Clinical Meetings at RH Year 2008

2008 Clinical Meeting AHNH - A Young Patient with Asthma and Haemoptysis

Dr LO Yi Tat and Dr CHAN Hok Sum
Department of Medicine, Alice Ho Miu Ling Nethersole Hospital

Case History

A 20 years-old never smoked man was diagnosed to have asthma in 2005 with infrequent attack and no prior hospitalization history. He was admitted for on and off haemoptysis since 2004. There was no constitutional symptom. Physical examination, including chest, was unremarkable. Previous CXR reports (in Oct 2004, Jan 2005, Nov 2005, Jun 2006 and May 2007) and this episode (Fig.1) were normal. Blood tests were essentially normal. Sputum for acid-fast bacilli was negative. He was given a course of Augmentin and there was no recurrence of haemoptysis during hospital stay. Contrast computed tomography (CT) of thorax showed a contrast enhanced 2.3cm soft tissue mass in the left main bronchus (LMB); lungs are clear and there was no lymphadenopathy (Fig 2). Bronchoscopy revealed an irregular mass at the left distal trachea extending to and obstructing LMB. The patient was transferred to cardiothoracic unit for further management subsequently. Emergency rigid bronchoscopy was performed for cored excision of the vascular tumour which resulted in massive bleeding; and Dumon stent was inserted to bypass obstruction.


The tumour biopsy showed focally ulcerated mucosae lined by ciliated columnar and hyperplastic squamous epithelium. They are infiltrated by sheets and lobules of polygonal cells, some with clear cytoplasm, some forming glandular structures (Figure 3). No necrosis nor haemorrhage was evident. The pathological diagnosis was mucoepidermoid carcinoma of salivary gland type, low to intermediate grade.



The patient received left pneumonectomy with excision of hilar and subcarinal lymph nodes. Histological examination confirmed clear resection margin and no lymph node metastasis. Molecular study of the tumour showed the presence of mucoepidermoid carcinoma translocated 1 – mastermine-like 2 (MECT1-MAML 2) fusion gene. The survillence bronchoscopy performed at 6 months and chest radiography taken at 1 year post-operatively showed no recurrence of tumour.

Discussion

1. Background
Mucoepidermoid carcinoma (MEC) of salivary gland was described in 1945 by Stewart1 with fairly well studied and understood histology and clinical behaviour. In 1952, Smetana2 first reported the tumour within the bronchi “as a type of bronchi adenoma” and was later found to have malignant potential with behaviour similar to MEC of salivary gland. MEC of the lung is now defined as a malignant epithelial tumour, composed of mucus-producing cells as well as intermediate and squamoid cells arranged in solid, glandular or cystic patterns3. The tumour was originated from the minor salivary glands of tracheobronchial tree. It is rare with frequency of 0.1% - 0.2% of all primary lung tumour4. It equally affects male and female with wide age range 3 - 78 years old. Whilst, it is more common in paediatric population (10% of all cases) and 50% of cases were younger than age 305.

The clinical presentation includes persistent cough, haemoptysis, dyspnoea, recurrent pneumonia or wheezing. Most of these symptoms are related to the tumour arising from the large airways: trachea, main or lobar bronchi; as a sessile, polypoid or pedunculated exophytic luminal mass6. However, some 9%-28% of the patients are asymptomatic4.

2. Classification, histology and cytogenetics
The classification of lung MEC was based on the relative frequency of the three cell types: mucus secreting cells (large with light blue-grey mucinous cytoplasm); squamous cells (containing intercellular bridge and may be admixed with mucus-secreting cells and intermediate cells); and intermediate cells (polygonal shape without specific differentiation), in a given tumour tissue sample. Low grade MEC is characterized by the coexistence of these 3 cell types. It is usually confined to the bronchus and does not involve adjacent lung parenchyma. Whilst, high grade MEC commonly demonstrate necrosis, nuclear pleomorphism, active mitosis (> 4 per 10 high power field), and a solid on nested pattern of growth for intermediate or squamous cells. It can infiltrate into the surrounding lung parenchyma6.

Cytogenetic analysis showed MEC involved multiple reciprocal translocations with t(11;19)(q21;p13) being the major chromosomal abnormality. This reciprocal translocation encodes a novel fusion protein, MECT1-MAML 2, capable of disrupting the Notch signaling pathway. Besides, 11q13 locus translocation can result in overexpression of cyclin D1 protein which has potential tumourigensis6.

3. Imaging of MECs On chest radiography, lung MEC can appear as a solitary nodule (up to 71% 5), consolidation, atelectasis or even normal7,8. The lesion is much more commonly located in the central than at the periphery7,9. On CT/HRCT, MECs appeared smooth with well defined margin; oval, round or lobulated in shape; and some with punctuate calcifications. Kim, et al10 in their series reported all MECs were homogeneous with mild contrast enhancement only. On the contrary, Ishizumi’s9 group reported marked heterogeneous contrast enhancement with foci of relatively low attenuation in four out of five cases studied. They suggested the presence of both hyper- and hypo-vascular components within MEC as demonstrated by the immunohistochemical staining. For the use of PET scan, there are only few case reports11,12,13 and more in the paediatric patients. The MECs demonstrated raised SUV which helps to differentiate it from some lesions, such as bronchogenic cysts, pulmonary carcinoid, and bronchoalveolar carcinoma.

4. Treatment and prognosis Lung MEC may be surgically treated by pneumonectomy, lobectomy, local resection, segmental resection, or endoscopic removal. Nevertheless, radiotherapy or chemotherapy is not effective. There is study demonstrated the presence of epidermal growth factor receptor (EGFR) mutation in MEC which indicated it may be a potential target for EGFR tyrosine kinase inhibitor in future14. The prognosis of lung MEC was better in patients with complete tumour resection margin and lymph node excision15, early stage (stage I or II) of disease (10 year survival 87.5%)7, and low grade tumour (1 year and 5 years survival of 80% and 57% respectively, versus 1 year survival of 20% in high grade MEC)7. Molecularly, the presence of MECT 1- MAML 2 fusion gene had lower risk of local recurrence, metastases or tumour related death, and longer median survival time (>10 years versus 1.6 years in patient without fusion gene)16.

References

1. Stewart FW, Foote FW, Becker WF. Mucoepidermoid tumours of salivary glands. Ann Surg 1945; 122: 820-44.
2. Smetana HF, Iverson L, Swan LL. Bronchogenic carcinoma. Analysis of 100 autopsy cases. Mil Surg 1952; 3: 335-51.
3. Brambilla E, Travis WD, Colby TV, et al. The new World Health Organization classification of lung tumours. Eur Respir J 2001; 18: 1059-68.
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7. Chin CH, Huang CC, Lin MC, et al. Prognostic factors of tracheobronchial mucoepidermoid carcinoma-15 years experience. Respirology 2008; 13: 275-80.
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9. Giusti RJ, Flores RM. Mucoepidermoid carcinoma of the bronchus presenting with a negative chest X-ray and normal pulmonary function in two teenagers: two case reports and review of the literature. Pediatr Pulmonol 2004; 37: 81-84.
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11. Kim TS, Lee KS, Im JG, et al. Mucoepidermoid carcinoma of the tracheobronchial tree : radiographic and CT findings in 12 patients. Radiology 1999; 212: 643-48.
12. Kinoshita H, Shimotake T, Furukawa T, et al. Mucoepidermoid carcinoma of the lung detected by positron emission tomography in a 5-year-old girl. J Pediatr Surg 2005; 40: E1-3.
13. Lee EY, Vargas SO, Sawicki GS, et al. Mucoepidermoid carcinoma of bronchus in a pediatric patient: (18) F-FDG PET findings. Pediatr Radiol 2007; 37: 1278-82.
14. Ishizumi T, Tateishi U, Watanabe S, et al. F-18 FDG PET/CT imaging of low-grade mucoepidermoid carcinoma of the bronchus. Ann Nucl Med 2007; 21: 299-02.
15. Han SW, Kim HP, Jeon YK, et al. Mucoepidermoid carcinoma of lung: potential target of EGFR-directed treatment. Lung Cancer 2008; 61: 30-34.
16. Yu CH, Li J, Yu JQ, et al. Clinicopathological features and prognosis of bronchial mucoepidermoid carcinoma : analysis of 21 cases. Natl Med J China 2007; 87: 41-43.
17. Behboudi A, Enlund F, Winnes M et al. Molecular classification of mucoepidermoid carcinomas – prognostic significance of the MECT1-MAML 2 fusion oncogene. Gene Chromosomes Cancer 2006; 45: 470-81.