Elsevier

Human Pathology

Volume 39, Issue 7, July 2008, Pages 1115-1120
Human Pathology

Case study
A case of α-fetoprotein–producing pulmonary carcinoma with restricted expression of hepatocyte nuclear factor-4α in hepatoid foci: a case report with studies of previous cases

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Summary

We report a case of α-fetoprotein (AFP)–producing pulmonary carcinoma with studies for messenger RNA (mRNA) expression of hepatocyte nuclear factor (HNF)-4α, which is a transcription factor that is highly expressed in the process of liver development. The patient was a 64-year-old man with a pulmonary tumor in his left lower lobe. Serum AFP was 673 ng/mL. The microscopic analysis of the surgical specimen revealed a large cell neuroendocrine carcinoma with occasional hepatoid foci. The competitive reverse transcriptase polymerase chain reaction analysis revealed that HNF-4α mRNA was expressed on the order of 102- to 103-fold more abundantly than control pulmonary carcinomas and normal lung tissues. In addition, AFP and HNF-4α expression was restricted in hepatoid foci. Two previously reported cases of AFP-producing pulmonary carcinoma were also positive, whereas all 18 control pulmonary carcinomas were negative for HNF-4α. These findings suggest that aberrant expression of HNF-4α is implicated in the emergence or maintenance of hepatoid foci in AFP-producing pulmonary carcinomas.

Introduction

α-Fetoprotein (AFP)–producing pulmonary carcinomas are relatively rare tumors [1], [2], [3], [4]. A fraction of the AFP-producing carcinomas have foci with microscopic features resembling hepatocellular carcinomas. These tumors are especially designated as hepatoid adenocarcinomas [5]. The prognosis of hepatoid adenocarcinomas is known to be very poor because of prominent vascular invasion and liver metastasis [6]; it is therefore important to fully identify the clinicopathologic implications of hepatoid foci. However, the molecular mechanism in the emergence of hepatoid foci is less understood.

Hepatocyte nuclear factor (HNF)-4α, a transcriptional factor of the nuclear hormone receptor family, has been known as a master molecule that regulates liver differentiation [7], [8]. HNF-4α can activate the promoter of human AFP gene [9] and other liver-specific proteins in hepatocytes [10]. Alternative promoter (P1 and P2) use and alternative splicing generate 9 isoforms of HNF-4α[11]. HNF-4α isoforms are differently distributed in adults. P1 promoter-driven HNF-4α is expressed in hepatocytes, although it is not expressed in pulmonary cells and lung carcinoma cells [12], [13]. We report herein a case of AFP-producing pulmonary carcinoma with a restricted expression of HNF-4α in hepatoid foci with investigations for the expression of HNF-4α. In addition, HNF-4α expression was studied in 2 previously reported cases of AFP-producing pulmonary carcinomas and 18 cases of control pulmonary carcinomas.

Section snippets

Cases of AFP-producing pulmonary carcinomas

Three cases of AFP-producing pulmonary carcinomas (cases 1, 2, and 3) were included in this study. Case 1 is an original case. The patient was a 64-year-old man with no previous history. Chest radiography revealed the pulmonary tumor in the lower lobe of his left lung. Computed tomographic scan demonstrated a relatively well-circumscribed tumor located medially in the left lower lobe of the lung, which partially compressed the left pulmonary arteries. Preoperational imaging studies for systemic

Microscopic findings of the present case

Microscopic examinations in the present case (case 1) revealed that the tumor was composed of 2 histologic patterns. In a small fraction, the tumor cells with eosinophilic and abundant cytoplasms proliferated in a solid and sheetlike arrangement with pseudoglandular structures. These features resembling hepatocellular carcinoma were considered to be hepatoid (Fig. 1A). The predominant pattern consisted of an organoid and nesting arrangement of round to polygonal tumor cells with often centrally

Discussion

We report herein a case of large cell neuroendocrine carcinoma with hepatoid foci, in which AFP was immunostained exclusively in hepatoid foci. Hepatoid carcinoma is usually associated with an adenocarcinomatous component with a tubular or papillary feature [5]; however, as well as the present case, histologic types other than adenocarcinoma can be the counterpart of hepatoid foci. Nasu et al [15] have reported a case of large cell carcinoma in the lung with AFP-producing hepatoid foci.

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