Pulmonary sarcomatoid carcinoma—a new hope
Authors: J.M. Boland, A.S. Mansfield, A.C. Roden
Journal: Annals of Oncology (2017)

Sarcomatoid change is a rare phenomenon in non-small cell lung carcinoma. Histologically, it is recognized as a change from the more typical epithelioid morphology of carcinoma, to spindle-shaped cells or bizarre tumor giant cells that morphologically mimic sarcoma [1.Travis W.D. Brambilla E. Burke A.P. et al.World Health Organization Classification of Tumours.in: Bosman F.T. Jaffe E.S. Lakhani S.R. WHO Classification of Tumours of the Lung, Pleura, Thymus, and Heart. IARC Press, Lyon2015Google Scholar]. Even more uncommonly, this may include true heterologous sarcomatous transformation, such as malignant cartilage or bone formation, or rhabdomyoblastic differentiation [1.Travis W.D. Brambilla E. Burke A.P. et al.World Health Organization Classification of Tumours.in: Bosman F.T. Jaffe E.S. Lakhani S.R. WHO Classification of Tumours of the Lung, Pleura, Thymus, and Heart. IARC Press, Lyon2015Google Scholar]. If these areas of sarcomatoid change constitute more than 10% of the tumor, a diagnosis of sarcomatoid carcinoma is rendered per current WHO criteria, and therefore this is a diagnosis which can only be confidently rendered based on surgical resection specimens [1.Travis W.D. Brambilla E. Burke A.P. et al.World Health Organization Classification of Tumours.in: Bosman F.T. Jaffe E.S. Lakhani S.R. WHO Classification of Tumours of the Lung, Pleura, Thymus, and Heart. IARC Press, Lyon2015Google Scholar]. In some cases of sarcomatoid carcinoma, areas of typical non-small cell carcinoma can be identified, divulging the tumor's true epithelial nature [1.Travis W.D. Brambilla E. Burke A.P. et al.World Health Organization Classification of Tumours.in: Bosman F.T. Jaffe E.S. Lakhani S.R. WHO Classification of Tumours of the Lung, Pleura, Thymus, and Heart. IARC Press, Lyon2015Google Scholar]. Most cases of sarcomatoid carcinoma also retain some degree of cytokeratin expression by immunohistochemistry, which is useful in the differential diagnosis with true sarcoma [2.Terra S.B. Aubry M.C. Yi E.S. et al.Immunohistochemical study of 36 cases of pulmonary sarcomatoid carcinoma–sensitivity of TTF-1 is superior to napsin.Hum Pathol. 2014; 45: 294-302Crossref PubMed Scopus (30) Google Scholar]. The differentiated areas and even the sarcomatoid regions may also retain expression of immunohistochemical markers typical of pulmonary adenocarcinoma or squamous cell carcinoma, such as TTF1 or p40 [2.Terra S.B. Aubry M.C. Yi E.S. et al.Immunohistochemical study of 36 cases of pulmonary sarcomatoid carcinoma–sensitivity of TTF-1 is superior to napsin.Hum Pathol. 2014; 45: 294-302Crossref PubMed Scopus (30) Google Scholar, 3.Weissferdt A. Kalhor N. Correa A.M. et al."Sarcomatoid" carcinomas of the lung: a clinicopathologic study of 86 cases with a new perspective on tumor classification.Hum Pathol. 2017; 63: 14-26Crossref PubMed Scopus (24) Google Scholar]. Sarcomatoid morphologic change seems to correspond with epithelial-mesenchymal transition of the tumor cells [4.Blaukovitsch M. Halbwedl I. Kothmaier H. et al.Sarcomatoid carcinomas of the lung–are these histogenetically heterogeneous tumors?.Virchows Arch. 2006; 449: 455-461Crossref PubMed Scopus (51) Google Scholar]. Since sarcomatoid change is generally a form of high-grade tumor progression in non-small cell carcinoma, it is not surprising that it is associated with a very poor prognosis [5.Yendamuri S. Caty L. Pine M. et al.Outcomes of sarcomatoid carcinoma of the lung: a surveillance, epidemiology, and end results database analysis.Surgery. 2012; 152: 397-402Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar]. Sarcomatoid carcinoma is most commonly observed in heavy smokers, and there is a male predominance [1.Travis W.D. Brambilla E. Burke A.P. et al.World Health Organization Classification of Tumours.in: Bosman F.T. Jaffe E.S. Lakhani S.R. WHO Classification of Tumours of the Lung, Pleura, Thymus, and Heart. IARC Press, Lyon2015Google Scholar, 5.Yendamuri S. Caty L. Pine M. et al.Outcomes of sarcomatoid carcinoma of the lung: a surveillance, epidemiology, and end results database analysis.Surgery. 2012; 152: 397-402Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 6.Fallet V. Saffroy R. Girard N. et al.High-throughput somatic mutation profiling in pulmonary sarcomatoid carcinomas using the LungCarta Panel: exploring therapeutic targets.Ann Oncol. 2015; 26: 1748-1753Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar]. Patients with sarcomatoid lung carcinoma respond poorly to platinum-based chemotherapy regimens [7.Vieira T. Girard N. Ung M. et al.Efficacy of first-line chemotherapy in patients with advanced lung sarcomatoid carcinoma.J Thorac Oncol. 2013; 8: 1574-1577Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar], and thus there is a critical need for 'new and improved' therapeutic options. Little was known about the molecular pathogenesis of sarcomatoid carcinoma until recently. This is likely due to a combination of factors that make it a difficult entity to study, including its rarity and heterogeneous morphology. Given the high-grade nature of this malignancy, patients also tend to present at high stage and many are not surgical candidates at the time of diagnosis. This precludes definitive diagnosis of sarcomatoid carcinoma, and hampers thorough pathologic examination and advanced genetic studies. Many of the recent genetic studies of sarcomatoid lung carcinoma have shown a mutational profile similar to high-grade pulmonary adenocarcinomas, including a high rate of TP53 and KRAS mutations, along with occasional mutations in STK11, NRAS, PIK3CA, and NOTCH1 [6.Fallet V. Saffroy R. Girard N. et al.High-throughput somatic mutation profiling in pulmonary sarcomatoid carcinomas using the LungCarta Panel: exploring therapeutic targets.Ann Oncol. 2015; 26: 1748-1753Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 8.Terra S.B. Jang J.S. Bi L. et al.Molecular characterization of pulmonary sarcomatoid carcinoma: analysis of 33 cases.Mod Pathol. 2016; 29: 824-831Crossref PubMed Scopus (48) Google Scholar]. Targetable mutations in ALK and EGFR have also been reported in sarcomatoid carcinoma, although they seem to be present in only a minority of cases [6.Fallet V. Saffroy R. Girard N. et al.High-throughput somatic mutation profiling in pulmonary sarcomatoid carcinomas using the LungCarta Panel: exploring therapeutic targets.Ann Oncol. 2015; 26: 1748-1753Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 8.Terra S.B. Jang J.S. Bi L. et al.Molecular characterization of pulmonary sarcomatoid carcinoma: analysis of 33 cases.Mod Pathol. 2016; 29: 824-831Crossref PubMed Scopus (48) Google Scholar]. A new hope for therapy in these aggressive tumors has burgeoned with the discovery of frequent intronic MET mutations leading to exon 14 skipping in sarcomatoid carcinoma, as well as MET amplification. These alterations lead to increased signaling through the MET receptor pathway, and can potentially be treated with targeted MET tyrosine kinase inhibitors [9.Liu X. Jia Y. Stoopler M.B. et al.Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations.J Clin Oncol. 2016; 34: 794-802Crossref PubMed Scopus (247) Google Scholar, 10.Awad M.M. Oxnard G.R. Jackman D.M. et al.MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression.J Clin Oncol. 2016; 34: 721-730Crossref PubMed Scopus (443) Google Scholar, 11.Schrock A.B. Frampton G.M. Suh J. et al.Characterization of 298 patients with lung cancer harboring MET exon 14 skipping alterations.J Thorac Oncol. 2016; 11: 1493-1502Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 12.Pelosi G. Gasparini P. Conte D. et al.Synergistic activation upon MET and ALK coamplification sustains targeted therapy in sarcomatoid carcinoma, a deadly subtype of lung cancer.J Thorac Oncol. 2016; 11: 718-728Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar]. Another promising new therapy in pulmonary sarcomatoid carcinoma is the group of immune checkpoint inhibitors, as PD-L1 overexpression has been observed in over half of sarcomatoid carcinomas [13.Vieira T. Antoine M. Hamard C. et al.Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1) and strong immune-cell infiltration by TCD3 cells and macrophages.Lung Cancer. 2016; 98: 51-58Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 14.Velcheti V. Rimm D.L. Schalper KA. Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1).J Thorac Oncol. 2013; 8: 803-805Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 15.Kim S. Kim M.Y. Koh J. et al.Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: Comparison of sarcomatous and carcinomatous areas.Eur J Cancer. 2015; 51: 2698-2707Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar]. In the current issue, Pécuchet et al. add to our current understanding of the molecular underpinnings of sarcomatoid carcinoma [16.Pécuchet N. Vieira T. Rabbe N. et al.Molecular classification of pulmonary sarcomatoid carcinomas suggests new therapeutic opportunities.Ann Oncol. 2017; 28: 1597-1604Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. They report the findings of a whole exome sequencing study including 15 cases of pulmonary sarcomatoid carcinoma, in which all of the studied patients were smokers. Interestingly, they found two distinct groups based on mutational signatures: one with tobacco-associated mutations, and one with APOBEC enzyme and homologous recombination deficiency, including BRCA1 and BRCA2 mutations. The group with tobacco-associated signatures had a higher rate of PD-L1 overexpression and MAP-kinase pathway mutations, while MET, EGFR, and IDH1 mutations were only seen in the second group. The patients with the tobacco-associated signature also had a poorer overall survival. The growing body of literature regarding the molecular mechanisms of pulmonary sarcomatoid carcinoma supports that these tumors are not only morphologically diverse, but quite genetically diverse as well. Since these patients seem to have a dismal response to conventional chemotherapy, the discovery of these genetic events is critical to improving therapy and potentially improving outcome for these patients. The description of genetic driver mutations has provided a new hope for personalized medicine going forward, bringing sarcomatoid lung carcinoma into the era of targeted therapy. While many of the traditional molecular targets observed in pulmonary adenocarcinoma seem to occur at low levels in sarcomatoid carcinoma (ALK, EGFR, etc.), PD-L1 overexpression and MET mutations seem to have a particular propensity for sarcomatoid carcinomas. It may be that MET mutations and/or PD-L1 tumor overexpression are a critical genetic event leading to the high-grade sarcomatoid transformation in these non-small cell carcinomas. Pécuchet et al. found that one tumor in their series had MET amplification that seemed to be localized to the sarcomatoid region of the tumor, and was absent in the non-small cell component. PD-L1 expression has also been noted to be significantly higher in sarcomatoid areas of the tumor, compared with areas showing a traditional non-small cell carcinoma appearance [15.Kim S. Kim M.Y. Koh J. et al.Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: Comparison of sarcomatous and carcinomatous areas.Eur J Cancer. 2015; 51: 2698-2707Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar]. While it appears based on the data from Pécuchet et al. that the sarcomatoid elements and non-small cell carcinoma components within sarcomatoid carcinoma have a common genetic origin, the possible role of MET and PD-L1 in the epithelial-mesenchymal transition of sarcomatoid carcinoma is an area that warrants further study. There also seem to be some novel potentially targetable mutations discovered in the current study by Pécuchet et al., including BRCA1/2 and IDH1. Based on this remarkable genetic variability, the search for targetable mutations in these tumors may best be undertaken by casting a wide net, with broad immunologic and molecular testing to direct therapeutic options. None declared.