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  Table of Contents    
Year : 2021  |  Volume : 64  |  Issue : 1  |  Page : 128-131
Hepatoid adenocarcinoma of lung: A diagnostic challenge - Series of six cases with histopathological, predictive molecular and PD.L1 assessment

1 Department of Pathology, RGCIRC, New Delhi, India
2 Department of Pathology, Sakra World Hospital, Bengaluru, Karnataka, India
3 Department of Medical Oncology, RGCIRC, New Delhi, India
4 Department of Radiology, RGCIRC, New Delhi, India

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Date of Submission09-Apr-2020
Date of Decision22-May-2020
Date of Acceptance27-Jul-2020
Date of Web Publication8-Jan-2021


Hepatoid adenocarcinoma of lung is a rare entity, accounting for 5% of all hepatoid adenocarcinoma. Distinguishing it from metastatic hepatocellular carcinoma is essential, but occasionally can be very challenging, especially with concurrent liver mass. A judicious immunohistochemical panel is warranted for accurate diagnosis and subsequent preservation of tissue for molecular testing. There is limited data on the mutational status, behavior and management strategies of this type of lung adenocarcinoma. We report largest series of six cases of hepatoid adenocarcinoma of lung citing the clinical, histopathological, immunohistochemical and molecular parameters including PD-L1 immunoexpression as a predictive biomarker for immunotherapy. None of the evaluated cases showed targetable mutation; however, four out of six cases showed significant PD-L1 expression. All the cases presented with advanced stage and received chemotherapy, however overall prognosis was dismal. In view of significant PD-L1 expression in these tumors and poor response to conventional chemotherapy, these cases might be considered for upfront immunotherapy.

Keywords: Adenocarcinoma, hepatoid, immunohistochemistry, lung, PD-L1

How to cite this article:
Pasricha S, Grover S, Kamboj M, Bansal D, Batra U, Gupta G, Sharma A, Durga G, Jajodia A, B. Koyyala VP, Mehta A. Hepatoid adenocarcinoma of lung: A diagnostic challenge - Series of six cases with histopathological, predictive molecular and PD.L1 assessment. Indian J Pathol Microbiol 2021;64:128-31

How to cite this URL:
Pasricha S, Grover S, Kamboj M, Bansal D, Batra U, Gupta G, Sharma A, Durga G, Jajodia A, B. Koyyala VP, Mehta A. Hepatoid adenocarcinoma of lung: A diagnostic challenge - Series of six cases with histopathological, predictive molecular and PD.L1 assessment. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Apr 21];64:128-31. Available from: https://www.ijpmonline.org/text.asp?2021/64/1/128/306504

   Introduction Top

Hepatoid adenocarcinoma of lung (HAL) is a rare tumor with features similar to hepatocellular carcinoma (HCC) and was first described in lung by Ishikura et al.[1],[2] Till date, 45 cases have been described in the literature[3],[4],[5],[6],[7],[8] so far and we present the largest series of 6 cases from a tertiary cancer center, along with comparison with their clinicopathological features. Since it has specific diagnostic criteria, it is important to recognize this distinct rare variant of adenocarcinoma as it may prompt an erroneous diagnosis of primary HCC with metastasis to lung, especially in cases with presence of a concurrent mass in lung and liver.[1],[2] We also accessed the actionable mutation status: epidermal growth factor receptor (EGFR) mutation, ROS-1 gene rearrangement, anaplastic lymphoma kinase (ALK) protein expression and programmed death-ligand 1 (PD-L1) immuno-expression as a predictive marker for targeted therapy in these tumors.

   Methods Top

A search for newly diagnosed cases of HAL in the medical records of our institution was made. We came across six cases of HAL over a period of 5 years. The clinical and radiological details were obtained from medical records and the hospital information system. Information regarding management, patient follow-up and overall survival was also retrieved where available. All the cases were diagnosed on formalin fixed paraffin embedded tissues, with 4 μm-thick sections of tumor taken and stained for hematoxylin and eosin (H and E) on autostainer (Medite slide stainer TST44C). Immunohistochemical (IHC) stains for CK7 (OV-TL 12/30, Thermo, 1:200 dilution), CK20 (Ks20.8, Dako, 1:100 dilution), TTF-1 (SP141, Ventana, RTU), p40 (BC28, Zitomed, RTU), EMA (E29, Dako, 1:50 dilution), Hep Par 1 (OCHIE5, PathnSitu, RTU), Glypican-3 (1G12, PathnSitu, RTU), AFP (Polyclonal Rabbit, Dako, FLEX RTU), WT1 (6F-H2, Cell Marque, 1:50 dilution), calretinin (SP13, Cell Marque, RTU), ALK-1 (D5F3, Ventana, RTU) and PD-L1 (SP263, Ventana, RTU) were performed using IHC autostainer (VENTANA BENCHMARK XT). All IHC stains were carried out with appropriate positive and negative controls. Mutational Analysis for EGFR by reverse transcription polymerase chain reaction (RT-PCR) and ROS-1 translocation by break-apart fluorescence in situ hybridization (FISH) was done in all cases.

   Results Top

The present case series comprised of 6 consecutive cases diagnosed at our institute. Age ranged from 26-74 years and all were males. All the cases had a significant single mass lesion in the lung associated with regional mediastinal lymphadenopathy. All the relevant and pertinent clinical, radiological, biochemical, histological [Figure 1a-c], immunohistochemical findings [Figures 1d and 2a-d] and follow-up data are summarized in Tables 1 and 2.

   Discussion Top

Hepatoid Adenocarcinoma (HA) is a rare entity, sharing morphologic, biochemical (elevated serum AFP in some) and most of the immunophenotypic features with HCC. The most common site of origin for HA is the stomach, accounting for 63% of cases, followed by ovary (10%), lung (5%), gall bladder (4%), pancreas (4%), and uterus (4%).[3]

Only 45 cases of HAL have been documented in the world literature.[3],[4],[5],[6],[7],[8] This rare tumor is seen more in male smokers, as is also evident in our series, with all patients being males (6/6) and most were smokers (93%). The age range in our series varied from 26-74 years, similar to other studies where the age ranged from 36-82 years with a mean age of 60 years.[3] Most of our patients (5/6) presented with productive cough, chest pain and dyspnea. One of the patients in our series presented with loss of consciousness attributed to brain metastasis. In our series, 5 out of 6 cases presented with stage IV and a single case was stage IIIB. There was a predilection for the upper lobe location (4/6, 66.7%), and these findings were similar to previous studies.[3],[4],[9]

The diagnosis of HAL is based on the histopathologic features and IHC profile, and mandates ruling out a primary HCC clinically and radiologically. Ishikura et al.[1] first proposed the diagnostic criteria for this entity in 1990, requiring 2 components – a typical papillary/acinar adenocarcinoma of lung along with a second component morphologically resembling HCC, producing AFP. Haninger et al.[2] modified the above criteria and proposed that AFP production is not necessary for diagnosis if the IHC markers of hepatoid differentiation are expressed. The morphology can be purely hepatoid or may have a component of conventional papillary/acinar adenocarcinoma of lung, with or without the presence of signet ring cells or a neuroendocrine component.[1],[2]

Grossman et al.[3] documented significantly elevated serum AFP levels in 17/20 cases with available pre-treatment assays. However, in our series, serum AFP was elevated in only 2/5 cases (not available in 1 case) with positive immunoexpression of AFP in 1 case [Table 1]. These findings are consistent with the opinion of Haninger et al.[2] and Grossman et al.[3] that AFP expression is not a pre-requisite for diagnosis of HAL.

Radiological investigations are helpful to rule out concurrent liver mass and other primary sites for HA. When there is associated liver mass, HAL on morphology can masquerade a metastasis from primary HCC as seen in one of our case (case 6). IHC is prudent to distinguish HAL from metastatic HCC. TTF-1 (cytoplasmic) and Hep Par 1 (cytoplasmic granular) immunoexpression is seen in both HAL and HCC, which is reminiscent of hepatoid differentiation. However, CK7 (positive in HAL, negative in HCC), EMA (often positive in HAL, usually negative or weak focal positive in HCC), and Glypican-3 (often negative in HAL, mostly positive in HCC) will help to differentiate between them.[1],[2],[8] We found this panel of markers helpful to establish the diagnosis of primary HAL in all cases [Figures 1d and Figure 2a-c] [Table 2].

Few authors have suggested use of CK19, mCEA and MOC-31 that are usually positive in HAL while typically negative in HCC.[2],[3] However, CK19 positivity has very well been reported in a subset of HCCs with biliary differentiation, and serves as a poor prognostic marker.[10] CK7 was positive in all our cases. However, a study by Haninger et al.[2] showed that it can also be negative in few cases owing to heterogenous expression in tumor (2/5). Another interesting observation was made by Haninger et al.[2] regarding expression of ERβ in HALs with variable intensity (weak to strong expression) while none of the HCCs were positive for the same.

Of all primary lung adenocarcinomas, nearly 25-30%, 5% and 2.2% are driven by EGFR, ALK-1 and ROS-1 targetable mutation, respectively, in Asian population.[11],[12] In our series, none of the cases had shown targetable mutation, findings in resonance with the previous reported case series.[2] A single case with ALK-1 rearrangement has been reported by Khozin et al.[8] in HAL.

IHC for PD-L1 was done on all our 6 cases, and was significant (>1% membranous expression) in 4/6 cases, with two cases having TPS of >50% [Figure 2d and Table 2]. Basse et al.[13] reported a single case of HAL showing partial response to durvalumab anti-PD-L1 therapy, though the IHC for PD-L1 expression was negative. Ours is the first series documenting positive expression of PD-L1 in HAL. This might have therapeutic implications, as most patients present in advanced stage with poor response to chemotherapy.

   Conclusion Top

To conclude, primary HAL is a distinct entity which presents in advanced stage and it can be challenging to differentiate it from metastatic HCC especially with concurrent liver mass or metastasis. A judicious and decisive IHC panel is warranted for accurate diagnosis and to conserve the tissue for further molecular studies. These tumors are not associated with targetable mutation. Majority of the patients present in advanced stage with poor response to conventional chemotherapy and dismal prognosis. Significant PD-L1 expression in these tumors as seen in our series can bring a new insight for consideration of upfront immunotherapy in this rare tumor.


The authors would like to acknowledge Ms. Sangeeta Arora and Mr. Arvind Bhuker for their technical assistance in performing immunohistochemical stain.

Financial support and sponsorship

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest

There are no conflicts of interest.

   References Top

Ishikura H, Kanda M, Ito M, Nosaka K, Mizuno K. Hepatoid adenocarcinoma: A distinctive histological subtype of alpha-fetoprotein producing lung carcinoma. Virchows Arch A Pathol Anat Histopathol 1990;417:73-80.  Back to cited text no. 1
Haninger D, Kloecker G, Bousamra M, Nowacki M, Slone S. Hepatoid adenocarcinoma of the lung: Report of five cases and review of the literature. Mod Pathol 2014;27:535-42.  Back to cited text no. 2
Grossman K, Beasley MB, Braman SS. Hepatoid adenocarcinoma of the lung: Review of a rare form of lung cancer. Respir Med 2016;119:175-9.  Back to cited text no. 3
Shao Y, Zhong DS, Wang D, Ma L. Hepatoid adenocarcinoma of the lung: Case report. Int J Clin Exp Pathol 2016;9:4067-72.  Back to cited text no. 4
Sun J, Zhang BL, Li KL, Yui HY, Wang B. Hepatoid adenocarcinoma of the lung without production of α-fetoprotein: A case report and review of the literature. Oncol Lett 2016;12:189-94.  Back to cited text no. 5
Shaib W, Sharma R, Mosunjac M, Farris AB III, Rayes EB. Hepatoid adenocarcinoma of the lung: A case report and review of the literature. J Gastrointest Canc 2014;45:99-102.  Back to cited text no. 6
Papatsimpas G, Kamposiorasa K, Goulab K, Papaparaskeva K, Loukides S, Kotoulas C, et al. Hepatoid pancoast tumor. A case report and review of the literature. Lung Cancer 2012;77:239-45.  Back to cited text no. 7
Khozin S, Roth MJ, Rajan A, Smith K, Thomas A, Berman A, et al. Hepatoid carcinoma of the lung with anaplastic lymphoma kinase gene rearrangement. J Thorac Oncol 2012;7:e29-31.  Back to cited text no. 8
Terracciano LM, Glatz K, Mhawech P, Vasei M, Lehmann FS, Vecchione R, et al. Hepatoid adenocarcinoma with liver metastasis mimicking hepatocellular carcinoma: An IHC and molecular study of eight cases. Am J Surg Pathol 2003;27:1302-12.  Back to cited text no. 9
Theise ND, Nakashima O, Park YN, Nakanuma Y. Combined hepatocellular cholangiocarcinoma. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO Classification of Tumors of the Digestive System. 4th ed. Lyon (France): International Agency for Research on Cancer (IARC) Press; 2009. p. 225.  Back to cited text no. 10
Doval D, Prabhash K, Patil S, Chaturvedi H, Goswami C, Vaid A, et al. Clinical and epidemiological study of EGFR mutations and EML4-ALK fusion genes among Indian patients with adenocarcinoma of the lung. Onco Targets Ther 2015;8:117-23.  Back to cited text no. 11
Zhou F, Zhou C. Lung cancer in never smokers-the East Asian experience. Transl Lung Cancer Res 2018;7:450-63.  Back to cited text no. 12
Basse V, Schick U, Guéguen P, Le Maréchal C, Quintin-Roué I, Descourt R, et al. A mismatch repair-deficient hepatoid adenocarcinoma of the lung responding to anti-PD-L1 durvalumab therapy despite no PD-L1 expression. J Thorac Oncol 2018;13:e120-2.  Back to cited text no. 13

Correspondence Address:
Divya Bansal
Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, Sector 5, Rohini, New Delhi - 110 085
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_334_20

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  [Table 1], [Table 2]


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