Enteric-type adenocarcinoma of the lung: A rare and aggressive variant of non-small cell lung cancer

Enteric-type adenocarcinoma of the lung (ETAC), previously known as pulmonary enteric adenocarcinoma, is a rare and unique form of non-small cell lung cancer (NSCLC) that closely resembles metastatic colorectal cancer (mCRC) in its pathological features.¹ ETAC is characterized by >50% cellular structures resembling colorectal adenocarcinoma, with tumour cells showing negativity for typical NSCLC markers, such as NAPSIN and TTF1, and positivity for intestinal markers like CK20, CDX2, and MUC2 on immunohistochemistry (IHC).² However, data on ETAC from the Indian subcontinent remains limited. We report our experience with 7 patients of ETAC managed at our centre.

Between January 2020 and June 2024, among the 756 lung cancer cases seen at our hospital, 683 were NSCLC, of which 470 were diagnosed as adenocarcinoma, and 7 (1%) were identified as ETAC. The median age of patients was 61 (range 44–75) years, with 3 females (43%), consistent with previously reported demographics.¹ All patients presented with stage IV disease, and all but 1 were non-smokers. Tissue was obtained through CT-guided core needle biopsies (6) or bronchoscopic biopsies (1). None of the patients underwent surgical resection. The diagnosis was suspected following a thorough clinical history, physical examination, positron emission tomography-computed tomography (PET-CT) scan, and upper and lower gastrointestinal (GI) endoscopies to exclude a GI primary. Diagnosis was confirmed by microscopic examination (Fig. 1), revealing tall, columnar tumour cells with eosinophilic cytoplasm, brush borders, vesicular nuclei, and prominent nucleoli arranged in glandular structures. IHC showed CK7 positivity in all patients (100%), CK20 positivity in 5/7 (70%) patients, and CDX2 positivity in 4/7 (57%) patients, with negative NSCLC markers, consistent with reported literature.³ All patients underwent targeted next-generation sequencing (NGS). In line with previous studies showing higher rates of HER2 and KRAS mutations,⁴ 2 of our patients exhibited KRAS G12C mutations, but could not afford the RAS inhibitor therapy. No targetable alterations were identified for EGFR, ALK, ROS1, or HER2. Programmed death-ligand 1 (PDL1) tumour proportion scores (TPS) were low across evaluable cases (0%–5%), with 1 patient showing a score of 10%.

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FIG 1. (a) Haematoxylin and eosin (H&E) staining (400 ) showing tumour cells arranged in nests and a focal glandular pattern with vesicular chromatin and prominent nucleoli, (b) cytokeratin 7 (CK7) positive, (c) cytokeratin 20 (CK20) positive, (d) thyroid transcription factor-1 (TTF1) positive, (e) caudal type homeobox 2 (CDX2) positive.

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Treatment outcomes were poor, reflecting ETAC’s aggressive nature.¹ Two patients received best supportive care due to poor performance status, surviving 1 and 3 months, respectively. Among the 5 patients who received palliative chemotherapy with pemetrexed-carboplatin combination therapy, progression-free survival (PFS) was 1, 1.5, 3, 6, and 10 months. Two patients received second-line docetaxel chemotherapy. Overall survival (OS) for these 5 patients was 2, 4, 6, 8, and 13 months. The patient with a PDL1-TPS of 10%, who was also treated with pembrolizumab, showed rapid progression and died after 4 months, potentially suggesting hyper-progression with immunotherapy, as previously reported.⁵

Our experience underscores that ETAC is an extremely aggressive variant of NSCLC, which requires timely differentiation from mCRC. Immunohistochemical profiling reveals high CK7 positivity with variable CK20 and CDX2 expression, which is crucial for distinguishing it from mCRC. SATB2, cadherin-17, and -catenin immunostaining are also valuable markers for differentiating ETAC from mCRC.^6,7 ETAC shows poor outcomes despite standard chemotherapy, with rapid progression and limited survival, necessitating urgent development of alternative therapeutic strategies.