Background

Pancreatitis is divided into acute and chronic forms. Chronic pancreatitis (CP) is characterized by progressive destruction of the gland with accompanying irregular fibrosis and chronic inflammation. Clinically, there is episodic or continuous upper abdominal pain. Alcohol is responsible for more than 80% of adult cases in the industrialized countries. Between 10% and 40% of all patients presenting with CP have no recognizable predisposing factor. Intractable abdominal pain is the main feature in more than 95% of patients with CP and can manifest as repeated attacks of mild to severe pain or as persistent epigastric or back pain.

OUTLINE

Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Prognosis
Treatment
Commonly Used Terms
Internet Links

DISEASE ASSOCIATIONS	CHARACTERIZATION
Complications of chronic pancreatitis	Cysts, pseudocysts, pancreatic calcifications, diabetes mellitus, or pancreatic exocrine insufficiency.
Abnormalities of the ductal system	Pancreas divisum and abnormalities of the duct system

 

PATHOGENESIS	CHARACTERIZATION
MAST CELLS
Mast cell distribution and activation in chronic pancreatitis Irene Esposito, MD Helmut Friess, MD Andreas Kappeler, PhD Shailesh Shrikhande, MD Jörg Kleeff, MD Hariharan Ramesh, MD Arthur Zimmermann, MD Markus W. Büchler, MD	Hum Pathol 2001;32:1174-1183. Abstract quote Chronic pancreatitis (CP) is characterized by mononuclear inflammatory cell infiltration and replacement of the destroyed parenchyma by fibrous tissue. Recently, mast cells have been implicated in chronic inflammatory processes with fibrous tissue deposition. Therefore, the number and distribution of mast cells and their state of activation were evaluated in 12 normal specimens and in 46 specimens of CP with different causes (alcoholic, tropical, and idiopathic). Furthermore, the presence of stem cell factor (SCF), the main mast cell growth factor, and of its receptor, c-kit, was also assessed. In CP tissues, mast cells were localized both in the fibrotic areas and in the residual acinar parenchyma. The total number of mast cells was significantly higher in CP than in the normal pancreas (P < .0001) and correlated positively with the extent of fibrosis and the intensity of inflammation. Immunoglobulin E (IgE)–dependent mast cell activation was higher in CP than in the normal pancreas. No differences in mast cell number or IgE positivity were found among the 3 causes of CP. SCF–and c-kit immunoreactive mast cells were mostly localized in fibrous tissue and around regenerating ducts, which were also positive for c-kit but were negative for SCF. These results suggest that mast cells, activated by an IgE-dependent mechanism and/or by an SCF–c-kit autocrine loop, are a relevant component of the inflammatory infiltrate in CP, independent of the underlying cause. Their localization near degenerating acini and regenerating ducts might indicate that they play a crucial role in tissue destruction and remodeling in CP.
p16
p16 Inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis. Rosty C, Geradts J, Sato N, Wilentz RE, Roberts H, Sohn T, Cameron JL, Yeo CJ, Hruban RH, Goggins M. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.	Am J Surg Pathol. 2003 Dec;27(12):1495-501. Abstract quote   Patients with long-standing chronic pancreatitis are thought to be at increased risk of developing pancreatic ductal adenocarcinoma, but the mechanism for this increased risk is unknown. Since increasing evidence supports the notion that infiltrating pancreatic ductal adenocarcinomas arise from pancreatic intraepithelial lesions (PanINs), we sought to determine if patients with chronic pancreatitis harbor PanINs with alterations in tumor suppressor genes that are associated with infiltrating pancreatic ductal adenocarcinoma. We identified 122 patients with a diagnosis of chronic pancreatitis and 29 patients with a well-differentiated pancreatic endocrine tumor that underwent pancreatic surgery at the Johns Hopkins Hospital from 1985 to 1999. PanINs from each resection specimen were identified, graded, counted, and correlated with smoking and alcohol history. The expression patterns of p16 and Smad4 were determined in a subset of PanINs by immunohistochemistry, and the pattern of labeling compared with that seen in PanINs associated with infiltrating adenocarcinoma of the pancreas as identified in prior studies, and to PanINs associated with pancreatic endocrine tumor. Duct lesions were present in 80 of the 122 pancreata with chronic pancreatitis (66%). Of 405 duct lesions identified in the chronic pancreatitis group, 7.6% were reactive changes, 65.5% were PanIN-1A, 18% were PanIN-1B, 7.4% were PanIN-2, and 1.5% were PanIN-3. Within the pancreatic endocrine tumor group, 22 PanINs were identified: 15 PanIN-1A, 4 PanIN-1B, and 3 PanIN-2. There were significantly fewer high-grade PanINs in the pancreata with chronic pancreatitis than in pancreata with pancreatic adenocarcinoma (P < 0.0001). Within the chronic pancreatitis group, the 80 patients with PanINs were significantly older than the 42 patients without PanINs (mean age 57.0 +/- 14.1 years vs. 50.9 +/- 14.7 years, P = 0.01). Smoking history was not associated with PanIN prevalence or grade, but patients who reported a history of excessive alcohol consumption had fewer PanINs (25 of 44 harbored PanINs, 57%) than those who did not (54 of 74, 73%, P = 0.07). In the chronic pancreatitis group, 0% of PanIN-1A, 11% of the PanIN-1B, 16% of the PanIN-2, and 40% of the PanIN-3 lesions showed loss of p16 expression, whereas all of the PanINs from patients with an pancreatic endocrine tumor retained p16 expression. All of the PanINs analyzed from patients with chronic pancreatitis retained normal Smad4 expression. We conclude that a significant minority of PanINs arising in patients with chronic pancreatitis show loss of p16 expression. This alteration, common to pancreatic cancer-associated PanINs, may contribute to the predisposition of patients with chronic pancreatitis to develop pancreatic ductal adenocarcinoma.

 

LABORATORY/ RADIOLOGY	CHARACTERIZATION
PROTEIN KINASE C
Expression Patterns of Protein Kinase C Isoenzymes Are Characteristically Modulated in Chronic Pancreatitis and Pancreatic Cancer James D. Evans, MD, FRCS Philip A. Cornford, FRCS Andrew Dodson John P. Neoptolemos, MA, MD, FRCS Christopher S. Foster, MD, PhD, DSc, FRCPath	Am J Clin Pathol 2003;119:392-402 Abstract quote We immunohistochemically identified protein kinase C (PKC) isoenzymes and the receptor for activated C-kinase (RACK-1) in normal, chronically inflamed, and malignant pancreas specimens. Expression patterns were specific and consistent for each microanatomic structure. In chronic pancreatitis, the expression patterns by epithelial cells were indistinguishable from those in normal pancreas. In the stroma, there was a gain of PKC-delta (P < .05) and loss of PKC-mu (P < .0001). Expression in pancreatic duct carcinomas, compared with control normal minor ductular epithelial cells, revealed relative loss of PKC-epsilon (P < .0001), PKC-iota (P = .005), and PKC-theta (P < .0001) but no gain in any isoenzyme. Compared with control normal major duct epithelial cells, the principal differences were a relative loss in PKC-gamma (P < .05) and a relative gain in PKC-beta (P < .05), PKC-iota (P < .05), and PKC-zeta (P < .005). The stroma adjacent to ductal carcinomas was characterized by prominent expression of PKC-mu and a gain in PKC-delta (P < .0001) and PKC-zeta (P > .005). Ampullary carcinomas revealed a relative gain of PKC-iota (P < .05) and RACK-1 (P < .05). In the adjacent stroma was enhanced expression of PKC-delta (P < .005) and PKC-gamma (P < .001) and loss of PKC-mu (P < .05). Specific changes in isoenzyme expression in stroma of chronic pancreatitis and in epithelial cells and stroma of ductal and ampullary pancreatic adenocarcinomas reflect specific modulation of intracellular signaling pathways that control critical homeostatic mechanisms.

 

CLINICAL VARIANTS	CHARACTERIZATION
AUTOIMMUNE
Autoimmune Pancreatitis: A Systemic Immune Complex Mediated Disease. Deshpande V, Chiocca S, Finkelberg D, Selig MK, Mino-Kenudson M, Brugge WR, Colvin RB, Lauwers GY. Departments of *Pathology, and daggerMedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.	Am J Surg Pathol. 2006 Dec;30(12):1537-1545. Abstract quote Autoimmune pancreatitis (AIP) is a mass forming inflammatory pancreatobiliary-centric disease. Recent reports of multiorgan inflammatory mass forming lesions with increased numbers of IgG4 positive plasma cells suggest that AIP may have a systemic component. In this study, we explore the systemic nature of AIP, investigate the relevance of subtyping AIP, perform a systematic study of tissue IgG4 immunoperoxidase, and ultrastructurally evaluate the presence of immune complexes. Our study group consisted of 36 patients with AIP, 21 of whom underwent a Whipple procedure. On the basis of the pattern of inflammation, pancreatic involvement was subtyped as ductocentric (AIP-D) or lobulocentric (AIP-L). Extrapancreatic lesions included bile duct (n=3), salivary glands (n=3), lung (n=2), gallbladder (n=11), and kidney (n=4). Clinical and radiologic data was recorded. Immunohistochemistry for IgG4 was performed on both pancreatic and extrapancreatic tissues and the numbers of IgG4 positive plasma cells were semiquantitatively scored. A control cohort composed of pancreatic adenocarcinoma (n=19) and chronic pancreatitis-not otherwise specified (NOS) (n=14) was also evaluated. Eleven pancreatic specimens, including 2 cases of chronic pancreatitis-NOS and 4 kidneys were evaluated ultrastructurally. The pancreas, bile duct, gall bladder, salivary gland, kidney, and lung lesions were characterized by dense lymphoplasmacytic infiltrates with reactive fibroblasts and venulitis. IgG4 positive plasma cells were identified in all pancreatic and extrapancreatic lesions. The AIP cases showed significantly more pancreatic IgG4 positive plasma cells than chronic pancreatitis-NOS or adenocarcinoma (P=0.001). However, IgG4 positive cells were identified in 57.1% of chronic pancreatitis-NOS and 47.4% of ductal adenocarcinoma. Fifteen of 21 resected cases were classified as AIP-D, and 6 as AIP-L, the latter notably showing significantly more IgG4 positive plasma cells than the former (P=0.02). Additionally, clinical and radiologic differences emerged between the 2 groups. Ultrastructurally, electron dense deposits of immune complexes were identified in the basement membranes of 7 of the 9 AIP cases and in 3 of the 4 renal biopsies evaluated. AIP represents the pancreatic manifestation of a systemic autoimmune disease. Clinical and immunologic findings justify the recognition of pancreatic lobulocentric and ductocentric subtypes. Documentation of increased numbers of tissue IgG4 positive plasma cells, although not an entirely specific marker for AIP, may provide ancillary evidence for the diagnosis of a IgG4-related systemic disease.
Autoimmune pancreatitis: more than just a pancreatic disease? A contemporary review of its pathology. Deshpande V, Mino-Kenudson M, Brugge W, Lauwers GY. Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.	Arch Pathol Lab Med. 2005 Sep;129(9):1148-54. Abstract quote   CONTEXT: Autoimmune pancreatitis (AIP) is a chronic inflammatory condition of the pancreas constituting one quarter of Whipple resections performed for benign conditions in North America. OBJECTIVE: We review the clinical, radiologic, and characteristic histopathologic patterns of this disease and discuss the extrapancreatic manifestations of AIP. DESIGN: We searched the literature using MEDLINE and OVID, related conference abstracts, and bibliographies of selected studies. RESULTS: Autoimmune pancreatitis predominantly affects elderly individuals, frequently presenting as obstructive jaundice and occasionally in association with other autoimmune diseases. The histology is characterized by a collar of periductal inflammation, obliterative phlebitis, and the absence of stigmata of alcoholic pancreatitis. A prepancreatectomy diagnosis can be rendered using a combination of clinical findings, radiologic features, elevated immunoglobulin G4 levels, endoscopic ultrasound-guided fine-needle aspiration biopsy, and response to steroids. The disease can involve the bile ducts (sclerosing cholangitis), gallbladder (lymphoplasmacytic sclerosing cholecystitis), and kidney (interstitial nephritis) and can form inflammatory masses in the lungs. CONCLUSIONS: Despite significant evolution in our understanding of AIP, a prepancreatectomy diagnosis remains a challenge in the North American and European population.
Autoimmune Pancreatitis: Pathological, Clinical, and Immunological Features. Kloppel G, Luttges J, Lohr M, Zamboni G, Longnecker D. *Department of Pathology, University of Kiel, Kiel, Germany; dagger Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; double dagger Department of Pathological Anatomy, University of Verona, Verona, Italy; section sign Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.	Pancreas. 2003 Jul;27(1):14-19. Abstract quote INTRODUCTION In recent years a type of chronic pancreatitis has been described that is clearly distinct from alcoholic chronic pancreatitis. It is characterized by its special pathology, immunologic features, clinical presentation, and steroid responsiveness. Because of its histologic hallmarks, i.e., ductal and periductal infiltration by lymphocytes, plasma cells, and granulocytes, it has been called duct-destructive chronic pancreatitis. The frequent association of this type of pancreatitis with other autoimmune diseases such as Sjogren's disease and a number of other immune phenomena has led to the concept that it is an autoimmune disease. Hence, the term autoimmune pancreatitis has been introduced and will be used in this review. AIMS This review focuses on the pathology and related clinical and immunologic features of this new type of pancreatitis. CONCLUSIONS As the ability to diagnose autoimmune pancreatitis on the basis of clinical, imaging, and laboratory findings improves, it seems likely that fewer patients with this diagnosis will undergo resection. Thus, there is a need to accumulate and study additional retrospective series of patients undergoing resection because of mass-forming chronic pancreatitis.
Clinical relevance of autoimmune-related pancreatitis. Okazaki K. Department of Gastroenterology and Endoscopic Medicine, Kyoto University Hospital, Sakyo, Kyoto, Japan.	Best Pract Res Clin Gastroenterol. 2002 Jun;16(3):365-78. Abstract quote Recently, a concept of 'autoimmune pancreatitis' (AIP) was proposed. Computed tomography, magnetic resonance imaging or ultrasonography show a diffusely enlarged pancreas with a so-called 'sausage-like' appearance. Hypergammaglobulinaemia, increased serum levels of total IgG or IgG4, positive autoantibodies such as antinuclear antibody, anti-lactoferrin antibody, anti-CA-II antibody, rheumatoid factor and anti-smooth muscle antibody, were often observed in patients with AIP. Microscopic findings showed fibrotic changes with infiltration of lymphocytes, plasmacytes and sometimes eosinophils in the pancreas. Major subgroups of lymphocytes infiltrating areas around pancreatic ducts were CD4(+) T-cells producing IFN-gamma. HLA-DR was expressed on pancreatic duct cells as well as CD4(+) cells. The diagnosis is made by a combination of clinical, laboratory and morphological findings. Laboratory data, pancreas images and diabetes mellitus in most patients do respond to steroid treatment. In conclusion, autoimmune-related pancreatitis appears to be a unique clinical entity. However, its importance in clinical practice needs further characterization.

HISTOPATHOLOGICAL VARIANTS	CHARACTERIZATION
AUTOIMMUNE (LYMPHOPLASMACYTIC SCLEROSING PANCREATITIS)
Endoscopic Ultrasound Guided Fine Needle Aspiration Biopsy of Autoimmune Pancreatitis: Diagnostic Criteria and Pitfalls. Deshpande V, Mino-Kenudson M, Brugge WR, Pitman MB, Castillo CF, Warshaw AL, Lauwers GY. From the Departments of *Pathology, daggerGastroenterology, and double daggerSurgery, Massachusetts General Hospital, Boston, MA.	Am J Surg Pathol. 2005 Nov;29(11):1464-1471. Abstract quote   Autoimmune pancreatitis (AIP) is a benign inflammatory disease of the pancreas that mimics pancreatic malignancy both clinically and radiologically. The fine needle aspiration biopsy (FNAB) features of AIP have not previously been documented. We report our experience with AIP, highlight pitfalls, and perform a comprehensive analysis of the cytomorphologic features of this condition. We identified 16 patients with AIP, initially evaluated by endoscopic ultrasound (EUS)-guided FNAB, 11 of whom subsequently underwent a pancreatoduodenectomy. We compared these to a cohort of EUS-guided aspirates from ductal carcinoma of the pancreas (n = 16) and chronic pancreatitis, not otherwise specified (NOS) (n = 19). On all 51 cases, we semiquantitatively evaluated presence and atypia of ductal cells, presence and cellularity of stromal fragments, and inflammatory cells, type and distribution. Fifty percent (8 of 16) of the AIP cases presented as obstructive jaundice. EUS and CT scan showed mass lesions in 10 and 6 cases, respectively. There were three false-positive cytologic diagnoses, an adenocarcinoma, a solid-pseudopapillary tumor and a mucinous neoplasm. Ductal epithelium was inconspicuous and was seen in 6 cases. The FNAB samples showed background lymphocytes in three AIP cases, a feature absent in the control cohort. Stromal fragments with embedded lymphocytes (greater than 30 per 60x) were seen in 37.5% of AIP cases and only rarely with adenocarcinoma (12.5%) and pancreatitis, NOS (0%). The cellularity of stromal fragments was significantly higher in AIP than in the control group. The presence of stromal fragments of high cellularity with a lymphoid infiltrate in conjunction with clinical and radiology findings could potentially both establish a diagnosis of AIP and exclude carcinoma, thus preventing pancreatic resection.
Lymphoplasmacytic sclerosing pancreatitis. Plaza JA, Colonna J, Vitellas KM, Frankel WL. Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, USA.	Ann Diagn Pathol. 2005 Oct;9(5):298-301. Abstract quote   Lymphoplasmacytic sclerosing pancreatitis is a rare entity that has been described under many different names and constitutes a diagnostic challenge as it may simulate a neoplastic process.   Herein, we report a case of a 61-year-old woman who presented to our institution complaining of left flank pain and was found to have normal levels of amylase and lipase. An abdominal magnetic resonance image showed thickening of the pancreatic tail and compression of the pancreatic duct. The radiographic differential included both chronic pancreatitis and a neoplastic process. She underwent an exploratory laparotomy, during which a pancreatectomy and splenectomy were performed. Grossly, the pancreas contained a yellowish white, firm homogeneous mass measuring 6.5 x 3.3 x 2.9 cm involving the entire pancreatic tail and hilum of the spleen.   Histologically, pancreatic sections showed extensive fibrosis admixed with an inflammatory infiltrate. This infiltrate was composed mainly of lymphocytes with multiple germinal centers, as well as plasma cells and eosinophils that surrounded pancreatic ducts and extended into the peripancreatic adipose tissue. No malignancy was identified, and the process was diagnosed as lymphoplasmacytic sclerosing pancreatitis.
Idiopathic chronic pancreatitis with periductal lymphoplasmacytic infiltration: clinicopathologic features of 35 cases. Notohara K, Burgart LJ, Yadav D, Chari S, Smyrk TC.	Am J Surg Pathol. 2003 Aug;27(8):1119-27. Abstract quote To clarify clinicopathologic features of idiopathic chronic pancreatitis with lymphoplasmacytic infiltration, we carried out a study of 35 cases. There were two histologic groups, which we have designated lymphoplasmacytic sclerosing pancreatitis and idiopathic duct-centric chronic pancreatitis. Lymphoplasmacytic sclerosing pancreatitis (22 cases) was a fibrosing process with diffuse lymphoplasmacytic infiltrates involving pancreatic lobules and ducts, adipose tissue, blood vessels, and common bile duct. Obliterative phlebitis was found in every case except for one. The histologic features were similar to other idiopathic fibrosclerosing disorders, and one patient also had retroperitoneal fibrosis. Affected patients tended to be elderly men. Idiopathic duct-centric chronic pancreatitis (13 cases) was characterized by inflammatory infiltrates (including neutrophils) that were denser in the lobules than in interlobular fibrotic areas. Neutrophils were also prominent in the ducts, and destruction of the duct epithelium was commonly seen. Patient ages were more broadly distributed than in lymphoplasmacytic sclerosing pancreatitis. Two patients had inflammatory bowel disease. We conclude that idiopathic chronic pancreatitis with lymphoplasmacytic infiltration, sometimes called autoimmune pancreatitis, consists of at least two different processes. One of these, lymphoplasmacytic sclerosing pancreatitis, is a histologically unique lesion and could be a pancreatic manifestation of idiopathic fibrosclerosing disorders.

 

PROGNOSIS AND TREATMENT

CHARACTERIZATION

Major Pancreatic Resections for Chronic Pancreatitis Histologic Findings and Their Association with Persistent Pain Daniela M. Proca, MD, E. Christopher Ellison, MD, Dan Hibbert, BS, and Wendy L. Frankel, MD From the Departments of Pathology (Drs Proca and Frankel and Mr Hibbert) and Surgery (Dr Ellison), The Ohio State University Medical Center, Columbus, Ohio.

Arch Pathol Lab Med 2001;125:1051–1054. Abstract quote Objective. —Indications for major pancreatic resections have been expanded to include complicated chronic pancreatitis (CP). We assessed clinical findings and outcomes and evaluated histology in patients who had major pancreatic resections for CP. We also determined if histologic findings were associated with persistent postoperative pain. Design.—We reviewed charts and slides from 44 patients who underwent major pancreatic resections for CP between 1989 and 1999. Results. —The etiology for disease included alcohol (n = 15), hereditary (n = 5), idiopathic (n = 6), pancreas divisum (n = 3), stricture (n = 2), trauma (n = 2), systemic lupus erythematosus (n = 1), and unknown (n = 10). Patients included 20 men and 24 women; ages ranged from 22 to 76 years. Perioperative mortality and morbidity were 0% and 4.5%, respectively. Persistent pain was present in 25 (57%) of the 44 patients, and pain was encountered more frequently in patients with alcoholic pancreatitis (67%) versus other etiologies (52%), and in those who underwent Whipple/Beger or total resections (68%) versus distal or subtotal pancreatectomy (42%). Metaplastic changes were present in 14 cases, and ductal atypia was seen in 9 cases. No malignancies were found. Acinar necrosis and acute inflammation were seen more often in patients with persistent pain than in those who were pain free (P = .081). Conclusions. —Major pancreatic resection for CP can be performed with low morbidity and mortality. This procedure relieves pain in nearly half the patients. There is a wide spectrum of histopathologic changes seen in CP, including ductal atypia and metaplastic changes. Acute exacerbations of CP identified histologically at the time of surgery and alcohol as etiology for CP may be associated more frequently with intractable pain.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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