Combined small-cell lung carcinoma revealed to be an intratumoural metastasis by genetic analysis.

Combined small-cell lung carcinoma (SCLC) consists of SCLC component and another histologic type of non-SCLC. Reports have shown that the subcomponents of combined SCLC originate from a common precursor tumour cell1Murase T. Takino H. Shimizu S. et al.Clonality analysis of different histological components in combined small cell and non-small cell carcinoma of the lung.Hum Pathol. 2003; 34: 1178-1184Crossref PubMed Scopus (26) Google Scholar,2Zhao X. McCutcheon J.N. Kallakury B. et al.Combined small cell carcinoma of the lung: is it a single entity?.J Thorac Oncol. 2018; 13: 237-245Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar or a collision of multiple primaries growing at a same site.3Buys T.P. Aviel-Ronen S. Waddell T.K. et al.Defining genomic alteration boundaries for a combined small cell and non-small cell lung carcinoma.J Thorac Oncol. 2009; 4: 227-239Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar We present a case of a 73-year-old male ex-smoker presenting with haemoptysis. Investigations identified a left lower lobe mass and a left mainstem endobronchial tumour. A bronchial sleeve resection was carried out revealing a 4.3-cm pulmonary combined SCLC and adenocarcinoma (Figure 1A and B). The endobronchial tumour showed only SCLC (Figure 1C). Regional lymph nodes showed foci of metastatic adenocarcinoma in stations 9 and 11 (Figure 1D and E). The patient received post-operative chemoradiotherapy and was without apparent evidence of disease recurrence at the time of submission of the manuscript (∼3.5 years post-operatively). Standard histological, histochemical and immunohistochemistry (IHC) assessments were carried out. The SCLC had an elevated mitotic index with large areas of necrosis. IHC showed neuroendocrine marker-positive staining limited to the SCLC, while napsin A and mucicarmine stains were positive in the adenocarcinoma only. All components were positive staining for Thyroid transcription factor-1 protein. The adenocarcinoma consisted of an acinar predominant architecture with some areas showing a solid architecture. Multi-region whole-exome sequencing (WES) was carried out from relevant areas of interest arising from formalin-fixed paraffin-embedded tissues (respective driver mutations in Figure 1). Both the SCLC components of the pulmonary and endobronchial sites harboured characteristic single-nucleotide variants or small insertions or deletions in multiple genes, including retinoblastoma 1 gene (RB1), tumour protein p53 (TP53) and mucin 16 (MUC16). By comparison, the adenocarcinoma components showed characteristic mutations in KRAS proto-oncogene GTPase (KRAS), filaggrin (FLG) and xin actin-binding repeat-containing protein 2 (XIRP2). Common mutations included ryanodine receptor 2 (RYR2), low-density lipoprotein receptor-related protein 1B (LRP1B) and usherin (USH2A). Notably, of the 152 established cancer susceptibility genes,4Huang K.L. Mashl R.J. Wu Y. et al.Pathogenic germline variants in 10,389 adult cancers.Cell. 2018; 173 (e14): 355-370Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar highly deleterious germline mutations were detected in six of these genes including the well-characterised tumour-suppressor gene neurofibromin 1 (NF1), in the normal lung. Overall, in-depth genetic analysis confirms that the combined SCLC in this case is a result of an endobronchial SCLC with intratumoural metastasis into a lung adenocarcinoma. Very distinct but non-overlapping mutation profiles were observed in the two tumour components; the SCLC showed hallmark mutations in known tumour-suppressor and histone-modifying genes,5Peifer M. Fernandez-Cuesta L. Sos M.L. et al.Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer.Nat Genet. 2012; 44: 1104-1110Crossref PubMed Scopus (912) Google Scholar while the adenocarcinoma showed a frequently observed KRAS (G12C) mutation.6Cancer Genome Atlas Research NetworkComprehensive molecular profiling of lung adenocarcinoma.Nature. 2014; 511: 543-550Crossref PubMed Scopus (3148) Google Scholar Several germline mutations may explain the patient's susceptibility to develop synchronous tumours. Clinical-grade liquid biopsy WES of preoperative blood was unable to detect driver mutations from both SCLC and adenocarcinoma tumours and therefore could not be used to predict the complex tumour landscape or clinical decision-making needed for this case (data not shown). This is the first case showing that tumour intratumoural metastasis collision is another mechanism of combined SCLC evolution, as opposed to a common precursor cancer stem cell model. Moreover, this is an example where extensive sequencing can resolve complex diagnostic quandaries. The study was reviewed and approved by the local institutional research board (Path1/2018-3450) and appropriate consent was obtained from the patient in this study.