Hepatoid adenocarcinoma of the lung and the review of the literature

Abstract

Introduction

Hepatoid adenocarcinoma of the lung is an extremely rare type of the non-small cell lung cancer. Treatment principles and prognosis are similar to that of lung adenocarcinoma.

Case report

A 62-year-old female smoker presented with a huge mass in the left upper lobe. After diagnostic biopsy, she underwent left pneumonectomy and mediastinal lymph node dissection. A diagnosis of stage T4N1M0 hepatoid adenocarcinoma of the lung with positive surgical margins was made.

Management and outcome

After the operation, the level of serum alpha fetoprotein was 9010 ng/ml (N: <10). The level of serum alpha fetoprotein was decreased with concurrent chemoradiotherapy and chemotherapy. Disease progression was detected at 11 months after diagnosis. No response was obtained to other therapies. The patient died at 14 months from the time of diagnosis.

Discussion

Usually, patients with hepatoid adenocarcinoma of the lung are male smokers. Hepatoid adenocarcinoma tends to settle in the upper lobes of the lung. The most important prognostic factor of the hepatoid adenocarcinoma of the lung is the disease stage at the diagnosis and patients with metastatic disease have poor survival.

Keywords

Hepatoid adenocarcinoma immunohistochemistry lung non-small cell lung cancer treatment

Introduction

Hepatoid adenocarcinomas (HACs) are prognostically poor extra hepatic tumors resembling the morphology of hepatocellular carcinoma (HCC). It was first described in stomach by Ishikura et al.¹ HAC of the lung is a rare entity. The most frequent locations for extra hepatic HACs are stomach (63%), ovaries (10%), lung (5%), gallbladder (4%), pancreas (4%) and uterus (4%).² There is no specific immunohistochemical markers to differentiate HAC from hepatocellular carcinoma.³ Ishikura et al. reported the very first HAC case originated from lung in 1990.⁴ After this report, there have been less than 30 cases reported in medical literature, in English language. In this paper, we present a female patient with HAC of the lung and provide a brief overview of the previously reported cases.

Case report

A 62-year-old female presented with back pain lasting for two months. Computed tomography (CT) scan showed a 6-cm mass lesion in the left upper lobe of the lung. A fluorodeoxyglucose positron emission tomography (FDG-PET) scan showed a hypermetabolic left hilar mass lesion with a standard uptake value (SUV) maximum of 12.27 and hypermetabolic left pleural effusion (Figure 1). The mass obliterated the left lower lobe bronchi and settled between the arcus aorta, pulmonary artery and brachiocephalic vein. Non-small cell lung cancer (NSCLC) was diagnosed via broncoscopic biopsy. There were no metastases on magnetic resonance imaging (MRI) of the brain. Mediastinal lymph node dissection and left pneumonectomy were performed on 10 May 2018. On gross examination, two masses measuring 8 × 7×7 cm and 3 × 2.5 × 2 cm were detected in the left upper lobe. Light microscopy examination revealed a tumor with trabeculated sinusoidal pattern similar to those seen in HCC of the liver and neoplastic cells with granular, eosinophilic cytoplasm, distinct cell boarders and prominent central nucleoli (Figure 2(a) and (b)). Mediastinal lymph nodes were free of metastasis; one hilar lymph node was positive. Surgical margin was positive on the parietal pleura. Immunohistochemistry stains were positive for pancytokeratine, arginase, alpha fetoprotein (AFP) and HepPar, but negative for cytokeratin 5/6, 7 and 20, thyroid transcription factor 1 (TTF 1, nuclear) and napsin (Figure 2(c) to (e)). The diagnosis of stage T4N1M0 HAC of the lung was made. Tumor was negative for EGFR and BRAF 600E mutation, anaplastic lymphoma kinase (ALK) gene rearrangement and ROS 1 fusion. After the operation, the level of serum AFP was 9010 ng/ml (N: <10). Other routine biochemical tests and complete blood count were unremarkable. She had a history of smoking 1 pack of cigarette daily for 45 years and gave up smoking 5 years ago. She had not used alcohol. She was on antihypertensives, anxiolytics and antidepressants (metoprolol, valsartan/hydrochlorothiazide, mirtazapine, clonazepam, escitalopram, pantoprazole) for years. Her performance score was 1. She received adjuvant chemoradiotherapy (CRT) (carboplatin 2 AUC plus paclitaxel 50 mg/m² weekly with concurrent radiotherapy to tumor bed (50 Gy of intensity-modulated radiotherapy (IMRT) in 25 fractions)) and chemotherapy after CRT (two cycles of carboplatin 5AUC plus paclitaxel 175 mg/m², every three weeks). After the treatment, serum AFP decreased to 99 ng/ml, and there was no detectable tumor on post-therapy PET CT imaging on October 2018, and the patient was scheduled for clinical and radiological follow-up every three months. Three months later, serum AFP increased to 640 ng/ml, but the patient was asymptomatic, and there was no clinical evidence of a relapse. A follow-up PET CT was done, which did not show an evidence of a recurrence or metastasis. On April 2019, progression of disease was observed and nivolumab (3 mg/kg, every two weeks) was started. After five cycles of nivolumab, disease progression occurred. Her performance status quickly deteriorated, weekly carboplatin plus paclitaxel was given again. Unfortunately, she died on 17 July 2019 due to disease progression.

Figure 1.

Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scanning. (a) CT imaging of the chest showing a 7.7 × 9.4 cm mass adjacent the mediastinal pleura in the left upper lung. (b and d) Fused imaging revealing FDG uptake by the left upper lung lobe mass with hypodense and non-metabolic areas and left hypermetabolic pleural effusion. (c) FDG uptake by the left lung upper lobe mass and left pleural effusion.

Figure 2.

(a) The tumor composed of solid sheets displaying trabeculated sinusoidal pattern similar to those seen in hepatocellular carcinoma of the liver (H&E, ×200), (b) the tumor cells have granular, eosinophilic cytoplasm, distinct cell boarders and prominent central nucleoli (H&E, ×400), (c) the tumor cells showing diffuse alpha-fetoprotein positivity (AFP immunostaining, ×400), (d) the tumor cells showing focal and weak positivity with arginase (arginase immunostaining, ×400), (e) the tumor cells showing focal and weak positivity with HepPar (HepPar immunostaining, ×400).

Discussion

Clinically, HAC of the lung has similar properties to that of pulmonary adenocarcinoma. Previously reported cases are summarized in Table 1. Median age at presentation was 56 years (36–82). Most of the patients were smokers and male. Our case is the third female patient reported in the literature. HAC of the lung usually involves upper lobes of lungs and presents as large masses. Only one patient with lower lobe involvement has been reported before.⁵

Table 1.

Clinocopathological characteristics of patients with hepatoid adenocarcinoma of the lung.

Year	Age (years)	Gender	Site	Smoker	AFP level	Tumor size (cm)	Stage	Survival (months)	Treatment
2017⁸	61	M	Left lung	NG	NG	NG	4A	55, D	Chemotherapy
2016¹³	54	M	Right upper lobe	Yes	2	4.1 × 5.1	pT4N0M1b	3, D	Chemotherapy
2016¹⁴	79	M	Right parahilar	Yes	698	2.7 × 2.6	cT1cN0M0	1, D	Erlotinib
2016¹⁵	59	M	Right upper lobe	Yes	N (AT)	4.5 × 3.5 × 3.5	pT2bN0M0	23, A	Curative surgery
2016¹⁶	69	M	Left upper lobe	Yes	4497	4.3	pT2bN0M0	51, A	Curative surgery and adjuvant chemotherapy
2015¹⁰	64	M	Right upper lobe	NG	181	3.8 × 2.9	cT2N2M1c	11, D	Palliative chemotherapy, sorafenib, RT
2014⁷	48	M	Left upper lobe	Yes	6283	10 × 7.9	cT4N2M0	20, D	Concurrent chemoradiation
2014¹⁷	53	F	Right upper lobe	Yes	37810	9.5 × 9×8	pT4N0M0	48, A	Curative surgery, adjuvant chemotherapy
2014¹¹	51	M	Right upper lobe	Yes	1.3 (AT)	4.3 × 3	cT2bN3M0	14, D	Concurrent chemoradiation
2014¹¹	52	M	Right upper lobe	Yes	NG	2.5	cT1cN0M1c	37, A	Surgery, chemoradiation
2014¹¹	64	M	Left upper lobe	Yes	1 (AT)	3. ×2.2	pT2aN0M1b	10, D	Surgery, chemoradiation
2014¹¹	54	F	Left upper lobe	Yes	NG	1	cT1aN0M1b	108, A	Chemoradiation
2014¹¹	60	M	Right upper lobe	Yes	4410	11.2 × 10.1 × 8.5	cT4N2M1b	1, A	Chemoradiation
2013¹⁸	66	M	Right upper lobe	Yes	8686	7.4 × 6 × 4.8	pT4N0M0	48, A	Surgery, adjuvant chemotherapy
2012¹⁹	52	M	Left upper lobe	Yes	5000	11.8 × 12 × 8	cT4N0M1a	NG	Palliative chemotherapy
2012⁹	56	M	Right middle lobe	Yes	2	1.5	cT1bN0M1a	6, D	Crizotinib
2002²⁰	55	M	Right upper lobe	Yes	89 (AT)	5 × 4.8 × 6.5	pT3N0M0	32, A	Surgery
2000⁵	82	M	Left lower lobe	Yes	NG	3.5	pT2aN0M0	82, A	Surgery
1997¹²	36	M	Upper left lobe	Yes	11600	11 and 6	pT4N1M0	7, D	Chemotherapy, surgery
1992²¹	49	M	Right upper lobe	NG	9300	6 × 5 × 5	pT3N0M0	11, A	Surgery
Present study	62	F	Left upper lobe	Yes	9010 (AT)	8 × 7 × 7 and 3 × 2.5 × 2	pT4N1M0	14, D	Surgery, concurrent chemoradiation, adjuvant chemotherapy

N: normal; NG: not given; A: alive; D: deceased; F: female; M: male; AT: after the treatment; AFP: alpha fetoprotein.

The most important prognostic factor is the disease stage at the diagnosis.⁶ The range of the survival was between 1 and 108 months. Surgery is the only curative treatment option for early stage disease. Chemoradiation and chemotherapy can be used in later stages. In one case, paclitaxel and cisplatin were used as radiosensitizers in concurrent chemoradiation and partial response was obtained.⁷ In a patient with stage 4 disease, front-line therapy with cisplatin and pemetrexed provided 55 months of survival.⁸ Tyrosine kinase inhibitors can also be used in HAC of lung. In a patient with ALK-positive disease, crizotinib produced a partial response and seven months of survival.⁹ In another case, a partial response was achieved with sorafenib addition to carboplatin and paclitaxel.¹⁰ But it is not clear whether the benefit achieved is related with sorafenib or chemotherapy. In our patient, we gave adjuvant treatment with CRT followed by chemotherapy. After the therapy, an apparent decrease in AFP was detected.

According to Ishikura et al.,⁴ histologic findings of HAC of the lung are hepatoid cells with abundant, eosinophilic cytoplasm and centrally located nuclei that are usually round, but occasionally elongated. In cytoplasm, spicular bodies and PAS-positive, diastase-resistant hyaline globules can be seen. Immunohistochemical findings are variable in HAC of the lung. In a study with five cases, tumors expressed CK5/6 (1/5), CK7 (3/5), CK 19 (4/5), CK 20 (1/5), AFP (3/5), CEA (3/5), napsin A (1/5) with varying frequencies. HAC of the lung stains similar to HCC, HepPar (5/5), TTF 1 (cytoplasmic) (5/5), CK8 (5/5) and CK18 (5/5) and does not stain for CK14 (0/5). Unlike HCC, it expresses MOC31 (5/5) and HEA 125 (5/5).¹¹ Another study showed that in eight patients with hepatoid carcinoma, arginase 1 was positive in five.³ Elevated serum AFP level does not necessarily indicate the diagnosis of HAC (Table 1). In our patient, elevated serum AFP level was detected after curative surgery, and immunostains of the tumor such as HepPar 1, arginase and AFP were positive (Figure 2(c) to (e)).

Differential diagnosis of HAC of the lung is similar to metastases of HCC, pulmonary large cell carcinoma and germ cell tumors. Imaging studies can exclude metastasis from HCC. Pulmonary large cell carcinoma does not usually secrete AFP. When an eosinophilic large cell tumor-secreting AFP is encountered, HAC should be considered, regardless of mucin secretion. If an AFP-secreting tumor was detected in the lung, a sheet-like growth of neoplastic cell with eosinophilic cytoplasm, specular bodies, tubular and papillary structure should be investigated.⁴

In some cases, when an AFP-secreting thoracic mass is detected, germ-cell tumors first come to mind and treatment can be given without a biopsy. Arnould et al. reported a patient with AFP-secreting left upper lung mass mimicking germ cell tumor clinically. The patient was treated with three cycles of BEP chemotherapy (bleomycin, etoposide and cisplatin) and no response was seen. After the biopsy, the diagnosis of HAC of the lung was made.¹² Hence, in case of AFP-secreting thoracic masses, biopsy is mandatory before starting the treatment.

In conclusion, HAC of the lung should be considered in a smoker patient with AFP-secreting upper lung mass. Biopsy is necessary for definitive diagnosis. Disease stage at presentation is the most important prognostic factor. Approach and principles of treatment of HAC of lung are similar to that of lung adenocarcinoma, unless otherwise specified.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Onder Tonyali

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