Cystic pancreatic neuroendocrine tumors: endoscopic ultrasound and fine-needle aspiration characteristics

• Introduction
• Patients and methods
• Patients
• EUS – FNA procedures
• EUS and FNA characteristics
• Statistical analysis
• Results
• Patient characteristics
• EUS and FNA features
• Cyst fluid characteristics
• Cyst fluid cytology
• Comparison of EUS and FNA features in CPanNet and mucinous cysts
• Discussion
• References

Background and study aims: Limited data are available on the endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) characteristics of cystic pancreatic neuroendocrine tumors (CPanNets). The aims of this study were to describe the EUS and FNA characteristics of pathologically confirmed CPanNets and to compare these characteristics with mucinous cysts from matched patients.

Patients and methods: From an EUS – FNA database (between 1999 and 2011), 19 patients with a pathologically confirmed CPanNet were identified. Patient characteristics, cyst fluid carcinoembryonic antigen (CEA) levels, pathology, and EUS findings were analyzed. For comparison, age- and sex-matched patients with mucinous cysts were randomly chosen from the same database.

Results: Of the 19 patients, two had multiple endocrine neoplasia type 1 and two had metastases. The median diameter of the lesions was 24 mm. EUS revealed unilocular lesions in 7 patients, thinly septated lesions with thin walls in 1, and mixed solid-cystic lesions in 11. EUS – FNA cytology confirmed neoplasm in 12 of the 19 patients (63.2 %). The median cyst fluid CEA level (n = 15) was 1.1 ng/mL (range 0.3 – 500 ng/mL). Compared with matched patients with mucinous cysts, the median cyst fluid CEA was lower (1.1 ng/mL vs. 400 ng/mL), thick walls were more common (66.7 % vs. 13.3 %), and diagnostic cytology was more likely (73.3 % vs. 20.0 %).

Conclusions: Analysis of EUS and FNA results showed that the cyst fluid from CPanNets had a lower CEA concentration, a higher frequency of thick walls on EUS, and higher diagnostic cytology compared with mucinous cysts. These findings may aid in the diagnosis of CPanNets.

Introduction

As a result of the increased utilization of cross-sectional imaging of the abdomen, pancreatic cystic lesions (PCLs) are being detected with increasing frequency [1]. Neoplastic cysts (i. e. pancreatic cystic neoplasms) are estimated to account for 60 % of PCLs [2]. Pancreatic cystic neoplasms, which reportedly account for up to 15 % of all pancreatic neoplasms [3], include intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystic neoplasm, solid-pseudopapillary neoplasm, cystic pancreatic neuroendocrine tumor (CPanNet), ductal adenocarcinoma with cystic degeneration, and acinar-cell cystic neoplasm [4]. Pancreatic neuroendocrine tumors (PanNets) account for 1 % – 2 % of all pancreatic neoplasms [5]. CPanNets are reported to account for less than 10 % of all pancreatic cystic neoplasms [4] [6] and 10 % – 17 % of all resected PanNets [7] [8] [9] [10] [11].

Endoscopic ultrasound (EUS) coupled with fine-needle aspiration (FNA) has enabled not only the detailed examination of PCLs but also cytological, biochemical, and DNA analyses [12]. Cyst fluid carcinoembryonic antigen (CEA) levels have been found to be an accurate marker of mucinous cysts (i. e. IPMN and MCN) [13] [14]. However, limited data are available on EUS and FNA characteristics of CPanNets. We hypothesized that CPanNets would have EUS and FNA features distinct from those of mucinous cysts. The aims of the current study, therefore, were to describe EUS and FNA characteristics of CPanNets and to compare these characteristics with those of mucinous cysts in matched patients

Patients and methods

Patients

A database of all patients who underwent EUS-guided FNA (EUS – FNA) at Massachusetts General Hospital since 1999 was compiled prospectively to evaluate PCLs. The endoscopist who performed EUS – FNA submitted the information at the time of each procedure to the research coordinator, who entered the data into a prospectively maintained database on a regular basis. In general, the EUS findings were entered immediately into the database. Additional data, such as cyst fluid CEA level and cytology, were collected from the electronic medical recording system of the institution.

The study was approved by the Partners Human Research Committee Institutional Review Board. Between 1999 and 2011, a total of 1185 patients underwent EUS – FNA. Patients were selected who were ultimately diagnosed with a CPanNet using pathological confirmation. Patient characteristics of sex, age, presenting symptom/sign, and presence of multiple endocrine neoplasia type 1 (MEN-1) were evaluated. For the matched comparison, 105 eligible patients with histological confirmation of a mucinous cyst and results of both cyst fluid CEA level and cytology reports were randomly selected from the same database in a 1:1 fashion; these patients were matched by sex and age (difference of no more than 3 years).

EUS – FNA procedures

EUS – FNA was used to principally differentiate between mucinous (IPMN and MCN) and non-mucinous cysts. All patients underwent EUS – FNA using a curvilinear echoendoscope and FNA needle(s) as previously described [13] [14] [15]. Briefly, standard EUS was performed by three experienced endosonographers using a curvilinear echoendoscope. Doppler imaging was used to identify and avoid blood vessels. The PCL was aspirated under EUS guidance using FNA needle(s). PCLs in the pancreatic head or uncinate process were aspirated via a transduodenal approach; lesions in the pancreatic body or tail were accessed via a transgastric approach. To prevent PCL infection, 2 g of ampicillin and 80 mg of gentamicin were administered intravenously during EUS – FNA; an oral quinolone was administered for 2 – 3 days after the procedure.

EUS and FNA characteristics

EUS characteristics (location, size in long diameter, presence of thick wall [ > 2 mm], septation, and associated mass lesion), FNA target (fluid and/or solid component), cyst fluid characteristics (viscosity, appearance, and CEA level), and cytology results were analyzed.

EUS appearance of the lesions was classified as follows: unilocular with thin wall, unilocular with thick wall, thinly septated with thin wall, and mixed solid-cystic. Mixed solid-cystic lesion was defined as a cystic lesion with associated mass lesion(s) and/or thick septations with or without thick wall.

Cyst fluid viscosity and appearance, when reported, were based on the endosonographer’s subjective description. Cyst fluid CEA level was evaluated as previously reported [13] [14]. When CEA level of a cyst was reported as a range, the lowest value of the range was considered to be the CEA level. For example, when cyst CEA level was reported to be greater than 500 ng/mL, the cyst CEA level was considered to be 500 ng/mL.

For pathology, the original cytology and surgical pathology reports were used. Cytology slides were originally interpreted by six experienced cytopathologists. Cytology slides were reviewed only in cases of discordance with the surgical resection histology. The final cytopathology diagnosis used in the study was made by a cytopathologist with more than 25 years of experience in cytopathology and special expertise in the pancreas (M.B.P.). Patients with CPanNets and cyst fluid CEA levels and cytology results were compared with patients with mucinous cysts with regard to EUS features, cyst fluid CEA levels, and diagnostic yield of cytology. Original cytology reports were used for classification. Accuracy of cytology was calculated for suspicious and positive interpretations.

Statistical analysis

For categorical data, the χ² test or the Fisher’s exact test was performed where appropriate. For comparison of continuous variables, the Wilcoxon rank-sum test was performed. All continuous variables were reported as the median (range). P values were interpreted after Bonferroni correction for multiple comparisons. All statistical analyses were performed using STATA 11.2 (StataCorp LP, College Station, Texas, USA).

Results

Patient characteristics

A total of 19 patients with CPanNets (1.6 % of the patients in the database) were identified and included in the study; 13 were male and 6 were female. The median age at diagnosis was 57 years (range 34 – 80 years). A total of 17 patients underwent surgery and were diagnosed on a histological basis; two patients were diagnosed on a cytological basis. Nine patients were asymptomatic. Among the symptomatic patients, one patient presented with Cushing syndrome attributable to the functioning CPanNet (adrenocorticotropic hormone-producing tumor). MEN-1 was present in two patients. One patient had a history of a CPanNet resected 3.5 years prior to the current CPanNet; the first lesion had not been evaluated using EUS – FNA. Two patients had documented metastasis (one in the liver and the other in a regional lymph node). Patient characteristics are summarized in [Table 1].

EUS and FNA features

All patients had a single PCL on EUS. Five CPanNets were located in the head, seven in the body, and seven in the tail of the pancreas. The median diameter of the lesions measured by EUS was 24 mm (range 13 – 70 mm). A thick wall was present in 11 patients. A total of 11 patients had associated mass lesions. Overall, the lesions were unilocular with thin wall in 3, unilocular with thick wall in 4, thinly septated with thin wall in 1, and mixed solid-cystic in 11 ([Table 1]). Examples are shown in [Fig. 1].

In one patient with MEN-1, a separate mass lesion was identified in the pancreas. The surgical specimen revealed one CPanNet and two solid PanNet lesions.

EUS – FNA was performed via a transduodenal approach in the five patients with CPanNets located in the head. A transgastric approach was used in the 14 patients with lesions located in the body or tail. A total of 13 patients underwent EUS – FNA with a 22-G needle, 4 patients with a 22-G and a 25-G needle, and 1 patient with a 25-G needle. (We usually use the 22-G needles for cyst aspiration as, in our experience, they offer low rates of complications, the ability to aspirate viscous fluid, and easy passage through the cyst wall.) No description of the gauge of the needle was available for one patient. The FNA target was fluid only in 12, fluid plus solid component in 6, and solid component only in 1. Therefore, a total of seven patients had FNA of the solid components of the cyst.

There were no EUS – FNA-related complications. EUS and FNA features are summarized in [Table 1].

Cyst fluid characteristics

Among the eight aspirates with the fluid viscosity reported, three were viscous and five were thin fluids. Among the 11 patients who had the fluid appearance reported, four were bloody and seven were clear. Cyst fluid CEA level was available for 15 patients, with a median level of 1.1 ng/mL (range 0.3 – 500 ng/mL). Only one patient had a cyst fluid CEA level greater than 192 ng/mL. Two patients had cyst fluid CEA levels greater than 5 ng/mL (6.0 and 500 ng/mL, respectively).

Cyst fluid cytology

The results of EUS – FNA cytology are summarized in [Fig. 2]. A total of 15 aspirates had neoplastic cytology, which consisted of 12 PanNet, 1 adenocarcinoma, and 2 suspicious for PanNet due to insufficient tissue for ancillary tests. Immunohistochemical staining of synaptophysin and/or chromogranin A was performed on nine cell block preparations of aspirates, which were all positive. A review of the cases diagnosed as adenocarcinoma confirmed that the cytology was misclassified due to the presence of very prominent nucleoli, a feature more consistent with adenocarcinoma than PanNet. Interestingly, although one cyst fluid CEA level was greater than 192 ng/mL, cytology revealed tumor cells diagnostic of PanNet, precluding an incorrect interpretation of a mucinous cyst with high-grade atypia.

For the four cases with nondiagnostic cytology, three fluids were acellular and one contained only inflammatory cells. These patients had high-risk features on EUS (thick wall, mass lesion, and/or large size) and underwent surgery.

If only the cytology of PanNet was considered as the diagnostic true positive, the diagnostic yield was 63.2 %. If the cytology diagnosis of a neoplasm was considered as the true positive, thus including the adenocarcinoma as diagnostic, the yield was 68.4 %. The diagnostic yield was 78.9 % when suspicious cases were also considered to be sufficiently diagnostic for patient management.

EUS characteristics showed no association with the diagnostic yield of neoplastic cytology. All seven patients (100 %) who had FNA of the solid components had diagnostic cytology, whereas 6 of 12 patients (50 %) who only had FNA of the cyst fluid had diagnostic cytology. However, this lost statistical significance after Bonferroni correction ([Table 2]).

Comparison of EUS and FNA features in CPanNet and mucinous cysts

As four patients with CPanNets had no cyst fluid CEA level reported, 15 patients were compared with the same number of patients with mucinous cysts. These matched patients comprised 10 patients with IPMN (four intermediate-grade dysplasia, two high-grade dysplasia, and four with an associated invasive carcinoma), four patients with MCN (three low-grade dysplasia and one intermediate-grade dysplasia), and one patient with a mucinous non-neoplastic cyst.

The CPanNet and mucinous cyst groups were comparable with respect to sex, age, and diameter of the lesion. The frequency of septated lesions and associated mass lesions were not significantly different. However, thick walls on EUS were found significantly more frequently in patients with CPanNet (P = 0.003). The cyst fluid CEA level of CPanNets (median 1.1 ng/mL; range 0.3 – 500 ng/mL) was significantly lower than that of mucinous cysts (median 400 ng/mL; range 2.8 – 6661 ng/mL) (P < 0.001, Wilcoxon rank-sum test). Moreover, CPanNets had a significantly higher frequency of diagnostic cytology than mucinous cysts (P = 0.003). These three parameters remained significant after Bonferroni correction. The results are summarized in [Table 3].

Discussion

To the best of our knowledge, the current study is the largest report that focuses on EUS and FNA features of CPanNets. In addition, EUS and FNA features of patients with CPanNets were compared with those from matched patients with mucinous cysts, adding objectivity to the interpretation of the data.

The age at diagnosis of CPanNet is between 50 and 60 years. Both sexes are affected nearly equally [9] [11]. CPanNets are usually nonfunctional. MEN-1 may be present in up to 21 % of patients with CPanNet [11]. CPanNets may be seen in patients with von Hippel–Lindau syndrome [16]. Little is known about the pathophysiology of CPanNet [7] [10]. In a recent, large-scale report, CPanNets were more likely to be symptomatic, nonfunctional, and associated with MEN-1 than solid PanNets [11]. However, only the nonfunctional feature of CPanNets was supported in another large-scale report [8]. With the exception of neuroendocrine microadenomas, all PanNets are considered to have malignant potential. The treatment for primary solitary PanNet is surgical resection [5] [17].

The rarity of CPanNets has resulted in very limited availability of data on EUS – FNA and cyst fluid characteristics of this disease. In the current study, 14 CPanNets (73.7 %) were located in the body or tail of the pancreas, consistent with previous reports [8] [9] [11] [18] [19]. No unique EUS finding could be demonstrated in the report by Kongkam et al. [19]: EUS morphology was mixed solid and cystic in 44.4 % and cystic in 55.6 %, and septations were present in 44.4 %. In the current study, comparison of EUS characteristics with matched mucinous cysts demonstrated that the frequency of a thick wall was higher in CPanNets.

Previous studies have suggested that cyst fluid CEA level is low in CPanNets. In a report by Deshpande and Lauwers of five patients with histologically confirmed CPanNet, cyst fluid analysis of two patients revealed low cyst fluid CEA levels [20]. Another report of nine CPanNet patients indicated that four patients with cyst fluid analysis had low cyst fluid CEA level [19]. In the report by Charfi et al. [21], two patients who had cyst fluid analysis also had low cyst fluid CEA levels. A recently published series of six patients with CPanNet reported a mean cyst fluid CEA level of 4.7 ng/mL [22]. Although the current results are in concordance with previous reports, there was one patient who had a cyst fluid CEA level greater than 192 ng/mL. There have been a few cases of CPanNets with cyst fluid levels greater than 5 ng/mL, with levels as high as 932 ng/mL [8] [19]. We speculate that these CPanNets are the cystic counterparts to the solid PanNets that express CEA [23] [24].

The typical solid PanNet is readily recognized by a cellular, monotonous population of plasmacytoid cells with granular cytoplasm and round nuclei with stippled, “salt and pepper” chromatin [25]. The diagnostic yield of EUS – FNA cytology of CPanNets in previous reports seems high, despite the possibility that CPanNets may not produce as rich a source of cyst lining neoplastic cells as their solid counterparts. In a report of 10 patients with CPanNet published in 2001, two patients underwent preoperative cytological analysis and one patient underwent biopsy of the cyst wall. The cytology revealed an acellular specimen in one patient and tumor cells in the other; the biopsy specimen showed features suggestive of an endocrine tumor, which was confirmed by immunohistochemical demonstration of synaptophysin and chromogranin A in tumor cells. Although EUS was performed in nine patients, it is unclear how many preoperative specimens were acquired under EUS guidance; only the cyst wall biopsy is stated to be done under EUS guidance [18]. Baker et al. [26] reported that preoperative EUS – FNA and immunocytology yielded cells that were strongly positive for the neuroendocrine markers synaptophysin and chromogranin A in all patients who underwent the procedure. In the report by Kongkam et al. [19], cytology and subsequent immunocytochemistry for synaptophysin and chromogranin A were confirmatory in all cases. In another report of six patients with CPanNets, four had undergone EUS – FNA, which contributed to an accurate diagnosis in all cases [21]. A report of five patients with histologically confirmed CPanNet who underwent EUS – FNA showed that tumor cells were present in three cases [20]. In the current study, which included four of the five patients included in the report by Deshpande and Lauwers [20], the diagnostic yield of EUS – FNA cytology ranged from 63.2 % to 78.9 % in patients with histological confirmation, depending on the definition of diagnostic cytology. Of four cases with nondiagnostic cytology, three aspirates were acellular.

Interestingly, one patient had cytology misclassified as an adenocarcinoma due to overlapping cytological features with PanNet. However, EUS – FNA led to a cytological diagnosis of a surgical neoplasm. This patient had a 16-mm, unilocular, thin-walled cyst without an associated mass lesion. Had it not been for the EUS – FNA, it is likely that this patient would have been put on surveillance for the presumed clinical diagnosis of a low-grade branch-duct IPMN, a strategy that is not advisable in CPanNet.

Comparison of cytology results between CPanNets and mucinous cysts showed that the frequency of diagnostic cytology was higher in CPanNets. The current data confirm that the cyst fluid of CPanNets contains more diagnostic cells than mucinous cysts, and, thus, are more likely than not to be diagnosed using EUS – FNA. In cases where any cells were present, a diagnosis of at least suspicious for a surgical neoplasm was made by cytology in 93.8 %.

The main limitation of the current study is the small patient population due to the rarity of CPanNets. The diagnostic yield of cytology for the matched mucinous cysts in this series may seem lower than the yields from previous reports from our institution, which ranged between 34.5 % and 43.3 % [13] [14]. However, a systematic review by Thosani et al. indicated that the diagnostic yield of EUS – FNA cytology in the diagnosis of mucinous cysts may be as low as 14 % [27]. In addition, the matched mucinous cysts demonstrated high cyst fluid CEA level, which has been shown to be the most accurate marker of mucinous cysts [13] [14].

In conclusion, the presence of a thick wall on EUS was more frequent in CPanNets compared with mucinous cysts. The median cyst fluid CEA level was lower than 5 ng/mL in CPanNet patients and was significantly lower than that of mucinous cyst patients. The yield of diagnostic cytology was high in CPanNets in general, and higher than that of mucinous cysts in particular. These findings may aid in the EUS – FNA diagnosis of CPanNets.

Competing interests: None.

Acknowledgments

This work was conducted with support from Harvard Catalyst – The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award 8UL1TR000170 – 05 and financial contributions from Harvard University and its affiliated academic healthcare centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University, and its affiliated academic healthcare centers, or the National Institutes of Health.

• References

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Corresponding author

• References

• 1 Scheiman JM. Cystic lesion of the pancreas. Gastroenterology 2005; 128: 463-469
  CrossrefPubMedSearch in Google Scholar
• 2 Basturk O, Coban I, Adsay NV. Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications. Arch Pathol Lab Med 2009; 133: 423-438
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• 3 Sakorafas GH, Smyrniotis V, Reid-Lombardo KM et al. Primary pancreatic cystic neoplasms revisited. Part III. Intraductal papillary mucinous neoplasms. Surg Oncol 2011; 20: e109-118
  CrossrefPubMedSearch in Google Scholar
• 4 Brugge WR, Lauwers GY, Sahani D et al. Cystic neoplasms of the pancreas. N Engl J Med 2004; 351: 1218-1226
  CrossrefPubMedSearch in Google Scholar
• 5 Klimstra DS, Arnold R, Capella C et al. Neuroendocrine neoplasms of the pancreas. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO classification of tumours of the digestive system. 4th. edn. Lyon: IARC; 2010: 322-326
  Search in Google Scholar
• 6 Yoon WJ, Yoon YB, Lee KH et al. The cystic neoplasms of the pancreas in Korea. Korean J Med 2006; 70: 261-267
  PubMedSearch in Google Scholar
• 7 Ahrendt SA, Komorowski RA, Demeure MJ et al. Cystic pancreatic neuroendocrine tumors: is preoperative diagnosis possible?. J Gastrointest Surg 2002; 6: 66-74
  CrossrefPubMedSearch in Google Scholar
• 8 Gaujoux S, Tang L, Klimstra D et al. The outcome of resected cystic pancreatic endocrine neoplasms: a case-matched analysis. Surgery 2012; 151: 518-525
  CrossrefPubMedSearch in Google Scholar
• 9 Boninsegna L, Partelli S, D’Innocenzio MM et al. Pancreatic cystic endocrine tumors: a different morphological entity associated with a less aggressive behavior. Neuroendocrinology 2010; 92: 246-251
  CrossrefPubMedSearch in Google Scholar
• 10 Goh BK, Ooi LL, Tan YM et al. Clinico-pathological features of cystic pancreatic endocrine neoplasms and a comparison with their solid counterparts. Eur J Surg Oncol 2006; 32: 553-556
  CrossrefPubMedSearch in Google Scholar
• 11 Bordeianou L, Vagefi PA, Sahani D et al. Cystic pancreatic endocrine neoplasms: a distinct tumor type?. J Am Coll Surg 2008; 206: 1154-1158
  CrossrefPubMedSearch in Google Scholar
• 12 Bhutani MS, Gupta V, Guha S et al. Pancreatic cyst fluid analysis – a review. J Gastrointestin Liver Dis 2011; 20: 175-180
  PubMedSearch in Google Scholar
• 13 Brugge WR, Lewandrowski K, Lee-Lewandrowski E et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004; 126: 1330-1336
  CrossrefPubMedSearch in Google Scholar
• 14 Cizginer S, Turner B, Bilge AR et al. Cyst fluid carcinoembryonic antigen is an accurate diagnostic marker of pancreatic mucinous cysts. Pancreas 2011; 40: 1024-1028
  CrossrefPubMedSearch in Google Scholar
• 15 Brugge WR. The role of EUS in the diagnosis of cystic lesions of the pancreas. Gastrointest Endosc 2000; 52: S18-S22
  CrossrefPubMedSearch in Google Scholar
• 16 Marcos HB, Libutti SK, Alexander HR et al. Neuroendocrine tumors of the pancreas in von Hippel–Lindau disease: spectrum of appearances at CT and MR imaging with histopathologic comparison. Radiology 2002; 225: 751-758
  CrossrefPubMedSearch in Google Scholar
• 17 Hruban RH, Pitman MB, Klimstra D. Tumors of the Pancreas. Atlas of tumor pathology. 4th. series, fascicle 6. Washington, DC: Armed Forces Institute of Pathology; 2007
  Search in Google Scholar
• 18 Ligneau B, Lombard-Bohas C, Partensky C et al. Cystic endocrine tumors of the pancreas: clinical, radiologic, and histopathologic features in 13 cases. Am J Surg Pathol 2001; 25: 752-760
  CrossrefPubMedSearch in Google Scholar
• 19 Kongkam P, Al-Haddad M, Attasaranya S et al. EUS and clinical characteristics of cystic pancreatic neuroendocrine tumors. Endoscopy 2008; 40: 602-605
  Thieme ConnectPubMedSearch in Google Scholar
• 20 Deshpande V, Lauwers GY. Cystic pancreatic endocrine tumor: a variant commonly confused with cystic adenocarcinoma. Cancer 2007; 111: 47-53
  PubMedSearch in Google Scholar
• 21 Charfi S, Marcy M, Bories E et al. Cystic pancreatic endocrine tumors: an endoscopic ultrasound-guided fine-needle aspiration biopsy study with histologic correlation. Cancer 2009; 117: 203-210
  PubMedSearch in Google Scholar
• 22 Croagh D, Forde C, Boulton R et al. Cyst fluid carcinoembryonic antigen in the investigation of cystic neuroendocrine tumors of the pancreas. Gastrointest Endosc 2011; 74: 1413-1416
  CrossrefPubMedSearch in Google Scholar
• 23 Kamisawa T, Tu Y, Egawa N et al. Ductal and acinar differentiation in pancreatic endocrine tumors. Dig Dis Sci 2002; 47: 2254-2261
  CrossrefPubMedSearch in Google Scholar
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