A Mismatch Repair–Deficient Hepatoid Adenocarcinoma of the Lung Responding to Anti–PD-L1 Durvalumab Therapy Despite no PD-L1 Expression

Major advances in the understanding of cancer mechanisms have led to an improved therapeutic management of patients with advanced non–small cell lung cancer (NCLC). Nevertheless, the treatment of some rare tumors remains poorly codified. We here report about a patient with Lynch syndrome and a rare pulmonary hepatoid adenocarcinoma. A 43-year-old 8–pack-years smoker with a history of Lynch syndrome and lieberkuhnian adenocarcinoma (treated at 31 years with no relapse) was diagnosed as having a metastatic cancer with a main right mediastinal-hilar tumor and several nodal, cerebral, adrenal, and bone metastases (Fig. 1A). Histopathologic examination of a left supraclavicular nodal metastasis revealed a carcinomatous metastasis with histopathologic and immunophenotypic hepatoid features. Immunohistochemistry was positive for cytokeratins 7, 19, and 20; hepatocyte antigen; carcinoembryonic antigen; and thyroid transcription factor-1 (cytoplasmic but no nuclear staining) and the tumors cells did not express the caudal type homeobox 2 protein (Figs. 1B and 1C). The patient did not present any hepatic or other digestive tumor. The tumor was diagnosed as a pulmonary hepatoid adenocarcinoma. The tumor did not present any EGFR, KRAS, ALK receptor tyrosine kinase (ALK), or ROS1 molecular alteration. Programmed death ligand 1 (PD-L1) immunohistochemistry (clone 22C3) was negative in tumor cells and immune cells. Replication error phenotyping revealed the instability of only 2 of 5 microsatellite markers but a loss of expression of mutL homolog 1 and PMS1 homolog 2, mismatch repair system component proteins using immunohistochemistry (mutS homolog 2 and mutS homolog 6 expressions were preserved) (Figs. 1D–1G). Molecular genetics analyses revealed a constitutional heterozygous mutL homolog 1 mutation (deletion of exons 1 to 5) of paternal origin. The patient was first treated with carboplatin area under the curve 5 – Gemzar 1000-mg/m2 therapy, then with docetaxel before being included in a clinical trial evaluating durvalumab anti–PD-L1 therapy. Despite a PD-L1–negative status, the patient presented a partial response to immunotherapy (Figs. 1H–1J). Nevertheless, anti–PD-L1 therapy was finally stopped because of infectious complications leading to the patient's death. Hepatoid adenocarcinoma of lung origin is a rare tumor with less than 40 cases reported in the literature.1Haninger D.M. Kloecker G.H. Bousamra Ii M. Nowacki M.R. Slone S.P. Hepatoid adenocarcinoma of the lung: report of five cases and review of the literature.Mod Pathol. 2014; 27: 535-542Crossref PubMed Scopus (68) Google Scholar Its diagnosis is based on the histopathologic, immunophenotypic, and sometimes biochemical (elevated serum alpha-fetoprotein) criteria similar to those of hepatocellular carcinoma, a liver tumor being discarded on the basis of clinical and radiological investigations. The therapeutic management of this rare tumor is not well codified to date. Our case is, to our knowledge, the first case treated using programmed cell death protein 1 /PD-L1 blockade. Despite a negative PD-L1 status, we observed partial response to immunotherapy. We hypothesize that the therapeutic effect of immunotherapy in our case can be due to the underlying mismatch repair (MMR)–deficient status. Indeed, MMR-deficient tumors, with higher mutational load and increased expression of neoepitopes are known to be immunogenic tumors and potential good responders to immunotherapy.2Le D.T. Durham J.N. Smith K.N. et al.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.Science. 2017; 357: 409-413Crossref PubMed Scopus (3808) Google Scholar, 3Le D.T. Uram J.N. Wang H. et al.PD-1 Blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015; 372: 2509-2520Crossref PubMed Scopus (6158) Google Scholar Less than 3% of NCLCs are MMR-deficient and replication error phenotypes are not systematically performed in patients with NCLC.4Warth A. Körner S. Penzel R. et al.Microsatellite instability in pulmonary adenocarcinomas: a comprehensive study of 480 cases.Virchows Arch. 2016; 468: 313-319Crossref PubMed Scopus (50) Google Scholar Given the potential response of MMR-deficient tumors to immunotherapy, even lacking PD-L1 expression, we believe that searching for MMR-deficiency in patients with NCLC could be a valuable predictive approach of responsiveness to immunotherapy, especially in young patients lacking indicated therapies or immunotherapies according to the current guidelines.