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. 2021 Mar 15;13(3):898–922.

Merged hepatopulmonary features in hepatoid adenocarcinoma of the lung: a systematic review

Jia-Xi Mao 1,*, Cong Liu 1,*, Yuan-Yu Zhao 1,*, Guo-Shan Ding 1, Ji-Qing Ma 2, Fei Teng 1, Wen-Yuan Guo 1
PMCID: PMC8014347  PMID: 33841629

Abstract

This study aimed to provide diagnostic clues for patients with elevated serum alpha-fetoprotein (AFP) in the absence of liver tumors and rectify some previously confused concepts about hepatoid carcinoma of the lung through a systematic review on hepatoid adenocarcinoma of the lung (HAL). A thorough search for original articles on HAL published prior to November 2020 was performed using the PubMed, EBSCOhost, Embase, WanFang Data, and China National Knowledge Infrastructure (CNKI) databases. Ninety-four patients from 88 studies met the eligibility criteria. HAL was rare and mainly occurred among male Asian smokers in their 60 s, presenting with cough, hemoptysis, chest pain, dyspnea and/or weight loss, as well as elevated serum AFP with a mass usually in the right upper lung lobe but no liver masses. Hepatoid differentiation regions, acinar or papillary structures in tumor tissues, and positive immunohistochemical expression of AFP, HepPar-1, and CK8/18 were crucial indicators for the diagnosis of HAL. Surgery-based strategies were recommended for stage I-III patients, while stage IV patients were mainly treated with chemotherapy-based strategy. The 1-, 3-, and 5-year overall survival rates were 40%, 35%, and 19%, respectively. The 1-year relapse-free survival rate was 58%. The postoperative monitoring of AFP contributed to the early detection of tumor recurrence, with a positive rate of 71.43%. In conclusion, patients with elevated serum AFP levels without any detectable hepatic lesions should be evaluated for the possibility of HAL.

Keywords: Pulmonary hepatoid adenocarcinoma, rare disease, alpha-fetoprotein

Introduction

Elevated serum alpha-fetoprotein (AFP) is usually associated with hepatocellular carcinoma (HCC) and some germ cell tumors. For patients with elevated AFP but no liver masses, what other diagnoses should be considered? Hepatoid adenocarcinoma (HAC) is a kind of extrahepatic malignant tumor similar to HCC, demonstrating both adenoid- and hepatocyte-like differentiation on immunohistochemical analysis. As a rare neoplasm, hepatoid adenocarcinoma of the lung (HAL) accounts for 2.3%-5% of all HACs [1,2]. Ishikura H et al [3] first put forward the concept of HAL in 1990, using two essential criteria for the diagnosis of HAL: 1) a mixture of tubular or papillary adenocarcinoma with a sheet-like or trabecular proliferation of neoplastic cells; and 2) a cancerous component producing AFP, with morphological similarity to HCC. However, later reports described HAL with components of neuroendocrine carcinoma or signet-ring cells [4-6], and morphology and immunophenotyping could support the diagnosis of HAL in AFP-negative patients [7-10]. In 2014, Haninger DM et al [11] proposed modified diagnostic criteria for HAL as follows: 1) the tumor can be pure HAC or have a component of typical acinar or papillary adenocarcinoma, signet-ring cells or neuroendocrine carcinoma; and 2) AFP elevation is not mandatory as long as other markers of hepatic differentiation are expressed.

Heretofore, HAL was usually described in case reports, with summaries mainly focused on English literature, lacking a systematic review on multilingual literature. In some previous reports, HAL was conceptually confused with hepatoid carcinoma of the lung [12-15]. Therefore, we aimed in this review to include and analyze all eligible cases using Haninger’s diagnostic criteria to provide more information about the clinical manifestation, management and prognosis of this rare disease.

Patients and methods

Search strategy

Studies on HAL were identified by searching electronic databases and scanning the reference lists of relevant articles. No limits were applied for language, and foreign papers were translated. The MESH search terms “hepatoid or AFP”, “adenocarcinoma” and “lung or pulmonary” were used. This search was applied in PubMed, EBSCOhost, Embase, WanFang Data, and China National Knowledge Infrastructure (CNKI). The last search was run on 5 November 2020.

Inclusion and exclusion criteria

The inclusion criteria consisted of the following: 1) HAL confirmed by pathology or clinical diagnosis based on the criteria proposed by Haninger DM et al in 2014 [11]; and 2) HAL mentioned in the title or full text. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [16], we did not impose language restrictions on the eligibility criteria.

The exclusion criteria were as follows: 1) duplicate data; 2) patients with simultaneous liver metastases; 3) other pathological subtypes such as fetal adenocarcinoma of the lung (FLAC), large cell lung carcinoma, pulmonary squamous cell carcinoma (SCC), small cell lung cancer (SCLC), and unclassified non-small cell lung cancer (NSCLC); and 4) patients with excessive missing data.

Data extraction

The data extracted from each study included the authors’ names, case reporting country, publication year, characteristics of the patients (sex, age, smoking history, liver and other medical history), symptoms, tumor information (location, size, tumor markers, clinical and pathological stages, and immunohistochemical and genetic testing), treatment and prognosis (relapse and cause of death). The relevant data were extracted from all the papers by two review authors (Jia-Xi Mao and Yuan-Yu Zhao) and checked by the another two authors (Cong Liu and Ji-Qing Ma) after full-text assessment, with the aid of two professional translators, to achieve a complete understanding of each paper and reduce selective reporting bias.

Statistical analysis

The data were analyzed using SPSS 22 software (IBM, Armonk, NY, USA). Quantitative variables with a normal distribution are expressed as the mean ± standard deviation. Nonnormally distributed variables are represented as the median (minimum-maximum). Postoperative survival was calculated using the lifetable method. Univariate and multivariate analyses of overall survival (OS) and relapse-free survival (RFS) were assessed using Cox proportional hazards regression models. The differences in survival times were compared using the log-rank test. A p-value <0.05 was considered statistically significant.

Results

General information

Eighty-eight studies meeting the eligibility criteria were included in the systematic review, including 46 reports in English, 29 in Japanese, 12 in Chinese and one in Korean. The flow diagram of the study selection process is presented in Figure 1. A total of 94 patients were enrolled for analysis and their characteristics are summarized in Table 1 [1,2,5-7,10-15,17-73].

Figure 1.

Figure 1

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Flow diagram for study selection.

Table 1.

Previously reported cases on hepatoid adenocarcinoma of the lung (HAL)

No Author/Year Centre Sex/Age Smoking history (pack-year) Liver disease and other history Symptom Location/Size (cm) Tumor markers AJCC 8th Edition Stage Pathological type Immunohistochemistry Gene mutation Treatment Tumor relapse site Prognosis/Cause of death
Morphology Differentiation Positive (+) Negative (-)
1 Tanabe H, 1979 Japan M/67 N/A N/A N/A LUL/N/A AFP↑ N/A N/A P AFP N/A N/A O N/A 18 mo alive
2 Kodama T, 1980 Japan M/73 N/A N/A N/A RML/5.5 AFP↑ N/A N/A P AFP N/A N/A O N/A 16 mo dead/N/A
3 Morino H, 1980 Japan M/68 N/A N/A N/A LUL/N/A AFP↑ N/A N/A M AFP N/A N/A R N/A 16 mo dead/N/A
4 Yasunami R, 1981 [17] Japan M/67 N/A N/A Back pain LUL/8 AFP↑, CEA↑ pT4N0M0 (IIIA) Atypical P AFP, A1AT, A1ACT, CEA HepPar-1 N/A R, Immuno, C Duodenojejunal flexure, bones (8 mo) 16 mo dead/peritonitis
5 Nakano M, 1984 Japan M/70 N/A N/A N/A RLL AFP↑ N/A N/A P N/A N/A N/A C, R N/A 4 mo dead/N/A
6 Nishimura, 1985 Japan F/47 N/A N/A N/A N/A AFP↑ N/A N/A P N/A N/A N/A O N/A 16 mo alive
7 Miyake M, 1986 [18] Japan M/55 N/A Pleurisy, subtotal gastrectomy, family history of malignant lymphoma Cough, back pain RUL/5 AFP↑, CEA→ pT4N2M1c (IVB) Atypical P AFP N/A N/A O No 0.13 mo dead/respiratory failure
8 Satake, 1986 Japan M/78 N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
9 Tamura T, 1986 [19] Japan M/80 41.25 N/A Bloody sputum, dyspnea, fever LLL/4.1×3.5 AFP↑, CEA→ cT4N3M1a (IVA) Atypical P AFP N/A N/A C No 36 mo alive
10 Yoshida, 1986 Japan M/66 N/A N/A N/A N/A AFP↑ N/A N/A W / N/A N/A O N/A 7 mo dead/N/A
11 Miyake M, 1987 [20] Japan M/73 N/A N/A Bloody sputum LUL/5×6×5 AFP↑, β-hCG↑ pT3N2M0 (IIIB) Atypical P AFP, A1AT, A1ACT, CEA, HCG N/A N/A O, R Brain (16 mo) 18 mo dead/heart failure
12 Sugiyama, 1987 Japan M/37 N/A N/A N/A N/A AFP↑ N/A N/A P N/A N/A N/A C N/A 4 mo dead/N/A
13 Tsuji H, 1987 [21] Japan M/60 44 Family history of esophageal cancer, uterine cancer, lung cancer Cough, chest pain RML/13×11×8 AFP↑, CEA→ pT4N2M0 (IIIB) Atypical P AFP N/A N/A O, C, R Brain (3 mo) 4 mo dead/relapse
14 Tsuji H, 1987 Japan M/57 N/A N/A N/A N/A AFP↑ N/A N/A M N/A N/A N/A O, C N/A 60 mo dead/N/A
15 Yamanaka, 1987 Japan M/73 N/A N/A N/A N/A AFP↑ N/A N/A W N/A N/A N/A O N/A 0.067 mo dead/N/A
16 Kizuka, 1988 Japan M/64 N/A N/A N/A N/A AFP↑ N/A N/A P N/A N/A N/A O, R N/A 6 mo dead/N/A
17 Saka H, 1988 [22] Japan M/73 N/A N/A Cough, sputum RUL/3.9×3×3 AFP↑, CA19-9→, CEA→ pT2aN0M0 (IB) Atypical W AFP HCG N/A O No 28 mo alive
18 Kawashima, 1989 Japan M/57 N/A N/A N/A N/A AFP↑ N/A N/A M N/A N/A N/A O N/A 1 mo alive
19 Kawashima, 1989 Japan M/62 N/A N/A N/A N/A AFP↑ N/A N/A P N/A N/A N/A O N/A 1 mo alive
20 Kurimoto I, 1989 [23] Japan M/75 40 Acute myocardial infarction (AMI), DM Cough, dyspnea RUL/5 AFP↑, elastase-1↑, β-hCG↑, NSE→, SCC→ cT3N2M0 (IIIB) Atypical P AFP N/A N/A N/A N/A N/A
21 Yokoi, 1989 Japan M/72 N/A N/A N/A N/A AFP↑ N/A N/A P N/A N/A N/A O,R N/A 16 mo alive
22 Matsutani, 1990 Japan M/63 N/A N/A N/A N/A AFP↑ N/A N/A N/A N/A N/A N/A O,C N/A 54 mo alive
23 Ogawa, 1990 Japan M/82 N/A N/A N/A N/A AFP↑ N/A N/A P N/A N/A N/A O,R N/A 18 mo alive
24 Sakuma, 1990 Japan M/69 N/A N/A N/A N/A AFP↑ N/A N/A P N/A N/A N/A N/A N/A N/A
25 Tachibana, 1990 Japan F/70 N/A N/A N/A N/A AFP↑ N/A N/A P N/A N/A N/A C,R N/A 6 mo dead
26 Fujita, 1991 Japan M/64 N/A N/A N/A N/A AFP↑ N/A N/A N/A N/A N/A N/A C N/A Dead/N/A
27 Nakajima, 1991 Japan M/79 N/A N/A N/A N/A N/A N/A N/A P N/A N/A N/A R N/A Dead/N/A
28 Matsutani, 1992 Japan M/62 N/A N/A N/A N/A AFP↑ N/A N/A W N/A N/A N/A O N/A alive
29 Kubota M, 1994 [24] Japan M/53 N/A Pulmonary tuberculosis Bloody sputum RML/13×10 AFP↑ pT4N0M0 (IIIA) Typical P AFP N/A N/A O No 22 mo alive
30 Okano R, 1994 [25] Japan M/71 100 Pleurisy, family history of lung and gastric cancer Shortness of breath, cough, expectoration, weight loss RLL/multiple, 0.3-1 AFP↑, CEA→, NSE→, β-hCG→, PIVKA-II→ cT4N2M1b (IVA) Atypical P N/A AFP N/A C No 4 mo dead/respiratory failure, septic shock
31 Hirabayashi H, 1995 [26] Japan M/57 N/A Pulmonary tuberculosis, right plantar fracture Cough, sputum LLL/7.5×5 AFP↑, CEA↑ pT4N0M0 (IIIA) Atypical W AFP N/A N/A O No 30 mo alive
32 Yoshino I, 1996 [27] Japan M/54 N/A adenosquamous cell carcinoma of the lung (pT3N0M0, 5 yrs ago) None RUL/2 AFP↑, CEA↑, β-hCG→, NSE→, SCC→ pT1bN0M0 (IA2) Atypical P AFP N/A N/A O No 24 mo alive
33 Hirota F, 1999 [28] Japan M/80 45 Gastric ulcer, gallstone Headache, aphasia RLL/5×4 AFP↑, CEA↑ pT2bN2M1b (IVA) Atypical M AFP N/A N/A C No 10 mo alive
34 Wang CS, 1999 [29] China M/65 N/A N/A None RML/3.5×3.0×2.5 N/A pT2aN0M0 (IB) Atypical N/A CEA, AFP N/A N/A O N/A N/A
35 Carlinfante G, 2000 [30] Italy M/65 Yes N/A Cough, dyspnea LLL/3.5 CEA→ pT2aN0M0 (IB) Atypical N/A AFP, CEA, A1AT, A1ACT, surfactant, ISH, albumin mRNA CgA N/A O No 84 mo alive
36 Genova S, 2001 [31] Plovdiv M/71 N/A N/A Dyspnea, weight loss, asthenia LUL/7.7×6.4 N/A pT4N0M0 (IIIA) Typical N/A AFP N/A N/A O No 24 mo alive
37 Hayashi Y, 2002 [12] Japan M/55 87.5 N/A None RUL/5×4.8×6.5 CEA↑, SCC→, CYFPA21-1→, NSE→, ProGRP→ pT3N0M0 (IIB) Typical N/A AFP, HNF-4a N/A N/A O No 32 mo alive
38 Lino K, 2003 [32] Japan M/63 200 AMI None RUL/2.8×2.6×2.4 CEA→, SCC→, CYFPA21-1→, NSE→, ProGRP→ cT1cN0M0 (IA3) Typical P AFP, HepPar-1 N/A N/A O No 5 mo alive
39 Terracciano LM, 2003 [33] Switzerland M/49 N/A N/A Cough, dyspnea, epigastric discomfort LLL/5 AFP↑ pT2bN0M0 (IIA) Typical N/A AFP, CEA, CK8, CK18, CK19 HepPar-1, CK7, CK20 N/A O Liver, adrenal, brain, hilar lymph nodes (1.2 mo) 2 mo dead/relapse
40 Oshiro Y, 2004 [34] Japan M/76 N/A N/A N/A RLL/18×17×12 N/A pT4N0M0 (IIIA) Typical P AFP, PIVKA-II N/A N/A O Liver (12 mo), bone (18 mo) 18 mo dead/multiple liver and bone metastasis
41 Bai CG, 2006 [13] China M/48 N/A N/A Back pain LUL/7×5×4 AFP→, CA19-9→, CEA→ pT3N0M1b (IVA) Atypical P CKpan (AE1/AE3), HepPar-1, AAT, prealbumin, albumin, CEA, p53 AFP, SP-A, CA19-9, INV, P63, NSE N/A O, C No 9 mo alive
42 No EJ, 2006 [35] Korea M/64 40 yr Pulmonary tuberculosis Chest pain, hemoptysis RUL/9×8 AFP↑, CEA↑, α-hCG→, PSA→ cT4N1M0 (IIIA) Atypical P AFP, CK, CEA N/A N/A C No 1 mo alive
43 Ivan M, 2007 [36] Canada M/54 40 N/A Hemoptysis, chest pain LUL (13×11) + RUL (3.3×2.6) AFP↑ pT4N2bM1b (IVA) Typical N/A CK20, CEA, AFP, CD10 CK7, TTF-1, PLAP, CD34, CD30 N/A C, R No N/A
44 Kishimoto T, 2008 [5] Japan M/64 N/A N/A N/A LLL/7.5×7×4 AFP↑ cT4N0M0 (IIIA) Atypical N/A HepPar-1, AFP, Syn, HNF-4a CgA, NSE N/A O No N/A
45 Li CJ, 2008 [37] China M/65 N/A Fatty liver None RLL/6 AFP↑, CEA→ cT4N2M1 (IVA) Atypical P N/A N/A N/A TACE, TCM Lung (13 mo), liver (14 mo) 16 mo dead/lung infection & respiratory failure
46 Wang PC, 2008 [14] China M/44 40 N/A Extremities numbness, aphasia, cough, hemoptysis RUL/10 AFP↑ cT4N2bM0 (IIIB) Typical N/A HepPar-1 N/A N/A C, R Brain (3 mo) 14 mo dead/disease progression
47 Kim L, 2009 [38] N/A M/49 N/A N/A N/A LUL/6 AFP↑ pT3N1M0 (IIIA) N/A N/A N/A N/A N/A O N/A N/A
48 Fornasa F, 2010 [8] Italy F/68 No N/A Shoulder pain LUL/4.5×4×4 AFP→ pT2bN0M1 (IVA) Typical N/A N/A N/A N/A C No 15 mo alive
49 Kitada M, 2011 [39] Japan M/69 90 Alcoholic hepatitis Epigastric pain RLL/6.5 AFP↑, CA19-9↑, CEA↑, β-hCG→, CYFPA21-1→, NSE→, ProGRP→, SLX→ pT3N2M0 (IIIB) Atypical M AFP, CK18, CK19, HepPar-1 P53 N/A O, C No 12 mo alive
50 Mokrim M, 2012 [40] Morocco M/52 20 N/A Dyspnea, chest pain, weight loss LUL/11.8×12×8 AFP↑, β-hCG→ cT4N1M0 (IIIA) Typical N/A CK20, AFP, CD10, HepPar-1 CK7, TTF-1, PLAP, CK5, CK6, CD30 N/A C No 7 mo alive
51 Papatsimpas G, 2012 [41] Greece M/48 N/A N/A Shoulder pain RUL/20×11×8 AFP↑ cT4N2bM0 (IIIB) Atypical P CK8/CK18, AFP, HepPar-1 CK7/CK20, TTF-1 N/A C, R Mediastinum (2 mo) 6 mo dead/respiratory failure
52 Valentino F, 2012 [42] Italy M/71 No N/A Intercostal pain RLL/2.8 & 1.9 AFP↑, CA19-9↑, CEA→, NSE→ pT3N3M1b (IVA) Typical N/A AFP, HepPar-1, 2, CK7, CK19 TTF1, CK20 N/A C, R, O, bevacizumab Adrenal, thoracic vertebral (10 mo) 14 mo dead/opportunistic infection
53 Cavalcante LB, 2013 [6] Brazil M/66 40 yrs N/A Cough, dyspnea, respiratory complaints, recurrent pneumonia, weight loss RLL/5×3 CEA↑, AFP→, β-hCG→ pT2bN0M0 (IIA) Atypical P CK7, CEA, AFP, HepPar-1, TTF-1, CK5/6 CK20, CgA, Syn, P63, β-hCG N/A Supportive treatment No 0.4 mo dead/pulmonary thromboembolism
54 Feng GW, 2013 [43] China M/46 N/A Calcification of the right lobe of the liver, cholecystolithiasis None LUL/2.0×2.4 AFP↑, CEA→ pT1cN0M0 (IA3) Atypical P HepPar-1, AE1/AE3, AFP, CK7, CK19, CD56, TTF-1 EP-10 N/A O, C No 6 mo alive
55 Che YQ, 2014 [15] China M/66 70 Hepatic hemangioma (1.5×1.5 cm) Back pain LUL/5.3×4.6 & 7.9×10.0 AFP↑, CEA→, CYFPA21-1→, NSE→, SCC→ pT4N0M0 (IIIA) Atypical N/A CK7, AFP, AE1/AE3, CK18, Vim, HepPar-1 CK20, RCC, TTF-1 N/A C, R Hilar LN (2 mo) 36 mo dead/lung infection
56 Haninger DM, 2014 [11] USA M/51 45 HCV (+), tuberculosis Cough, congestion RUL/4.2×3.7 N/A cT2bN3M0 (IIIB) N/A N/A CK5/6 (1/5), CK7 (3/5), CK8 (5/5), CK14 (0/5), CK18 (5/5), CK19 (4/5), CK20 (1/5), AFP (3/5), HepPar-1 (5/5), TTF-1 (5/5), HEA125 (5/5), MOC31 (5/5), CEA (3/5) ERb (5/5) ALK 1 (0/5) Napsin-A (1/5) N/A C, R, O No 14 mo dead/disease progression
57 Haninger DM, 2014 [11] USA M/52 40 HCV (+), emphysema, alcoholism Chest pain, headaches, hearing loss, paresthesias, loss of balance RUL/2.5 N/A pT1cN0M1c (IVB) N/A N/A N/A O, C, R No 37 mo alive
58 Haninger DM, 2014 [11] USA M/64 75 Emphysema and degenerative disc disease, family history of lung cancer None LUL/3.2×2.2 N/A pT2aN0M1b (IVA) N/A N/A EGFR (-) O, C, R Liver (N/A) 10 mo dead/disease progression
59 Haninger DM, 2014 [11] USA F/54 35 N/A Sternal border pain LUL/1 N/A pT1aN0M1b (IVA) N/A N/A N/A C, R, O Lung, skull bone, mediastinal LN, pericardium (48 mo) 108 mo alive
60 Haninger DM, 2014 [11] USA M/60 40 Emphysema Emphysema, cough, weight loss, muscle spasms of right arm, hand and face RUL/11.2×10.1×8.5 AFP↑ cT4N2M1b (IVA) N/A N/A N/A C, R No 1 mo alive
61 Liu HY, 2014 [44] China M/64 20 yrs N/A Cough, hemoptysis RLL/8×5.5×5.0 AFP↑, CA153→, CEA→, NSE→ pT4N0M0 (IIIA) Typical N/A HepPar-1, AFP, CK8/18, CK19, CKpan, P53, CDX2, CK20 CD56,Syn, CgA, NSE, S-100, CK7, CK14, CK5/6, CK10/13, 34βE12, P63, PLAP, CD117, CD30, CD10, ALK, TTF-1, CEA, Napsin-A, Vim N/A O No 6 mo alive
62 Shaib W, 2014 [45] USA F/53 40 Alcohol abuse, COPD, rheumatoid arthritis, pleuritis N/A RUL/9.5×9.0×8.0 AFP↑ pT4N0M0 (IIIA) Typical N/A CK, CAM 5.2, HepPar-1, CD34, PTF-1 CK7, CK20 N/A O, C No 48 mo alive
63 Al-Najjar H, 2015 [46] UK M/71 30 yr, cease 28 yr knee replacement due to osteoarthritis, T2DM, cholecystectomy due to gallstones Fatigue, weight loss, cough RLL/multiple AFP↑ cT4N3M1a (IVA) Typical N/A MNF116, HepPar-1, Ber-EP4, CK7, TTF1 N/A N/A C Spine (4 mo) 12 mo dead/relapse
64 Gavrancic T, 2015 [47] USA M/64 N/A N/A Hemoptysis RUL/3.8×2.9 AFP↑ cT2aN2M1 (IVA) Typical N/A AFP, HepPar-1, CK7, Napsin-A, TTF-1 CK5, CK6, CK20, histochemical mucicarmine EGFR (-) C, Sorafenib, R Lung (3 mo); mediastinal/hilar/subcarinal LN, liver (after 3 cycles of vinorelbine and sorafenib) 11 mo dead/disease progression
65 Udovicic-Gagula D, 2015 [48] Bosnia and Herzegovina M/68 N/A N/A Chest pain, blood sputum RUL/multiple (max = 8.5) AFP↑ N/A Atypical N/A CKpan, AFP, HepPar-1, hCG N/A no overrepresentation of 12p C N/A N/A
66 Zhong MY, 2015 [49] China M/61 N/A N/A Cough, sputum, hemoptysis LUL/5.7×4.3 AFP↑, CEA→ cT3NxM1c (IVB) Atypical N/A AFP, AAT, CK7, TTF-1 P63, Syn, Vim, HepPar-1, CEA, CK20 N/A C, R No alive without following time
67 Grossman Kate, 2016 [10] USA M/54 Yes Polysubstance abuse Cough, shortness of breath, hemoptysis, weight loss RUL/5.1×4.1 AFP→, cT3N0M1b (IVA) Typical N/A HepPar-1, CK7, CAM 5.2 (CK8/18), CEA AFP, CK20, P63, CDX-2, PSA, S-100, CgA, TTF-1 ALK (-), EGFR (-), K-ras (-) C, R Brain (2 mo) 3 mo dead/brain metastasis & disease progression
68 Liu ZJ, 2016 [50] China M/59 N/A N/A Cough, sputum RUL/4.5×3.5×3.5 CEA→, CYFPA21-1→, HSP→, NSE→ pT2bN0M0 (IIA) Atypical M HepPar-1, CD3, CD10 AFP, CK8/18, TTF1, CD56, CgA, Syn, NapsinA N/A O N/A N/A
69 Qian GQ, 2016 [51] China M/79 50 N/A Cough, sputum RUL/2.7×2.6 AFP↑, CEA↑, CA153→, CA19-9→, CYFPA21-1→, NSE→ cT1cN0M0 (IA3) Atypical N/A N/A N/A N/A Erlotinib No 0.83 mo dead/lung infection
70 Sun JN, 2016 [52] China M/59 Yes (ceased 9 yrs) Mild alcohol consumption; T2DM for 8 years Cough RUL/4.5×3.5×3.5 CEA→, CYFPA21-1→, NSE→ pT2bN0M0 (IIA) Atypical P HepPar-1, CD10, CD34 AFP, TTF-1, CK8/18, CD56, CgA, Syn, Napsin-A N/A O No 23 mo alive
71 Wang S, 2016 [53] China M/56 N/A N/A None RUL/4.0×4.1×4.8 N/A cT4N1M0 (IIIA) Atypical N/A AFP / N/A N/A N/A N/A
72 Hou Q, 2017 [54] China M/59 Yes N/A Cough, bloody sputum RUL/4.5×3.5×3.5 AFP→, CA153→, CEA→, NSE→ pT2bN0M0 (IIA) Atypical N/A HepPar-1, CD10, CD34 GPC-3, CEA, AFP, CK8/18, TTF-1, CD56, CgA, Syn, Napsin-A N/A O No 24 mo alive
73 Long ZH, 2017 [55] China M/50 40 N/A Cough, hoarseness, chest pain, dysphagia, weight loss LUL/N/A AFP→, CEA→, NSE→, CA125→, CYFRA21-1→, Serum ferritin→ cTxN3M1c (IVB) Typical P HepPar-1, CK7, CK8/18, CEA, Syn Gly-3, TTF-1, Naspin-A, CK20, villin, AFP, S100, CgA, CD56 N/A Supportive treatment No 4 mo dead/disease progression
74 Long ZH, 2017 [55] China M/58 30 N/A Cough, sputum, fever, chest pain, weight loss LLL/3.8×4.2×5.2 AFP→, CEA→, NSE→, CA125→, CYFRA21-1→, Serum ferritin→ cT3N3M1c (IVB) Typical N/A Gly-3, AFP, CK, CD34 HepPar-1, CK7, TTF-1, P63, Syn, CgA N/A Anti-infection N/A 18 mo alive
75 Basse V, 2018 [56] France M/43 8 Lynch syndrome and lieberkuhnian adenocarcinoma (treated at 31 years with no relapse) N/A N/A N/A cTxN3M1c (IVB) Atypical N/A CK7, 19, 20, HepPar-1, CEA, TTF-1 caudal type homeobox 2 protein, Programmed death ligand 1 (PD-L1) EGFR (-), KRAS (-), ALK (-), ROS1 (-), a loss of expression of mutL homolog 1 and PMS1 homolog 2 C, durvalumab anti-PD-L1 therapy No dead without following time/infectious complications
76 Esa NYM, 2018 [57] Malaysia M/50 40 Family history of breast malignancy Shoulder pain, numbness and weakness of arm LUL/6×5×6 AFP↑ IIIB Typical P CK, AE1/3, HepPar-1, TTF-1, CK7 CK20, AFP, Napsin-A, S-100, PLAP, P63 N/A R, C No 7 mo dead/disease progression, sepsis, shock
77 Li Q, 2018 [58] China M/52 60 N/A Cough, bloody sputum RUL/N/A CA19-9↑, CA724↑, CEA↑, AFP→ cT2N2M0 (IIIA) Atypical N/A HepPar-1, CK, CK19 TTF-1, Napsin-A, P63, P40, CK5/6, GATA-3, Gly-3, Arg, Vim N/A C, R Brain (1 mo) 2 mo dead/pulmonary thromboembolism
78 Nakashima K, 2018 [59] Japan M/60 40 Emphysema, sinusitis None RUL/6.3×4.8 AFP↑, CEA↑ pT3N0M0 (IIB) Atypical N/A HepPar-1, TTF-1 / N/A O No 8 mo alive
79 Ruiz CD, 2018 [60] N/A F/69 70 N/A Cough, dyspnea, weight loss LUL/8×8×5 AFP→ cT4N1M0 (IIIA) Atypical N/A CK7, HepPar-1 CK20, CK5/6, P63, TTF-1 N/A R Adrenal (1 mo) 1 mo dead
80 Ayub A, 2019 [61] USA M/61 40 COPD N/A RUL/2.3 N/A pT1cN0M0 (IA3) Typical M TTF-1, HepPar-1, CK7, CK8, CEA, CK19 AFP, P40, Napsin-A, CD10 N/A O, R Spine and sacrum (3 mo) 6 mo dead/disease progression
81 Barbara CD, 2019 [62] N/A M/63 N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A EGFR (-), ALK(-) C, R, nivolumab Skin (N/A) 7 mo dead/disease progression
82 Chen HF, 2019 [1] China M/53 no N/A Cough, phlegm, fever RUL/5.3×3.5 AFP↑ pT3N0M0 (IIB) Atypical N/A TTF-1, HepPar-1, AFP, CK Napsin-A, CK5/6, P63, CD56, Syn EGFR p.L747_P753delinsS; EGFR exon 20 T790M mutation O, C, icotinib, R, osimertinib, anlotinib Pleural effusion, bone (9 mo), brain (21 mo) 36 mo alive
83 Chen Y, 2019 [63] China M/47 45 N/A Chest pain, cough, dyspnea, fatigue RLL/9.7×6.1×6.9 AFP→ cT4N3M1c (IVB) Atypical N/A CK7, HepPar-1, AFP PAX8, CK5/6, TTF-1 / C No 2 mo dead/disease progression
84 EI Khoury A, 2019 [64] UK M/59 >30 Family history of colon cancer Chest pain RUL/9.3×7.2×6.8 CEA↑, AFP→ cT4N2M1b (IVA) Typical P CK7, HepPar-1 TTF1, CK5/6 EGFR (-), ALK (-), BRAF w/t. ROS-1 (-), PDL1≥50% C No 14 mo alive
85 Fan XL, 2019 [65] China M/70 120 Fatty liver, alcohol abuse Cough, bloody sputum LLL/6.0×6.0×1.5 CEA↑, CYFPA21-1↑, NSE↑ pT3N1M0 (IIIA) Atypical N/A HepPar-1, CKpan, AFP, CEA, CD34, Syn Agr-1, SALL-4, CK7, TTF-1, Napsin-A, P40, P63, P53, EGFR, ALK, CD56, CD31, D2-40 N/A O No 23 mo dead/lung infection & respiratory failure
86 Kuan K, 2019 [66] USA M/47 Yes N/A Chest pain, fatigue, edema RUL/14 N/A cT4N0M0 (IIIA) Typical N/A CK7, EMA, CEA, HepPar-1 TTF-1, Napsin-A, CK20, AFP EGFR (-), ALK (-),PD-L1 (high) O Malignant pleural effusion (1 mo) 4 mo dead/relapse
87 Li J, 2019 [67] China M/71 No N/A Stomachache, fatigue, constipation RLL/7×4.5 AFP↑ cT3N3M1b (IVA) Typical P CK, SALL-4, CK18, CK8, CK7, AFP, HepPar-1, STAT-6, CD117 CK20, P63, P40, CK5/6, Syn, CD56, CgA, Vim, Calretinin, TTF-1, Napsin-A, CD34, D2-40, ALK, PD-L1 EGFR, ALK, ROS1, PD-L1, BRAF, HER2, KRAS, MET, RET-Wild type; FAT1-Mutated, Copy number loss; MSI-Stable; TMB-1.69 mutations/Mb R No 5.5 mo dead/respiratory failure
88 Malik SA, 2019 [68] N/A F/56 Yes N/A Shortness of breath RLL/2×2 AFP→ N/A N/A N/A CK7, HepPar-1, MOC31, Napsin-A TTF1, CK20, CDX2, GATA3, S-100 N/A N/A No 2 mo dead/multiorgan failure, septic shock
89 Shi YF, 2019 [69] China M/60 No HBcAb (+), HBeAb (+), HbsAb (+), esophageal polypectomy, gastric ulcers Cough, sputum RUL/7×7×5 AFP↑, CA153→, CA724→, CEA→ pT3N2M0 (IIIB) Atypical N/A EGFR, CKpan, CK18, Napsin-A, CK8, CD117, HepPar-1 TTF-1, Syn, CgA, PD-1, PAS, Villin, Vim, CK7 N/A O, C No 15 mo dead/disease progression
90 Wang C, 2019 [70] China M/70 50 N/A None RUL/6.0×4.6 N/A cT3N2M0 (IIIB) Typical N/A HepPar-1, CK, EA, CDX-2 AFP, TTF-1, Napsin-A, P63, P40, CD56, Syn TP53 mutation C, R, bevacizumab Gingiva, submandibular LN (3 mo) 9 mo dead/disease progression
91 Wang XP, 2019 [71] China M/48 Yes N/A Cough, shortness of breath LUL/multiple AFP↑, CA19-9↑, CA724↑, NSE↑ cT4N3M1a (IVA) Typical N/A AFP, HepPar-1, Arg-1 P40, CK5/6, P63, TTF-1, ALK, CgA, Syn, CD56, PGP9.5, Napsin-A EGFR (-), ALK (-), ROS1 (-), KRAS (-), BRAF (-) C Bone (N/A) 12 mo alive
92 Yang K, 2019 [2] China M/70 120 Alcoholic intake over 30 years Cough, bloody sputum LLL/6×6×5.5 CEA↑, CYFPA21-1↑ pT3N1M0 (IIIA) Typical P HepPar-1, CKpan, CK8/18, CK19, MOC31, AFP, CEA, CD34 Arg-1, SALL-4, CK5/6, CK7, CK14, CK20, Syn, CD56, TTF-1, Napsin-A, P40, P63, P53, EGFR, ALK N/A O Multiple organ distant metastases (18 mo) 18 mo dead/multiple organ failure caused by distant metastases
93 Chen JX, 2020 [72] China M/63 N/A N/A Lumbar soreness, skin tear sensation LLL+RUL/N/A CEA↑, CA19-9↑, CA724↑, CYFPA21-1↑ pT4N3M1c (IVB) Atypical P N/A N/A N/A N/A No 4 mo dead/multiple organ failure caused by distant metastases
94 Chen LL, 2020 [73] China F/65 No N/A N/A Left lobe (7×5.1) + Right lobe (9.2×4.6) AFP↑ pT4NxM1b (IVA) Typical N/A SALL4, AFP, GPC3, CK7, Villin TTF, Napsin-A, HepPar-1 ALK (-), EGFR (-), KRAS hotspot G12V (c. 35G>T) mutation C, bevacizumab, anlotinib, Sintilimab No 52 mo dead/interstitial pneumonia
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A1AT, α1-antiitrypsin; A1ACT, α1-antichymotrypsin; AFP, α-fetoprotein; ALK, anaplastic lymphoma kinase; AMI, acute myocardial infarction; Arg, arginase; β-hCG, beta-human chorionic gonadotropin; BRAF, b-rafproto-oncogene; C, chemotherapy; CD, cluster of differentiation; CEA, carcinoembryonic antigen; CgA, chromogranin A; CK, cytokeratin; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; EGFR, epidermal growth factor receptor; EMA, epithelial membrane antigen; FAT, FAT atypical cadherin1; Gly-3, glypican-3; HepPar-1, hepatocyte paraffin 1; HER2, human epidermal growth factor receptor 2; LLL, left lower lobe; LN, lymph node; LUL, left upper lobe; MSI, microsatellite instability; mo, month; N/A, not mentioned; NCAM, neural cell adhesion molecule; NSE, neuron-specific enolase; O, operation; P53, protein 53; PD-L1, programmed death ligand 1; R, radiotherapy; RCC, renal cell carcinoma; RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe; SALL-4, spalt like transcription factor 4; STAT-6, signal transducer and activator of transcription 6; Syn, synaptophysin; T2DM, type-2 diabetes mellitus; TACE, transarterial chemoembolization; TCM, traditional Chinese medicine; TMB, tumor mutation burden; TTF-1, thyroid transcription factor-1; VEGF, vascular endothelial growth factor; Vim, vimentin.

The 94 included patients comprised 86 men and 8 women (male-to-female ratio of 10.75:1), with an average age of 61.98±9.97 years. The regional distribution of the patients is shown in Figure 2, with most patients in Asia. Of these 94 patients, 44 had a history of smoking (Brinkman index = 160-4000 number per day × years, with a median of 800 number per day × years), 6 had no history of smoking, and the smoking history of the other 44 patients was not mentioned in the original studies. Six patients had a history of alcohol consumption, 3 patients were diagnosed with diabetes, and 1 patient had a history of multiple drug abuse. Other past and family histories are shown in Table 1.

Figure 2.

Figure 2

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The geographical distribution of 94 patients with hepatoid adenocarcinoma of the lung.

The patients were initially admitted because of cough (30/94), hemoptysis/bloody sputum (14/94), chest or intercostal pain (13/94), dyspnea (12/94), weight loss (10/94), sputum (9/94), shoulder or back pain (7/94), and/or asthenia (5/94), occasionally accompanied by numbness of the extremities (4/94), epigastric discomfort (3/94), fever (2/94), aphasia (2/94), headache (2/94), hearing loss (1/94), loss of balance (1/94), oedema (1/94), constipation (1/94), hoarseness (1/94), or dysphagia (1/94) (Table 1).

Tumor information

Except for 19 patients without concrete location information, 46 patients developed tumors in the right lung (29 in the right upper lobe, 4 in the right middle lobe and 13 in the right lower lobe), 26 patients developed tumors in the left lung (18 in the left upper lobe and 8 in the left lower lobe), and 3 patients presented with bilateral lung tumors. The maximum tumor diameter ranged from 1 cm to 20 cm, with a median of 6 cm.

According to the American Joint Committee on Cancer (AJCC) 8th edition of cancer staging, 8 patients were classified as stage I, 8 as stage II, 28 as stage III, and 26 as stage IV, while 24 patients could not be staged due to incomplete information.

An analysis of tumor markers demonstrated that HAL could be positive for AFP (83.10%), CA724 (75.00%), CA19-9 (62.50%), CEA (44.12%), HCG (37.50%), CYFRA21-1 (25.00%) and NSE (11.76%) but negative for SCC, CA153, ferritin, Pro-GRP, PSA, CA125, SLX, TPA, HSP, and PIVKA-II (Supplementary Table 1).

Pathology

In gross appearance, the tumors were solid and grey-white/white (11/2 cases) at the section, soft/firm/brittle (6/5/1 cases) in texture, irregular in shape (1 case), with necrotic areas (8 cases), clear/unclear boundaries (2/1 cases), and no capsule (1 case).

Microscopically, the tumors could either be pure HACs or have a component of typical acinar or papillary adenocarcinoma, signet-ring cells or neuroendocrine carcinoma. In terms of pathomorphology, we divided HAL into two types: typical and atypical. In typical type, both adenocarcinoma and hepatocyte-like components were easy to be identified under microscopy. While in atypical type, the adenocarcinoma and/or hepatocyte-like components needed to be further confirmed by immunohistochemistry due to the unclear morphology. Except for 29 cases with unclear pathomorphological classification, 27 cases were typical HAL and 38 cases were atypical HAL. Among the 48 cases with descriptions of tumor differentiation, 5 were well-differentiated, 7 were moderately-differentiated, and 36 were poorly-differentiated.

Immunohistochemistry showed that HAL was positive for CKpan (AE1/AE3), MOC31, A1AT, Erb, and HEA125; mostly positive for CK19, HepPar-1, CK7, CK18, CK8, CEA, AFP, CD10, and CD34; partly positive for P53, TTF-1, CK20, Syn, Napsin-A, Vim, CK5, CK6, and CD56; and negative for P63, CgA, ALK, CK14, P40, and S-100 (Table 2). Additionally, the Ki67 index was reported at 20-80% in 12 cases, and the MIB-1 index was reported at 40% in 1 case.

Table 2.

Immunohistochemistry markers of hepatoid adenocarcinoma of the lung (HAL) (N≥5) compared with hepatocellular carcinoma (HCC)

Markers HAL HCC positive rate
Positive/negative/N/A Positive rate
CKpan (AE1/AE3) 15/0/79 100.00% 75%-95%
MOC31 7/0/87 100.00% Not typically performed
A1AT 5/0/89 100.00% 35%-55%
Erb 5/0/89 100.00% Not typically performed
HEA125 5/0/89 100.00% Not typically performed
CK19 13/1/80 92.86% 5%-15%
HepPar-1 42/4/48 91.30% 75%-95%
CK7 15/3/76 83.33% 15%-35%
CK18 15/3/76 83.33% 75%-95%
CK8 14/3/77 82.35% 75%-95%
CEA 19/5/70 79.17% 55%-75%
AFP 47/13/34 78.33% 35%-55%
CD10 5/2/87 71.43% 55%-75%
CD34 5/2/87 71.43% 75%-95%
P53 2/3/89 40.00% 15%-35%
TTF-1 15/24/55 38.46% <5%
CK20 5/20/69 20.00% 5%-15%
Syn 3/12/79 20.00% 5%-15%
Napsin-A 4/19/71 17.39% 5%-15%
Vim 1/5/88 16.67% 5%-15%
CK5 2/15/77 11.76% <5%
CK6 2/15/77 11.76% 5%-15%
CD56 1/11/82 8.33% 5%-15%
P63 0/14/80 0.00% <5%
CgA 0/12/82 0.00% Not typically performed
ALK 0/10/84 0.00% <5%
CK14 0/7/87 0.00% Not typically performed
P40 0/7/87 0.00% <5%
S-100 0/5/89 0.00% 5%-15%
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Thirteen patients underwent genetic testing, which showed a highly enhanced expression of PD-L1 (2 cases) [64,66], KRAS mutation (1 case of KRAS hotspot G12V c. 35G>T mutation) [73], EGFR mutation (1 case of EGFR p.L747_P753delinsS; EGFR exon 20 T790M mutation) [1], TP53 mutation (1 case) [70], and FAT1 and TMB mutation (1 case) [67], as well as wild type or negative status for EGFR (10 cases), ALK (8 cases), KRAS (4 cases), ROS1 (4 cases), BRAF (3 cases), PD-L1 (2 cases), HER2, MET and RET (1 case).

Treatment

The therapeutic methods for HAL varied among individual cases with different tumor stages and general conditions. These methods were categorized into three strategies. The first one was surgery-based strategy, which included surgery combined with or without chemotherapy, radiotherapy, targeted drugs or immunotherapy. The second one was chemotherapy-based strategy, which included chemotherapy combined with or without radiotherapy, targeted drugs or immunotherapy. Other therapeutic methods, including radiotherapy alone, targeted drug alone, TACE, traditional Chinese medicine and supportive treatment, were categorized as other strategies.

Surgery-based strategies were recommended for stage I-III patients, while stage IV patients were principally managed with chemotherapy-based strategy (Supplementary Table 2). Chemotherapy played an important role in the treatment of HAL and was also adopted in a surgery-based comprehensive therapy, especially in patients with high risk of relapse. The recommended chemotherapy regimen was platinum-based double or triple combination with gemcitabine, taxol or both.

Follow-ups

Among the 59 patients with elevated AFP, 3 patients had further increases in their AFP levels after treatment and were confirmed to have tumor relapse. Twenty patients experienced AFP reduction (including 12 patients with AFP levels decreased to the normal range 0.33-6 months after treatment, with a median time of 1.5 months), while AFP levels were not reported for 36 patients after treatment.

The survival status of 12 patients was not described in the original reports, while 37 patients were alive and 45 died in 2 days-108 months of follow-up after treatment. The 1-, 3-, and 5-year OS rates were 40%, 35%, and 19%, respectively, with a median of 19.08 months (Table 3). The cause of death was not mentioned for 13 patients, and the remaining 32 patients died of disease progression or relapse (16 cases), infection (7 cases), respiratory failure (4 cases), respiratory failure combined with pulmonary infection (2 cases), pulmonary embolism (2 cases) or heart failure (1 case). Multivariate analysis showed that therapeutic method and tumor relapse correlated with OS (HR = 2.539, P<0.001; HR = 2.172, P = 0.034, respectively, Table 4).

Table 3.

Overall survival (OS) and relapse-free survival (RFS) rates of HAL patients

Overall survival rate Relapse-free survival rate
1-year 3-year 5-year Median (year) χ2, P 1-year 3-year 5-year Median (year) χ2, P
Sex χ2 = 1.190, P = 0.275 χ2 = 1.301, P = 0.254
    Male (N = 86) 37% 30% 15% 1.53 54% 54% 54% 7.00
    Female(N = 8) 63% 63% 38% 4.50 85% 85% / 4.82
AJCC 8th Edition stages* χ2 = 3.640, P = 0.056 χ2 = 1.526, P = 0.217
    Early (N = 16) 70% 70% 70% 7.00 76% 76% 76% 7.00
    Advanced (N = 54) 32% 26% 15% 1.45 47% 47% / 1.86
Pathomorphological classification** χ2 = 0.010, P = 0.920 χ2 = 1.141, P = 0.286
    Typical (N = 27) 36% 36% / 1.50 35% 35% / 1.62
    Atypical (N = 38) 42% 28% 28% 1.67 60% 60% 60% 7.00
Pathological differentiation*** χ2 = 1.353, P = 0.508 χ2 = 2.236, P = 0.327
    Well-differentiated (N = 5) 56% / / 2.00 100% / / 2.00
    Moderately-differentiated (N = 7) 49% 49% 0% 1.97 78% / / 1.00
    Poorly-differentiated (N = 36) 28% 28% / 1.30 41% 41% / 1.80
Therapeutic methods**** χ2 = 35.027, P<0.001 χ2 = 5.613, P = 0.060
    Surg (N = 49) 53% 53% 36% 5.18 66% 66% 40% 4.61
    Chemo (N = 30) 30% 18% / 1.00 51% 51% / 4.00
    Others (N = 8) 0% / / 0.75 0% / / 1.38
Total (N = 94) 40% 35% 19% 1.59 58% 58% 39% 4.41
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*

26 patients with unclear AJCC 8th Edition stage;

**

29 cases with unclear pathomorphological classification;

***

45 cases with unclear pathological differentiation;

****

7 patients with unclear therapeutic method.

Chemo, chemotherapy-based strategy; Surg, surgery-based strategy.

Table 4.

Uni- and multivariate analysis of risk factors affecting the overall survival (OS) of HAL patients

Variables Univariate analysis Multivariate analysis
HR 95% CI P value HR 95% CI P value
Age (year) 0.990 0.961, 1.020 0.505
Sex (M/F) 0.666 0.235, 1.888 0.445
Smoking (Y/N) 1.286 0.441, 3.748 0.645
Brinkman index (number per day × years) 1.000 1.000, 1.001 0.453
Elevated AFP (Y/N) 0.564 0.242, 1.317 0.186
Maximum diameter (cm) 1.043 0.956, 1.138 0.338
AJCC 8th Edition stage (early/advanced tumor) 2.471 0.866, 7.052 0.091
Pathomorphological classification (typical/atypical) 0.986 0.490, 1.983 0.968
Pathological differentiation (well-/moderately-/poorly-differentiated) 1.252 0.619, 2.533 0.532
Therapeutic method (Surg/Chemo/Others) 2.535 1.661, 3.867 <0.001 2.539 1.520, 4.240 <0.001
Tumor relapse (Y/N) 2.350 1.207, 4.576 0.012 2.172 1.060, 4.452 0.034
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Notes: The variables with P value <0.1 in univariate analysis were included in multivariate analysis. AFP, alpha-fetoprotein; Chemo, chemotherapy-based strategy; F, female; HAL, hepatoid adenocarcinoma of the lung; M, male; N, no; Surg, surgery-based strategy; Y, yes.

During the follow-up period, 24 patients presented with tumor relapse, which was defined as recurrence after surgery or newly-occurred lesions after non-surgical treatments, 42 patients did not experience relapse, and 28 patients did not have relapse information, displaying 1-year RFS rate of 58% (Table 3). The tumor relapse sites consisted of bone (8 cases), brain (7 cases), liver (5 cases), lung (3 cases), adrenal gland (3 cases), hilar lymph node (3 cases), mediastinal lymph node (2 cases), malignant pleural effusion (2 cases), peritoneum (1 case), duodenojejunal flexure (1 case), mediastinum (1 case), gingiva (1 case), submandibular lymph node (1 case) and cutaneous metastases (1 case). The time to relapse ranged from 1 to 48 months (with a median of 3 months). Multivariate analysis showed that maximum tumor diameter was the only independent risk factor for tumor relapse (HR = 1.109, P = 0.049, Table 5). Among the 24 patients with tumor relapse, 5 presented with elevated AFP and 2 with AFP in normal range, while the AFP levels of 17 were not mentioned when relapse was confirmed, which resulted a positive predictive rate of AFP of 71.43% for the relapse of HAL after treatment.

Table 5.

Uni- and multivariate analysis of risk factors affecting the relapse-free survival (RFS) of HAL patients

Variables Univariate analysis Multivariate analysis
HR 95% CI P value HR 95% CI P value
Age (year) 0.987 0.944, 1.032 0.568
Sex (M/F) 0.543 0.110, 2.671 0.452
Smoking (Y/N) 1.337 0.297, 6.022 0.705
Brinkman index (number per day × years) 1.000 0.999, 1.001 0.905
Elevated AFP (Y/N) 0.994 0.279, 3.540 0.992
Maximum diameter (cm) 1.110 1.002, 1.229 0.045 1.109 1.000, 1.228 0.049
AJCC 8th Edition stage (early/advanced tumor) 2.015 0.591, 6.866 0.263
Pathomorphological classification (typical/atypical) 0.683 0.282, 1.653 0.398
Pathological differentiation (well-/moderately-/poorly-differentiated) 2.145 0.445, 10.352 0.342
Therapeutic method (Surg/Chemo/Others) 1.868 0.990, 3.525 0.054
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Notes: The variables with P value <0.1 in univariate analysis were included in multivariate analysis. AFP, alpha-fetoprotein; Chemo, chemotherapy-based strategy; F, female; HAL, hepatoid adenocarcinoma of the lung; M, male; N, no; Surg, surgery-based strategy; Y, yes.

The OS and RFS rates were analyzed separately in terms of sex, tumor staging, pathomorphology and pathological differentiation. The 1-, 3-, and 5-year OS rates of male patients were 37%, 30%, and 15%, respectively, with a median OS of 18.36 months and a 1-year RFS rate of 54%, while the 1-, 3-, and 5-year OS rates of female patients were 63%, 63%, and 38%, respectively, with a median OS of 54.00 months and a 1-year RFS rate of 85%. The 1-year OS rate of patients with early tumors (stage I-II) was 70%, with a median OS time of 84 months and a 1-year RFS rate of 76%. The 1-, 3-, and 5-year OS rates of patients with advanced tumors (stage III-IV) were 32%, 26% and 15%, respectively, with a median OS time of 17.40 months and a 1-year RFS rate of 47%. The 1-year OS rates for typical and atypical tumors were 36% and 42%, with median survival times of 18.00 and 20.04 months and 1-year RFS rates of 35% and 60%, respectively. The 1-year OS rates for well-, moderately- and poorly-differentiated tumors were 56%, 49%, and 28%, with median OS times of 48.00, 23.64, and 15.60 months and 1-year RFS rates of 100%, 78% and 41%, respectively. The 1-year OS rate of patients using surgery-based strategy, chemotherapy-based strategy and other strategies were 53%, 30% and 0%, respectively and 1-year RFS rates of 66%, 51% and 0%, respectively (Table 3).

Among the patients using surgery-based strategy, the 1-year OS rates of typical and atypical HAL patients were 39% and 61%, respectively, while among those using chemotherapy-based strategy, the 1-year survival rates of typical and atypical HAL patients were 35% and 33%, respectively (Supplementary Table 3).

Hepatoid large cell carcinoma of the lung (HLCCL)

In previous studies, the pooled analyses of the pathological types of HAL were somewhat vague, and some other pathological types, especially large cell carcinoma, were mistakenly included as HAL. We established a preliminary definition of HLCCL as follows: 1) typical large cell carcinoma without glandular or squamous differentiation by morphology or immunohistochemistry; and 2) AFP expression is not mandatory to confirm the diagnosis as long as other markers of hepatic differentiation are expressed. The main difference between HAC and HLCCL is the morphological and immunohistochemical type.

We summarized data on previously reported HLCCL cases (Table 6) [4,7,9,18,26,74-82], including 17 men and 2 women (male-to-female ratio of 8.5:1), with a mean age of 61.58±10.02 years. Aside from 5 patients without reporting concrete tumor location, the tumors in 10 patients were in the right lung (5 in the right upper lobe, 1 in the right middle lobe and 4 in the right lower lobe), and those in 4 patients were in the left lung (2 in the left upper lobe and 2 in the left lower lobe). The maximum tumor diameter ranged from 3.5 cm to 12 cm, with a median of 7.4 cm. Nine patients had a history of smoking (Brinkman index: 460-3000 number per day × years, with a median of 850 number per day × years), and the histories of the other 10 patients were not disclosed. Tumor markers were positive for AFP (89.47%), HCG (16.67%), and CEA (11.11%). Among the 17 patients with elevated AFP at admission to hospital, 2 had AFP increased after treatment and were confirmed as tumor relapse, 8 had AFP reduced, while 7 patients had AFP levels unreported after treatment. According to the AJCC 8th Edition, 1 patient was classified as stage I, 2 patients as stage II, 8 patients as stage III, and 2 patients as stage IV, while the other 6 patients could not be staged due to incomplete information. Surgery-based therapies were recommended for stage I-III patients, while stage IV patients were essentially managed with chemotherapy. One HLCCL patient with ALK gene rearrangement was treated by crizotinib (250 mg orally every 12 hours), which improved his symptoms of chest pain, cough, intermittent night sweats and anemia after 2 weeks of therapy. However, this regimen was discontinued due to tumor progression after 6 months of therapy [9]. The immunohistochemical markers of HLCCL were positive for AFP (100%) and CEA (60%). Five patients relapsed 6-8 months after treatment (median = 7 months), with AFP elevated again in 3 of them and unmentioned in 2 at the time of relapse. The 1- and 2-year OS rates were 37% and 28%, respectively. The cause of death of four patients was unmentioned, while six patients died of tumor relapse (3 cases) or infection (3 cases).

Table 6.

Previously reported cases of hepatoid large cell carcinoma of the lung (HLCCL)

No Author/Year Centre Sex/Age Smoking history (pack-year) Liver disease and other history Symptom Location/Size (cm) Tumor markers AJCC 8th Edition Stage Treatment Immunohistochemistry Tumor relapse site Prognosis/Cause of death
Positive (+) Negative (-)
1 Koizumi, 1979 Japan M/63 N/A N/A N/A N/A AFP↑ N/A C,R N/A N/A N/A 5 mo dead/N/A
2 Yokoyama K, 1981 [74] Japan M/69 N/A N/A Bloody sputum, fever, cough RLL/11×11×7 AFP↑ pT4N0M1b (IVA) C, Immuno AFP, A1AT, A1ACT, CEA N/A Kidney, brain (N/A) 2 mo dead/N/A
3 Saga, 1983 Japan M/64 N/A N/A N/A N/A AFP↑ N/A C, R N/A N/A N/A 30 mo dead
4 Miyake M, 1986 [18] Japan M/40 23 History of appendectomy and gastric ulcer, family history of gastric cancer and tuberculosis Bloody sputum, cough RUL/8×9×7 AFP↑, CEA→ pT4N2M0 (IIIB) O AFP N/A Peritoneum (8 mo) 14 mo dead/intraperitoneal metastasis
5 Sakamoto O, 1987 [75] Japan M/72 50 None Dry cough, weight loss RLL/8×12 AFP↑ cT4N1M0 (IIIA) C,R AFP N/A No 4.5 mo dead/cancerous pleurisy and empyema
6 Yoshimoto T, 1987 [76] Japan F/61 N/A N/A Bloody sputum LUL/N/A AFP↑, CEA↑, β-hCG↑ N/A C N/A N/A brain (6 mo) 7 mo dead/relapse
7 Kamishiro, 1987 Japan M/73 N/A N/A N/A N/A AFP↑ N/A C N/A N/A N/A 19 mo dead/N/A
8 Taguchi, 1989 Japan M/58 N/A N/A / N/A AFP↑ N/A O, C N/A N/A N/A 9 mo alive
9 Okunaka T, 1992 [77] Japan M/49 N/A N/A Cough, bloody sputum RUL/6×5×5 AFP↑, CA19-9→, CEA→ pT3N0M0 (IIB) O AFP N/A No 11 mo alive
10 Ohshima, 1992 Japan M/55 N/A N/A / N/A AFP↑ N/A O N/A N/A N/A N/A
11 Hayashi A, 1995 [78] Japan M/54 35 Family history of gastric cancer, alcohol abuse Cough, sputum LML/3.5×2.5 AFP↑, CEA→, SCC→, CA19-9→, β-hCG→ pT2aN0M0 (IB) O AFP CEA N/A 18 mo alive
12 Hirabayashi H, 1995 [26] Japan M/55 N/A Pulmonary tuberculosis, diabetes, chronic hepatitis None RLL/5×5 AFP↑ pT2bN0M0 (IIA) O AFP N/A N/A 132 mo alive
13 Bessho T, 1996 [79] Japan M/81 150 Gastric ulcer surgery Fatigue LLL/10×8×5 AFP↑, TPA↑, IAP↑, NSE↑ pT4N0M0 (IIIA)* O N/A N/A No 10 mo alive
14 Nasu M, 1997 [80] Japan M/63 N/A Pleuritis Bloody sputum, fever RUL/8 AFP↑, β-hCG→, CA19-9→, CEA→, PIVKA-II ↑ cT4N1M1c (IVB) C AFP, PIVKA-II, A1AT, A1ACT CgA Lung, right adrenal, brain (N/A) 11 mo dead/bronchopneumonia
15 Hiroshima K, 2002 [4] Japan M/71 45 N/A Common cold RLL/10.5×8.5×7 AFP↑, CA19-9↑, CEA→ pT4N1M0 (IIIA)** O, R AFP, CgA, NCAM, VEGF Syn, CEA Brain (5 mo), left lung (6 mo) 12 mo dead/brain metastasis
16 Wu ZY, 2007 [7] China M/50 40 N/A Weight loss RUL/6×5×5 AFP→, CEA→, NSE→ cT4N1M0 (IIIA) O AFP HepPar-1, CA199 No 45 mo alive
17 Khozin S, 2012 [9] USA F/56 Yes N/A Chest pain, cough, intermittent night sweats, weight loss RML/5.5&1.8 AFP→, β-hCG→ cT4N0M0 (IIIA) Crizotinib*** AE1/AE3, CAM5.2, CK7, CK5/6, HepPar-1, Claudin 4, EMA, OCT4, CEA, CD10 TTF-1, BHCG, CK20, Vim, GCDFP-15, P63, CHG, thyroglobulin, RCC No 6 mo alive
18 Yu JH, 2012 [81] Korea M/70 50 N/A None LLL/6×5.2 AFP↑, PIVKA-II↑, CEA→, α-hCG→ cT3N3M0 (IIIC) C N/A N/A No 12 mo dead/lung infection, respiratory failure
19 Lin SF, 2013 [82] China M/66 40 Hepatitis B virus carrier for 30 years, gallbladder polyps, rheumatoid arthritis Cough RUL/7.4×6×4.8 AFP↑, β-hCG→, CEA→, SCC→ pT4N2M0 (IIIB) O, C AE1/AE3, AFP, Gly-3, CEA CK7, CK20, TTF-1, HepPar-1, CgA, Syn, CD56 No 48 mo alive
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*

Pathology showed HLCCL complicated with squamous cell carcinoma;

**

Pathology showed large cell neuroendocrine carcinoma;

***

Gene mutation examination showed EGFR (exons 18-21), KRAS (exons 2, 3), BRAF (exon 15), AKT (exon 1), PIK3CA (exons 9, 20), NRAS (exons 2, 3): Wild type; HER2 rearrangement (46%); ALK (72.8%).

A1AT, α1-antiitrypsin; A1ACT, α1-antichymotrypsin; AFP, α-fetoprotein; ALK, anaplastic lymphoma kinase; β-hCG, beta-human chorionic gonadotropin; BRAF, b-rafproto-oncogene; C, chemotherapy; CD, cluster of differentiation; CEA, carcinoembryonic antigen; CgA, chromogranin A; CK, cytokeratin; EGFR, epidermal growth factor receptor; EMA, epithelial membrane antigen; Gly-3, glypican-3; HepPar-1, hepatocyte paraffin 1; HER2, human epidermal growth factor receptor 2; LLL, left lower lobe; LN, lymph node; LUL, left upper lobe; N/A, not mentioned; NCAM, neural cell adhesion molecule; NSE, neuron-specific enolase; O, operation; P53, protein 53; PD-L1, programmed death ligand 1; R, radiotherapy; RCC, renal cell carcinoma; RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe; Syn, synaptophysin; TTF-1, thyroid transcription factor-1; VEGF, vascular endothelial growth factor; Vim, vimentin.

Discussion

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death worldwide [83]. The lung is also the third most common site for extrahepatic HACs, following the stomach (63%) and ovary (10%) [2]. The clinical manifestations, treatments and prognosis of HAC largely depend on the primary site. There are four major histological types and more specific subtypes of lung cancer, among which the responses to treatments, as well as prognosis, are varied [83]. The clinical manifestations of HAL are similar to those of common lung cancers, and most HAL patients have a history of smoking, with a Brinkman index >400 number per day × years. Unlike other lung adenocarcinomas, which are more common in women, the incidence of hepatoid adenocarcinoma is higher in men in their 60 s. Despite the finding that the majority of female patients were diagnosed at an advanced stage (stage III or IV), their prognosis seemed better, and one female patient even survived for 9 years. Estrogen protection may contribute to the better prognosis in women, but the exact mechanism is still unknown.

HAL needs to be distinguished from pulmonary metastasis secondary to HCC, which is morphologically similar to HAL but histologically different, usually without an acinar or papillary structure. In terms of immunohistochemistry, pulmonary metastatic HCC can express AFP, HepPar-1, and CK8/18, rather than CK7, CK19, CK5/6 and CK20. We outlined the immunohistochemical results of HAL compared with those of typical HCC in Table 2.

Approximately 50% of lung adenocarcinomas harbor somatic mutations in genes that encode proteins in the EGFR signaling pathway, such as K-RAS, EGFR, HER2, HER4, BRAF and PIK3CA [11]. Gene detection and targeted drugs are increasingly being utilized in the diagnosis and management of advanced lung cancers, combined with chemotherapy and radiotherapy. One unresectable HAL patient with the KRAS-G12V mutation received multiline chemotherapy with the PD-1 inhibitor sintilimab and achieved an OS of 52 months [73]. Chen et al [1] reported EGFR mutations of p.L747_P753delinsS and exon 20 T790Min a HAL patient with multiple bone and brain metastases after surgery. The patient was treated with icotinib, osimertinib and anlotinib, and stable during a follow-up of 36 months. A stage IV HAL patient with wild-type EGFR was treated with chemotherapy (switching from carboplatin/paclitaxel to vinorelbine and then gemcitabine), sorafenib and radiotherapy. He achieved partial response during the course and survived for 11 months after diagnosis [47]. Another HAL patient with TP53 mutations was given erlotinib followed by chemotherapy (docetaxel and nedaplatin), radiotherapy and bevacizumab, and survived for 9 months after admission [70]. Basse V et al observed a partial response to anti-PD-L1 durvalumab after chemotherapy (carboplatin, gemcitabine and docetaxel) in a HAL patient with PD-L1 negative but mismatch repair deficiency status [56].

Our systematic review has several advantages. First, we did not impose language restriction on the eligibility criteria, and all eligible cases were included according to the unified definition for HAL to reduce publication bias. Second, HLCCL cases, which were previously considered to be HAL cases, were summarized separately for the first time. Third, the survival rates were analyzed separately in terms of sex, tumor staging and pathological types, and the risk factors affecting the OS and RFS of HAL patients were investigated, providing more comprehensive information about this rare disease. There are also some limitations in our study. First and foremost, the sample size was still relatively small due to the rarity of this disease and limited access to some databases such as Ichushi. On the other hand, HAL cases were reviewed only from a clinical perspective, but its pathogenesis is still unclear and necessitates more investigations.

In conclusion, HAL is a rare but highly aggressive malignant disease with a median OS of 19.08 months and a 1-year RFS rate of 58%. HAL should be considered in elderly male smokers presenting with large lung masses and elevated serum AFP level. Moreover, hepatoid differentiation regions and/or acinar or papillary structures in lung tumor tissues, as well as positive immunohistochemical expression of AFP, HepPar-1, and CK8/18, can assist in the diagnosis of HAL. Surgery-based strategy is recommended for stage I-III patients, while chemotherapy-based strategymay provide a survival benefit for stage IV patients. The postoperative screening of serum AFP levels is important for evaluating tumor relapse. The control of disease progression and prevention of infections contribute to a better prognosis.

Acknowledgements

This project was supported by the National Natural Science Foundation of China (81702923, 81971503), the Foundation of Shanghai Science and Technology Commission (18ZR1439300), the Precision Medicine Project of Naval Medical University, China (2017JZ50).

Disclosure of conflict of interest

None.

Supporting Information

ajtr0013-0898-f3.pdf (165.9KB, pdf)

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