Neuroendocrine Tumorsof the Liver and Pancreas Associated With

CASE REPORT

Neuroendocrine Tumorsof the Liver and Pancreas Associated with Elevated Serum Prostatic Acid Phosphatase Yoshiyasu Kaneko, Noriko Motoi*, Atsushi Matsui, Torn Motoi*, Teruaki Oka*, Rikuo Machinami* and Kiyoshi Kurokawa

A58-year-old manwasrevealed to have multiple liver tumors with elevated prostatic acid phosphatase (PAP) during a medical examination. The tumors were ofneuroendocrine nature, but no abnormal findings were obtained in other organs in which neuroendocrine tumors develop frequently. Repeated transarterial embolization was partially effective. However, the tumors became resistant to the therapy three years later, continued growing and ruptured. Autopsy disclosed neuroendocrine tumors in the pancreas, which were immunohistologically positive for PAP. Neuroendocrine tumors of the pancreas and liver producing PAPare rare; this case is reported with a review of literature. (Internal Medicine 34: 886-891, 1995) Key words: carcinoid tumor, islet cell tumor, tumor marker, hepatoma

Introduction abdominal organs even with numerous diagnostic procedures including various imaging techniques and histological exami- Primary carcinoid tumor of the liver is extremely rare (1 , 2). nation of biopsy specimens. Autopsy disclosed multiple neu- The diagnosis of primary liver carcinoid is not simple, since roendocrine tumors in the pancreas which were immunohisto- histological examination of the biopsy specimen does not logically positive for PAP. With these results, however, it distinguish it from a metastatic tumor, and since the possible seemed difficult to determine whether it was the liver or presence of small primary carcinoids in other organs from pancreas tumor which was the primary tumor. Onthe other which liver metastasis occurs frequently cannot be ruled out hand, PAPproduction by a neuroendocrine tumor of the liver or completely (3-5). Primary liver carcinoid is considered to arise pancreas is considered to be very rare, and only a few cases have from neuroendocrine cells (Kulchitsky cells) of the intrahepatic been reported in whichislet cell tumors and insulomas are cholangioles and produces serotonin (3, 4). In addition to such shownto produce PAP(9-12). Here, we report this case with a typical carcinoids, hepatocellular carcinomas and hepato- review of literature on PAP-producing neuroendocrine tumors. blastomas rarely contain a carcinoid tumor component or show carcinoid features (6, 7). More intriguing are the primary Case Report hepatic tumors which do not show the morphology ofcarcinoids or apudoma, but nevertheless display neuroendocrine features A 58-year-old manwaspointed out to have multiple space revealed by immunohistochemical or ultrastructural studies occupying lesions (SOLs) in the liver during a medical exami- (8). Therefore, the differential diagnosis between primary car- nation six years previously. Tumors detected with abdominal cinoid tumorof the liver and hepatocellular carcinomawith ultrasonography were 4 and 2 cm in diameter (Fig. 1). Labora- carcinoid features is also not easy in somecases of liver tumors tory data were: aspartate aminotransferase (AST) 7 IU//, alanine with neuroendocrine features. aminotransferase (ALT) 5 IU//, y-glutamyl transpeptidase Recently, we treated a case of multiple liver tumors of (7GTP) 19 IU//, alkaline phosphatase (Alp) 5.8 KAU, ICG neuroendocrine nature which were associated with elevated 6.9%, HBsAg negative, a-fetoprotein (AFP) 2.2 ng/ml, car- serum prostatic acid phosphatase (PAP). The liver tumor was cinoembryonic antigen (CEA) 0.8 ng/ml, CA19-9 10 U/ml, and initially thought to be a metastatic carcinoid, but no abnormal PAP 5. 1 ng/ml (normal <2. 1 ng/ml). Histological examination findings were obtained in prostate, rectum and other intra- of biopsy specimen disclosed carcinoid features, but 5-hydroxy From the First Department of Medicine and *the Department of Pathology, Faculty of Medicine, University of Tokyo, Tokyo Received for publication December 13, 1994; Accepted for publication May 31, 1995 Reprint requests should be addressed to Dr. Yoshiyasu Kaneko, the First Department of Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 1 13

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indol acetic acid (5-HIAA) was 1.9 ng/day (normal 0.8-4.5) and symptoms and signs suggestive of excessive serotonin production were not observed. Prostate, colon and rectum gave no histological evidence of malignancy. Computerlized tomog- raphy (CT), magnetic resonance imaging (MRI), galium-scintigraphy and 1 23I-metaiodobenzylguanidine (MIBG) scintigraphy gave no abnormal findings in other organs. Angiography disclosed multiple hypervascular liver tumors and transarterial embolization (TAE) using 1.5 ml lipiodol, 20 mg adriamycin, and spongel was carried out. The follow-up CT confirmed lipiodol uptake by the tumor (Fig. 2). The number and size of liver tumors analyzed by ultrasonography, CTand angiography decreased significantly (photographs, not shown), and PAP decreased from 5.4 to 3.3 ng/ml (Fig. 3). Then, close surveil- lance with ultrasonography and CT was instituted, and TAE was repeated on tumor recurrence (Fig. 3). The therapeutic effects well correlated with decreases in serum PAP(Fig. 3). Figure 1. Abdominal ultrasonography taken at the first Serum level of serotonin and gastrin four years earlier was 0.27 admission six years ago. Space-occupying lesions (SOLs) jig/ml (normal <0.25) and 54.5 pg/ml (normal 30-150), respec- were observed as indicated by arrows. A) SOL 2 cm in tively. Urine 5-HIAA was 3. 1 ng/day. Three years previously, diameter. B) SOL4 cm in diameter. bone pain appeared, and bone scintigraphy disclosed multiple metastasis to vertebraes and ribs. Two years previously, transarterial injection (TAI) using lipiodol and adriamycin was performed because no feeding arteries were accessible. The TAIwasnot effective and the size and numberof liver tumors increased in parallel with the serum levels of PAP(Fig. 3). Prostate-specific antigen (PSA) was 1.3 ng/ml (normal <3.0). One year earlier, PAPwas elevated to 642 ng/ml, while PSA was 1.7 ng/ml. Six months previously, he became drowsy and flapping tremor appeared. Blood counts were; red blood cell (RBC) 279xlO4/jnl hemoglobin (Hb) 7.9 g/dl, white blood cell

TAE TAI 1,000- UJ »* »» * *^^ 500 - ^*^*^ PAP 100 - /*^ (ng/ml) 50 " TV

1,000 - /^ Alp 500- X /T ^^'r^/ ^

Figure 2. Abdominal angiography and CT taken (IU/ 10I/) 1 W 1 1 1 1 1 1 at the first admission six years ago. A) Hepatic arteri- '87 '88 '89 '90 '91 '92 '93 ography before the transarterial embolization (TAE), showing multiple tumor staining. B) Follow-up CT after the first TAE, showing lipiodol uptake by the main tumor (arrow). Figure 3. Clinial course showing the effects ofTAE and TAI on serum prostatic acid phosphatase (PAP) (upper) and Alp and YGTP(lower).

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(WBC) 6,900/nl, and platelet 35.9xlO4/ml. Total protein (TP) neuron specific enolase (NSE) and chromogranin A (Fig. 5). was 6.5 g/dl, while albumin (Alb) was 2.3 g/dl. Serum globulin PAPwas positively stained as shown in Fig. 5C. However, was increased, but electrophoresis of patient's serum gave no insulin, glucagon, somatostatin, pancreatic polypeptide, va- findings suggestive of the presence of myelomaprotein. Other soactive intestinal peptide (VIP), gastrin and serotonin were laboratory data were; AST 36 IU//, ALT 22 IU//, lactate undetectable. By electron microscopy, numerous uniform, dehydrogenase (LDH) 160 IU//, 7GTP 337 IU//, Alp 2,000 U/ membranebounded, electron-dense granules, measuring about / (normal 74-223), total bilirubin (T.Bil) 1.0 mg/dl, amylase 200-300 nmin diameter were found in the cytoplasm (photo- 444 U/dl (normal 60-190), blood urea nitrogen (BUN) 32 mg/ graphs, not shown). The liver (6,400 g) was markedly enlarged, dl, creatinine 1.2 mg/dl, corrected calcium (cCa) 9.5 mg/dl, with numerous tumor nodules, measuring up to 8x6 cmin size inorganic phosphate 3.8 mg/dl, glucose 165 mg/dl, Fe 37 |Ug/dl, (Fig. 4). The immunohistochemical nature of the tumor cells HCVAb negative, PAP 709 U//, serum NH3 200 jig/dl. One was similar to that of the pancreas (Fig. 6). Metastatic vertebrae week earlier, pneumonia was recognized and respiratory and tumors (LI to L5) were osteoblastic. Tumornodules up to 5 mm cardiac arrest occurred, likely due to airway obstruction. On autopsy, several tumors, measuring up to 2 cm in diameter, were recognized in the body and tail of the pancreas (Fig. 4). Tumor cells, which had abundant eosinophilic and granular cytoplasm and relatively uniform oval nuclei, were arranged in trabecular structure. These cells were positively stained by Grimelius method, and were immunohistologically positive for

Figure 4. Macroscopic appearance of autopsy materials. Multiple tumors are seen in the pancreas and the liver. A) the Figure 5. Histological and immunohistochemical study of pancreas; B) sliced surface of the pancreas; C) cut surface of the the tumor of the pancreas. A) HE stain (xl70); B) Grimelius liver. Scale bars, 3 cm. staining (xlTO); C) PAP (xl70).

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The incidence of primary liver carcinoid is very low, and as far as we know, only 22 cases have been reported (4, 13-21). The incidence of the primary liver cancer metastasizing to the pancreas is also very low (22). In contrast, carcinoid tumors of the intraabdominal cavity with liver metastasis are occasionally seen (23, 24). From these statistic data, the possibility that a neuroendocrine tumor had developed in the pancreas and then metastasized to the liver and other organs appears to be high. However, the incidence of primary liver tumor with carcinoid features maybe higher than expected, and the metastasis of hepatocellular carcinoma to the gastrointestinal tract and pancreas is rarely seen (6-8, 22). In the present case, a pancreas tumor wasnot found whenliver tumors were recognized. In addition, extensivemetastaseswerefoundin various organson autopsy. Therefore, the possibility that the neuroendocrine tumor had originated from the liver and then metastasized to various organs including pancreas cannot be ruled out completely. Tumorcells of the present case which were stained positive for NSEand chromogranin A had neuro-secretory granules (2, 17). However, peptide hormones such as insulin, glucagon and gastrin were not detected in the tumor cells. 5-HIAAand serotonin were not significantly increased and symptomsand signs of carcinoid syndromewere not seen (25). In contrast, PAP was immunohistologically stained, indicating that PAP production by the neuroendocrine tumors of the pancreas and the liver was the cause of markedly elevated serum PAP(Figs. 3 and 5) (26-28). PAP production by neuroendocrine tumors reported in the past literature is summarized in Table 1 (29, 30). PAPproduction is rare in carcinoid tumors of the stomach which are offoregut origin; it is seen in approximately 10-20% of carcinoid tumors of the small intestine which are of midgut origin, and is frequent in the carcinoid tumors of the rectum which are ofhindgut origin (9, 12). As far as we know, PAP production has not been reported in primary liver carcinoid and in non-endocrine apudoma of the pancreas (3, 10, 23, 28). In contrast, PAPproduction has been reported in two cases of islet cell tumor of the pancreas, insuloma and in occasional cells in Figure 6. Histological and immunohistochemical study of normal Langerhans islets ( 1 2-14). Therefore, if the primary site the tumor of the liver. A) HEstain (x226); B) Grimelius (xl70); of the PAP-producing neuroendocrine tumor in the present case C) Chromogranin A (xl70). was the pancreas, the tumor cells mayhave originated from insulin-producing cells, occasional cells of normal Langerhans islets or their ancestral cells (12, 29, 31). PAPis a sensitive but not a specific marker of prostatic in diameter were seen in the bilateral lungs. Theperipancreatic, carcinoma (12, 32), and high serum PAP associated with hepatic hilar, and left inguinal lymph nodes were conglomer- normal PSAis characteristic of neuroendocrine tumors of non- ated and formed tumors of up to 3 cm in diameter. No tumors prostate origin (9). Whether PAPproduction is one of the were found in the prostate, which showed stromal and glandular characteristics of islet cell tumors is of interest, since measuring hyperplasia. No abnormal findings were obtained in the serum PAPmay be useful for the differential diagnosis. Early gastrointestinal tract including duodenum,appendix, and rec- diagnosis of non-functioning pancreas tumors is very difficult tum. even with CT, MRIand endoscopic ultrasonography (33). Localization of islet cell tumors by catheterization of the Discussion pancreatic vein or with radioiodinated analogues of somatostatin maynot be applicable to all of the patients suspected of In the present case multiple neuroendocrinetumorswere neuroendocrine tumors (34, 35). In contrast, measurement of found in the liver and pancreas, lung, bone, and lymph nodes. serum PAPis a routine clinical test which can be applicable to

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Table 1. Neuroendocrine Tumors Producing Prostatic Acid Phosphatase (PAP) Neuroendocrine tumor PAP-positive/total (%) References

Foregut Pancreas Islet cell tumor1} 1/1 (100%) Mick 1972 (13) Islet cell tumor1} 1/1 (100%) Choe 1978 (14) Insuloma 6/10 (60%) Jobsis 1981 (12) Non-endocrine apudoma 0/3 (0%) Fishleder 198 1 (28) Stomach 1/13 (8%) Sobin 1986 (9) Midgut Liver NS2)/6 (?) Andreola 1990 (3) 0/2 (0%) Azumi 1991 (10) Small intestine 1/10 (10%) Jobsis 1981 (12) 4/31 (12.9%) Sobin 1986 (9) Colon 2/8 (25%) Sobin 1986 (9) Appendix 5/25 (19%) Sobin 1986 (9) Ovary 5/53) (100%) Sidhu 1993 (29) Hindgut Rectum 29/35 (82%) Federspiel 1990(30) 16/24 (66%) Sobin 1986 (9) Prostate 1/1 (100%) Azumi 1984 (26) Others Lung 0/16 (0%) Azumi 1991 (10)

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