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Hepatoid Adenocarcinoma of the Lung Responsive to Frontline Combination Chemotherapy With Immunotherapy: Case Report

Hepatoid adenocarcinoma of the lung (HAL) is a rare extrahepatic tumor characterized by histologic features of hepatocellular carcinoma. The standard treatment for nonresectable HAL has not been established, though traditionally, these tumors have been treated with platinum-based chemotherapy. Here, we report the use of combination chemotherapy and immunotherapy in a patient presenting with metastatic HAL and an elevated alpha-fetoprotein. The patient had an excellent clinical, radiographic, and biomarker response. This case supports the use of chemoimmunotherapy, which is now the standard of care first-line treatment in NSCLC, for HAL.

Ó 2020 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

Case Report
A 54-year-old man with a 25-pack-year smoking history presented with several months of cough and dyspnea in March 2020. Computed tomography of the chest, abdomen, and pelvis revealed a right lower lobe mass, multiple right-sided pleural masses, large pleural effusion, extensive lymphadenopathy, and a right fifth rib lytic lesion (Fig. 1). Positron emission tomography scan revealed fluorodeoxyglucose avidity of these lesions, and a left adrenal gland and an inferior right scapular lesion. No liver lesions were identified. Brain magnetic resonance imaging revealed no evidence of intracranial disease.
He underwent a biopsy of a right pleural mass. Pathologic examination revealed diffuse sheets and solid nests of neoplastic cells with abundant granular cytoplasm and prominent nucleoli. Rare cells had intracytoplasmic vacuoles suggestive of adenocarcinoma. The diagnosis on the basis of morphologic and immunohistochemical (IHC) staining pattern (Table 1 and Fig. 2) was consistent with hepatoid adenocarcinoma (HAC). Programmed death-ligand 1 (PD-L1) expression as measured by the 22C3 pharmDx assay (Dako, Carpinteria, CA) was less than 5%.
He started carboplatin, paclitaxel, and pembrolizumab. After three cycles, imaging revealed a marked decrease in the size of the multiple pleuralbased nodules and mediastinal lymphadenopathy (Fig. 1). AFP downtrended to 2.1 ng/mL. Clinically, his breathing improved, and treatment was well-tolerated. At the time of article submission, the patient continues on maintenance pembrolizumab and has received treatment for a total of 7 months.

Discussion
HAC are rare tumors of extrahepatic origin with histologic features of hepatocellular carcinoma (HCC). Most arise in the gastrointestinal tract and approximately 5% in the lung. 1 HAC of the lung (HAL) is associated with poor prognosis and heightened mortality. With fewer than 50 HALs reported, limited data exist regarding its epidemiology and optimal treatment. Patients are typically men, heavy smokers, with a median age of 63.6 years, and most are diagnosed at an advanced stage. 2 Though there are IHC differences between HAC and HCC, such as a lack of CDX-2 staining in HCC, there are insufficient data to conclude that IHC can definitively segregate the two. 1,3 In addition, positive staining for AFP or elevated serum AFP is common but not required. 1 Most patients with advanced HAL receive first-line platinum-based chemotherapy, although a standard regimen is not established. The reported survival for patients with unresectable HAL has generally been 6 to 11 months. Alternative approaches have included tyrosine kinase inhibitors for patients with driver mutations and sorafenib added to chemotherapy. 1 Immunotherapy has been trialed after progression on chemotherapy. A patient with Lynch syndrome received third-line durvalumab with a partial response after 4 cycles but developed infectious complications. 4 On progression after adjuvant chemoradiation, another patient received nivolumab but

IHC Stain
Positive Negative progressed after five cycles. 1 In a third case, pembrolizumab was used for a patient with PD-L1greater than 50% after frontline chemotherapy, with an initial response but eventual progression after 10 cycles. 5 To our knowledge, this is the first case to be reported using combination chemotherapy with immunotherapy for HAL. This is especially critical given these combinations have mostly surpassed chemotherapy as the new standard first-line treatment in NSCLC. It is worth noting the patient's disparate serum and IHC AFP, and low PD-L1 and high TMB, which may be the driving force behind his response. Interestingly, SMARCA4-deficient thoracic tumors are often associated with high TMB. 6 We also note that AFP can be a valuable tumor marker in these cases and may be used to follow-up the response.