Hepatopancreaticobiliary pathology Jemimah Denson

EXOCRINE PANCREAS

Specimen cut-up Margins: –Transection: Pancreatic Bile duct (cystic, CHD, CBD) Gastric and duodenal –Dissection: SMV SMA Posterior CRM around CBD stump

Specimen cut-up From RCPath dataset copyright Paul Brown St James’s University Hospital, Leeds

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Chronic pancreatitis Causes: –ETOH + smoking (act synergistically) –Obstruction –hereditary Macro –Diffuse or focal – mimic tumour on imaging –Shrunken and very hard –Dilated ducts with concretions.

Chronic pancreatitis Micro: –Acinar atrophy –Fibrosis –Pancreatic duct changes –Inflammation often mild –Islets remain –Enlarged peripheral nerves –Perineural invasion!! Complicatons – DM, pseudocyst, vascular

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Autoimmune pancreatitis Two types: Type 1 – part of IgG4 disease spectrum Type 2 – don’t have raised IgG4 & rarely develop extrapancreatic IgG4 disease. Requires tissue for diagnosis.

Autoimmune pancreatitis Macro –Usually diffuse but can be focal & mass forming –Main PD is diffusely or segmentally narrowed (cf other forms of pancreatitis) –60% pancreatic head involved with narrowing of CBD –May involved peripancreatic fat & enlarge LNs – mimics Ca

Autoimmune pancreatitis Micro –Common to both types: Periductal lymphoplasmacytic inflammation Inflammation of acinar parenchyma Patchy distribution –Type I Storiform fibrosis Obliterative phlebitis Involvement of peripancreatic fat –Type II Granulocytic epithelial lesion (GEL)

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IgG4 What is positivity?? Depends on tissue and criteria HISORt –>10 positive cells per hpf –Better for biopsy material Boston –>50 positive cells per hpf AND IgG4:IgG >40% –Better for resection specimens Interpret with caution

Groove pancreatitis I have yet to see an example Aka paraduodenal pancreatitis Clinical history Underlying cause is ectopic pancreatic tissue within wall of duodenum – usually between ampulla of Vater and minor ampulla. Impaired drainage of pancreatic secretions leads to duct dilatation, cyst formation, rupture and inflammation. Worsened by ETOH

Groove pancreatitis Cysts in duodenal wall and pancratoduodenal groove Cystic spaces lined by flattened ductal epithelium or granulation tissue Acute and chronic inflammation Thickened duodenal MP with other foci of ectopic pancreas Brunner’s gland hyperplasia

Case history 25 year old female Abdominal and back pain, N&V, early satiety Imaging – large solid and cystic neoplasm in head of pancreas

Microscopy

Solid pseudopapillary neoplasm Characteristically young females Low grade malignant but usually excellent prognosis Usually solitary Anywhere in pancreas Solid or cystic and anything in between, cyst is degenerative Usually encapsulated

Solid pseudopapillary neoplasm Poorly cohesive monomorphic cells Pseudopapillae Degnerative changes Cells: –Eosinophilic, foamy or vacuolated –Nucleus often indented or grooved –Eosinophilic globules

SPN immunohistochemistry Positive Vimentin, CD10, β-catenin (nuclear and cytoplasmic), PR, ORA beta, CD56, NSE A1AT/A1ACT highlight eos. globules +/- Synaptophysin, epithelial markers Negative CK 7 & 19, chromogranin A, ORA alpha

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Pancreatic cysts Neoplastic epithelial: Serous cystic neoplasm Mucinous cystic neoplasm IPMN SPN Acinar cell cystadenoma Cystic teratoma Cystic ductal adenocarcinoma Cystic pancreatoblastoma Cystic mets Nonneoplastic epithelial: Congenital cyst Duplication Choledochal cyst Cystic hamartoma Lymphoepithelial cyst Retention cyst Groove pancreatitis Endometrial cyst Neoplastic non-epithlieal: Lymphangioma Haemangioma Cystic schwannoma Cystic degeneration in LMS Cystic degeneration in GIST Cystic degeneration in MPNST Cystic degeneration in paraganglioma Nonneoplastic non-epithelial: Pseudocysts Parasitic cysts

Serous cystic neoplasms Serous cystadenoma or cystadenocarcinoma (very rare) Microcystic (more♀) or macrocystic (more ♂) Solid serous adenoma Often asymptomatic – incidentally detected Characteristic imaging for microcystic with ‘starburst’ pattern Associations – minority vHL & NETs

Serous cystadenoma Macro –Microcystic mostly body/tail. Sponge like with stellate scar –Macrocystic mostly head. Few thin walled cysts with watery fluid –Don’t usually communicate with duct system. Micro –Single layer cuboidal cells with clear cystoplasm ICC and ∆∆ Malignancy diagnosed on clinical behaviour

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Mucinous cystic neoplasms Classification –Premalignant Low-grade, intermediate & high-grade dysplasia. –Malignant i.e. invasive carcinoma Mostly female Mean age 45 Most in body or tail Solitary – uni or multilocular Don’t communicate with duct system Lined by tall, columnar, mucin-producing cells with characteristic ovarian-type stroma

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Intraduct papillary mucinous neoplasia Grossly and radiologically visible papillary mucin forming lesion arising from main PD or its branches Classification: –Premalignant Low to high grade dysplasia –Malignant Mean 65 yrs, ♂:♀ = 1.5:1 Associations ??P-J & FAP. Synchronous & metachronous extrapancratic malignancies in 10-40%

IPMN Further subtyped into: –Main duct type, branch duct type or mixed –Epithelial subtype: Gastric (BD > MD) Intestinal (MD > BD) Pancreaticobiliary (BD > MD) Oncocytic (BD > MD) Gastric type most likely to be LG, rest more likely to be HG

PanIN Precursor lesion for pancreatic ca Classification –PanIN 1A = mucinous (pyloric) metaplasia, flat lesion –PanIN 1B = papillary architecture –PanIN 2 = atypical hyperplasia (LG dysplasia) –PanIN 3 = HG dysplasia Microscopic diagnosis ∆∆ Show 29021/13

Ductal adenocarcinoma Risk factors –Age –Sex –Race –Chronic pancreatitis –Smoking –Familial/inheritied (10%) FAMMM BRCA2 Peutz-Jeghers HNPCC & FAP

Ductal Adenocarcinoma Site –Distal BD, ampulla, pancreas Epithelial subtypes –Pancreaticobiliary, intestinal, clear cell, foamy cell etc.. Mixed tumours/variants –Adenosquamous (squame at least 30%) –Colloid (mucin pools at least 80%) –Signet ring, Medullary, hepatoid, undifferentiated etc –MANEC (both at least 30%)

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Acinar cell carcinoma Mostly adults, mean 60 yrs, but account for 15% of paediatric exocrine pancreatic neoplasms. May get lipase hypersecretion syndrome 50% present with mets Macro – large, well circumscribed or encapsulated tumours. Pushing border. Occur anywhere in pancreas.

Acinar cell carcinoma Lobules of cellular tumour sep’d by fibrous bands. Acinar pattern, solid or trabecular Granular eosinophilic cytoplasm Prominent nucleoli Zymogen granules PAS/D positive ICC: –Trypsin, chymotrypsin, lipase, (amylase) –Bcl10, A1AT, AE1/AE3

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Other pancreatic tumours Non-epithelial –Very rare <1% of pancreatic neoplasms –More often spread from extrapancreatic primary Paediatric Mets –Lung, kidney, breast, colon and MM most common

LIVER

Classification Hepatocellular Biliary Other

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Focal nodular hyperplasia Young women Aetiology ?abnormal blood flow Can have more than 1 lesion Characteristic macroscopic appearance with central scar Large, thick walled vessels within fibrous septae Bile ductules at periphery Features of cholestasis Bland, normal appearing hepatocytes

Sounds like FNH?? Nodular regenerative hyperplasia –Hyperplastic hepatocytes form small nodules, without fibrous tissue. More diffuse, part of a process of disorder blood flow in liver Partial nodular transformation –Very rare, nodule at the hilum, similar to NRH Macroregenerative nodule –At least 8mm diam. Usually a large nodule of cirrhosis. May be pre-neoplastic (see later)

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Hepatocellular adenoma Steatotic –HNF1α mutated – usually somatic but can be inherited – association with hereditary DM, multiple colonic adenomas –Least associated with malignancy Inflammatory (telangiectatic) –OCP association and obesity, fatty liver, ETOH excess –Present with inflammatory syndrome Β-catenin activated –More often male –More malignancy risk, may be precursor lesion –??FAP association Other

Hepatocellular adenoma General features –Occur in non-cirrhotic liver –Often unencapsulated –Bland hepatocytes, 2-3 cell thick plates, retained retic network. –No bile ducts although ductules may be seen. Specific features –Steatotic –Β-cat mutated may show mild atypia & rosettes –Inflammatory – inflamed portal tracts with no veins/BDs, thick walled vessels, ductular reaction, sinusoidal dilatation & peliosis

Hepatocellular adenoma Special stains –No specific marker –Reticulin –Steatotic LFABP negative (cf normal liver and other HCA types) –β-catenin activated Nuclear β-cat & GS positive –CD34 –Serum amyloid A

Premalignant/early malignant lesions Macroscopic lesions –Large regenerative nodule = MRN –Dysplastic nodule – low and high grade –Early HCC <2cm Microscopic features –Large cell change - ?if premalignant or not –Small cell change - premalignant –Dysplastic foci = <1mm diameter Definition of HCC = stromal invasion

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HCC Liver disease Environment Geographical Unless patient is being screened it often presents late Pt may have raised serum AFP

HCC Macroscopic –Classic appearance = …… –Usually soft tumour Microscopic –Varied but classically: pseudoglandular/trabecular growth cells look like hepatocytes Bile production Various inclusions esp eosinophilic globules

Diagnosing HCC Hopefully characteristic macro and microscopic appearances On biopsy can be very difficult to ∆∆ low- grade HCC from dysplastic nodule or even adenoma. Histochemistry –Reticulin, DPAS ICC

HCC ICC Malignant or not? –CD34, glypican 3, HSP70, glutamine synthetase all more +ve in HCC –CK7/19 can help differentiate between true or pseudo invasion (+ve ductular reaction in pseudo) HCC vs non-hepatic –HepPar 1, AFP, TTF-1, CD10, pCEA Show ICC & 21521/13

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Fibrolamellar HCC Younger patients Not associated with chronic liver disease/cirrhosis Better prognosis Polygonal eosinophilic cells within abundant fibrous stroma

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Benign biliary tumours Von Myenburg complex Bile duct adenoma Bile duct cyst Ciliated hepatic foregut cyst Intraductal papillary neoplasms & biliary papillomatosis Mucinous cystic neoplasm (hepatobiliary cystadenoma)

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Cholangiocarcinoma Intrahepatic vs hilar vs extrahepatic Aetiology less clear than HCC Increased risk in chronic biliary dx, cirrhosis, parasitic infections (SE Asia), mucinous cystic neoplasm, biliary papillomatosis Diagnostic difficulties: –Intrahepatic CC vs met adenocarcinoma –HCC vs CC or mixed tumour

Mixed HCC-CC Peripheral mass forming intrahepatic CC thought likely to have a hepatic progenitor cell origin which may explain mixed tumours (which tend to behave like CC)

Non-epithelial liver lesions Vascular –Haemangiomas, epithelioid haemangioendothelioma Other mesenchymal –Inflammatory pseudotumour –angiomyolipoma Leukaemias & lymphomas