Abstract
Silicosis is an important form of pneumoconiosis, which is caused by significant exposure to crystalline silica. The carcinogenicity of silica, despite traditional beliefs, in relation to lung cancer has been controversial. Lymphoepithelioma-like carcinoma of the lung, an Epstein-Barr virus-associated undifferentiated carcinoma, is a rare entity of pulmonary malignancy, which tends to affect young nonsmoking Asians.
The first case of silicosis, initially complicated by pulmonary tuberculosis, which later developed into advanced lymphoepithelioma-like carcinoma of the lung is reported. A combination of 5‐fluorouracil, cisplatin and calcium folinate resulted in partial tumour response.
Inhalation of dusts is an important cause of interstitial lung disease in many countries. Silicosis, pneumoconiosis of coal workers, and asbestosis are the three most commonly recognised forms of pneumoconiotic pulmonary fibrosis 1. Although the pathogenetic role of crystalline silica in silicosis has been well described 2–4, the association between silica exposure and lung cancer remains controversial 5, 6.
Begin et al. 7 first reported lymphoepithelioma-like carcinoma (LELC) of the lung in 1987. LELC of the lung tends to affect young nonsmoking patients and the mean age of affected patients was reported to be 10 yrs younger than that in other histological types of nonsmall cell lung carcinoma in a Taiwanese series 8. The mean age was 48 yrs in a Hong Kong series 9. Probably due to the racial distribution of LELC, most of the major series on LELC of the lung have been reported from Southern China 8, 10, 11. Pathological, epidemiological and histopathological studies have unequivocally shown an association between LELC of the lung and Epstein-Barr virus (EBV) infection 8, 9, 12–18. However, the treatment of LELC is controversial, and little is known regarding the precise role of chemotherapy and radiotherapy in this rare condition 10, 12–14, 19, 20.
The first case of LELC of the lung occurring in a patient with silicosis is reported. This rare association between silicosis and a nonsmoking-related lung cancer lends support to a carcinogenic role of silica. The efficacy of combination chemotherapy (5‐fluorouracil, cisplatin and calcium folinate) has also been demonstrated in this case 20.
Case report
A 71-yr-old exsmoker (cumulative cigarette consumption 25 pack-yrs), who was an iron miner for >10 yrs, was diagnosed as having silicosis, based on radiographical features and a history of dust exposure, in 1987. He presented with haemoptysis, cough and weight loss in 1999. Chest radiography revealed diffuse nodular shadows in both lungs consistent with silicosis and a right middle lobe mass (fig. 1⇓). Radiologically, the mass could still have represented atypical progressive massive fibrosis, although neoplastic or infective lesions had to be excluded. There were no other symptoms or signs on detailed history evaluation and physical examination. The patient underwent fibreoptic bronchoscopy, the results of which were macroscopically normal. Bronchoalveolar lavage fluid (BALF) gave negative acid-fast bacilli stain results. Percutaneous transthoracic needle biopsy (PTNB) of the mass lesion, performed under computed tomographic guidance, showed small noncaseating epithelioid granulomata, with positive Ziehl-Neelsen staining for acid-fast bacilli. Standard antituberculous treatment (2 months of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by another 7 months of isoniazid and rifampicin) was commenced. Subsequent microbiological culture of BALF confirmed the presence of Mycobacteria tuberculosis with favourable sensitivity tests to the above first-line antituberculous drugs.
Chest radiograph showing diffuse nodular shadows over both lungs and a right middle lobe mass.
However, there was no improvement in radiographical appearance after completion of the antituberculous treatment, despite the lack of respiratory or other systemic symptoms. One year after completion of antituberculous treatment, the right middle lobe mass progressively enlarged on follow-up chest radiographs. Fibreoptic bronchoscopy showed a tumour at the right middle lobe bronchus. Bronchial biopsy revealed fragments of cohesive tumour cells arranged in syncytial sheets, and intermixed with lymphoplasmacytic inflammatory cells. The tumour cells had plump-spindled hyperchromatic nuclei, distinct nucleoli and indistinct cytoplasmic borders (fig. 2⇓). Insitu hybridisation was strongly positive for EBV-encoded small ribonucleic acids (RNAs), compatible with LELC (fig. 3⇓). PTNB at the right middle lobe mass revealed a silicotic nodule and nests of infiltrating tumour. Computed tomography (CT) of the thorax showed an 8.2×8.8×6.5-cm mass in the right middle lobe with eccentric and amorphous calcification, against a background of multiple noncalcified silicotic lung nodules and calcified mediastinal lymph nodes (fig. 4⇓). It was relatively well defined apart from its anterior borders, which were spiculated. Encasement of the right descending pulmonary artery and right middle lobe bronchus was present. An 18-fluorodeoxyglucose positron emission tomography scan showed a hypermetabolic tumour in the right middle lobe, with diffuse increased activity in multiple areas of the mediastinum, suggesting extensive malignant mediastinal lymphadenopathy (radiologically staged IIIA; tumour 3, node 2, metastasis 0). As a routine investigation for LELC of the lung and to exclude a nasopharyngeal origin of the tumour, nasopharyngeal examination and magnetic resonance imaging of the nasopharynx were performed, which revealed no abnormalities. Anti-EBV immunoglobulin A serology (enzyme-linked immunosorbent assay) was negative.
Bronchial biopsy specimen showing fragments of cohesive tumour cells arranged in syncytial sheets and intermixed with lymphoplasmacytic inflammatory cells. The tumour cells show oval nuclei, prominent nucleoli and indistinct cytoplasmic borders. Haematoxylin and eosin stain; internal scale bar=250 µm.
In situ hybridisation study showing strong positivity for Epstein-Barr virus- encoded small ribonucleic acids in tumour nuclei, in contrast to negative signals in the lymphocytes. Internal scale bar=250 µm.
Contrast-enhanced computed tomography scan of the thorax showing a) an 8.2×8.8×6.5-cm mass in the right middle lobe (arrows) with amorphous and eccentric calcification (arrowheads). b) The borders are relatively well-defined apart from spiculation at the anterior border (arrowheads). Multiple noncalcified silicotic lung nodules are also present.
Systemic chemotherapy, consisting of four 4‐weekly cycles of 5‐fluorouracil (1,000 mg·m−2 body surface area (BSA)·day−1 on days 1–4), calcium folinate (200 mg·m−2 BSA·day−1 on days 1–4) and cisplatin (100 mg·m−2 BSA·day−1 on day 1), was commenced. After completion of four cycles of chemotherapy, the tumour had significantly reduced in size, i.e. >50% compared with baseline CT scan (fig. 5⇓). The chemotherapy was well tolerated with only mild anaemia, thrombocytopenia, nausea, vomiting and stomatitis.
Contrast-enhanced computed tomography scan of the thorax showing a >50% reduction in tumour size (arrows) after completion of four courses of systemic chemotherapy.
Discussion
The present patient illustrates the commonly encountered difficulty in the management of silicotic patients who develop new lung shadows, the diagnosis of which may be confused with complications associated with the silicotic process such as tuberculosis or progressive massive fibrosis. Silicosis is an important form of pneumoconiotic pulmonary fibrosis related to exposure to silica dusts. Pulmonary tuberculosis represents a common complication seen in up to 50% of patients with silicosis in some clinical series 1. However, the relationship between silicosis and lung cancer, despite the adoption of crystalline silica as a group 1 human carcinogen by the International Agency for Research on Cancer, is still controversial 5, 6. Tumour suppressor p53 gene messenger RNA is suppressed by intratracheal injection with crystalline silica in mice 21. The mutation frequencies of the p53 gene were high among lung cancers in silicotics, but the mutation distributions in exons differed from those without silicosis 22. However, silica has not been shown to be directly genotoxic and has only been proven to be a pulmonary carcinogen in rats 6. Epidemiological studies on the carcinogenicity of silica have shown inconsistent and sometimes even contradictory results 23. Apart from factors related to study design and concomitant exposure to other potential carcinogens such as cadmium, polycyclic aromatic hydrocarbons 24 and radon daughters 25, smoking has been a major confounding and uneliminated factor in these studies 25.
LELC is pathologically a distinct entity classified as a typeof nonsmall cell lung cancer 8, 9. Primary LELC of the lung is histologically indistinguishable from the prototypical LELC occurring in the nasopharynx 8, and it is therefore imperative that a nasopharyngeal origin is actively excluded in all cases. Major differential diagnoses for LELC are non-Hodgkin's lymphoma and metastatic nasopharyngeal carcinoma, both of which are common among the Chinese 12. Immunohistochemical staining helps to differentiate lymphoma from LELC 8. Endoscopic examination and random biopsy of the nasopharynx together with CT or preferably magnetic resonance imaging are often necessary to exclude primary nasopharyngeal carcinoma.
Experience with systemic chemotherapy in the treatment of LELC of the lung is limited. Postoperative chemotherapy with four cycles of carboplatin and etoposide (VP-16) had been used for stage II LELC of the lung in one report 13. There was another report of induction chemotherapy consisting of 5‐fluorouracil, calcium folinate and cisplatin in a child with LELC of the lung resulting in significant tumour reduction 19. In a series of advanced LELC of the lung treated with palliative chemotherapy comprising 5‐fluorouracil and cisplatin, 71.4% showed a partial response and 28.6% had progressive disease 10. Similarly, in previously reported series, the combination of 5‐fluorouracil, cisplatin and calcium folinate achieved a partial response rate of 67% in advanced LELC of the lung 20. The addition of calcium folinate to 5‐fluorouracil, as in the present chemotherapy regimen, has been shown to enhance the effect of 5‐fluorouracil 20.
The present case demonstrates the rare association between silicosis and lymphoepithelioma-like carcinoma of the lung in which silica dust exposure might have been contributory to carcinogenesis. An interesting observation was the degree of amorphous and eccentric calcification within the mass, suggesting the presence of progressive massive fibrosis, at least initially. Subsequent development of lymphoepithelioma-like carcinoma would have resulted in uneven soft tissue growth, causing eccentricity of the calcification. Advanced lymphoepithelioma-like carcinoma of the lung has previously been described to comprise large relatively well-defined tumours closely associated with the mediastinum 11. Despite the relatively high prevalence of Epstein-Barr virus infection among the Chinese, and the relatively high frequency of silicosis, there have not been any previous reports on an association between lymphoepithelioma-like carcinoma and silicosis. The potential carcinogenic effects of silica 5, 21–23 could have contributed to the development of lymphoepithelioma-like carcinoma in the present case, albeit probably not as a strong trigger. It is also possible that previous cases of nonsmall cell lung cancer in silicosis could have been lymphoepithelioma-like carcinoma misdiagnosed by unwary pathologists or clinicians. The good clinical response in the present case of lymphoepithelioma-like carcinoma of the lung to a combination of 5‐fluorouracil, cisplatin, and calcium folinate warrants further studies.
- Received December 11, 2002.
- Accepted February 17, 2003.
- © ERS Journals Ltd
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