J Gastrointest Canc DOI 10.1007/s12029-013-9558-7


Hepatoid Adenocarcinoma of the Lung: A Case Report and Review of the Literature Walid Shaib & Rahul Sharma & Marina Mosunjac & Alton B. Farris III & Bassel El Rayes

# Springer Science+Business Media New York 2014

Abbreviations HAC Hepatoid adenocarcinoma AFP Alpha-fetoprotein AJCC American Joint Committee on Cancer

Background Hepatoid adenocarcinoma (HAC) is a rare type of extrahepatic cancer, with pathologic features largely indistinguishable from hepatocellular carcinoma. Thirty cases of HAC have been described. The majority of HAC cases arise in the lung. Extrapulmonary HAC occurs in the stomach [1], and cases have been reported in the mediastinum, esophagus, gallbladder, pancreas, ampulla of Vater, renal pelvis, bladder, endometrium, ovary, and testicle [2–5]. In addition to the pathologic similarities to hepatocellular cancer, a large proportion of HACs produce AFP, and plasma levels may be very high [6]. Alpha-fetoprotein (AFP) was first detected in the serum of a patient with a primary liver tumor in 1965 [7] and has since been used as a tumor indicator for either primary liver or yolk sac tumors [8,9]. Certain gastrointestinal tumors such as gastric, rectal, and pancreatic carcinomas as well as lung cancer also secrete AFP [10–12]. We are reporting the second female case of pulmonary HAC who presented with elevated AFP and was treated with lobectomy and 3 cycles of adjuvant platinum-doublet chemotherapy. W. Shaib : R. Sharma (*) : M. Mosunjac : A. B. Farris III : B. El Rayes Winship Cancer Institute, Emory University, Atlanta, GA, USA e-mail: [email protected] B. El Rayes e-mail: [email protected]

Case Presentation A 53-year-old female with prior history of alcohol abuse, 40pack-year tobacco abuse, chronic obstructive pulmonary disease, and rheumatoid arthritis presented in May 2008 to the emergency room for evaluation of chest pain. Pain was described as pleuritic, sharp, substernal, continuous, 5/10 intensity, and non-radiating, without exacerbating or alleviating factors or shortness of breath on exertion. Her vital signs were stable, and physical exam was unrevealing except for expiratory wheezing on bilateral lung fields. Chest computed tomography (CT) revealed a right upper lobe mass measuring 6.7×4.0×5.0 cm in diameter without apparent invasion of the chest wall (Fig. 1). She underwent fine needle aspiration which revealed adenocarcinoma with hepatoid features (Fig. 2). A subsequent magnetic resonance imaging of the abdomen was negative for liver masses, ovarian masses, or abdominal lymphadenopathy (Fig. 3). Positron emission test showed no metabolic activity except at the right upper lobe mass. AFP level measured at the time of diagnosis was 37,

Fig. 1 CT scan of the chest showing a right lung apex mass; the 6.7× 4.6×5.3 cm mass abuts the lateral pleural surface but does not invade the chest wall

J Gastrointest Canc

Fig. 2 A hepatoid adenocarcinoma of the lung has the following features: a trabecular arrangement at relatively low power, similar to that seen in hepatocellular carcinoma (hematoxylin and eosin, original magnification: ×50); b pseudoacinar structures (arrow) that can be appreciated at medium power (×100); c pseudoacinar structures (arrow) composed of cells with abundant eosinophilic cytoplasm, similar to those seen

in hepatocellular carcinoma (×200); d mitotically active (arrow) pleomorphic cells (×200); e mitotically active cells (blue arrow), many of which have conspicuous nucleoli (green arrow) (×400); f mitotically active cells (blue arrow) with prominent nucleoli (green arrow); g, h positive HepPar1 immunohistochemistry on cell block material; and i negative TTF1 immunohistochemistry on cell block material

810 ng/ml (Fig. 4). Hepatitis serologies were negative for hepatitis B surface antigen, core IgM, and hepatitis C antibody. Liver enzymes were within normal limits.

The patient underwent right upper and middle lobectomies with multiple lymph node excisions. The pathologic stage was determined to be IIb (pT3 N0 M0) according to the American Joint Committee on Cancer (AJCC) version 5. Pathology specimen revealed 9.5×9.0×8.0 cm, and immunohistochemical

Fig. 3 Magnetic resonance imaging of the abdomen showing no liver masses

Fig. 4 AFP levels before and after resection

J Gastrointest Canc Table 1 Summary of case reports in the English literature

A alive, D deceased, M male, F female, RUL right upper lobe, LUL left upper lobe, LLL left lower lobe, RLL right lower lobe





AFP (ng/ml)

Size (cm)


Papatsimpas et al. [13] Saka et al. [18] Yoshino et al. [19] Yamagata et al. [17] Arnould et al. [20]

28 73 54 44 36



39,000 289 696 8438 1,160

– 3.9 2 3.5 10

D 6 months – A 24 months A 2 years D 7 months

Hayashi et al. [21] Yasunami et al. [12] Nasu et al. [22] Carlinfante et al. [23] Terracciano et al. [24] Genova [25] Hiroshima et al. [26] Wu et al. [27] Kitada et al. [28] Mokrim et al. [29] Shaib et al. (this study)

55 67 63 82 44 71 71 50 69 52 53



– 19,000 14,000 – 203,320 – 7,417 2.14 4,620 5,000 37,810

6.5 8 8 3.5 5 7.7 10.5 4.6 6.5 11.8 9.5

A 30 months D 16 months D 11 months A 7 years D 2 months A 2 years D 1 year A 45 months A 1 year A 2 months A 4 years

staining was positive for cytokeratin CAM 5.2, HEPPAR, and CD34 in the vessels. PTF-1 was negative in the nuclei but focally positive in the cytoplasm. CK7 and CK20 immunostains were negative along with reticulum stain (Fig. 2). The patient was treated with cisplatin and docetaxel for 3 cycles as adjuvant chemotherapy and was followed up with chest CT and AFP levels. At the 4-year follow-up visit, the patient was asymptomatic, with no CT evidence of disease recurrence, and her AFP level was decreased to 1.5 ng/ml (Fig. 3).

Conclusions HAC is a unique clinicopathologic entity. Histologically, it is a composition of tubular or papillary adenocarcinoma with a proliferation of AFP producing neoplastic cells [11,13]. Clinically, the lung is the most common site of HAC. Diagnosis requires biopsy and exclusion of a liver and testicular or ovarian primary. AFP production is commonly observed in HAC and can be used as a tumor marker to follow up disease response to therapy. AFP-producing lung cancer was first reported by Corlin et al. [14] and has since been reported to account for about 2 % of all lung cancers [15]. Adenocarcinomas account for most AFP-producing lung cancers, followed by large-cell carcinoma which accounts for 25 % of all AFP-producing lung cancers. Rare cases of AFP-producing squamous cell carcinoma [16] and AFPproducing carcinoid [1,17] have also been reported. HAC of the lung tends to occur more commonly in men, while non-lung HAC has equal prevalence in men and women. The limited literature regarding lung HAC is summarized in Table 1. The data suggests that HAC has a worse prognosis

than non-small cell lung cancer. The limitations in the published literature regarding prognosis include the limited number of patients, short follow-up, and variable disease stages at diagnosis. Our patient had over a 4-year follow-up. Aggressive surgical therapy for early stage lung HAC appears to be effective [13,18]. The majority of the published literature has focused on treating pulmonary HAC with platinum-based therapy similar to the management of lung cancer. The outcome of patients with advanced stage disease has been dismal. The role of adjuvant therapy after resection is not established in lung HAC. Given the similarities to hepatocellular cancer, the effectiveness of sorafenib in the treatment of advanced HAC should be evaluated. Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Conflict of interest None.

References 1. Ishikura H et al. Hepatoid adenocarcinomas of the stomach. An analysis of seven cases. Cancer. 1986;58(1):119–26. 2. Ishikura H, Scully RE. Hepatoid carcinoma of the ovary. A newly described tumor. Cancer. 1987;60(11):2775–84. 3. Ishikura H et al. Hepatoid adenocarcinoma of the renal pelvis producing alpha-fetoprotein of hepatic type and bile pigment. Cancer. 1991;67(12):3051–6. 4. Tanno S et al. Alpha-fetoprotein producing mucin-producing carcinoma of the pancreas: a case report with immunohistochemical study and lectin-affinity profile. Dig Dis Sci. 1997;42(12):2513–8.

J Gastrointest Canc 5. Lopez-Beltran A et al. Hepatoid adenocarcinoma of the urinary bladder. Virchows Arch. 2003;442(4):381–7. 6. Fornasa F. Soft-tissue localization of hepatoid adenocarcinoma: first case report. Case Rep Oncol. 2010;3(2):212–7. 7. Tatarinov Iu S. [Content of the embryo-specific alpha-globulin in the serum of the fetus, newborn infant and adult man with primary liver cancer]. Vopr Med Khim 1965; 11(2): p. 20–4. 8. O'Conor GT et al. A collaborative study for the evaluation of a serologic test for primary liver cancer. Cancer. 1970;25(5):1091–8. 9. Palmer PE, Safaii H, Wolfe HJ. Alpha1-antitrypsin and alphafetoprotein. Protein markers in endodermal sinus (yolk sac) tumors. Am J Clin Pathol. 1976;65(4):575–82. 10. McIntire KR et al. Serum alpha-fetoprotein in patients with neoplasms of the gastrointestinal tract. Cancer Res. 1975;35(4):991–6. 11. Ishikura H et al. Hepatoid adenocarcinoma: a distinctive histological subtype of alpha-fetoprotein-producing lung carcinoma. Virchows Arch A Pathol Anat Histopathol. 1990;417(1):73–80. 12. Yasunami R et al. Primary lung cancer producing alpha-fetoprotein: a case report. Cancer. 1981;47(5):926–9. 13. Papatsimpas G et al. Hepatoid pancoast tumor. A case report and review of the literature. Lung Cancer. 2012;77(2):239–45. 14. Corlin RF, Tompkins RK. Serum alpha1-fetoglobulin in a patient with hepatic metastases from bronchogenic carcinoma. Am J Dig Dis. 1972;17(6):553–5. 15. Walop W et al. The use of biomarkers in the prediction of survival in patients with pulmonary carcinoma. Cancer. 1990;65(9):2033–46. 16. Asamura H et al. AFP-producing squamous cell carcinoma of the lung in an adolescent. Jpn J Clin Oncol. 1996;26(2):103–6. 17. Yamagata T et al. A case of primary lung cancer producing alphafetoprotein. Can Respir J. 2004;11(7):504–6.

18. Saka H et al. Successful resection of alpha-fetoprotein-producing lung cancer. Chest. 1988;94(4):879–80. 19. Yoshino I et al. Alpha-fetoprotein-producing adenocarcinoma of the lung. Lung Cancer. 1996;15(1):125–30. 20. Arnould L et al. Hepatoid adenocarcinoma of the lung: report of a case of an unusual alpha-fetoprotein-producing lung tumor. Am J Surg Pathol. 1997;21(9):1113–8. 21. Hayashi Y et al. Hepatoid adenocarcinoma in the lung. Lung Cancer. 2002;38(2):211–4. 22. Nasu M et al. Hepatoid carcinoma of the lung with production of alpha-fetoprotein and abnormal prothrombin: an autopsy case report. Mod Pathol. 1997;10(10):1054–8. 23. Carlinfante G et al. Hepatoid carcinoma of the lung: a case report with immunohistochemical, ultrastructural and in-situ hybridization findings. Histopathology. 2000;37(1):88–9. 24. Terracciano LM et al. Hepatoid adenocarcinoma with liver metastasis mimicking hepatocellular carcinoma: an immunohistochemical and molecular study of eight cases. Am J Surg Pathol. 2003;27(10): 1302–12. 25. Genova, S. et al. [Hepatoid adenocarcinoma of the lung: a case report]. Khirurgiia (Sofiia) 2003; 59(4): p. 45–7. 26. Hiroshima K et al. Alpha-fetoprotein-producing lung carcinoma: report of three cases. Pathol Int. 2002;52(1):46–53. 27. Wu Z et al. Hepatoid adenocarcinoma: computed tomographic imaging findings with histopathologic correlation in 6 cases. J Comput Assist Tomogr. 2007;31(6):846–52. 28. Kitada M et al. Alpha-fetoprotein-producing primary lung carcinoma: a case report. World J Surg Oncol. 2011;9:47. 29. Mokrim M, et al. Hepatoid adenocarcinoma of the lung: a case report and literature review. J Gastrointest Cancer 2011.

Hepatoid adenocarcinoma of the lung: a case report and review of the literature.

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