Primary Hepatoid Adenocarcinoma of the Lung: A Systematic Literature Review

Abstract

Background: Hepatoid adenocarcinoma (HAC) of the lung (HAL) is a rare and aggressive extrahepatic adenocarcinoma with an unknown etiology and unfavorable prognosis, which is similar to the pathophysiological characteristics of hepatocellular carcinoma (HCC).

Methods: We first presented a 67-year-old patient diagnosed with HAC in the right middle lobe of the lung. Then, a systematic literature search was performed for HAL cases recorded between 1990 and 2020 based on three databases. The clinicopathological features, therapeutic method, and prognosis of this rare disease were reviewed, and corresponding prognostic factors were explored using Kaplan-Meier (K-M) curve and Cox proportional hazards regression model. Additionally, the potential biological mechanisms of HAL were further explored and compared with HCC and lung adenocarcinoma (LUAD) based on online databases.

Results: In the present study, we reported an HAL patient who underwent surgical resection combined with chemotherapy and succumbed to disease 13 months after surgery. Additionally, a total of 43 experimental studies with 49 HAL patients, including the present case, met the inclusion criteria and were included in the present review. We found that HAL is characterized by a male-dominated incidence and is more common in the right lung. Patients in the surgical subgroup have a better prognosis than those in the non-surgical subgroup (p = 0.034). Moreover, the Cox proportional hazards regression model demonstrated that surgical resection can significantly improve the prognosis of HAL patients (p = 0.016). HAL is a rare disease associated with gene mutations that has a distinctive cause and unique pathogenesis. Additionally, Afatinib and Gefitinib may be new effective agents to better combat HAL.

Conclusion: In conclusion, males may exhibit an increased risk of developing HAL and poorer prognosis than females. Surgical resection combined with chemotherapy may prolong the survival of patients with HAL. HAL has its unique clinicopathological characteristics and biological mechanisms.

Keywords: HAL; biological mechanisms; hepatoid adenocarcinoma; prognosis; review.

Figure 1

The flowchart of literature selection.

Figure 2

Preoperative enhanced computed tomography images of the chest. (A) A plain chest CT scan reveals a mass-like lesion in the right upper lung with an irregular margin (white arrow). (B) The mass is markedly enhanced in the arterial phase (white arrow). (C) The enhancement of the venous phase is slightly weaker than that of the venous phase (white arrow). (D) Coronal sections reveal an irregular lesion in the right upper lung.

Figure 3

The image of fiber bronchoscopy, endobronchial ultrasonography (EBUS), and pathology. (A) Fibronchofibroscope examination reveals a focal mucosal thickening of the right tracheal wall. (B) EBUS shows right pulmonary neoplasm. (C) The bronchoalveolar lavage fluid is composed of inflammatory cells with few heteromorphic cells. (D) The pathologic evaluation suggests hepatoid adenocarcinoma of the lung.

Figure 4

Enhanced computed tomography findings of the chest after chemotherapy (white arrow). A significant decrease in the size of the lesions in plain chest CT (A), arterial phase (B), venous phase (C), and coronal sections (D).

Figure 5

The pathological findings of the resected pulmonary mass. (A) The mass combines two components, including hepatoid adenocarcinoma (HAC) of the lung and lung adenocarcinoma. (B) The pathological results of pulmonary hepatoid adenocarcinoma. The cytoplasm of tumor cells is abundant, and nuclei are markedly enlarged with prominent eosinophilic nucleoli. The individual neoplastic cells resemble hepatocytes. (C) The pathological results of lung adenocarcinoma. The tumor cells show acinar, micropapillary, and papillary with significant atypia. (D) The lymph nodes show HAC cells metastasis.

Figure 6

The immunohistochemistry results of hepatoid adenocarcinoma. The hepatoid adenocarcinoma of the lung of our patient is positive for TTF1 (A), SP-B (B), PAS (C), and P53 (D) and negative for AFP (E). (F) The proliferation index by Ki-67 staining is above 70%.

Figure 7

Kaplan-Meier survival curves of patients with hepatoid adenocarcinoma of the lung in different clinicopathological subgroups. (A) Overall survival of all patients with HAL. (B) Overall survival according to the T classification (T1+T2 vs T3+T4). (C) Overall survival according to the age of patients (≤ 61 years vs > 61 years). (D) Overall survival according to the gender of patients (male vs female). (E) Overall survival according to the serum AFP levels (increase vs normal). (F) Overall survival according to the maximal tumor size (≤ 6.0 cm vs > 6.0 cm). (G) Overall survival according to the tumor localization (left lung vs right lung). (H) Overall survival according to the therapeutic method (surgery vs non-surgery). (I) Overall survival according to the therapeutic method (surgery vs surgery + chemotherapy).

Figure 8

Potential biological functions of genes related to hepatoid adenocarcinoma of the lung. (A) Protein-protein interaction network for HLA-related genes using STRING. (B) Protein-function interaction network for HLA-related genes using GeneMANIA. (C) Gene Ontology functional enrichment for HLA-related genes. (D) Kyoto Encyclopedia of Genes and Genomes pathway for HLA-related genes.

Figure 9

Comprehensive analysis of mutated FAT1. (A) The alteration frequency with mutation type in liver hepatocellular carcinoma (LIHC) and lung adenocarcinoma (LUAD). (B) Summary of alterations in FAT1 expression in LIHC and LUAD. (C and D) Correlation between FAT1 mutation and EGFR mutation in LUAD (C) and LIHC (D). (E) Differential expression levels of FAT1 in LIHC and LUAD, *p < 0.05. (F) Immunohistochemical staining for FAT1 in normal liver and lung tissues as well as LIHC and LUAD tissues using Human Protein Atlas database. (G) The prognostic value of FAT1 in LIHC and LUAD patients. (H) Genomics of cancer drug sensitivity. (I and J) The chemical formula and structural formula of Afatinib (I) and Gefitinib (J).