Diagnosis of Combined Adenocarcinoma Small Cell Lung Cancer by Endobronchial Ultrasound Transbronchial Needle Aspiration

To the Editor: Combined small cell lung carcinoma (c-SCLC) is a small cell carcinoma mixed with any additional component of non–small cell histologic type, including adenocarcinoma (ADC), squamous cell carcinoma, and large cell carcinoma. While pure histology is the more prevalent presentation, c-SCLC has been reported in combination with squamous (3%) and adenocarcinoma (9%).1 Much of the knowledge about the c-SCLC arises from dated surgical case series, because preoperative diagnosis of c-SCLC may be difficult to achieve when small samples are evaluated. Endobronchial ultrasound–guided transbronchial needle (EBUS-TBNA) provides access to hilar, interlobar and mediastinal lymph nodes. While samples from EBUS have previously been shown to be adequate for lung cancer phenotyping and genotyping, the samples obtained are generally smaller compared with other modes of tissue acquitision such as forceps biopsy and surgical biopsy. The diagnosis of the combined phenotypes of lung cancer by EBUS-TBNA has not previously been reported. We report a case of combined SCLC-ADC diagnosed by EBUS-TBNA. A 78-year-old man was referred with 7 kg unintentional weight loss over 2 months. He was a heavy smoker with a 60 pack year smoking history and a medical background of atrial fibrillation with impaired systolic left ventricular function and type II diabetes mellitus. He had no respiratory symptoms and the physical examination was normal. Following an abnormal chest radiograph, a CT scan of the thorax and abdomen was performed showing a right lower lobe 6.5 mm nodule with a 17 mm station 7 lymph node (Fig. 1A). EBUS-TBNA was carried out under local anesthesia and conscious sedation using midazolam and fentanyl. The procedure was performed using a 22-G needle using a suction with 5 mL syringe. Six passes were obtained from the subcarinal lymph node; samples were expelled from the needle using the stylet and placed into liquid fixative for cell-block processing. Pathologic review of the cell block revealed 2 different clusters of malignant cells. The first, more abundant, showed a high nuclear cytoplasmic ratio, scanty cytoplasm, stippled salt and pepper chromatin, nuclear moulding and frequent mitoses, consistent with SCLC; another group of nested malignant epithelial cells had a high nuclear cytoplasmic ratio, stippled irregular chromatin, atypical mitoses and moderate amounts of cytoplasm consistent with ADC; both the cell populations were TTF1, CK7, and CD56 positive while S100 and CK5 were negative (Fig. 1B–D). The final diagnosis was small cell carcinoma mixed with an adenocarcinoma. Molecular testing for EGFR PCR and ALK immunohistochemistry were negative, while PD-L1 expression, evaluated with antibody clone 22C3 (mouse anti-human PD-L1, Dako), was weak positive and the patient was referred to a medical oncologist. The patient was treated with a standard platinum-based doublet.FIGURE 1: PET/CT heavy avid subcarinal lymph node (A), endobronchial ultrasound specimen showing 2 tumor components (H&E, ×200 magnification) (B), CD56 (×200 magnification) (C), TTF-1 (×200 magnification) (D).Two different mechanisms have been postulated to account for combined lung adenocarcinoma and SCLC: (1) SCLC can result from dedifferentiation from a previously well-defined cancer. This concept is supported by identification of cases where the patient has not received a first-line TKI and the small cell component shares the same EGFR mutation as the adenocarcinoma.2 (2) Both NSCLC and SCLC could arise from the same cancer stem cell or progenitor cell with adenocarcinoma differentiated and present as the first cancer. Activation (or deactivation) of specific signalling pathways can lead to dormant stem cells undergoing SCLC transformation.3 Furthermore, in some cases both components are present at initial diagnosis (ie, true c-SCLC) but limited material available for analysis renders some synchronous cancers mistaken as metachronous.1 Although in our case the presence of the adenocarcinoma component did not influence the therapeutic choice, it is unclear whether c-SCLC may benefit from different therapeutic options. In 2007, Fukui and colleagues have described a case of a female patient who had never smoked with a missense mutation of EGFR. Molecular analysis revealed that both the SCLC and adenocarcinoma cells shared the same mutation in exon 21 (L858R)4 but treatment response is not reported. The presented case is to our knowledge the only report of mixed small cell and adenocarcinoma diagnosed by EBUS-TBNA. The combination of phenotype, immunohistochemistry, and studies of biomarkers (both genetic and mechanistic) may be needed to determine the optimal targeted therapies for patients with tumors of mixed morphology. Fabio Perrotta, MD*† Reena Khiroya, MD‡ Peter Russell, MD§ Ugo Ekeowa, MD§ Amer Saleem, MD∥ Elaine Borg, MD‡ Tanya Ahmad, MD¶ Mary Falzon, MD‡ Martin Forster, PhD¶ Neal Navani, PhD**Department of Thoracic Medicine University College London Hospitals and Lungs for Living Research Centre University College London Respiratory Departments of‡Histopathology¶Medical Oncology, University College London Hospitals (UCLH), London§Department of Respiratory Medicine, The Princess Alexandra Hospital, Harlow∥Department of Respiratory Medicine Bedford Hospital NHS Trust, Bedford, UK†Department of Medicine and Health Sciences, University of Molise, Campobasso Italy