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The pancreas is two organs in one.  The exocrine portion is involved with production and secretion of several enzymes key in the breakdown of proteins and fats.  The endocrine portion is composed of the islets of Langerhans which secrete insulin as well as other important hormones such as glucagon, somatostatin, and pancreatic polypeptide.  A biopsy of the pancreas is almost always to rule out the diagnosis of cancer.  Despite all of medicine's advances, there is no good laboratory screening test for this cancer.

Ampulla of Vater Carcinomas
Diabetes mellitus
Intraductal Papillary Mucinous Tumor of the Pancreas (IPMT)
Islet Cell Tumors
Pancreatic Carcinoma (Ductal Adenocarcinoma)
Sclerosing Cholangitis
Solid and Cystic Neoplasm of the Pancreas (Solid-Pseudopapillary Tumor of the Pancreas)


Laboratory/Radiologic/Other Diagnostic Testing  
Histopathological Features and Variants  
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Endoscopic Ultrasound–Guided Fine-Needle Aspiration A Cytopathologist's Perspective

Nirag C. Jhala, MD, MIAC, Darshana N. Jhala, MD, David C. Chhieng, MD, Mohamad A. Eloubeidi, MD, MHS, and Isam A. Eltoum, MD, MBA

Am J Clin Pathol 2003;120:368-376 Abstract quote

Endoscopic ultrasound (EUS) is used to detect and delineate the extent of lesions in the gastrointestinal tract, periluminal lymph nodes, pancreas and hepatobiliary tree, left kidney, spleen, and adrenal glands. EUS-guided fine-needle aspiration (FNA) has added a new dimension to the capabilities of EUS because it permits characterization of the lesion, thereby enabling triage of patients for more efficient and effective management.

This review focuses on the advantages and limitations of EUS-FNA, including a discussion of potential pitfalls in the diagnosis of commonly aspirated deep-seated lesions, such as those of the pancreas and lymph nodes. It also addresses the practical considerations associated with establishing an effective service and the importance of an integrated approach in which the cytopathologist undertakes a key role, interacting extensively with the endoscopist and the patient management team. EUS-FNA is a sensitive modality that enables specific and accurate diagnosis of deep-seated lesions. Samples can be obtained effectively from small lesions (<25 mm), irrespective of the organ site.

On-site assessment permits a highly accurate preliminary diagnosis of malignancy for samples obtained by EUS-FNA and provides an opportunity to increase the diagnostic yield of samples.



Cytologic diagnosis of adenocarcinoma in biliary and pancreatic duct brushings.

Henke AC, Jensen CS, Cohen MB.

Adv Anat Pathol 2002 Sep;9(5):301-8 Abstract quote

Biliary and pancreatic duct brush specimens are relatively uncommon specimens seen by pathologists. Not only can the findings of malignancy be subtle, the implications of a malignant diagnosis can be significant.

This review focuses on cholangiocarcinoma and pancreatic ductal adenocarcinoma sampled by endoscopic brush cytology, with an emphasis on diagnostic criteria for adenocarcinoma. In addition, assessment of specimen adequacy, utilization of liquid-based preparations, molecular diagnosis, and timing of liver transplantation in patients with primary sclerosing cholangitis are also briefly discussed


Frozen section diagnosis of pancreatic lesions.

Cioc AM, Ellison EC, Proca DM, Lucas JG, Frankel WL.

Departments of Pathology (Drs Cioc, Proca, Lucas, and Frankel) and Surgery (Dr Ellison), Ohio State University, Columbus.


Arch Pathol Lab Med 2002 Oct;126(10):1169-73 Abstract quote

Background.-The clinical and radiologic diagnosis of pancreatic cancer and the safety of pancreatic resections have improved. These improvements, together with the indication for resection in some cases of complicated chronic pancreatitis, have reduced the necessity for confirmed preoperative tissue diagnosis. We investigated the clinical use and accuracy of frozen section diagnosis for pancreatic lesions.

Design.-We searched archival files for the years 1989-2000 for patients with pancreatic lesions who had received a diagnosis based on frozen section results. We compared the diagnosis of all frozen section slides with that of the permanent sections and reviewed the clinical follow-up notes. We evaluated histologic features useful in differentiating between malignant and benign pancreatic lesions.

Results.-A total of 538 patients underwent surgical biopsy and/or resection for suspected pancreatic lesions. Frozen section was requested in 131 cases (284 frozen sections). Ninety cases had frozen section of the pancreatic lesions, 70 cases had frozen section of metastatic sites, and 29 cases had frozen section of surgical margins. Of the 90 cases in which frozen section of the pancreatic lesions was requested, malignancy was diagnosed in 44, a benign lesion was diagnosed in 37, and the diagnosis was atypical and deferred in 9. In total, 3 false-negative frozen sections and 1 false-positive frozen section were identified for respective rates of 1.2% and 0.3%. In all cases in which the frozen section diagnosis was deferred or was inconsistent with the operative impression, and the surgeon acted on his/her impression, the operative diagnoses were subsequently confirmed by additional permanent sections and/or clinical follow-up. The most useful histologic features for the diagnosis of pancreatic adenocarcinoma in frozen sections were variation in nuclear size of at least 4:1, disorganized duct distribution, incomplete duct lumen, and infiltrating single cells.

Conclusions.-Frozen sections are useful in conjunction with the impression at surgery for the management of patients with pancreatic lesions. Frozen sections of resection margins were 100% accurate; frozen sections of pancreatic lesions or metastatic sites were accurate in 98.3% of cases. We found an acceptable rate of deferred frozen section (6.6%). The experienced surgeon's impression of malignancy is reliable in cases in which frozen section is deferred or has negative findings.


Adenomatoid tumor of the pancreas: a case report with comparison of histology and aspiration cytology.

Overstreet K, Wixom C, Shabaik A, Bouvet M, Herndier B.

Department of Pathology, University of California, San Diego Medical Center, San Diego, California 92103, USA.

Mod Pathol. 2003 Jun;16(6):613-7. Abstract quote

We present a 58-year-old woman who presented with a 1.5-cm, hypodense lesion in the head of the pancreas. Endoscopic ultrasound-guided fine-needle aspiration yielded bland, monotonous cells with wispy cytoplasm, slightly granular chromatin, and small nucleoli.

A presumptive diagnosis of a neuroendocrine lesion was rendered. Whipple procedure yielded a well-circumscribed, encapsulated lesion with dense, hyalinized stroma and a peripheral rim of lymphocytes. Spindled and epithelioid cells formed short tubules, cords, and nests. The neoplasm stained for CK 5/6, calretinin, vimentin, CD 99, pancytokeratin, and EMA, consistent with mesothelial origin. This characteristic histology and immunohistochemistry is consistent with an adenomatoid tumor.

We believe we are the first to report this benign neoplasm in such an unusual location. Herein we address the diagnosis of adenomatoid tumor by histology, immunohistochemistry, and aspiration cytology. Our case is particularly unique in that the histology and cytology are compared and correlated.


Adenomyoma and adenomyomatous hyperplasia of the Vaterian system: clinical, pathological, and new immunohistochemical features of 13 cases.

Handra-Luca A, Terris B, Couvelard A, Bonte H, Flejou JF.

Department of Pathology, Beaujon Hospital, Clichy, France.

Mod Pathol. 2003 Jun;16(6):530-6. Abstract quote

Adenomyoma and adenomyomatous hyperplasia of the Vaterian system are consistently benign lesions. Clinically, adenomyoma mimics frequently ampullary adenoma or carcinoma, and biopsy analysis is often difficult. The histogenesis of ampullary adenomyoma and adenomyomatous hyperplasia is still subject to debate.

We present a retrospective study of clinicopathological features of 13 cases of surgically resected ampullary adenomyoma. The age of our patients was between 38 and 78 years (mean: 63 y). The preoperative diagnosis was ampullary tumor or tumor of the head of the pancreas. On macroscopy, a white, firm lesion of the ampullary wall was observed; its size ranged between 10 and 30 mm. Histologically the lesion consisted of multiple glandular structures surrounded by a fibroblastic/myofibroblastic proliferation, resulting in a "pseudo-hypertrophy" of the Vaterian system.

The immunophenotype of the epithelial component was cytokeratin 7+/cytokeratin 20-, similar to that of the normal biliary and pancreatic duct system. The epithelial cells exhibited low proliferative activity. The hyperplastic myofibroblastic cells expressed smooth muscle actin. A complete pancreatic heterotopy contiguous with the adenomyoma was noted in three cases.

Adenomyoma and adenomyomatous hyperplasia of the Vaterian system are benign lesions frequently treated by extensive surgery because of long-term biliary obstruction. The clinicopathological characteristics suggest either a reactive and/or a malformative, nonneoplastic nature for this lesion, which could, in some cases, develop from heterotopic pancreas. The immunophenotype of epithelial cells may be a useful tool for differentiating it from ampullary adenoma on biopsy specimens.

Congenital Hyperinsulinism: Intraoperative Biopsy Interpretation Can Direct the Extent of Pancreatectomy.

Suchi M, Thornton PS, Adzick NS, MacMullen C, Ganguly A, Stanley CA, Ruchelli ED.

*Department of Pathology and Laboratory Medicine, daggerDivision of Endocrinology, Department of Pediatrics, and double daggerDepartment of Surgery, The Childrens' Hospital of Philadelphia and University of Pennsylvania School of Medicine; section signDepartment of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA.; Paul S. Thornton's current affiliation is Endocrinology, Cook Children's Health System, Fort Worth, TX.
Am J Surg Pathol. 2004 Oct;28(10):1326-1335. Abstract quote  

Most cases of congenital hyperinsulinism (HI) manifest as either a diffuse or focal form. Diffuse HI is characterized by the presence of enlarged islet cell nuclei, defined as those occupying an area 3 times larger than the surrounding nuclei, throughout the pancreas, and usually requires near total pancreatectomy. Focal HI contains, within an otherwise normal pancreas with islet cell nuclei of normal size, a focus of adenomatous hyperplasia characterized by endocrine cell overgrowth occupying more than 40% of a given area. This form of HI is amenable to partial pancreatectomy.

The current study assesses whether intraoperative frozen section evaluation can distinguish the 2 forms and guide the extent of pancreatectomy. By frozen section analysis, diffuse HI is diagnosed when enlarged islet cell nuclei are present in random intraoperative biopsies from the head, body, and tail of the pancreas. Focal HI is suggested when random biopsies contain no large islet cell nuclei, prompting a further search for a focal lesion. Fifty-two HI patients who underwent pancreatectomy from October 1, 1998 to September 30, 2002 were reviewed. On permanent sections, 18 were classified as diffuse HI, 30 had focal HI, and 4 could not be categorized as either. Among 18 diffuse HI patients, 17 were correctly diagnosed by frozen section; all underwent near total pancreatectomy. One case was interpreted as not belonging to typical diffuse or focal HI; however, the permanent sections showed diffuse HI. Twenty-six of 30 focal HI cases were correctly diagnosed by frozen section. The remaining 4 focal HI cases posed diagnostic difficulties on frozen sections because of one the following reasons: 1) presence of equivocally large islet cell nuclei or rare truly large islet cell nuclei in areas nonadjacent to the focal lesion, and 2) large and/or ill defined focus of adenomatous hyperplasia. Twenty-one of 30 focal HI patients eventually had 10% to 93% (mean, 41.8%) of their pancreas resected. In addition to cases typical for diffuse and focal HI, there were 4 other cases whose pancreata did not fit well with either category. These pancreata showed islet cell nuclear enlargement, as characteristically seen in diffuse HI, but only in confined areas of the pancreas. Examination of routinely processed tissue confirmed frozen section findings in all 4 cases.

Intraoperative frozen section evaluation, therefore, can assume an essential role in identifying patients with focal HI to limit the extent of pancreatectomy. However, a small number of cases with unusual histology warrant caution when performing frozen section evaluation.
Persistent Hyperinsulinemic Hypoglycemia in 15 Adults With Diffuse Nesidioblastosis: Diagnostic Criteria, Incidence, and Characterization of beta-Cell Changes.

Anlauf M, Wieben D, Perren A, Sipos B, Komminoth P, Raffel A, Kruse ML, Fottner C, Knoefel WT, Monig H, Heitz PU, Kloppel G.

From the *Department of Pathology and section signFirst Department of Medicine, University of Kiel, Kiel, Germany; daggerDepartment of Pathology, University Hospital Zurich, Zurich, Switzerland; double daggerDepartment of General and Visceral Surgery, University of Dusseldorf, Dusseldorf, Germany; and parallelFirst Department of Medicine, University of Mainz, Mainz, Germany. Some of the results of this study are part of Daniel Wieben's MD thesis.
Am J Surg Pathol. 2005 Apr;29(4):524-533. Abstract quote  

Persistent hyperinsulinemic hypoglycemia (PHH) in adults that is not caused by an insulinoma is a rare and not well-characterized disease that has been named nesidioblastosis. In this study, we defined and scrutinized criteria for its histologic diagnosis, assessed its relative incidence, and discussed its pathogenesis. In pancreatic specimens from 15 adult patients with PHH in whom no insulinoma was detected and in 18 adult control patients, the endocrine tissue was screened for islet and beta-cell changes. The diagnostic reliability of the findings was checked by an interobserver analysis. The relative frequency of the disease was assessed in a series of 232 patients with PHH. Finally, genetic analysis of the menin gene was performed.

Among the various indicators of islet changes, beta-cell hypertrophy characterized by enlarged and hyperchromatic beta-cell nuclei was the most significant and diagnostic finding in patients with PHH. The interobserver analysis revealed 100% specificity and 87.7% sensitivity. The hyperfunctional state of the beta-cells was not associated with changes in the subcellular distribution of insulin and proinsulin, proliferative activity, or mutations of the menin gene.

Our results indicate that diffuse nesidioblastosis in adult patients with PHH resembles that seen in neonates suffering from PHH. The most important criterion for the diagnosis is the beta-cell hypertrophy. As approximately 4% of adult patients with PHH are affected by diffuse nesidioblastosis, this disease is not as rare as it has been thought to be. Pathogenetically, the defective insulin secretion could be based on a molecular defect.
Pancreatic Solid and Cystic Hamartoma in Adults: Characterization of a New Tumorous Lesion.

Pauser U, Kosmahl M, Kruslin B, Klimstra DS, Kloppel G.

From the *Department of Pathology, University of Kiel, Kiel, Germany; daggerDepartment of Pathology, Sestre Milosrdnice University Hospital, Zagreb, Croatia; and double daggerDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
Am J Surg Pathol. 2005 Jun;29(6):797-800. Abstract quote  

Nonneoplastic tumor-like lesions ("pseudotumors") of the pancreas include cystic and noncystic varieties.

We report on a solid and cystic tumor-like lesion of the pancreas that occurred in 2 adult patients. The lesions, located in the head and neck of the gland, respectively, were well demarcated and composed of cystic ductal structures embedded in focally inflamed stromal tissue. In addition, one of the lesions showed irregularly arranged but well-differentiated acini and small intralobular and interlobular ducts embedded in hypocellular, fibrotic tissue.

Discrete islets were lacking, but immunohistochemical staining for chromogranin A revealed individual scattered endocrine cells evenly distributed between acinar and ductal cells. The surrounding pancreatic parenchyma did not show significant chronic pancreatitis. After tumor removal, the follow-up of the patients was uneventful.

Because of the irregular arrangement of otherwise mature tissue components of the pancreas, the lesions were considered solid and cystic hamartomas. Their pathogenesis is so far unknown.

Eosinophilic pancreatitis and increased eosinophils in the pancreas.

Abraham SC, Leach S, Yeo CJ, Cameron JL, Murakata LA, Boitnott JK, Albores-Saavedra J, Hruban RH.

Am J Surg Pathol 2003 Mar;27(3):334-42 Abstract quote

Prominent eosinophilic infiltrates are an unusual finding in the pancreas. Eosinophilic pancreatitis is one rare etiology of pancreatic eosinophilia, but other described causes of eosinophilic infiltrates have also included pancreatic allograft rejection, pancreatic pseudocyst, lymphoplasmacytic sclerosing pancreatitis (LPSP), inflammatory myofibroblastic tumor, and histiocytosis X.

In this study we describe the clinicopathologic features of three new cases of eosinophilic pancreatitis and conduct a retrospective 18-year institutional review of the myriad disease processes associated with pancreatic eosinophilia. In the files of the Johns Hopkins Hospital, <1% of all pancreatic specimens had been noted to show increased numbers of eosinophils. Eosinophilic pancreatitis itself was a rare etiology for pancreatic eosinophilia, with only one in-house case over the 18-year study period and two additional referral cases. Other disease processes associated with prominent eosinophilic infiltrates were more common and included pancreatic allograft rejection (14 cases), LPSP (5 of 24 total LPSP cases evaluated), inflammatory myofibroblastic tumor (4 cases), and systemic mastocytosis (1 case).

Patients with eosinophilic pancreatitis showed two distinct histologic patterns: 1) a diffuse periductal, acinar, and septal eosinophilic infiltrate with eosinophilic phlebitis and arteritis; and 2) localized intense eosinophilic infiltrates associated with pseudocyst formation. All three patients with eosinophilic pancreatitis had peripheral eosinophilia, and all had multiorgan involvement. One patient with LPSP also had marked peripheral eosinophilia, and 5 of 24 LPSP cases demonstrated prominent eosinophilic infiltrates in the gallbladder, biliary tree, and/or duodenum. Notably, not all of these patients with LPSP with prominent eosinophils in other organs had increased eosinophils in the pancreas itself.

These results emphasize the infrequent nature of pancreatic eosinophilia and its multiple potential disease associations. True eosinophilic pancreatitis, although a fascinating clinicopathologic entity, is one of the rarest causes of pancreatic eosinophilia.


Serous Cystic Neoplasms of the Pancreas: An Immunohistochemical Analysis Revealing Alpha-Inhibin, Neuron-specific Enolase, and MUC6 as New Markers

Kosmahl, Markus MD; Wagner, Janning MD; Peters, Katharina MD; Sipos, Bence MD; Klöppel, Günter MD

From the Department of Pathology, University of Kiel, Kiel, Germany.

The American Journal of Surgical Pathology : Volume 28(3) March 2004 pp 339-346 Abstract quote

Serous cystic neoplasms (SCNs) of the pancreas include serous microcystic adenoma (SMA), serous oligocystic ill-demarcated adenoma (SOIA), solid serous adenoma (SSA), von Hippel-Lindau-associated cystic neoplasm (VHL-CN), and serous cystadenocarcinoma (SCC). These neoplasms are histologically similar but differ in their localization, gross appearance, gender distribution, and biology. A centroacinar origin is assumed but has not been proven. To clarify whether the various subtypes of SCN may be distinguished from each other by marker profiles that might also provide evidence of their origin, the immunoprofiles of 38 SCNs (21 SMAs, 13 SOIAs, 2 VHL-CNs, 1 SSA, and 1 SCC) were defined by applying antibodies against cytoskeletal, neuroendocrine, hormone receptor, and mucin markers.

In addition, we examined the expression of calretinin and alpha-inhibin. The various types of SCN showed a very similar immunoprofile, characterized by positivity for cytokeratins and neuron-specific enolase and negativity for vimentin and synaptophysin. Further markers that were commonly expressed in SCNs were alpha-inhibin (SMAs: 76%, SOIAs: 92%, VHL-CNs: 100%), MUC6 (SMAs: 60%, SOIAs: 85%, VHL-CNs: 100%), and MUC1 (SMAs: 24%, SOIAs: 38%, VHL-CNs: 50%). Western blot analysis in one SMA revealed a distinct band that stained with neuron-specific enolase antiserum. Alpha-inhibin was only expressed in 4 of 11 acinar cell carcinomas and not in five ductal adenocarcinomas, five neuroendocrine tumors, one mixed ductal-endocrine carcinoma, and one acinar cell cystadenoma of the pancreas.

These results suggest that, despite their biologic differences, the various types of SCNs are composed of the same (or a very similar) cell type and may therefore have a common direction of differentiation. This notion is further supported by the finding that neuron-specific enolase, alpha-inhibin, and MUC6, which may be regarded as new markers for this pancreatic tumor type, were also expressed in most SCNs. Because a number of SCNs share MUC1 and MUC6 expression with the pancreatic centroacinar cells, the possibility of a histogenetic relationship has to be considered



Pancreaticoduodenectomy (whipple resections) in patients without malignancy: are they all 'Chronic Pancreatitis'?

Abraham SC, Wilentz RE, Yeo CJ, Sohn TA, Cameron JL, Boitnott JK, Hruban RH.


Am J Surg Pathol 2003 Jan;27(1):110-20 Abstract quote

Pancreaticoduodenectomy (Whipple resection) has evolved into a safe procedure in major high-volume medical centers for the treatment of pancreatic adenocarcinoma and refractory chronic pancreatitis. However, some Whipple resections performed for a clinical suspicion of malignancy reveal only benign disease on pathologic examination.

We evaluated the frequency of such Whipple resections without tumor in a large series of pancreaticoduodenectomies and classified the diverse pancreatic and biliary tract diseases present in these specimens. Of 442 Whipple resections performed during 1999-2001, 47 (10.6%) were negative for neoplastic disease and, in 40 cases, had been performed for a clinical suspicion of malignancy. Most Whipple resections revealed benign pancreatic disease, including 8 (17%) alcohol-associated chronic pancreatitis, 4 (8.5%) gallstone-associated pancreatitis, 1 (2.1%) pancreas divisum, 6 (12.8%) "ordinary" chronic pancreatitis of unknown etiology, and 11 (23.4%) lymphoplasmacytic sclerosing pancreatitis.

In particular, patients with lymphoplasmacytic sclerosing pancreatitis were all thought to harbor malignancy, whereas only 13 of 19 (68.4%) of Whipple resections showing histologically "ordinary" forms of chronic pancreatitis were performed for a clinical suspicion of malignancy.

Benign biliary tract disease, including three cases of primary sclerosing cholangitis, two cases of choledocholithiasis-associated chronic biliary tract disease, and four fibroinflammatory strictures isolated to the intrapancreatic common bile duct, was a common etiology for clinically suspicious Whipple resections (22.5% of cases). Pancreatic intraepithelial neoplasia (PanIN) was a common finding among all pancreata, whether involved by pancreatitis or histologically normal.

Overall, PanIN 1A/1B was present in 68.1%, PanIN 2 in 40.4%, and PanIN 3 in just 2.1%. These findings indicate that "benign but clinically suspicious" Whipple resections are relatively common in high-volume centers (9.2%) and reveal a diverse group of clinicopathologically distinctive pancreatic and biliary tract disease.

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Normal islets of Langerhans
Normal islets with immunoperoxidase staining

Last Updated June 6, 2005

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