Hepatoid Adenocarcinoma of the Lung with EGFR Mutation and the Response to Tyrosine Kinase Inhibitors
Authors: Hua-fei Chen, Wen-xian Wang, Xing-liang Li, Chun-wei Xu, Kai-qi Du, You-cai Zhu, Mei-yu Fang
Journal: Journal of Thoracic Oncology (2019)

Hepatoid adenocarcinoma (HAC) is a rare type of tumor that frequently originates from the stomach, with pathologic features indistinguishable from those of hepatocellular carcinoma. In addition to the stomach, HAC has been found in the lung, mediastinum, gallbladder, pancreas, etc. Hepatoid adenocarcinoma of the lung (HAL) is rare, with an incidence of 2.3% of all HACs. The biological significance of HAL is not fully elucidated, and its clinical symptoms are generally atypical. Generally, HAL has a high mortality rate and a poorer prognosis because of its strong invasiveness and metastasis to other organs.1Grossman K. Beasley M.B. Braman S.S. Hepatoid adenocarcinoma of the lung: review of a rare form of lung cancer.Respir Med. 2016; 119: 175-179Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Most patients with HAL are reported to present with increased serum α-fetoprotein (AFP) levels on histopathologic analysis that are commonly associated with poor prognosis. In contrast, the molecular markers of therapeutic significance, such as EGFR mutations, are frequently absent from HAC. Mounting evidence from studies supports the idea that EGFR mutations serve as driver oncogenes in lung cancer, and tyrosine kinase inhibitors (TKIs) present remarkable therapeutic efficacy against EGFR-mutated tumors.2Ghafoor Q. Baijal S. Taniere P. O'Sullivan B. Evans M. Middleton G. Epidermal growth factor receptor (EGFR) kinase inhibitors and non-small cell lung cancer (NSCLC)-advances in molecular diagnostic techniques to facilitate targeted therapy.Pathol Oncol Res. 2018; 24: 723-731Google Scholar To the best of our knowledge, this is the first report of HAL harboring EGFR mutation and being responsive to TKI therapy. A 53-year-old nonsmoking man was referred to our hospital in December 2015 with 1-month history of cough, phlegm, and fever. His AFP level was 3296 ng/mL. A chest computed tomography (CT) scan demonstrated a soft-tissue mass in the upper lobe of his right lung (Fig. 1A). A right upper lobectomy with dissection of multiple lymph nodes was successfully performed in January 2016. Afterward, pathological examination of the specimen revealed adenocarcinoma (5.3 × 3.5 cm) (Fig. 2A). Histologically, routine paraffin sectioning and immunohistochemistry were performed and suggested positivity for thyroid transcription factor 1, hepatocytes, AFP, and cytokeratin (Fig. 2B–D) and negativity for Napsin A, cytokeratin 5/6, P63, CD56, and synaptophysin. The patient's Ki-67 score was observed to be 20% (Fig. 2E). The tumor had invaded the pleura with no lymphatic metastasis. Thus, the histological type was determined to be HAC.Figure 2(A) Surgical examination of the tumor showed adenocarcinoma (hematoxylin and eosin; original magnification, ×200). (B) Immunohistochemical (IHC) analysis revealed that the lung tumor cells were positive for thyroid transcription factor 1 (original magnification, ×200). (C) IHC analysis revealed that the lung tumor cells were positive for hepatocytes (original magnification, ×200). (D) IHC analysis revealed that the lung tumor cells were positive for α-fetoprotein (original magnification, ×200). (E) IHC analysis revealed that the lung tumor Ki-67 index was 20% (original magnification, ×200).View Large Image Figure ViewerDownload Hi-res image Download (PPT) The patient received regular adjuvant therapy with pemetrexed and cisplatin for four cycles. His serum AFP level gradually decreased to within the normal range. At 9.0 months after surgery, a regular examination with CT and enhanced CT revealed pleural effusion and multiple bone metastases (Fig. 3). Of note, genomic testing detected EGFR p.L747_P753delinsS (Fig. 4). Thus, the patient was given orally administered icotinib (125 mg three times a day) and had a partial response. However, its long-term efficacy was not sustained. In October 2017, cranial magnetic resonance imaging revealed an extensive brain metastasis (Fig. 1B), and the patient received brain radiotherapy combined with nutrition support. A second analysis of gene expression was performed in April 2018; it revealed an EGFR exon 20 T790M mutation. Subsequently, the patient received orally administered osimertinib (80 mg every day) and attained a progression-free survival of 8.0 months. After drug resistance to osimertinib occurred, anlotinib was used in January 2019 and stable disease was achieved. Thus far, the disease has remained stable and the patient is still alive.Figure 4Schematic showing the tumor with EGFR p.L747_P753delinsS. chr, chromosome; bp, base pairs.View Large Image Figure ViewerDownload Hi-res image Download (PPT) EGFR mutations are present in 30% to 60% of Asian patients with lung cancer.3Zhao D. Chen X. Qin N. et al.The prognostic role of EGFR-TKIs for patients with advanced non-small cell lung cancer.Sci Rep. 2017; 7: 40374Crossref PubMed Scopus (34) Google Scholar In our case, we detected EGFR mutations and applied icotinib therapy, achieving an obvious therapeutic efficacy. Subsequently, EGFR T790M mutation, which is mainly responsible for drug resistance, was discovered and the patient was sequentially given osimertinib and anlotinib, which have proved to be effective for EGFR T790M–induced drug resistance in lung cancer.4Singh D. Attri B.K. Gill R.K. Bariwal J. Review on EGFR inhibitors: critical updates.Mini Rev Med Chem. 2016; 16: 1134-1166Google Scholar It is estimated that the median age of onset HAC is 65 years (range 21–88 years), with a 1-year survival rate of 55% and a median overall survival time of 11.0 months, indicating a poor prognosis of HAC cases.5Metzgeroth G. Ströbel P. Baumbusch T. Reiter A. Hastka J. Hepatoid adenocarcinoma - review of the literature illustrated by a rare case originating in the peritoneal cavity.Onkologie. 2010; 33: 263-269Crossref PubMed Scopus (80) Google Scholar In our case, the survival time of this patient has been more than 29.0 months and he remains alive so far. In summary, HAL is a rare type of tumor with morphological features resembling the histological features of hepatocellular carcinoma. The heterogeneity of HAL complicates the diagnosis. In addition, the poor prognosis of HAL requires molecular profiling for potential application of targeted therapy with a TKI. This study was supported in part by grants from the Science and Technology Planning project of Zhejiang Province (grant LGF19H160002), the Medical Scientific Research Foundation of Zhejiang Province of China (grant 2019RC027), the Technology Bureau of Jiaxing City of Zhejiang Province (grant 2017BY18050), and Xisike-Hanson Cancer Research Foundation (grant Y-HS2019-20).