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Immunotherapeutic approach to a case of advanced hepatoid adenocarcinoma of the lung

  • Anthony El KhouryEmail author
  • Marc El Khoury
  • Russel De Luca
Open Access
case report
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Summary

Rationale

Hepatoid adenocarcinoma (HAC) is an extrahepatic primary tumor that expresses morphological features resembling hepatocellular carcinoma. This rare malignant tumor has been described in the gastrointestinal (GI) tract, the testes, the ovaries, and rarely, the lungs. Despite there being no standardized management protocol for this case with poor prognosis, the literature describes responses to treatment with cisplatin–etoposide chemotherapy.

Objective

We present an updated review of all cases of HAC of the lung and the favorable results of a novel management method for this type of tumor.

Results

A table including all the HAC of the lung cases on the electronic database PubMed since 1980 is compiled. Here we present a case of primary HAC of the lungs, initially managed with cisplatin–etoposide without favorable response to treatment. The immunohistochemical profile of the tumor allowed for the novel use of immunotherapy in the setting of primary lung HAC, with favorable response.

Conclusion and outlook

The case presented here is of interest as it adopts a novel immunotherapeutic approach to HAC, yielding a promising outcome. This highlights the importance of molecular typing and immunohistochemical profiling in the diagnosis and management of non-small cell lung cancer.

Keywords

Neoplasm Non-small cell lung cancer Novel therapy Pembrolizumab Adenocarcinoma 

Abbreviations

AFP

Alpha fetoprotein

CDX

Caudal type homeobox

CEA

Carcinoembryonic antigen

CK

Cytokeratin

HAC

Hepatoid adenocarcinoma

HCC

Hepatocellular carcinoma

PAX

Paired box gene

PSA

Prostate-specific antigen

TTF

Thyroid transcription factor

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)

Autor

Publication year

Age (years)

Gender

Location

Size (cm)

Smoker

AFP level (ng/uil)

Stage

Progression

Treatment

Yasunami et al. [7]

1981

67

Male

Left Upper Lobe

“Fist-sized”

Not given

19,000

pT3 N2

Rib and vertebra metastases

XRT, Immuno tx (BCG)

Yokoyama et al. [8]

1981

69

Male

Right Lower Lobe

11 × 11 × 7

Not given

5050

pT3 M1b

Not applicable

N/A

Miyake et al. [9]

1986

40

Male

Right Upper Lobe

8 × 9 × 7

Not given

3090

pT3M1b

Not applicable

Surg

Miyake et al. [9]

1986

55

Male

Right Upper Lobe

5

Not given

2123

pT2a M1b

Not applicable

Surg

Miyake et al. [10]

1987

73

Male

Left Upper Lobe

5 × 6 × 5

Not given

1039

pT2b N2

Mediastinal, LN, brain metastases

Surg, XRT

Okunaka et al. [11]

1992

49

Male

Right Upper Lobe

6 × 5 × 5

Not given

9300

eT3

No progression at 11 months

Surg

Arnould et al. [2]

1997

36

Male

Left Upper Lobe

10

Yes

11,600

pT4 N2

Brain Metastasis

Chemo, Surg

Nasu et al. [12]

1997

63

Male

Right Upper Lobe

14 × 13 × 12

Not given

14,000

cT4 N2

Lung, right adrenal, brain metastases

Chemo

Carlinfante et al. [13]

2000

82

Male

Left Lower Lobe

3.5

Yes

Not Assayed

cT2a N0 M0

No progression 7 years after surgery

Surg

Genova [14]

2002

71

Male

Left Upper Lobe

7.7 × 6.4

Not given

Not Assayed

pT3 N0

No progression at 24 months

Surg

Hayashi et al. [15]

2002

55

Male

Right Upper Lobe

5 × 4.8 × 6.5

Yes

89

pT2b N0

No progression at 32 months

Surg

Hiroshima et al. [16]

2002

71

Male

Right Lower Lobe

10.5 × 8.5 × 7

Yes

7417

pT3 N1

Lung and brain metastases

Surg

Iino et al. [17]

2003

63

Male

Right Upper Lobe

2.8 × 2.5

Not given

N/A

cT1 N0 M0

No progression 5 months after surgery

Surg

Oshiro et al. [18]

2004

77

Male

Right Lower Lobe

Not Reported

Not given

Not Assayed

cT2 N0 M0

Liver metastasis

Surg

Ivan et al. [19]

2007

54

Male

Left Upper Lobe

13 × 11

Yes

14,540

pT4 N3 M1

N/A

Chemo, XRT

Kishimoto et al. [20]

2008

64

Male

Left Lower Lobe

7.5 × 7 × 4

Not given

673

cT3 N0 M0

Not reported

Surg

Kim et al. [21]

2009

49

Male

Left Upper Lobe

6

Not given

14,707

pT2b N1

Not reported

Surg

Valentino et al. [22]

2012

71

Male

Right Lower Lobe

1.8 × 1.5 × 1.5

No

34,791

pT1 N0 M1

Died 4 months after presentation

Chemo, XRT, Surg

Lin et al. [23]

2013

66

Male

Right Upper Lobe

7.4 × 6 × 4.8

Yes

8686

cT3 N2 MO

Alive 57 months after presenting

Surgery, adjuvant chemo

Haninger et al. [24]

2014

51

Male

Right Upper Lobe

4.2 × 3.7

Yes

1.3 (post-tx)

cT2a N3 M1b

Died 14 months after presentation

Chemo, XRT, Surg

Haninger et al. [24]

2014

52

Male

Right Upper Lobe

2.5

Yes

Not Assayed

cT1b N0 M1b

Alive 37 months after presented

Surg, Chemo, XRT

Haninger et al. [24]

2014

64

Male

Left Upper Lobe

3.2 × 2.2

Yes

1 (post-tx)

cT2a N0 M1b

Died 10 months after presentation

Surg, Chemo, XRT

Haninger et al. [24]

2014

54

Female

Left Upper Lobe

1

Yes

Not Assayed

cT1a N0 M1b

Alive 9 years after presentation

Chemo, XRT, Surg

Haninger et al. [24]

2014

60

Male

Right Upper Lobe

11.2 × 10.1 × 8.5

Yes

4410

cT3 N2 M1b

Alive 1 month after presentation

Chemo, XRT

Shaib et al. [25]

2014

52

Male

Left Upper Lobe

11.8 × 12 × 8

Yes

5000

cT3 N0 M1

Alive 6–7 months after presenting

Palliative Chemo

Che et al. [26]

2014

48

Male

Left Upper Lobe

7.8 × 7.9 × 10

Yes

6283

pT4 N1 M0

Died 36 months after presentation

Chemo, XRT

Gavrancic and Park [27]

2015

64

Male

Right Upper Lobe

3.8 × 2.9

Not given

181

cT2 N2 M1

Died 11 months after presentation

Chemo, Sorafenib, XRT

Grossman et al. [5]

2016

54

Male

Right Upper Lobe/Paratracheal

4.1 × 5.1

Yes

2

pT4 N0 M1b

Died 4 months after presentation

XRT

Qian et al. [28]

2016

79

Male

Right Parahilar

2.7 × 2.6

Yes

698

Not reported

Died 25 days after tx start by lung infection

Chemo

Motooka et al. [29]

2016

69

Male

Left Upper Lobe

4.3

Yes

4497

pT2a N0 M0

Alive 51 months after surgery

Surg, Adjuvant chemo

Sun et al. [30]

2016

59

Male

Right Upper Lobe

4.5 × 3.8 × 3.5

Yes

Not assayed

pT2a N0 M0

Alive with no recurrence or metastasis 23 months after surgery

Surg

Valle et al. [31]

2017

61

Male

Left sided

Not reported

Not given

Not assayed

Stage IV A

Further metastasis to tonsil

Chemo

Basse et al. [32]

2018

43

Not given

Right Hilar

Not reported

Yes

Not assayed

Metastatic

Died after partial immunotx response due to infectious complications

Chemo, Immuno

Tx treatment, XRT Radiotherapy, Chemo Chemotherapy, Surg Surgery, AFP Alphafetoprotein

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 <10ng/ml). CEA level was 32 ng/ml (reference range <3ng/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: 1500–8000mm3). 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

Date

Clinical course

AFP (ng/mL)

CEA (ng/mL)

Imaging

April 19, 2018

Prior to treatment

1.5

32.0

Chest CT showing a 9.3 × 7.2 cm mass located in the upper lobe of the right lung (RUL) PET-CT hilar lymphadenopathy and left adrenal metastasis

June 6, 2018

Status post 2 cycles of cisplatin–etoposide

1.5

31.7

N/A

August 29, 2018

Status post 2 cycles of pembrolizumab

n/a

5.7

N/A

October 10, 2018

Status post 5 cycles of pembrolizumab

n/a

5.3

Chest CT shows 45% reduction in mass

December 2018

Status post 9 cycles of pembrolizumab

n/a

6.2

N/A

January 23, 2019

Status post 10 cycles of pembrolizumab

n/a

17.3

Chest CT shows growth of primary mass in RUL

PET-CT shows a RUL mass measuring 8.4 × 9.0 cm and a right thoracic inlet mass measuring 3.1 × 3.6 cm

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.

Notes

Author Contribution

A. El Khoury and M. El Khoury wrote the manuscript under guidance and direction from R. De Luca.

Compliance with ethical guidelines

Conflict of interest

A. El Khoury, M. El Khoury and R. De Luca declare that they have no competing interests.

Ethical standards

Written consent for the publication of this case has been obtained from the patient.

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© The Author(s) 2019

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.St Georges’, University of LondonLondonUnited Kingdom
  2. 2.St Edmund’s College, Cambridge UniversityCambridgeUnited Kingdom
  3. 3.Tate Cancer CenterUniversity of Maryland Medical SystemsGlen BurnieUSA

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