material. Immunoperoxidase staining with antibodies to cytokeratin (CK) 7 and thyroid transcription factor 1 (TTF- 1) may be useful, for example, in differentiating mucoepidermoid carcinoma of the bronchus from primary lung adenocarcinoma (Figure 4, A and B). In a recent small series of 6 cases, Shilo et al4 showed that all mucoepidermoid carcinomas of the bronchus in their series were negative for TTF-1 (5/5 cases tested) and CK20 (4/4 cases tested), but the tumor cells were positive for CK7 (4/4 cases tested) and CK5/6 (2/3 cases tested). Other diagnostic considerations may occasionally include metastatic renal cell carcinoma or sugar tumor (PEComa), given that they may contain abundant bubbly mucoid cytoplasm. Immunohistochemistry should help ascertain the correct diagnosis, as clear cell renal cell carcinomas are generally not immunoreactive for CK7 or CK5/6, and PEComas usually express HMB-45.18,19
TREATMENT AND PROGNOSIS
Mucoepidermoid carcinoma of the lung may be surgically treated by lobectomy, sleeve resection, local resection, segmental resection, or even endoscopic removal.10 In 1 review report involving 45 patients with disease-free follow- up ranging from 8 months to 21 years, 1 patient had lymph node metastasis and died, 1 patient developed lymph node metastasis at 5 years of follow-up, and 1 patient had questionable lymph node metastasis.10 These data suggest that patients with mucoepidermoid carcinoma of the lung should be provided with long-term clinical follow-up.
CONCLUSIONS
Mucoepidermoid carcinoma of the bronchus is a rare primary lung malignancy. It usually presents with symptoms of airway obstruction and recurrent pneumonia. Familiarity with the entity on the part of the clinician, the radiologist, and the pathologist may allow a preoperative diagnosis of mucoepidermoid carcinoma to be reached. With difficult cases when primary lung adenocarcinoma is the major differential diagnosis, an immunohistochemical stain for TTF-1 may be helpful. Recent cytogenetic studies independently demonstrated several reciprocal chromosomal translocations frequently involving chromosome 11, including t(1;11)(p22;q13) with resultant overexpression of cyclin D1, t(11;19)(q14-21;p12), and t(11; 19)(q21;p13), which encodes a novel fusion product, MECT1-MAML2, capable of disrupting the Notch signaling pathway. The role of these reciprocal translocations, overexpression of cell cycle protein(s), and the novel fusion protein in the tumorigenesis of mucoepidermoid carcinoma requires further studies in a large series of cases, which will greatly enhance our understanding of the tumorigenesis of this unique carcinoma.
We thank Gene P. Siegal, MD, PhD, and Omar Hameed, MBChB, for their editorial assistance in the preparation of this manuscript.
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Xiuli Liu, MD, PhD; Amy L. Adams, MD
Accepted for publication March 22, 2007.
From the Department of Pathology, University of Alabama at Birmingham.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Amy L. Adams, MD, University of Alabama at Birmingham, 1802 Sixth Ave S NP 3548, Birmingham, AL 35249 (e-mail: aladams@uab.edu).
Copyright College of American Pathologists Sep 2007
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