A Novel Approach Using Sorafenib in Alpha Fetoprotein–Producing Hepatoid Adenocarcinoma of the Lung

Authors:
Tatjana GavrancicFrom Icahn School of Medicine at Mount Sinai Bronx program, James J. Peters Veterans Affairs Medical Center, and Columbia University, New York, New York.

Search for other papers by Tatjana Gavrancic in
Current site
Google Scholar
PubMed
Close
 MD
and
Yeun-Hee Anna ParkFrom Icahn School of Medicine at Mount Sinai Bronx program, James J. Peters Veterans Affairs Medical Center, and Columbia University, New York, New York.
From Icahn School of Medicine at Mount Sinai Bronx program, James J. Peters Veterans Affairs Medical Center, and Columbia University, New York, New York.

Search for other papers by Yeun-Hee Anna Park in
Current site
Google Scholar
PubMed
Close
 MD

Hepatoid adenocarcinoma of the lung (HAL) is an extremely rare cancer without clear treatment guidance and with a poor prognosis. This report discusses a 64-year-old man who presented with complaints of hemoptysis and was found to have a right upper lobe (RUL) lung mass on chest CT with presence of a right hilar mass and retrocaval lymphadenopathy, and metastasis to the vertebral spine and rib. The patient was diagnosed with T2N2M1 (stage IV) unresectable disease. A biopsy of the RUL mass revealed hepatoid variant adenocarcinoma. Immunohistochemical stains showed tumor cells positive for CK7, AFP, Hep Par 1, napsin A, and cytoplasmic TTF-1 staining. In contrast, CK5, CK6, and CK20 were negative, and EGFR was wild-type. Serum alpha fetoprotein (AFP) level was elevated at 181 ng/mL. The patient was treated with platinum-based doublet chemotherapy and sorafenib, and his AFP level decreased to 25 ng/mL. This case report presents the novel use of sorafenib in combination with platinum-based doublet chemotherapy in EGFR wild-type HAL, which led to a partial response. Single-agent sorafenib led to stable disease overall, achieving a survival among the longest reported for unresectable stage IV, all while maintaining an ECOG performance status of 0 to 1.

NCCN: Continuing Education

Accreditation Statement

This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.

NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

This activity is accredited for 1.0 contact hours. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/64368; and 4) view/print certificate.

Release date: April 17, 2015; Expiration date: April 17, 2016

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Describe the differential diagnosis of HAL and previously used treatment described in the literature

  • Examine the use of sorafenib in combination with platinum-based doublet chemotherapy in EGFR wild-type HAL

Hepatoid adenocarcinoma of the lung (HAL) is an extremely rare cancer that lacks treatment guidance and has a poor prognosis. It is defined as an alpha fetoprotein (AFP)–producing primary lung carcinoma with pathologic findings of acinar and papillary adenocarcinoma resembling hepatocellular carcinoma (HCC). Globally, only 24 cases have been reported. This report presents a case of unresectable stage IV (T2N2M1) HAL with elevated AFP levels that was treated with the multitargeted tyrosine kinase inhibitor sorafenib along with standard treatment for non–small cell lung cancer (NSCLC). This approach led to a decrease in AFP levels and radiologic findings of regression during combination therapy and stable disease during sorafenib monotherapy.

Case Report

A 64-year-old man presented with hemoptysis and was found to have right upper lung (RUL) opacity on chest radiograph. Results of a chest CT showed a RUL mass (38.0 × 29.4 mm) with the presence of a right hilar mass (43.0 × 29.6 mm) and retrocaval lymphadenopathy with metastasis to the vertebral spine and rib. No liver masses were noted on abdominal CT. CT-guided fine-needle aspiration biopsy of the RUL mass showed adenocarcinoma, hepatoid variant (Figure 1). Immunohistochemical stains showed tumor cells to be positive for AFP (Figure 2A), Hep Par 1 (Figure 2B), CK7 (Figure 2C), and napsin A (Figure 2D), and TTF-1 was positive in the cytoplasm in a granular fashion. In contrast, CK5, CK6, CK20, and histochemical mucicarmine were

Figure 1
Figure 1

CT-guided fine-needle aspiration biopsy of the right upper lobe mass showing adenocarcinoma, hepatoid variant.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 4; 10.6004/jnccn.2015.0054

Figure 2
Figure 2

Immunohistochemical stains showed tumor cells to be positive for (A) AFP, (B) Hep Par 1, (C) CK7, and (D) napsin A.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 4; 10.6004/jnccn.2015.0054

all negative; EGFR was wild-type. The serum AFP level was found to be elevated (181 ng/mL).

The patient was diagnosed with stage IV HAL and started on palliative chemotherapy with carboplatin/paclitaxel and sorafenib (400 mg orally twice daily), followed by palliative radiation to the vertebrae for a total dose of 30 Gy. After 2 cycles of carboplatin/paclitaxel and oral sorafenib, results of a chest CT showed a partial response with a decrease in size of the RUL mass (to 24 × 21 mm) and right hilar mass (to 24 × 21 mm) (Figure 3A–D). After 4 cycles of chemotherapy, his AFP level was 25 ng/mL and chest CT results showed stable disease. At this point, the patient continued sorafenib daily for 2 months.

At follow-up, 3 months after his last chemotherapy treatment, a chest CT showed increased lung nodules, but an abdominal CT continued to show absence of liver nodules. His AFP level was 25 ng/mL. The patient was switched from carboplatin/paclitaxel to vinorelbine with continued sorafenib. After 3 cycles of vinorelbine and daily sorafenib, chest CT results showed a new mediastinal lymphadenopathy, an increase in hilar/subcarinal lymphadenopathy and RUL lung mass, and a new hepatic mass on abdominal CT. His AFP level increased to 189 ng/mL. At this point, the decision was made to proceed with gemcitabine with sorafenib. However, the patient received 1 cycle of gemcitabine at the end, and had a total of 9 months of sorafenib daily during the disease course before he was admitted for failure to thrive and transferred to palliative care. The patient survived for a total of 11 months after diagnosis and therapy administration.

Figure 3
Figure 3

(A–D) After 2 cycles of carboplatin/paclitaxel and oral sorafenib, results of a chest CT showed a partial response with a decrease in size of the right upper lobe mass (to 24 × 21 mm) and right hilar mass (to 24 × 21 mm).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 4; 10.6004/jnccn.2015.0054

Discussion

Hepatoid adenocarcinoma is a type of extrahepatic adenocarcinoma morphologically similar to HCC, which can occur in the lungs, stomach (more common), pancreas, esophagus, ampulla of Vater, colon, urinary bladder, renal pelvis, ovaries, uterus, and cervix.1,2 A diagnosis of HAL is determined through biopsy results with histologic findings of acinar and papillary adenocarcinoma architecture resembling HCC with elevated AFP levels, followed by immunostaining for AFP, Hep Par 1, pCEAm, pCEAc, CK7, CK8, CK18, CK19, and CK20.

Although immunostaining patterns are used for diagnosing HAL and HCC and for differentiating between primary versus metastatic HAL and HCC, no consensus exists among experts regarding what exact immunohistochemistry panel is diagnostic for HAL. Recent case reports and review articles on HAL showed variable immunohistochemistry characteristics among cases reported to date. Mokrim et al3 reported a case of HAL that was negative for CD7 and TTF-1, but positive for CK20 and Hep Par 1. Lin et al4 discussed a case that was negative for CK7, CK20, TTF-1, and Hep Par 1. Lastly, Haninger et al5 reported 5 cases of HAL that demonstrated HAL to be negative for CK20, and positive for CK7, cytoplasmic TTF-1, and Hep Par 1, which is identical to the present case. Furthermore, because the present case had positive cytoplasmic staining for TTF-1, which is considered highly specific and sensitive for HCC, and nuclear TTF-1 staining is usually found in lung adenocarcinomas, Lei et al6 found that cytoplasmic TTF-1 staining in the tumor is strongly suggestive but not diagnostic of HCC. Both HCC and HAL are positive for AFP. Haninger et al5 also described additional immunostaining that should be performed (ie, HEA-125, MOC-31, and monoclonal CEA, which should be positive in HAL vs HCC) (Table 1).

Treatment for HAL includes at least a platinum-based doublet therapy, which is standard treatment for NSCLC. Results of the SHARP trial demonstrated that monotherapy with oral sorafenib prolonged median overall survival (10.7 months in the sorafenib group vs 7.9 months for placebo), with a 31% relative reduction in the risk of death, and delayed the median time to progression for 3 months in patients with advanced HCC.7 However, sorafenib in addition to standard NSCLC treatment failed to show improvement in overall survival in 2 phase III trials. The NExUS trial showed no survival prolongation when sorafenib was added to platinum-based chemotherapy (cisplatin/gemcitabine) compared with cisplatin/gemcitabine alone in patients with advanced nonsquamous NSCLC.8 The ESCAPE trial failed to show that sorafenib added to carboplatin/paclitaxel improved overall survival.9 However, the BATTLE trial, a biopsy-mandated, biomarker-based, adaptively randomized study that evaluated the clinical efficacy of sorafenib monotherapy in patients with previously treated NSCLC, demonstrated that clinical activity of sorafenib in NSCLC, especially wild-type EGFR, was associated with improved progression-free survival in

Table 1

Immunohistochemistry of HAL and HCC

Table 1
the sorafenib-sensitivex subgroup.10 In addition, Metro et al11 reviewed available phase II and III studies using sorafenib in lung cancer to demonstrate that sorafenib provides a disease control rate in 53% to 90% of patients with advanced NSCLC with aberrant KRAS activation and wild-type EGFR, therefore supporting the use of sorafenib in individual molecularly selective settings. The targeting of the RAS/RAF/MEK/ERK pathway with clinically available surrogate markers harboring KRAS and/or BRAF mutations could be a strategy for selecting more responsive personalized cancer therapy using molecular signatures, compared with administering sorafenib in large unselected patient populations.

A review of all of the cases reported in the literature has shown that resectable cases of HAL and those presenting at an earlier stage have longer survival.1220 Survival for surgical resection followed by chemoradiation ranged from 10 to 37 months for stage IV to 4 years for stage IIB4,5; a 9-year survival was reported for one case involving a debulked stage IV tumor.5 However, for unresectable HAL, survival ranges from 6 to 11 months, similar to the present case with a survival of 11 months (Table 2).

The present case appears to be the only one reported in the literature to date (Table 2) that used sorafenib in addition to standard NSCLC platinum-based doublet treatment of EGFR wild-type HAL with a survival duration at the upper end of unresectable stage IV HALs (although longer survival rates

Table 2

Survival Rate and Treatment Type for All Reported Literature Cases of HAL Treated With Chemotherapy

Table 2
were reported in operable and lower-stage cases). In this patient, no additional side effects were reported that were attributable to sorafenib and the patient maintained an ECOG performance status of 0 to 1 until 3 weeks before his death. In addition, the patient showed stable disease after 2 months of monotherapy with sorafenib.

Conclusions

Sorafenib in AFP-producing, EGFR wild-type HAL in combination with platinum-based doublet chemotherapy was tolerated well, and was associated with a survival time comparable to that of the longest surviving patient with unresected HAL reported in the literature. Future use of sorafenib in EGFR wild-type HAL as a rare subset of NSCLC represents a reasonable application of multitargeted tyrosine kinase inhibitors limited to tumors that are EGFR wild-type and KRAS- and/or BRAF-positive as biomarker-targeted therapy.

The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network

Ms. Green has disclosed that she has no relevant financial relationships.

CE AUTHORS

Deborah J. Moonan, RN, BSN, Director, Continuing Education, has disclosed that she has no relevant financial relationships.

Ann Gianola, MA, Manager, Continuing Education Accreditation & Program Operations, has disclosed that she has no relevant financial relationships.

Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations, has disclosed that she has no relevant financial relationships.

Rashmi Kumar, PhD, Senior Manager, Clinical Content, has disclosed that she has no relevant financial relationships.

Miranda Hughes, PhD, Oncology Scientist/Senior Medical Writer, has disclosed that she has no relevant financial relationships.

References

  • 1.

    Terracciano L, Glatz K, Mhawech P et al.. Hepatoid adenocarcinoma with liver metastasis mimicking hepatocellular carcinoma: an immunohistochemical and molecular study of eight cases. Am J Surg Pathol 2003;27:13021312.

    • Search Google Scholar
    • Export Citation
  • 2.

    Ishikura H, Kanda M, Ito M et al.. Hepatoid adenocarcinoma: a distinctive histological subtype of alpha-fetoprotein-producing lung carcinoma. Virchows Arch A Pathol Anat Histopathol 1990;417:7380.

    • Search Google Scholar
    • Export Citation
  • 3.

    Mokrim M, Belbaraka R, Allaoui M et al.. Hepatoid adenocarcinoma of the lung: a case report and literature review. J Gastrointest Cancer 2012;43(Suppl 1):125127.

    • Search Google Scholar
    • Export Citation
  • 4.

    Lin SF, Hsu WH, Chou TY. Primary pulmonary hepatoid carcinoma: report of a case and review of the literature. Kaohsiung J Med Sci 2013;29:512516.

    • Search Google Scholar
    • Export Citation
  • 5.

    Haninger D, Kloecker G, Bousamra M et al.. Hepatoid adenocarcinoma of the lung: report of five cases and review of the literature. Modern Pathol 2014;27:535542.

    • Search Google Scholar
    • Export Citation
  • 6.

    Lei JY, Bourne P, diSant’Agnese PA, Huang J. Cytoplasmic staining of TTF-1 in the differential diagnosis of hepatocellular carcinoma vs cholangiocarcinoma and metastatic carcinoma of the liver. Am J Clin Pathol 2006;125:519525.

    • Search Google Scholar
    • Export Citation
  • 7.

    Llovet JM, Ricci S, Mazzaferro V et al.; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378390.

    • Search Google Scholar
    • Export Citation
  • 8.

    Paz-Ares LG, Biesma B, Heigener D et al.. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol 2012;30:30843092.

    • Search Google Scholar
    • Export Citation
  • 9.

    Scagliotti G, Novello S, von Pawel J et al.. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 2010;28:18351842.

    • Search Google Scholar
    • Export Citation
  • 10.

    Blumenschein GR Jr, Saintigny P, Liu S et al.. Comprehensive biomarker analysis and final efficacy results of sorafenib in the BATTLE trial. Clin Cancer Res 2013;19:69676975.

    • Search Google Scholar
    • Export Citation
  • 11.

    Metro G, Minotti V, Crino L. Years of sorafenib investigation in advanced non-small cell lung cancer: is there a ‘NExUS’ linking an unsuccessful treatment and a potential active one? J Thorac Dis 2012;4:635638.

    • Search Google Scholar
    • Export Citation
  • 12.

    Keating GM, Santoro A. Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs 2009;69:223240.

  • 13.

    Carlinfante G, Foschini MP, Pasquinelli G et al.. Hepatoid carcinoma of the lung: a case report with immunohistochemical, ultrastructural and in-situ hybridization findings. Histopathology 2000;37:8889.

    • Search Google Scholar
    • Export Citation
  • 14.

    Nasu M, Soma T, Fukushima H et al.. Hepatoid carcinoma of the lung with production of alpha-fetoprotein and abnormal prothrombin: an autopsy case report. Mod Pathol 1997;10:10541058.

    • Search Google Scholar
    • Export Citation
  • 15.

    Hiroshima K, Iyoda A, Toyozaki T et al.. Alpha-fetoprotein-producing lung carcinoma: report of three cases. Pathol Int 2002;52:4653.

  • 16.

    Kishimoto T, Yano T, Hiroshima K et al.. A case of alpha-fetoprotein-producing pulmonary carcinoma with restricted expression of hepatocyte nuclear factor-4 alpha in hepatoid foci: a case report with studies of previous cases. Hum Pathol 2008;39:11151120.

    • Search Google Scholar
    • Export Citation
  • 17.

    Arnold L, Drout F, Fargeot P et al.. Hepatoid adenocarcinoma of the lung: report of a case of an unusual alfa-fetoprotein-producing lung tumor. Am J Surg Pathol 1997;21:11131118.

    • Search Google Scholar
    • Export Citation
  • 18.

    Hayashi Y, Takanashi Y, Ohsawa H. Hepatoid adenocarcinoma in the lung. Lung Cancer 2002;38:211214.

  • 19.

    Wu Z, Upadhyaya M, Zhu H et al.. Hepatoid adenocarcinoma: computed tomographic imaging findings with histopathologic correlation in 6 cases. J Comput Assist Tomogr 2007;31:846852.

    • Search Google Scholar
    • Export Citation
  • 20.

    Ivan M, Koss M, Chang CF. Hepatoid adenocarcinoma of the lung [abstract]. Chest 2007;132(Suppl):Abstract 690.

Correspondence: Tatjana Gavrancic, MD, 21–24 31st Street, Queens, New York 11105. E-mail: tatjanadr@yahoo.com

Supplementary Materials

  • Collapse
  • Expand
  • View in gallery

    CT-guided fine-needle aspiration biopsy of the right upper lobe mass showing adenocarcinoma, hepatoid variant.

  • View in gallery

    Immunohistochemical stains showed tumor cells to be positive for (A) AFP, (B) Hep Par 1, (C) CK7, and (D) napsin A.

  • View in gallery

    (A–D) After 2 cycles of carboplatin/paclitaxel and oral sorafenib, results of a chest CT showed a partial response with a decrease in size of the right upper lobe mass (to 24 × 21 mm) and right hilar mass (to 24 × 21 mm).

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 430 98 8
PDF Downloads 303 89 4
EPUB Downloads 0 0 0