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12.06.2019 | case report | Ausgabe 3/2019 Open Access

memo - Magazine of European Medical Oncology 3/2019

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

Zeitschrift:
memo - Magazine of European Medical Oncology > Ausgabe 3/2019
Autoren:
Anthony El Khoury, Marc El Khoury, Russel De Luca
Wichtige Hinweise

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.

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.
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.

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