Diazoxide

A coexisting of intraductal papillary mucinous hyperplasia (IPMH) and islet cell tumor with nesidioblastosis of the pancreas in a 51-year-old man is reported. All of the clinical data indicated an insulinoma. A distal pancreatectomy was performed. A discrete mass measuring 1.9 x 2.0 cm was grossly identified in the tail of the pancreas. There were no other gross lesions. An islet cell tumor with nesidioblastosis was confirmed by immunostains and ultrastructural study. In addition, an IPMH was found that involved mainly branches of the pancreatic duct. The islet cell tumor and IPMH were topographically separated; however, there was a histologically intimate relationship between the nesidioblastosis and the IPMH. These findings indicate that the IPMH may have derived from autocrine and paracrine influences on the existing duct epithelial cells. To the best of our knowledge, this is the first report of nesidioblastosis coexisting with islet cell tumor and IPMH.

(Arch Pathol Lab Med. 2001;125:1344-1347)

Mixed exocrine (ductal and acinar tumors) and endocrine (islet cell tumor) tumors of the pancreas are rare. Scattered endocrine cells have been reported to be present in exocrine pancreatic carcinomas, including ductal, mucinous cystic, and acinar cell carcinomas.1

Intraductal papillary mucinous tumor (IPMT) of the pancreas is a rare and unique form of pancreatic neoplasm characterized by proliferation of the epithelium lining the pancreatic ducts. This intraductal proliferation produces a variable amount of mucin that causes dilation of the main pancreatic duct or its major branches. Four cases of mucinsecreting pancreatic cancer were first reported in 1982. 2 Since then, an increasing number of IPMTs of the pancreas have been reported.3 Although this tumor usually shows a slow evolution and a low malignancy rate, all gradations-from benign-appearing epithelium to in situ or invasive carcinoma-may be encountered 4 Chronic pancreatitis and/or ductal epithelial papillary hyperplasia may play a role in the pathogenesis of this tumor. A diverse spectrum of intraductal epithelial changes (ie, nonpapillary hyperplasia, papillary hyperplasia, atypical hyperplasia/severe dysplasia) has been described around invasive pancreatic carcinomas.5 Mucinous cell hyperplasia has been reported to be the most important precursor in the histogenesis of human pancreatic duct carcinoma.6 In addition, endocrine cells have rarely been reported in IPMT.7

Nesidioblastosis is a hyperfunctional disorder of pancreatic insulin-producing cells characterized by hypertrophic beta cells within enlarged or normal-appearing islets, small scattered endocrine cell clusters, and ductuloinsular complexes. This condition is the most common cause of persistent neonatal hypoglycemia, but it is exceedingly rare in adults.6 A spectrum of proliferation from nesidioblastosis to islet cell hyperplasia to multiple adenomas to metastases has previously been reported.8

Herein we report an extremely rare case of a combination intraductal papillary mucinous hyperplasia (IPMH) and endocrine neoplasm (islet cell tumor) of the pancreas. The islet cell tumors appeared closely related to nesidioblastosis. In addition, a close relationship between endocrine cells and the IPMH is identified. To the best of our knowledge, this is the first case report of topographically separated endocrine and exocrine tumors coexisting with nesidioblastosis. Coexistence of endocrine and exocrine tumors of the pancreas with nesidioblastosis is of particular interest because of the direct implication as to the origin and histogenesis of pancreatic endocrine cells and the relationship between endocrine and exocrine cells.

REPORT OF A CASE

The patient was a 51-year-old white man with a history of chronic undifferentiated paranoid schizophrenia who presented with a 2-year history of hypoglycemia and hyperinsulinemia at Harbor-UCLA Medical Center on November 1, 1998. He had been found to have low blood sugars (1.6-2.2 mmol/L) and was relatively asymptomatic, but he had reported weight loss of approximately 27 kg over the previous 4 years and also 2 episodes of syncope over the previous several months. A significant family history included a mother with breast and colon cancers and a maternal aunt with breast cancer. The patient's physical examination was unremarkable except for his mental status exam, which was consistent with paranoid schizophrenia. The lab results were as follows: glucose, 1.9 to 3.1 mmol/L; insulin fasting, 573.7 pmol/L (normal, 34.7 to 173.6 pmol/L); and C peptide fasting, 0.4 nmol/L (normal, 0.3 to 1.3 nmol/L). He underwent a 72hour fast on December 5, 1998. The test was terminated early secondary to symptomatic hypoglycemia. Glucose measurements through the fast ranged between 1.9 and 2.4 mmol/L. Fasting insulin levels ranged between 208.4 and 368.1 pmol/L, with C peptides of 0.6 to 0.8 nmol/L. An endoscopic ultrasound was done on December 16, 1998, and showed a 1.5 x 0.9-cm hypoechoic tumor with a few tiny echogenic areas in the pancreatic tail. The patient was diagnosed as having an insulinoma. He was well controlled on diazoxide 100 mg taken orally 3 times per day.

The patient was admitted on May 26, 1999, for an exploratory laparotomy and enucleation of insulinoma or possible distal pancreatectomy. During the procedure, a mass of approximately 1.5 cm in size was palpated in the tail of the pancreas. An intraoperative ultrasound confirmed the presence of a solitary mass. An islet cell tumor was confirmed by frozen section. Because of the presence of the IPMH that was identified at the margins of the resected specimen, a distal pancreatectomy was performed. The patient tolerated the procedure well. Postoperatively, the patients hyperglycemia was controlled with insulin administered every 4 hours using sliding-scale coverage. The patient suffered a Klebsiella pneumonia on the seventh postoperative day and was treated with antibiotics. Subsequently he tolerated a regular diet without difficulty. The patient was discharged on June 21, 1999, with a small postoperative pseudocyst of the pancreas confirmed by computed tomographic scan.

On July 2, 1999, the patient was readmitted with a history of fever without nausea or vomiting. There was no evidence of pneumonia or other infections. A computed tomographic scan of the abdomen showed the remaining pancreas to be edematous in its entirety with persistence of the pseudocyst. The patient was treated with antibiotics and was discharged on July 7, 1999, without an insulin prescription. A subsequent outpatient computed tomographic scan showed resolution of the pseudocyst. The patient was contacted recently and was stable and asymptomatic.

MATERIALS AND METHODS

All surgical tissues were fixed in 10% formalin and were routinely processed for paraffin embedding except for 1-mm cubes of tumor, which were processed in glutaraldehyde for electron microscopy. Multiple 6-(mu)m sections were stained with hematoxylin-eosin, Alcian blue/periodic acid-Schiff, mucicarmin, Fontana, and Congo red. Immunocytochemistry was performed by the streptavidin-biotin-peroxidase complex (streptavidin-biotinylated horseradish peroxidase, Dako Corporation, Carpinteria, Calif). The primary antibodies used included the following: CAM 5.2 (prediluted, Becton Dickinson, San Jose, Calif); CA 19-9 (1: 200, Dako); carcinoembryonic antigen (1:1600, Dako); Ki-67 (monoclonal, 1:50, Zymed Lab, Inc, San Francisco, Calif); p53 (1: 100, Dako); chromogranin A (monoclonal, 1:200, Dako); synaptophysin (1:80, Dako); glucagon (prediluted, Dako); insulin (prediluted, Dako); gastrin (polyclonal, 1:1000, Dako); somatostatin (prediluted, Dako); pancreatic polypeptide (1:10, BioGenex, San Ramon, Calif); Amylin (1:200, Accurate Chemical & Scientific Corporation, Westbury, NY).

Tissue for electron microscopic examination was fixed in 2.5% glutaraldehyde and postfixed in osmium tetroxide. The tissue was embedded in Epon, and ultrathin sections were cut using a Porter-Blum MT2-B ultramicrotome (LKB Instruments, Inc, Rockville, Md). The sections were stained with uranyl acetate and lead citrate and were examined using a Hitachi H-600 electron microscope (Hitachi Ltd, Tokyo, Japan).

PATHOLOGIC FINDINGS

Gross Pathologic Findings

The specimen consisted of one irregular fragment of hemorrhagic, red-tan soft tissue and a separated segment of pancreas (tail portion) with surrounding fibroadipose tissue. The cut surface of the irregular fragment revealed a well-circumscribed nodular lesion that measured 1.9 x 2.0 cm and showed a gray, soft, and homogeneous cut surface. The separated segment of pancreas measured 13 x 6 x 3 cm. On cross-sectioning, no grossly visible tumor was identified in the second specimen. The pancreatic duct and main branches were patent and grossly unremarkable.

Light Microscopic Findings

Sections of pancreas tissue showed an islet cell tumor and surrounding adjacent IPMH. The islet cell tumor grew in a nodular pattern and was surrounded by fibrotic stroma. The tumor consisted of nests, islands, and solid sheets of neoplastic cells with intervening amylin-staining-positive stroma. Focally, islet cells and ductules were intermixed (Figure 1). At the edge, the islet cell tumor infiltrated into acinar tissue as nests that could be differentiated from the islets. The neoplastic cells were relatively uniform, with round to irregular nuclei and abundant clear or eosinophilic cytoplasm (Figure 1). Mitoses were very difficult to find. The neoplastic cells stained positive only for synaptophysin (Table). The proliferation index was moderate by Ki-67 immunohistochemistry stain. In addition to the nodular islet cell tumor, a significant increase in islets was found throughout the specimen. These islets were variable in size and irregularly distributed in the acinar tissue and interlobular stroma. These hyperplastic islets revealed different immunohistochemistry stain patterns compared to the islet cell tumor (Table). Multifocal distributions of periductuloinsular complexes and peri-IPMH of the islets were evident (Figures 2 and 3).

The IPMH displayed an intraductal growth pattern. The walls of the ducts were lined by mucin-producing epithelial cells (Figure 3). The tumor cells were tall and columnar, with basally located flat or round vesicular nuclei and abundant pale to light pink mucinous cytoplasm. Foci of epithelial pseudostratification, stratification, and papillary configuration were present. Focal intraductal mucinous accumulation was found. In addition, a focus of microinvasion with desmoplastic stromal reaction was noted. The IPMHs were multifocal. They did not involve the main pancreatic duct at the surgical margin. Interestingly, the IPMH surrounded and formed an intercepted wreath around the islet cell tumor capsular tissue (Figures 4 and 5). In addition, multiple islets were found next to the IPMH (Figure 2). The immunohistochemistry stains revealed that the hyperplastic cells were positive for CAM 5.2, carcinoembryonic antigen, and CA 19-9 (Table). In addition, they were strongly positive in Alcian blue/periodic acid-Schiff stain.

Electronic Microscopic Findings

Electron microscopy on the mixed ductal and endocrine tumor showed the neoplastic islet cell to contain abundant free ribosomes and moderate amounts of rough endoplasmic reticulum. Several neuroendocrine granules within scattered endocrine tumor cells were present. The neuroendocrine granular cells did not show the typical morphologic features of insulin granules (Figure 6).

COMMENT

Traditionally, the exocrine and endocrine components of the pancreas have been viewed as distinct morphologically, embryologically, and functionally, to the extent that most authors have addressed only one component or the other. However, it is now clear that both exocrine and endocrine elements of the pancreas have a common embryologic origin, and there has been a growing awareness that endocrine cells do participate in exocrine neoplasms, both in the pancreas and in many other organs. These mixed "endocrine-exocrine" tumors are of great pathologic interest because of their histogenetic implications.7 However, all of the previously reported mixed tumors have been topographically mixed tumors, ie, involving both endocrine and exocrine components in a single neoplasm. It is possible that these exocrine and endocrine tumor cells arise from ductuloinsular complexes that are normal developmental structures. In the present report, the IPMH and islet cell tumors were topographically separated, but the islet cell tumor had a ductule component. In addition, diffuse (multifocal) islet cell hyperplasia, ie, nesidioblastosis coexisting with a discrete islet cell tumor, is also uncommon.

In adults, hyperinsulinemic hypoglycemia is usually caused by an insulinoma. In the present case, however, the cells of the islet cell tumor stained positive only for synaptophysin and did not have the features of insulin granules by electron microscopy. Therefore, the clinical symptoms of hypoglycemia and the hyperinsulinemia of the patient in the present case could not have been caused by the islet cell tumor. In other words, this islet cell tumor was a nonfunctional tumor. Therefore, the hyperinsulinemic hypoglycemia of this patient may have resulted from the nesidioblastosis that coexisted with the islet cell tumor in this patient. The discrete islet cell tumor could represent a neoplastic transformation of a focal islet cell hyperplasia. It has been reported that islet cell proliferation can be localized, resulting in a pancreatic adenoma and even in a spectrum of proliferation ranging from nesidioblastosis, islet cell hyperplasia, and multiple adenomas to malignancy and metastases.8 Therefore, a neoplastic transformation with a loss of function is a reasonable explanation for the islet cell tumor in the present case. In addition, the presence of the ductular component in the islet cell tumor supports the theory that the endocrine cells originated from the ductal component.7

Although the intraductal papillary mucinous changes (the IPMHs) in the present case do not meet the diagnostic criteria of IPMT because of the lack of dilatation of the main pancreatic ducts, the IPMH may represent an early stage or a precursor lesion of IPMT. The IPMH coexisted with the islet cell tumor but was topographically separated from it and involved the entire specimen submitted. It is interesting to speculate that there is a relationship between the IPMH and the islet cell tumor or nesidioblastosis, or, more likely, the IPMH may have derived from autocrine and paracrine influences on the existing duct epithelial cells. The theory of islet cell proliferation from ductal cells has been used for decades.8 Scattered endocrine cells have been reported to be present in exocrine pancreatic carcinoma, including ductal, mucinous cystic, and acinar cell carcinomas.1,9 Among the exocrine tumors of the pancreas, IPMT is a relatively new entity in pancreatic pathology. The tumor development and growth regulation are not well understood. Much effort has been devoted to the characterization of this neoplasm. It has been shown that IPMT occasionally expresses oncofetal antigens. Abnormalities of oncogenes and anti-oncogenes also have been reported in IPMT.10 In addition, there have been a few reports on the endocrine cells in IPMT,7 but there has been no systematic study of endocrine cells in IPMT Argyrophil, argentaffin, and chromogranin A cells have been present in many cases of IPMT.7 The origin of these cells is obscure; they may be pre-existing endocrine cells, or, alternatively, they may be the result of endocrine differentiation of IPMT. The latter explanation seems more likely, as no argentaffin, serotonin, or gastrin cells are present in normal pancreatic ducts, whereas such cells have been found in IPMT Although the function of endocrine cells in IPMT is not known, it seems possible that hormones secreted from endocrine cells may regulate tumor cell growth via an autocrine and/or paracrine loop IPMT, as is suspected in other tumors.7 In the present case, the histologic pattern of intraductal papillary mucinous changes was mainly located in the duct branches rather than the main duct, and there was only modest dilation of some of the involved ducts. Therefore, the term IPM, not IPMT, is used. The IPMH in the present case was surrounded by hyperplastic islets. This indicates that a close relationship existed between the IPMH and endocrine cells and supports the hypothesis that IPMH could have derived from autocrine and paracrine influences on the existing duct epithelial cells.

References

1. Solcia E, Capella C, Kloppel G. Tumor of the exocrine pancreases. In: Rosai J, Sobin LH, eds. Tumors of the Pancreas. Washington, DC: Armed Forces Institute of Pathology; 1997:31-144. Atlas of Tumor Pathology, 3rd series, fascicle 20.

2. Ohhashi K, Murakami Y, Takekoshi T, et al. Four cases of "muci-producing" cancer of the pancreas on specific findings of the papilla Vater [in Japanese; abstract in English]. Prog Dig Endosc. 1982;20:348-351.

3. Nakagohri T, Kenmochi T, Kainuma 0, Tokoro Y, Asano T. Intraductal papillary mucinous tumors of the pancreas. J Surg. 1999;178:344-347.

4. Sessa F, Solcia E, Capella C, et al. Intraductal papillary-mucinous tumors represent a distinct group of pancreatic neoplasma: an investigation of tumor cell differentiation and K-ras, p53 and c-erbB-2 abnormalities in 26 patients. Virchows Arch. 1994;425:357-367.

5. Yamano M, Fujii H, Takagaki T, Kadowaki N, Watanabe H, Shirai T. Genetic progression and divergence in pancreatic carcinoma. Am j Pathol. 2000;156: 2123-2133.

6. Solcia E, Capella C, Kloppel G. Tumor-like lesions of the endocrine pancreases. In: Rosai J, Sobin LH, eds. Tumors of the Pancreas. Washington, DC: Armed Forces Institute of Pathology; 1997:215-246. Atlas of Tumor Pathology; 3rd series, fascicle 20.

7. Terada T, Ohta T, Kitamura Y, Ashida K, Matsunaga Y, Kato M. Endocrine cells in intraductal papillary-mucinous neoplasms of the pancreas: a histochemical and immunohistochemical study. Virchows Arch. 1997;431:31-36.

8. Leong ASY, Slavotinek AH, Higgins BA. Nesidioblastosis, islet cell hyperplasia, and adenomatosis in a case of metastasizing insulinoma: contribution to the genesis of the islet of Langerhans. Diabetes Care. 1980;3:537-542.

9. Leteurtre E, Brami F, Kerr-Conte J, Quandalle P, Lecomte-Houcke M. Mixed ductal-endocrine carcinoma of the pancreas. Arch Pathol Lab Med. 2000;124: 284-286.

10. Satoh K, Sasano H, Shimesegawa T, et al. An immunohistochemical study of the c-erbB-2 oncogene product in intraductal mucin-hypersecreting neoplasms and in ductal cell carcinomas of the pancreas. Cancer. 1993;72:51-56.

Xiaohui Zhao, MD, PhD; Bruce E. Stabile, MD; Junqin Mo, MD; Jun Wang, MD; Samuel W French, MD

Accepted for publication April 20, 2001.

From the Departments of Pathology (Drs Zhao and French) and Surgery (Dr Stabile), Harbor/UCLA Medical Center, Torrance, Calif; Department of Pathology, School of Medicine, University of Cincinnati, Cincinnati, Ohio (Dr Mo); and Department of Pathology, City of Hope National Medical Center, Duarte, Calif (Dr Wang).

Reprints: Xiaohui Zhao, MD, PhD, Department of Pathology, Harbor/ UCLA Medical Center, 1000 W Carson St, Box 12, Torrance, CA 90509 (e-mail: xzhao@prl.humc.edu).

Copyright College of American Pathologists Oct 2001
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