□ CASE REPORT □

Primary Hepatic Tumor with and Carcinoid Heart Disease: A Case Report of a Patient on Long-Term Follow-up

Tatsuhiko TOHYAMA, Kazuhiro MATSUI* and Kiyohide KITAGAWA**

Abstract PHCT (5). When PHCT is confined to a single lobe, surgical resection should be taken into consideration. Otherwise, We report a 57-year-old woman with a primary he- transarterial (TAE) might be effective for some patic carcinoid tumor who had been suffering from cases (1, 5). For unresectable PHCT, acetate symptoms due to carcinoid syndrome and carcinoid heart (OA), a analogue, has been used to prevent disease for more than 9 years. Long-term injection of various symptoms derived from carcinoid (6–8). octreotide acetate was fairly effective to relieve the symp- This report refers to a case of PHCT that showed severe toms due to carcinoid syndrome, but its tumor contrac- attacks of carcinoid syndrome at the onset of the disease and tion effect was not confirmed. The massive ascites in the cardiac insufficiency due to CHD in the latter stage. follow-up period appeared to be diminished to a certain Continuous treatment with OA was fairly effective in reliev- extent by timely including cisplatin. The ing the symptoms, which reappeared frequently for more patient died of multi-organ failure about 9 years after the than 9 years. onset of disease. Autopsy confirmed a primary hepatic carcinoid tumor with limited distant metastases. Clinical Summary (Internal Medicine 44: 958–962, 2005) A 51-year-old woman visited our clinic in June 1994, be- Key words: primary hepatic carcinoid tumor, carcinoid heart cause of paroxysmal in the face and extremities for disease, carcinoid syndrome, octreotide acetate, two years, severe watery for one year, and bouts of carcinoid tumor, primary hepatic epigastric pain appearing for no specific reason. On the first medical examination, flushing was observed in extensive areas of the skin including her face; no cardiac murmurs were audible; was palpable in the epigastric Introduction region. The essential laboratory data recorded on her first ad- mission are shown in the left columns of Table 1. The Carcinoid tumors seldom occur primarily in the liver, al- function tests were within normal limits, except for a slight though extrahepatic counterparts, especially those in the gas- increase of total bilirubin. The serum levels of and trointestinal tract, are common. The rarity of primary hepatic urinary 5-hydroxyindoleacetic acid (5-HIAA) were markedly carcinoid tumor (PHCT) makes it difficult for clinicians to increased. The level of human antinatriuretic peptide diagnose it precisely, which is not until autopsy ascertains (HANP) showed a slight increase. Computed tomography PHCT (1). Since carcinoid tumors frequently show an indo- (CT) revealed a hypervascular tumor, measuring 182.4 cm3 lent clinical course, clinicians have to confront various com- in volume, in the right superior segment of the liver, and plications such as carcinoid syndrome and carcinoid heart daughter nodules up to 1 cm in diameter scattered in the bi- disease (CHD) during a long-term follow-up period. CHD is lateral lobes (Fig. 1A). Histological examination of the bi- one of the common complications of carcinoid tumor (2–4), opsy specimens from the main tumor revealed a carcinoid whereas carcinoid syndrome is seldom present at the onset of tumor. The primary site was radiologically investigated

From the Department of Internal Medicine, Kohryo Clinic, Takaoka, *the Department of Legal Medicine, Toyama Medical and Pharmaceutical University, Toyama and **the Department of Radiology, Takaoka Kohseiren Hospital, Takaoka Received for publication September 16, 2004; Accepted for publication May 11, 2005 Reprint requests should be addressed to Dr. Tatsuhiko Tohyama, the Department of Internal Medicine, Kohryo Clinic, 23-1 Nomura, Takaoka, Toyama 933-0014

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Table 1. Laboratory Results in Early and Late Stage: December 1994 and June 2001

December 1994 June 2001 normal range

Hemoglobin 12.6 10.2 12–16 g/dl Erythrocyte sediment rate 6 90 3–8 mm/h AST/ALT 13/8 125/54 12–31/8–40 IU/l 120 7,460 100–330 IU/l Total bilirubin 1.25 5.2 0.22–1.20 mg/dl Creatinine 0.9 1.3 0.2–0.8 mg/dl Serotonin 143.0 139.2 10–20 mcg/dl Urinary 5-HIAA 97.9 82.1 0.5–5.0 mg/day HANP 97.0 – <43 pg/ml Plasma renin activity 0.5 – 0.1–2.0 ng/ml/h Plasma aldosterone 8.2 – 3.6–24 ng/dl

AST: aspartate aminotransferase, ALT: alanine aminotransferase, Urinary 5-HIAA: urinary 5-hydoxyin- doleacetic acid, HANP: human antinatriuretic peptide.

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Figure 1. Computed tomography (CT) of the liver. (A). The CT image in December 1994 shows a hypervascular tumor with a volume of 182.4 cm3 in the right upper segment. (B). The CT image in February 2001 reveals not only the main tumor but also numerous daughter tumors in the bilateral lobe (total volume of the tumors, 450 cm3).

throughout the systemic organs, including the gastro-intesti- patient suffered from so-called “carcinoid peritonitis”, char- nal tract and pulmonary system, but no lesions other than the acterized by massive ascites due to implantation of carcinoid liver tumors were discovered. cells in the . Ascites was accompanied by hemor- The clinical course of the patient is summarized in sche- rhage and a cell count of 304/l. The cells consisted of lym- matic diagram (Fig. 2). Briefly, hormonal therapy with a phocytes (52%) and carcinoid cells (46%). On this occasion, somatostatin analogue, octreotide acetate (OA), was begun at the ascites was controlled with intraperitoneal infusion ther- an initial dose of 50 to 100 mcg day, since the patient refused apy of cisplatin. One year before death, her liver function . Shortly after the commencement of therapy, the gradually worsened with flushing attacks and she had symptoms such as flushing and diarrhea appeared to be im- marked edema of the lower limbs. However, the serum level proving and the serum level of serotonin and urinary 5- of serotonin and urinary 5HIAA remained unchanged (see HIAA decreased. One year later, however, her symptoms the right columns of Table 1). The hepatic main tumor en- relating to the carcinoid syndrome were accelerated again. larged to two and half times of the initial size ( Gradual OA dose escalation to 400–600 mcg day relieved volume by CT-image analyses, 450 cm3 ), and numerous these symptoms. Six years after onset of the disease, the intrahepatic metastases were detected in the bilateral lobe

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Figure 2. Schematic diagram of the clinical course.

(Fig. 1B). On the other hand, a two-dimensional echocardi- ography showed remarkable dilatation of the right ventricu- lar chamber and subsequent compression of the left ventri- cular chamber with paradoxical motion of the interventri- cular septum. Thus, the patient died of multi-organ failure in July 2001, about 9 years after the onset of disease.

Pathological Findings

The liver measured 18×15×12 cm and weighed 1,520 g. The cut surfaces of the liver revealed a massive10 cm- diameter tumor in the right lobe and several daughter tumors of up to 3 cm in diameter in the bilateral lobes. The main tumor was light-gray to yellowish in color with extensive ne- crosis and focal hemorrhage (Fig. 3). Metastatic tumors were not discovered in the lung but observed in the vertebral bones, including the thoracic and lumbar vertebrae. Detailed macroscopic investigation did not show any tumors in the other organs including the gastro-intestinal tract. Figure 3. Macroscopic findings of the liver. The cut surface re- The right atrium and ventricle of the heart were markedly veals the main tumor in the right lobe and several daughter tu- dilated with patchy thickening of the endocardium, and the mors in the bilateral lobe. tricuspid and pulmonary arterial valves were remarkably hypertrophic with fibrous thickening, which caused valvular stenosis and regurgitation (Fig. 4). The lower lobe of the left Microscopic findings lung was atelectatic with diffuse fibrinous pneumonia. There The main tumor and satellite lesions of the liver were were no infectious foci in the other organs. composed of round and columnar cells with a uniform round

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Figure 4. Horizontal cut surface of the heart. The right-sided chambers were markedly dilated. Note patchy or diffuse fibrous thickening of the tricuspid valve and endocardium. nucleus in a pale eosinophilic cytoplasm. Mitotic figures were very rare (0–1/10 HPF). The cells were arranged in nests and trabeculae, with fibrous septa in some location (Figs. 5A and 5B). An organoid pattern was also observed in some areas. The main tumor had extensive necrosis, which appeared to be caused partly by chemotherapy during the clinical course and chiefly by circulatory insufficiency at the terminal stage. Argyrophilic granules of varying stainability in tumor cells were demonstrated by Grimelius stain. Based Ｂ on these histological features, the liver tumors were diag- nosed as (typical) carcinoid tumors according to the criteria proposed by the WHO (9). The metastatic tumors in the ver- tebral bones and lymph nodes of the mesenterium showed the histological features similar to those of the liver tumors. The representative tissue sections of 4 m-thickness were cut from the tissue blocks for immunohistochemistry. Im- munohistochemical staining for pan-cytokeratin (AE1/AE3, Boehringer, Manheim, Germany; dilution, 1 : 200), chromo- granin A (DAKO, Kyoto, Japan; dilution, 1 : 100) (Fig. 5C) and CD56 (NOVO, Clayton, NC; dilution, 1 : 50) were dif- fusely and strongly positive in most of the tumor cells. Synaptophysin (DAKO, Kyoto, Japan; dilution, 1 : 100) was expressed in some of the tumor cells. Staining for somato- statin (DAKO, Kyoto, Japan; dilution, 1 : 100) and serotonin (DAKO, Kyoto, Japan; dilution, 1 : 100) was negative or Ｃ equivocally positive in the tumor cells. Figure 5. Microscopic findings of the liver tumor. (A). A low- The endocardium of the right ventricle showed fibrous power microphotograph shows a cellular tumor without con- thickening with myxoid degeneration in part. The pulmonary spicuous necrosis in the liver (HE, ×200). (B). A high-power and tricuspid valves also showed marked thickening with an microphotograph shows tumor cells with uniform cytologic fea- increase of collagenous fiber. tures, arranged in nests and trabeculae (HE, ×400). (C). Immunohistochemical reactivity for chromogranin A is diffuse and intense in many tumor cells (peroxidase methods with Mayer’s hematoxylin counterstain (×250).

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Discussion aggravate CHD. In the present case, a high value of serum HANP was detected even in the early period of the clinical The present case is clinically instructive on the following course. Nevertheless, CHD did not cause a serious change of points; 1) carcinoid syndrome caused by PHCT could be cardiac insufficiency until the terminal stage, which may be controlled by continuous administration of octreotide acetate due, to a large extent, to the effectiveness of OA. To our (OA) over a prolonged period; 2) intraperitoneal injection knowledge, there are no records on peritoneal involvement therapy with cisplatin was effective, to a certain extent, in of carcinoid tumor. Timely intraperitoneal infusion with controlling intractable massive ascites; and 3) serious cardiac cisplatin was useful in relieving massive ascites, although it insufficiency resulted from carcinoid heart disease (CHD) at remains controversial whether cisplatin is effective for carci- the terminal stage. In addition, PHCT of the present case was noid tumors (6, 13). an extremely rare example in that it was accompanied by In summary, we reported a unique case of PHCT. carcinoid syndrome even at the early stage of the disease (5). Conservative but careful clinical treatment with continuous Carcinoid tumors can originate from the neuroendocrine sys- injection of OA and targeted chemotherapy for “carcinoid tem, which is distributed throughout the body including the peritonitis” with cisplatin might have a beneficial effect on biliary tree of the liver. These tumors are most frequently the quality of life and recuperation over a long follow-up. found in the , and next most frequently in the lung (10, 11). It is difficult to diagnose PHCT pre- References cisely even on careful investigation, because the liver is a fa- vorite metastatic site for carcinoid tumors. In their review, 1) Sano K, Kosuge T, Yamamoto J, et al. 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An analysis of 2,837 cases. 36:560–569, 1975. argyrophilic granules and were immunohistochemically posi- 11) Lips CJ, Lentjes EG, Höppener JW. The spectrum of carcinoid tumours tive for neuroendocrine markers including chromogranin A and carcinoid syndrome. Ann Clin Biochem 40: 612–627, 2003. and synaptophysin. 12) Zuetenhorst JM, Bonfrer JM, Korse CM, Bakkec R, van Tinteren H, CHD is one of the most problematic complications caused Taal BG. Carcinoid heart disease: The role of urinary 5-hydroxy- by carcinoid tumors. The incidence of CHD in patients with indoleacetic acid excretion and plasma levels of atrial natriuretic pep- tide, transforming growth factor-and fibroblast growth factor. Cancer primary or metastatic carcinoid tumors ranges from 20 to 97:1609–1615, 2003. 70% (2, 12). Serotonin released from carcinoid tumor has a 13) Moertel CG, Kvols LK, O’Connell MJ, Rubin J. 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