Introduction

Hepatoid adenocarcinomas (HAC), first described in 1985 by Ishikura et al. [1], are a rare type of extrahepatic alpha-fetoprotein secreting tumor with hepatocellular carcinoma (HCC) like morphology. Since that time, only 33 cases of HAC of the lung have been published in PubMed, and the main features of all these cases are summarized in Table 1.

Table 1 Summary of previously reported cases of hepatoid adenocarcinoma of the lung. Table compiled from adaptation of Grossman, Beasley and Braman (2016) and a PubMed search (keywords: Hepatoid adenocarcinoma AND Lung between June 2015 and present)
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Two criteria are usually described for the diagnosis of hepatoid adenocarcinoma, the first being a mixture of tubular or papillary adenocarcinoma with sheet-like or trabecular proliferation of neoplastic cells within an AFP-producing carcinoma. The second criterion is cells with abundant, eosinophilic cytoplasm and centrally located nuclei, in the sheet-like or trabeculated portion [2]. The immunohistochemical profile of HAC tumors has shown to be variable. It has been found that 91.6% of HAC tumors stain positive for AFP [3, 4].

Primary HAC of the lung comprises 5% of all reported cases of hepatoid adenocarcinoma, with the stomach being the most common site of occurrence [5]. The literature shows that 100% of HAC stain positive for AFP, CEA, CK18 and CK19 [3]. Furthermore, a report by Shao et al. [6] extensively discusses the various management approaches used in previous cases of HAC of the lung, and concludes that an optimal regiment for the systematic treatment of advanced HAC of the lung remains elusive.

Case history

A 59-year-old African–American male presented to the emergency department with right sided chest pain of recent onset, and numbness in the right upper extremity (RUE). The patient is a former smoker with >30 pack–year history and is currently employed as a transportation supervisor. The patient’s family history is significant for colon cancer in the father. A chest CT showed a 9.3 × 7.2 × 6.8 cm mass located in the upper lobe of the right lung. The mass presented with hilar lymphadenopathy. The CT scan did not exhibit contralateral adenopathy, and the CT-guided lung biopsy was inconclusive. The patient was scheduled for a repeat biopsy and a brain MRI to rule out brain metastases.

Patient underwent navigational bronchoscopy with core needle biopsy. The pathological findings were as follows: poorly differentiated carcinoma with hepatoid features. Brain MRI ruled out brain metastases. The surgical pathology report (processed at the University of Maryland Baltimore Washington Medical Center Laboratories) reads as follows:

  • Fragments of lung tissue showing a poorly differentiated carcinoma consistent with hepatoid carcinoma

  • Tumor cells are positive for CK7 immunohistochemical stain and negative for TTF1, CK5/6

  • The PSA, CK20, CDX2, PAX8, GATA3 and PSA immunohistochemical stains are non-contributory

  • Cytology specimen from 4R Lymph Node aspirate is positive for HEPAR immunohistochemical stain consistent with hepatoid carcinoma

PET-CT ruled out a primary hepatocellular carcinoma and showed a 4.6 × 4.4 cm left adrenal mass. At that time, the patient’s symptomatology was significant for decreased appetite, weight loss of 2 kg, and RUE numbness. Complete blood count was normal. AFP level was 1.5 ng/ml (reference range <10 ng/ml). CEA level was 32 ng/ml (reference range <3 ng/ml). The patient was started on a combination of cisplatin and etoposide chemotherapy.

Tumor was confirmed as primary hepatoid adenocarcinoma of the lung, stage IV-A. TNM staging: cT4N2M1b: metastases were found in the mediastinal and hilar lymph nodes and the left adrenal gland. The immunohistochemical profile of the tumor was obtained: histological grade 3. EGFR negative. ALK-rearrangement: negative. BRAF w/t. ROS-1: negative. MSI: unknown. PD-L1 ≥50%. The patient by that time had received two cycles of cisplatin–etoposide therapy. Symptomatology was significant for decreased appetite, weight loss of 4 kg, and myelosuppression with an absolute neutrophil count of 600 mm3 (reference range: 1500–8000 mm3). TNM stage cT4N2M1b.

Patient was initiated on pembrolizumab and the combination of cisplatin–etoposide was discontinued after two cycles. Immunotherapy was well tolerated by the patient. After 3 cycles of immunotherapy, the CEA level was 5.3 ng/mL, and the complete blood count was within reference range. The patient did not suffer from electrolyte abnormalities, and gained 3 kg. After the 5th cycle of pembrolizumab, follow-up CT showed a reduction of 45% in tumor size. Symptomatology was relevant for iron-deficiency anemia which is being treated with iron supplementation. After the 10th cycle of pembrolizumab, the patient’s CEA increased to 17.3. Scheduled chest CT showed progression at the primary site without evidence of progression at metastatic sites. PET-CT showed a large upper lobe mass consistent with the patient’s known NSCLC primary with interval growth of lesion in the right thoracic inlet, but with decrease in size and activity of right hilar lymphadenopathy and left adrenal metastasis. Findings are consistent with a mixed response but large amount of persistent residual disease.

Patient therapy after 10 cycles of pembrolizumab has been switched to 3rd line therapy with ramucirumab and docetaxel. Patient’s symptomatology is negligible.

Discussion

The diagnosis of HAC is a complicated process as it is difficult to differentiate from metastatic hepatocellular carcinoma (HCC), even in the absence of a visible primary tumor in the liver. The data in Table 1 shows that 21 of the listed patients had their AFP measured prior to the initiation of treatment. Although 20 patients presented with elevated serum AFP levels, our case and the case reported by Grossman et al. [5] showed normal serum AFP levels. As a result, serum AFP cannot be used as a diagnostic criterion for HAC. Furthermore, a study has shown that when the cut-off value is of 20 ng/ml, serum AFP has a sensitivity of 41–65% and a specificity of 80–94% [33]. This low sensitivity indicates that serum AFP level is not reliable for the detection of HCC. In the setting of an extrahepatic tumor showing hepatic-like features and an absence of a primary tumor in the liver on diagnostic imaging, the reported specificity supports the ruling out of HCC on the basis of negative serum AFP test. There have also been reports of CEA-producing HAC in the literature, but not enough evidence suggests the use of CEA levels as a diagnostic criterion. This marker can however be used in a clinical setting to monitor disease progression. This patient presented with an elevated CEA that did not change in response to treatment with cisplatin–etoposide. This was expected due to the lack of any positive response to the chemotherapeutic treatment. CEA levels had decreased and stabilized after switching to pembrolizumab and had been stable until December 2018, a period of 6 months. A serial rise in CEA (Table 2) prompted a CT scan which indicated progression at the primary site. This evidence is suggestive that CEA could be used to clinically monitor CEA-producing NSCLC.

Table 2 Summary of the patient’s clinical course
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The rarity of this type of tumors does not allow to define a standard treatment. There is no generalized consensus about the treatment of HAC, but based on previously published case reports, surgical resection and neoadjuvant chemotherapy is the treatment of choice for non-advanced HAC of the lung ([4]; Table 1). In the case we bring forward, the patient’s stage at presentation did not make them eligible for surgery and they were thus started on cisplatin and etoposide. The use of this combination is reported as both a primary intervention in the setting of advanced disease or as neo-adjuvant therapy in the setting of a resectable tumor (Table 1).

The disappointing response to chemotherapy prompted the decision to change the treatment regimen to an immunotherapeutic agent. Pembrolizumab is a PD-L1 receptor antagonist that has been approved by the FDA for the treatment of NSCLC with high PD-L1 expression and as first line treatment of advanced NSCLC regardless of PD-L1 expression. The PD-L1+ immunohistochemical profile of the tumor supports the use of pembrolizumab for treatment. This is the first reported use of pembrolizumab in a case of hepatoid adenocarcinoma. We believe that this highlights the importance of immunohistochemical analysis in the management of HAC specifically, and NSCLC generally. We recommend that all patients with NSCLC be investigated for immunohistochemical markers prior to initiation of treatment, which will allow for targeted therapy. The adoption of an immunotherapeutic treatment regimen has allowed for a treatment course less burdened with symptoms, 6 months after the discontinuation of cisplatin–etoposide. The reduction in tumor activity seen in previously highly active hilar area and left adrenal gland is indicative of the efficacy of pembrolizumab in the management of PD-L1 positive NSCLC. Unfortunately, the primary mass had progressed to its approximate size at presentation and the mixed response to immunotherapy has warranted an escalation to third line therapy with ramucirumab and docetaxel in accordance with FDA-approved guidelines for the management of treatment-resistant NSCLC. As previous case reports indicate, prognosis of HAC of the lung is poor [5], especially for non-resectable disease (Table 1). Patient’s clinical course has spread over 10 months as of February 10, 2019. This also indicated a promising result for the use of immune-targeted therapy in the management of advanced HAC of the lung.

Patient is status post 3 cycles of ramucirumab. Tolerating therapy well and with negative symptomatology. Last CT shows a regression of the primary mass in the RUL and the mass in the right thoracic inlet. Time since diagnosis: 14 months.