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Japanese Journal of Clinical Oncology Pages 401-404

Undifferentiated Carcinoma of the Liver with Neuroendocrine Features: a Case Report
Introduction
Case Report
Discussion
Acknowledgment
References
Undifferentiated Carcinoma of the Liver with Neuroendocrine Features: a Case Report

Undifferentiated Carcinoma of the Liver with Neuroendocrine Features: a Case Report

Hidekazu Nakasuka1, Shuichi Okada1, Takuji Okusaka1, Hiroshi Ishii1, Masahumi Ikeda1, Ryoji Ito1, Hiroki Kosakamoto1, Masayoshi Yoshimori1, Yukihiro Nakanishi2, Michiie Sakamoto2

1Department of Internal Medicine, National Cancer Center Hospital, Tokyo and 2Pathology Division, National Cancer Center Research Institute, Tokyo, Japan

Undifferentiated carcinoma of the liver is very rare. A 54-year-old man was admitted to our hospital for a detailed examination of multiple liver tumors. These tumors were high or low echoic on ultrasonography, but not enhanced by contrast medium in dynamic computed tomography. A fine-needle aspiration biopsy specimen of the tumor showed undifferentiated carcinoma. The serum level of neuron-specific enolase was high (357 ng/ml) and the immunohistochemical stain of the biopsy specimen was positive for synaptophysin. We diagnosed the patient as having undifferentiated carcinoma of the liver with neuroendocrine features. The patient was treated with combined systemic chemotherapy: etoposide 100 mg/m2/day for three days plus cisplatin 80 mg/m2/day on day one. He achieved a partial response, the duration of which was 7+ months. The serum neuron-specific enolase levels were decreased to the normal range after chemotherapy. Primary liver carcinoma with neuroendocrine features is extremely rare, but in a suspicious case it is important to measure the serum levels of neuroendocrine markers and make a histological confirmation, because chemotherapy may be effective for this disease.

Key words: undifferentiated carcinoma - liver cancer - neuroendocrine marker - neuron-specific enolase - PVP therapy

INTRODUCTION

Undifferentiated carcinoma of the liver is extremely rare, and therapeutic methods for this disease in unresectable patients have not been established. We report here the case of a 54-year-old man with undifferentiated liver carcinoma characterized by a high serum level of neuron-specific enolase (NSE). He was treated with combined systemic chemotherapy, which produced a good tumor response.

CASE REPORT

A 54-year-old man suffered from epigastric pain and left back pain for four weeks. He was admitted to a local hospital complaining of these pains. Abdominal ultrasonography (US) and computed tomography (CT) revealed multiple liver tumors. He was referred to the National Cancer Center Hospital for a detailed examination of the liver tumors in November 1996. On physical examination, the liver edge was palpated two fingers below the costal margin. The surface of the liver was smooth, but rubber-like in consistency. He had a little tenderness in his right hypochondrium at the palpation. He was an occasional alcohol drinker, but had no history of heavy alcohol intake (ethanol intake [ge]80 g/day for [ge]5 years).

The laboratory results were as follows: erythrocyte count 428 × 104/mm3, hemoglobin 12.6 g/dl, white blood cells 13 000/mm3, platelets 33.6 × 104/mm3, total protein 7.9 g/dl, albumin 3.7 g/dl, total bilirubin 2.2 mg/dl, aspartate aminotransferase 123 IU/l, alanine aminotransferase 79 IU/l, [gamma]-glutamyl transpeptidase 1560 IU/l, alkaline phosphatase 1049 IU/l, lactase dehydrogenase 984 IU/l, carcinoembryonic antigen (CEA) 2.9 ng/ml, carbohydrate antigen 19-9 (CA 19-9) 40 U/ml, [alpha]-fetoprotein (AFP) 7.9 ng/ml, NSE 357 ng/ml (normal limits: [le]15 ng/ml), hepatitis B surface antigen (-), hepatitis B surface antibody (-), hepatitis C antibody (-).


Figure 1. Abdominal ultrasonography on admission. Multiple low- or high-echoic masses measuring from 1 to 3 cm in diameter were observed.
Figure 2. Abdominal CT on admission. (a) Plain CT. Multiple space-occupying lesions with low density were observed. (b) Enhanced CT (arterial phase). The lesions were not enhanced by contrast medium.

Figure 3. Histological features of the liver tumor. (a) A fine-needle aspiration biopsy specimen of the liver masses showed undifferentiated carcinoma growing in nests (H & E, original magnification ×100). (b) Solid nests are composed of small tumor cells with oval finely granular nuclei, inconspicuous nucleoli and scanty cytoplasm with ill-defined borders (H & E, original magnification ×400). (c) Intense cytoplasmic staining is present in almost all tumor cells (synaptophysin staining, original magnification ×400).


Figure 4. Abdominal CT after chemotherapy. (a) CT after one cycle. (b) CT after two cycles.


Figure 5. Clinical course of the patient.

US revealed multiple low- or high-echoic masses, measuring from 1 to 3 cm in diameter, in the swollen liver (Fig. 1). Intrahepatic bile ducts were not dilated. These masses were not enhanced by contrast medium in dynamic CT (Fig. 2). There was no abnormal finding in the gallbladder in the US and CT. A fine-needle aspiration biopsy specimen of the liver masses showed undifferentiated carcinoma growing in nests (Fig. 3). The tumor cells were relatively small, and had hyperchromatic oval nuclei and little cytoplasm. In the immunohistochemical study, the chromogranin A stain, AFP stain, CEA stain and CA 19-9 stain were negative, and the positivity for NSE stain was not clarified; only synaptophysin was positive (Fig. 3). Primary tumor sites other than the liver were not found through the physical examination, chest X-ray, upper gastrointestinal endoscopy and colonoscopy. We therefore diagnosed this patient as having undifferentiated carcinoma of the liver with neuroendocrine features.

He received combined systemic chemotherapy: etoposide 100 mg/m2/day for three days plus cisplatin 80 mg/m2/day on day one. This regimen was repeated every four weeks. It was tolerated well and was continued for four cycles. After the first course, a CT scan showed remarkable shrinkage of the multiple liver masses (Fig. 4). The NSE level was decreased to the normal range (12.4 ng/ml) 48 days after the beginning of the chemotherapy. According to the WHO criteria, the patient achieved a partial response, the duration of which was 7+ months. During chemotherapy, he experienced grade 3 leukocytopenia and grade 4 neutropenia, but he had no complications such as pneumonia. The hematological toxicities were transient and disappeared within two weeks after the chemotherapy, although the patient received a subcutaneous injection of granulocyte colony-stimulating factor. His erythrocytopenia was grade 3. Thrombocytopenia was not seen throughout the clinical course (Fig. 5). Grade 3 alopecia was seen when all four of the cycles were finished. No other severe non-hematological toxicities ([ge]grade 3) were seen. As of eight months after the initiation of the chemotherapy, the tumors were well controlled.

DISCUSSION

In this patient, the biopsy specimen of the liver tumor revealed the pattern of undifferentiated carcinoma with neuroendocrine features. Immunohistochemical study of the specimen showed immunoreactivity to synaptophysin, which is one of the endocrine markers (1). In addition, the serum level of NSE, another neuroendocrine marker, was high at diagnosis, although the positivity for NSE stain was not clarified on the immunohistochemical examination (1). We therefore diagnosed this patient as having undifferentiated carcinoma of the liver with neuroendocrine features.

Malignant neoplasms with neuroendocrine features have generally been classified as `neuroendocrine tumors' (2,3). The nature of neuroendocrine tumors is demonstrated by the histological appearance, positive argyrophil reaction and ultrastructural identification of neuroendocrine-type granules. Abnormal serum NSE and synaptophysin levels are regarded as additional evidence for neuroendocrine differentiation (1). Neuroendocrine tumors can be divided into two types: `neuroendocrine carcinoma', which shows highly malignant features such as high mitotic activity and nuclear polymorphism; and `carcinoids', the low-malignant counterpart, generally well differentiated, with minimal pleomorphism (2). With respect to primary liver neuroendocrine tumors, neuroendocrine carcinoma is extremely rare, and virtually all reports of them described carcinoids (4,5). However, because of the characteristic histological and immunohistochemical appearance of undifferentiated carcinoma, the tumor of our patient belonged to neuroendocrine carcinoma.

Moertel et al. (6) reported the results of chemotherapy for metastatic undifferentiated carcinoma with endocrine features. The chemotherapy consisted of etoposide and cisplatin (PVP therapy): the overall regression rate was 67% (12/18) and the median duration of regression was eight months. They concluded that this type of tumor was strongly responsive to PVP therapy. We treated our patient with the same regimen, resulting in a good clinical course.

In conclusion, primary liver cancer with neuroendocrine features is extremely rare. However, once the diagnosis of this disease is made, PVP therapy may be effective. Therefore, it is important to measure the serum levels of neuroendocrine markers and make a histological confirmation in patients suspected of having this disease.

Acknowledgment

This study was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan.

References

1. Erlandson RA, Nesland JM. Tumors of the endocrine/neuroendocrine system: an overview. Ultrastruct Pathol 1994;18:149-70. MEDLINE Abstract

2. Staren ED, Gould VE, Warren WH, Wool NL, Bines S, Baker J, et al. Neuroendocrine carcinomas of the colon and rectum: A clinicopathologic evaluation. Surgery 1988;104:1080-90. MEDLINE Abstract

3. Chejfec G, Falkmer S, Askensten U, Grimelius L, Gould VE. Neuroendocrine tumors of the gastrointestinal tract. Pathol Res Pract 1988;183:143-54. MEDLINE Abstract

4. Hsueh C, Tan XD, Gonzalez-Crussi F. Primary hepatic neuroendocrine carcinoma in a child. Cancer 1993;71:2660-5. MEDLINE Abstract

5. Yasoshima H, Uematsu K, Sakurai K, Ueno Y, Hori K, Kanazawa N, et al. Primary hepatic carcinoid tumor. Acta Pathol Jpn 1993;43:783-9. MEDLINE Abstract

6. Moertel CG, Kvols LK, O'Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 1991;68:227-32. MEDLINE Abstract

Received January 7, 1998; accepted March 23, 1998
For reprints and all correspondence: Shuichi Okada, Department of Internal Medicine, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104, Japan
Abbrevations: NSE, neuron-specific enolase; US, ultrasonography; CT, computed tomography; CEA, carcinoembryonic antigen; CA 19-9, carbohydrate antigen 19-9; AFP, [alpha]-fetoprotein; PVP, etoposide and cisplatin

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Last modification: 24 Jul 1998
Copyright©Japanese Journal of Clinical Oncology, 1998.
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