Nonneoplastic Entities
Chronic Pancreatitis
Clinical Features
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Defined by irreversible loss of pancreatic parenchyma and function caused by inflammation
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Patients present with recurrent attacks of abdominal and back pain and evidence of loss of pancreatic function including exocrine insufficiency (malabsorption and steatorrhea) and diabetes mellitus
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Alcohol abuse is the leading cause of chronic pancreatitis in Western countries. Other common causes include obstruction of the ducts by biliary calculi or a neoplasm, smoking, and hereditary pancreatitis. Cystic fibrosis is the leading cause of chronic pancreatitis in the pediatric population
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Chronic pancreatitis has a poor long-term prognosis with a 20-year mortality rate of 50%
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When localized, chronic pancreatitis can be mass forming and clinically, radiologically, and pathologically mimic pancreatic cancer
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Pancreatic cancer can cause chronic pancreatitis, and long-standing chronic pancreatitis, particularly hereditary pancreatitis, can increase the risk of developing pancreatic cancer
Gross Pathology
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Diffuse atrophy of the gland with firm white fibrosis
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Chronic pancreatitis may produce a localized ill-defined masslike lesion that may mimic pancreatic cancer
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When caused by alcohol abuse may have associated pseudocysts and intraductal calculi
Histopathology
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Defined by inflammation with destruction of pancreatic parenchyma and replacement of the parenchyma by fibrous connective tissue and fat ( Figure 8.1 )
Figure 8.1
Chronic pancreatitis.
Low-power view shows fibrosis and acinar drop-out; however, the lobular architecture is maintained (left) . Note the aggregation of islets (right) .
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Lobular architecture of the parenchyma is often retained
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Extensive loss of acinar tissue is seen (“acinar drop-out”) with additional acinar-ductal metaplasia
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Remaining ductal epithelium can be atrophic or reactive
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Residual islets of Langerhans may aggregate producing enlarged islets of Langerhans that mimic a neuroendocrine neoplasm
Special Stains and Immunohistochemistry
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Noncontributory
Other Techniques for Diagnosis
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Germline testing for inherited mutations in the PRSS1 and other genes available for familial pancreatitis
Differential Diagnosis
Infiltrating Ductal Adenocarcinoma
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Haphazard arrangement of glands with loss of lobular architecture at low-power
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Glands immediately adjacent to muscular vessels
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Perineural invasion
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Vascular invasion
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Variation in the area of nuclei in a single gland by more than 4 to 1 (“4 to 1 rule”)
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Incomplete lumina
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Luminal necrosis
Well-Differentiated Pancreatic Neuroendocrine Tumor
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Larger size and tendency to produce a single hormone (monoclonal)
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Chronic pancreatitis can clinically and pathologically mimic pancreatic cancer, yet the two entities are treated vastly differently.
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Growth pattern and location are the two most helpful features in distinguishing reactive from neoplastic glands.
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Avoid over-diagnosing the aggregated islets of Langerhans in chronic pancreatitis as a neuroendocrine neoplasm.
Selected References
1. Hruban R.H., Pitman M.B., Klimstra D.S.: Tumors of the Pancreas. Atlas of Tumor Pathology. Fourth Series.Fascicle 6th ed.2007.American Registry of Pathology and Armed Forces Institute of PathologyWashington, DC
2. Shimosegawa T., Chari S.T., Frulloni L., et. al.: International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas 2011; 40: pp. 352-358.
3. Zamboni G., Capelli P., Scarpa A., et. al.: Nonneoplastic mimickers of pancreatic neoplasms. Arch Pathol Lab Med 2009; 133: pp. 439-453.
Autoimmune Pancreatitis
Clinical Features
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Defined by irreversible loss of pancreatic parenchyma and function caused by the body’s own immune system targeting the pancreas.
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Patients present with signs and symptoms of pancreatitis including recurrent attacks of abdominal and back pain and evidence of loss of pancreatic function including exocrine insufficiency (malabsorption and steatorrhea) and diabetes mellitus
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Patients also often have other autoimmune diseases such as chronic sclerosing sialadenitis (Küttner tumor), primary sclerosing cholangitis, inflammatory bowel disease, retroperitoneal fibrosis (Ormond disease), and Reidel thyroiditis
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Typically diffusely enlarges the gland, imparting a “sausage-like” appearance on imaging
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Autoimmune pancreatitis can form a mass lesion, and can therefore clinically, radiologically, and pathologically mimic pancreatic cancer
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Autoimmune (lymphoplasmacytic sclerosing) pancreatitis is associated with elevated serum IgG4 levels and is considered part of the spectrum of IgG4 (immunoglobulin G4)-related systemic disease
Gross Pathology
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Typically, diffusely enlarges the gland, but in some instances it may produce a localized ill-defined mass-like lesion that may mimic pancreatic cancer.
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Autoimmune pancreatitis often affects the head of the pancreas.
Histopathology
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Type I autoimmune (lymphoplasmacytic sclerosing)/IgG4-related pancreatitis is characterized by a duct-centric mixed plasma cell–rich inflammatory infiltrate, storiform interstitial fibrosis, and venulitis ( Figure 8.2 ) .
Figure 8.2
Autoimmune (lymphoplasmacytic sclerosing) pancreatitis. A, Characteristic mixed duct-centric inflammatory cell infiltrate. B, Immunolabeling for IgG4 highlighting an increased number of IgG4 expressing cells. C and D, Venulitis almost obliterating the vein. D is a Verhoeff van Gieson stain.
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Type II autoimmune pancreatitis has granulocytic epithelial lesions (GELs) defined by granulocytes within the ductal epithelium.
Special Stains and Immunohistochemistry
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Immunolabeling for IgG4 reveals increased numbers of IgG4 expressing plasma cells (ratio of IgG4:IgG expressing plasma cells >0.30 and/or >50 IgG4 expressing plasma cells in a single high power field).
Other Techniques for Diagnosis
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Not applicable
Differential Diagnosis
Other Forms of Chronic Pancreatitis
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Alcohol-related
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Obstructive
Infiltrating Ductal Adenocarcinoma
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Haphazard arrangement of glands with loss of lobular architecture at low power
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Glands immediately adjacent to muscular vessels
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Perineural invasion
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Vascular invasion
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Variation in the area of nuclei in a single gland by more than 4 to 1 (“4 to 1 rule”)
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Incomplete lumina
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Luminal necrosis
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Autoimmune pancreatitis is important to recognize because it may respond to treatment with steroids.
Selected References
1. Detlefsen S., Klöppel G.: IgG4-related disease with emphasis on the biopsy diagnosis of autoimmune pancreatitis and sclerosing cholangitis. Virchows Arch 2018; 472: pp. 545-556.
2. Shinagare S., Shinagare A.B., Deshpande V.: Autoimmune pancreatitis: a guide for the histopathologist. Semin Diagn Pathol 2012; 29: pp. 197-204.
3. Shimosegawa T., Chari S.T., Frulloni L., et. al.: International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas 2011; 40: pp. 352-358.
Pancreatic Pseudocyst
Clinical Features
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Account for 75% of cystic lesions of the pancreas
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The abnormal release of pancreatic enzymes causes the localized digestion of intrapancreatic and extrapancreatic tissues
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A complication of acute pancreatitis, often in the setting of chronic alcoholic pancreatitis
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May spontaneously resolve, may become infected, or may perforate adjacent organs
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Cyst fluid analysis typically demonstrates high amylase levels (>250 U/L) and low carcinoembryonic antigen (CEA) levels (<5 ng/mL)
Gross Pathology
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Usually solitary
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Usually extrapancreatic; often involving peripancreatic tissues such as the lesser omental sac, the retroperitoneum between the stomach and transverse colon, and the space between the stomach and the liver
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Cysts filled with hemorrhagic necrotic debris rich in pancreatic enzymes
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Associated with peripancreatic hemorrhagic fat necrosis
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Range in size from 2 to 30 cm
Histopathology
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Cysts contain necrotic and hemorrhagic debris with hemosiderin-laden macrophages
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Pseudocysts lack a true epithelial lining
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Locule lined by granulation and fibrous connective tissue
Special Stains and Immunohistochemistry
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Noncontributory
Other Techniques for Diagnosis
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Noncontributory
Differential Diagnosis
Cystic Neoplasms of the Pancreas
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Cystic neoplasms have a true epithelial lining and typically contain mucous or serous fluid.
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Solid-pseudopapillary neoplasms can contain hemorrhagic and necrotic debris, but they will have poorly cohesive epithelial cells surrounding delicate branching blood vessels.
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Mucinous cystic neoplasms often show extensive degenerative changes with areas of epithelial loss, hemorrhage, and necrotic debris, extensive sampling should demonstrate a mucinous epithelial lining and will always demonstrate ovarian-type stroma.
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Serous cyst adenomas may show extensive degenerative changes with hemorrhage, particularly following fine needle aspiration, that may obscure the epithelial lining. Cytokeratin immunolabeling may help highlight the residual cyst lining in this setting.
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Suspect a mimicker of a pseudocyst if the patient does not have a clinical history of acute or chronic pancreatitis, and when the pancreatic parenchyma is normal.
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Extensive sampling may be necessary to demonstrate an epithelial lining in a cystic neoplasm.
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Cyst fluid amylase levels should be high in pseudocysts.
Selected References
1. Hruban R.H., Pitman M.B., Klimstra D.S.: Tumors of the Pancreas. Atlas of Tumor Pathology. Fourth Series.Fascicle 6th ed.2007.American Registry of Pathology and Armed Forces Institute of PathologyWashington, DC
2. Klöppel G.: Pseudocysts and other nonneoplastic cysts of the pancreas. Semin Diagn Pathol 2000; 17: pp. 7-15.
3. Panarelli N.C., Park K.J., Hruban R.H., et. al.: Microcystic serous cystadenoma of the pancreas with subtotal cystic degeneration: another neoplastic mimic of pancreatic pseudocyst. Am J Surg Pathol 2012; 36: pp. 726-731.
Lymphoepithelial Cyst
Clinical Features
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Often an incidental finding
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Very rare with only ∼50 cases reported
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Predominantly in men with a 4 to 1 male to female ratio
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Mean age ∼55 years
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Sharp delineation from pancreatic parenchyma on imaging; may be extrapancreatic
Gross Pathology
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Typically unilocular
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Mean size ∼5 cm
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Well-demarcated, filled with keratinaceous (cheesy) debris ( Figure 8.3A )
Figure 8.3
A, Lymphoepithelial cyst. The cyst is well-defined and filled with keratinaceous debris. B, Lymphoepithelial cyst. The cyst is lined by mature squamous epithelium with an underlying lymphoid infiltrate.
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Cysts have thin walls
Histopathology
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Cysts lined by mature keratinizing squamous epithelium (see Figure 8.3B )
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Subepithelial layer of lymphoid tissue often with germinal center formation
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May have scattered sebaceous glands, but NO significant skin adnexal structures and NO components with other directions of differentiation
Special Stains and Immunohistochemistry
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Noncontributory
Other Techniques for Diagnosis
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Noncontributory
Differential Diagnosis
Mature Cystic Teratoma (Dermoid Cyst)
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In addition to the squamous epithelium, these will have other elements including skin adnexal structures and often mature mesenchymal elements such as cartilage.
Epidermoid Cyst in Heterotopic Spleen
Distinctive cystic lesion can also be lined by mature squamous epithelium. Instead of a lymphoid infiltrate, the associated cells are those of normal splenic parenchyma.
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The keratinous debris can resemble the necrotic contents of a pseudocyst.
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Unlike their counterparts in the head and neck, no relationship to immunosuppression and Epstein-Barr virus (EBV) infection has been found.
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CEA levels may be high in cyst fluid analysis, causing clinical confusion with a mucinous cyst.
Selected References
1. Adsay N.V., Hasteh F., Cheng J.D., et. al.: Lymphoepithelial cysts of the pancreas: a report of 12 cases and a review of the literature. Mod Pathol 2002; 15: pp. 492-501.
2. Groot V.P., Thakker S.S., Gemenetzis G., et. al.: Lessons learned from 29 lymphoepithelial cysts of the pancreas: institutional experience and review of the literature. HPB 2018; 20: pp. 612-620.
3. Hruban R.H., Pitman M.B., Klimstra D.S.: Tumors of the Pancreas. Atlas of Tumor Pathology. Fourth Series.Fascicle 6th ed.2007.American Registry of Pathology and Armed Forces Institute of PathologyWashington, DC
Neoplasms With Exocrine Differentiation
Serous Cystic Neoplasms
Clinical Features
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Slightly more common in women than in men with a female to male ratio of 7 to 3
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Mean age ∼65 years
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Can be associated with the von Hippel-Lindau syndrome (VHL)
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Present nonspecifically as large abdominal masses
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Vast majority are entirely benign with only a few case reports of aggressive behavior
Gross Pathology
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Typically composed of innumerable small cysts (microcystic) ( Figure 8.4A )
Figure 8.4
A, Serous cystadenoma. The lesion has a central scar with innumerable thin-walled small cysts. B, Serous cystadenoma. The relatively small cysts are lined by a single layer of glycogen-rich cuboidal epithelial cells with round uniform nuclei.
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Rarely composed of a few larger cysts (macrocystic), solid (solid serous adenoma), or combined with a well-differentiated pancreatic neuroendocrine neoplasm (especially in patients with VHL)
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Well-demarcated, often with a central stellate scar; the scar may contain calcifications
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Cysts are thin-walled and contain watery straw-colored fluid
Histopathology
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Cysts are lined by a flat cuboidal epithelium. The epithelial cells have optically clear cytoplasm and round, centrally placed, uniform nuclei (see Figure 8.4B ).
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Mitoses and nuclear pleomorphism are not seen.
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Stroma between the cysts is composed of relatively acellular fibrous connective tissue.
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Solid variant is composed of sheets and nests of cells cytologically identical to the more common cystic variety.
Special Stains and Immunohistochemistry
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The cells contain abundant glycogen and therefore stain with the periodic acid–Schiff (PAS) stain and this staining is sensitive to diastase digestion (PAS-D).
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The epithelial cells label with antibodies to cytokeratin (AE1/AE3 and CAM5.2) and a third label for epithelial membrane antigen (EMA).
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Immunolabeling for CEA is negative.
Other Techniques for Diagnosis
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Some harbor mutations in the VHL gene. These include point mutations or loss of the entire allele.
Differential Diagnosis
Mucinous Cystic Neoplasm
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Cysts have a thick wall and contain gooey tenacious mucin
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Cysts lined by tall columnar cells containing large quantities of mucin
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Distinctive ovarian-type stroma
Intraductal Papillary Mucinous Neoplasm
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Cysts contain tenacious mucin
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Cysts lined by tall columnar cells containing mucin
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Cysts communicate with larger pancreatic ducts
Lymphangioma
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Flat cells lining spaces
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Associated lymphoid aggregates in cyst walls
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Express CD31 and factor VIII–related antigen
Metastatic Renal Cell Carcinoma (Particularly for Solid Serous Adenoma)
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Nuclear atypia and prominent nucleoli
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Nests invested with delicate capillaries
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Immunolabel for paired box 8 protein (PAX8) and carbonic anhydrase IX (CAIX)
Well-Differentiated Neuroendocrine Tumor With Clear Cell Change (Particularly for Solid Serous Adenoma)
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Salt and pepper chromatin with cleared cytoplasm
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Organoid architectural patterns with nesting, ribbons, trabeculae
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Immunolabel for synaptophysin and chromogranin
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The relationship of the cysts to the pancreatic ducts (lack of connection), the cyst contents, and the morphology of the cells lining the cysts can all be used to establish the diagnosis.
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Radiologic feature of a central stellate scar with calcifications can be characteristic.
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Serous cystadenomas often show extensive degenerative changes after fine needle aspiration, and immunolabeling cytokeratins can be helpful to identify the residual cyst lining.
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Serous cystadenocarcinomas are extremely rare and can be distinguished from benign serous neoplasms only by their aggressive behavior (spread to other organs).
Selected References
1. Galanis C., Zamani A., Cameron J.L., et. al.: Resected serous cystic neoplasms of the pancreas: a review of 158 patients with recommendations for treatment. J Gastrointest Surg 2007; 11: pp. 820-826.
2. Hruban R.H., Pitman M.B., Klimstra D.S.: Tumors of the Pancreas. Atlas of Tumor Pathology. Fourth Series.Fascicle 6th ed.2007.American Registry of Pathology and Armed Forces Institute of PathologyWashington, DC
3. Panarelli N.C., Park K.J., Hruban R.H., et. al.: Microcystic serous cystadenoma of the pancreas with subtotal cystic degeneration: another neoplastic mimic of pancreatic pseudocyst. AJSP 2012; 36: pp. 726-731.
Mucinous Cystic Neoplasms
Clinical Features
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Much more common in women than in men with a female to male ratio of 20 to 1
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Mean age ∼45 years
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Present nonspecifically as a large abdominal mass
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A third harbor an associated invasive adenocarcinoma
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The presence or absence of an associated invasive carcinoma drives prognosis; those without an associated invasive carcinoma are cured when completely resected
Gross Pathology
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Vast majority occur in the body or tail of the pancreas
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Usually solitary and multilocular
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Composed of large 1- to 3-cm thick-walled cysts containing tenacious mucin ( Figure 8.5A )
Figure 8.5
A, Mucinous cystic neoplasm. The neoplasm is composed of large well-demarcated mucin-containing cysts. As is typical, this tumor arose in the tail of the pancreas. B, Mucinous cystic neoplasm with low-grade dysplasia: The cyst is lined by tall columnar cells with abundant intracellular mucin. Note the characteristic ovarian-type stroma. C, Mucinous cystic neoplasm with high-grade dysplasia: The mucin-producing epithelium is now architecturally complex and there is significant nuclear pleomorphism.
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The cysts do not communicate with the larger pancreatic ducts
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The lining of the cysts can be smooth or prominent papillary structures can project into the lumina
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Some locules may contain hemorrhagic fluid
Histopathology
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Cysts are lined by tall columnar epithelium with varying degrees of architectural and cytologic atypia.
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Noninvasive tumors are classified into low-grade and high-grade dysplasia (see Figures 8.5B and C ).
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High-grade dysplasia and even invasive cancer can be very focal and one-third of cases harbor an associated invasive ductal adenocarcinoma.
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The stroma is cellular, comprised of plump, spindled cells and is histologically similar to ovarian stroma.
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Degenerative changes are common, with hemorrhage, hemosiderin deposition, foamy macrophage accumulation, and chronic inflammation that can obscure the cyst lining.
Special Stains and Immunohistochemistry
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PAS, PAS with diastase treatment, and mucicarmine positive
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The epithelium labels with antibodies to cytokeratin and CEA
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The stroma labels with antibodies to inhibin, and to progesterone (PR) and estrogen receptors (ER)
Other Techniques for Diagnosis
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The neoplastic epithelium may harbor KRAS2, RNF43, p16/CDKN2A, and TP53 gene mutations.
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Most noninvasive mucinous cystic neoplasms have intact Smad4 expression, while half of the invasive cancers associated with mucinous cystic neoplasms show loss of Smad4 expression
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The mutations present in the neoplastic epithelial cells can be detected in the cyst fluid.
Differential Diagnosis
Intraductal Papillary Mucinous Neoplasm
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Located in the head more frequently than in the body/tail of the gland
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The cysts connect to the larger pancreatic ducts
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Have a paucicellular, collagenous stroma, not ovarian-type stroma
Serous Cystic Neoplasm
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Cysts contain thin watery straw-colored fluid
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Cysts are usually smaller (microcystic) and have a thinner wall
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Central stellate scar
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Cysts lined by cuboidal glycogen-rich cells
Pseudocyst
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Cystic space contains hemorrhagic and necrotic material.
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Pseudocysts lack an epithelial lining.
