Combined small cell carcinoma of the lung: a case diagnosed on bronchoscopic wash cytology and bronchial biopsy

Dear Editor, Lung carcinomas comprise a heterogeneous group of neoplasms encompassing numerous histological variants. Their treatment and clinical management depends primarily on the histopathological subtype. Combined small cell lung carcinoma (c-SCLC) is the only subtype of SCLC recognised by the World Health Organization: it may be combined with any non-small cell histological type. Preoperative diagnosis of this entity is difficult because of the small-sized biopsy specimens and sampling error and it has rarely been diagnosed on cytology. However, 28% of surgically resected SCLCs have been found to be combined tumours. Clinical features of pure and combined SCLC are similar but it has been suggested that surgical resection may be more useful in c-SCLC. In cytological samples, it is important to distinguish the small cell component from other neuroendocrine tumours. We describe a rare case of c-SCLC in which both components were seen on the cytology bronchial wash sample and confirmed on the accompanying biopsy. A 42-year-old man presented with a history of cough and streaky haemoptysis for 1 month and dull aching right upper chest pain. The patient was a heavy smoker, had lost 5 kg in weight over the preceding 3 months and had lost his appetite. Physical examination was unremarkable except for reduced intensity of breath sounds in the right infraclavicular area. A chest radiograph demonstrated a mass-like opacity in the right paratracheal area, and computed tomography (CT) of the thorax demonstrated a right upper lobe mass (4.5 cm 9 3 cm) with extensive mediastinal lymphadenopathy. Flexible bronchoscopy demonstrated submucosal infiltration and stenosis of the right upper lobe bronchus. Bronchoscopic wash and endobronchial biopsy were performed. The bronchoscopic wash specimen was processed by membrane filtration concentration and stained with a Papanicolaou method. The smears showed two populations of malignant cells. The first comprised atypical squamous cells, lying singly as well as in small groups, with hyperchromatic nuclei with condensed chromatin and a moderate to abundant amount of orangeophilic cytoplasm; some showed abnormal cytoplasmic shapes, including tadpole or fibre-like forms (Figure 1a). The second population comprised small cells with a high nucleocytoplasmic ratio, hyperchromatic nuclei and scant cytoplasm. These cells were predominantly arranged in small groups with focal nuclear moulding (Figure 1b). The bronchial biopsy also showed a biphasic tumour predominantly comprised of small round cells with scant cytoplasm and round nuclei with coarse chromatin and inconspicuous nucleoli. Mitotic activity was brisk [6–7/10 high power field (hpf)]. There were areas with crush artefact and focal nuclear moulding. The small cell component was intermingled with a few tiny foci of malignant squamous islands showing cellular keratinization and occasional keratin pearl formation (Figure 1c,d). There was no necrosis. The small cell component was immunopositive for pancytokeratin, chromogranin and synaptophysin. The MIB-1 labelling index was approximately 40–50% in the small cell areas. The squamous cell carcinoma component showed immunopositivity for p40 (dilution 1 : 3000; Calbiochem, Darmstadt, Germany), but was negative for neuroendocrine markers. Biologically, c-SCLC represents divergent morphological differentiation to SCLC and non-small cell types as a result of evolution from a common cancer stem cell: the individual elements are closely related genotypically, immunophenotypically and clonally supporting c-SCLC being classified as a type of SCLC. In cytological specimens, it is important to differentiate the small cell component from other neuroCorrespondence: Dr D. Jain, Department of Pathology, All India Institute of Medical Sciences, New Delhi-110029, India Tel.: +91-9868895112; Fax: +91-11-2658863; E-mail: deepalijain76@gmail.com