Tadrous P.J. Diagnostic criteria handbook in histopathology: a surgical pathology vade mecum

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Liver, Biliary Tract and Pancreas 169

Veno-Occlusive Disease (VOD)

Minor hepatic veins (i.e. <1mm  and commonly <

mm )

Plant extracts/bush teas, chemo/radioRx, azathioprine, immune↓/AIDS, heroin, arsenicals, etc.

Youths, acute (pain, jaundice, ascites), chronic (insidious, cirrhosis-like)

Subintimal oedema/haemorrhage → heal with concentric ﬁbrosis and obliteration/multilumena

Perisinusoidal ﬁbrosis ± cholestasis (the latter esp. in chemo/radioRx-induced VOD)

Perivenular congestion (± severe) → regenerative nodules → venocentric

cirrhosis (spared PTs)

± Bile ductular proliferation

d/dg VOD-like change in Budd-Chiari, hepatic haemangioendothelioma and constrictive pericarditis

Budd-Chiari Syndrome

Major hepatic vein thrombosis (due to Virchow’s triad, CIBD, CTD, coeliac, etc.)/obstruct

at the level

of the IVC (! exclude d/dg constrictive pericarditis); ±2

◦

portal vein thrombosis (varices and cirrhosis)

Dilatat

of central veins and sinusoids, RBC extravasat

and variable necrosis

± Regenerative nodules (may be FNH-like)

± Bile ductular proliferation

± Thrombosis of smaller veins (VOD-like) → ﬁbrosis → venocentric cirrhosis with dilated PT veins

◦

Portal vein thrombosis → venoportal cirrhosis and parenchymal extinct

with obliterated PT veins

Patchy distribution and caudate may be spared/hyperplastic (because its veins drain directly into the

IVC)

Bx (bilateral) to guide therapy (ﬁbrosis → Tx; necrosis → shunt) and monitor its success

Tumours and Nodules

Incomplete Septal Cirrhosis

Fibrous septa are very thin (not obvious on H&E) and often broken/incomplete/blind ended

Nodules are vague and regenerative with PTs and central veins (but unevenly spaced w.r.t. each other)

Inﬂammation/necrosis is sparse or absent; ± sinusoidal dilatation

Nodular Regenerative Hyperplasia (NRH)

F = M,

die a liver death, assoc

with autoimmune/vascular disease, MPD, drugs, portal HT

Nodules 1mm to few cm in  (clin. d/dg cirrhosis/mets)

Hyperplastic nodules (± periportal) not obvious until retic is done, but the presence of two

Internodular atrophy and congest



populations of cells (large and small) is suggestive

± Cholestatic rosettes

d/dg cirrhosis or incomplete septal cirrhosis: NRH shows a paucity of ﬁbrosis – but ! a cirrhotic nodule

may contain several NRH-like nodules within it

CPC is important as focal NRH-like change may occur in HCC, cirrhosis or in pre-cirrhotic PBC

Focal Nodular Hyperplasia (FNH, ‘mixed hamartoma of childhood’)

FM, vascular malformations, age: 20

/30

; incidental ﬁnding/mass

Macro: subcapsular, well-circ., <5cm , ﬁbrous septa from stellate scar(s) – no bile stains

Multinodular (‘focal cirrhosis’), hyperplastic hepatocyte cords <3 cells thick

Septa contain: bile ductules (± surrounding cholate stasis ± Mallory hyaline), arteries, inﬂam

Central scar contains thick-walled vessels (or multiple and dilated channels in telangiectatic FNH)

Lobules: liver cells like HCA with Kupffer cells, ± cholestasis but no mitoses/pleomorphism

Multiple FNH: assoc

with vascular anomalies in other organs and brain tumours

d/dg cirrhosis, BD obstruction: use CPC and the radiological information of a discrete mass

d/dg haemangioma/peliosis vs. the telangiectatic variant of FNH

d/dg MRN: surrounding liver is usu. normal in FNH

d/dg HCA (vide infra)!NB: bile ductular structures may be hard to ﬁnd in some FNH

Hepatocellular Adenoma (HCA)

F>M, age 20

/30

, acute abdomen (±haemorrhage/rupture)/mass/incidental; ≈all cases have a source

of hepatic stimulation: OCP, anabolic androgens, DM, childhood IEM (also have ↑ risk of HCC)

i.e. ‘reversed lobulation’ – regeneration of periportal hepatocytes → parenchymatous nodule with a PT at the centre rather than a

central vein

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Liver, Biliary Tract and Pancreas 170

Subcapsular ± pedunculated, right lobe, solitary (except androgenic/metabolic), well-circ., a few cm

to >10cm

, variegate cut surface (haemorrhage, infarct, bile) ± central ﬁbrosis (! d/dg FNH)

Cytology:  normal sized hepatocytes (± pigments, fat, glycogen, 

AT bodies)

 ± fat (d/dg focal fatty change, but this mass lesion has normal architecture)

 inconspicuous nucleoli

 no nuclear vacuoles

 ± multi-(bland)nucleate forms

 Kupffer cells present but fewer than in normal liver

Arch.: cords (<3 cells thick), rosettes with bile but no BDs or PTs (except for trapped normal PTs)

Mitoses are rare and vascular/capsular invasion is absent

Androgenic ones may show cytol. atypia and pseudogland formation (with ↓NCR) or HCC-like foci

and are diagnosed as ‘atypical adenoma’ or ‘hepatocellular neoplasia of uncertain malignant potential’

Multiple HCA: >10 tumours, older, no steroid association, d/dg NRH (different clinical background)

Degenerative changes:  peliosis/haemorrhage (inside tumour or in adjacent liver)

 epithelioid granulomas

 extramedullary haemopoiesis

 necrosis and infarction →ﬁbrous scars: d/dg FNH (but FNH septa contain

BDs); d/dg ﬁbrolamellar HCC (different cytology)

d/dg MRN: in HCA the surrounding liver is ≈ normal and there is no ductular proliferation

d/dg FNH: even spacing of arteries and lack of BD favour HCA

d/dg HCC – see Table 12.3:

TABLE 12.3 Adenoma or carcinoma?

Feature HCC HCA

Plate thickness >3 cells <3 cells

Invasion (vasc./capsular) may be present absent

Reticulin weak or absent good staining (except infarcts)

Kupffer cells sparse or absent present

Mallory hyaline often present & may be clustered rare

Mitoses ± rare

Immuno (typical) AFP +ve, CD34 shows diffuse & AFP −ve, CD34 is focal

continuous +vity in sinusoids

Tyrosinaemia

Cholestasis, cholestatic rosettes, siderosis

Fibrosis (pericellular, PT and cirrhosis), fatty nodules

MRN, liver cell dysplasia (large cell and small cell), dysplastic nodules, HCC

d/dg HCC vs. large MRN can be problematic

Liver Cell Dysplasia

General deﬁnitions

Dysplasia = altered prolif

/genetics that may manifest abnormal histology in a cluster/nodule of cells

Single cells or small groups with these features are not considered diagnostic of dysplasia

If the cluster is <1mm  =dysplastic focus (else = dysplastic nodule and this is usu. in a background

of cirrhosis)

Associations: cirrhosis, HBV, HCV, HCC, 

AT↓ and tyrosinaemia

Dysplastic nodules may be low grade (≈ MRN) or high grade (≈ AAN) or NOS if insufﬁcient tis-

sue/features are present on Bx to grade reliably (HCC cannot be excluded on Bx – even with low

grade)

Large cell dysplasia (= large cell change)

No ↑ prolif

(some demonstrate aneuploidy cf. normal polyploidy) and occurs in 1% of normals

Large cells (upto 4 × normal) with large nuclei (≈normal NCR) and prom nucleoli ± multinucleation

± Hyperchromasia with patchy chromatin clearing, abnormal nuclear shapes and multiple nucleoli

Small cell dysplasia (= small cell change)

↑ Proliferative activity (? pre-cancerous)

Smaller, amphophilic cells with ↑NCR form irregular crowded trabeculae ± multinucleation

Low grade dysplastic nodule

≈ Normal hepatocytes in plates ≤2 cells thick (discounting tangential sections)

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Liver, Biliary Tract and Pancreas 171

± Mallory hyaline, small cell/large cell dysplastic foci, displacement of nuclei towards sinusoids

d/dg NRH: no central PT and no peripheral compressed rim

High grade dysplastic nodule

As for low grade plus any focus showing any of: Fe resistance, rare mitoses, pseudoglands, nuclear

anomalies (↑ NCR, irregular membrane, hyperchromasia), basophilic cytoplasm, plates >2 cells

thick

d/dg HCC: no invasion or other, more subjective, features favouring HCC (i.e. ↑ mitoses, ↓ retic,

marked atypia, clustering of Mallory bodies, ﬂoating trabeculae, lack of PTs, ↑ non-PT arteries)

Macro-Regenerative Nodule, Atypical Adenomatous Nodule (MRN/AAN)

Def

: a nodule of ≥ 0.5 cm  (some say ≥ 0.8 cm) in a background of cirrhosis/chronic liver disease

Contains PTs (± ductular reaction) but no stellate scar with septa and not AFP +ve

± Infarction with regenerative mitoses (mitoses should not be present in other circumstances)

Large hepatocytes with mostly low NCR and plates ≤2 cells thick; no tumour necrosis

AAN: this is an MRN with dysplastic areas (‘nodule within nodule’) or wholly dysplastic showing:

 cells are usu. smaller and show liver cell dysplasia (q.v.)

 trabeculae may be 2 or 3 cells thick ± pseudoglandular acini but PTs are still present

 different H&E/Perls characteristics cf. rest of liver ± AFP +vity

Clustering of Mallory bodies and clearing of haemosiderin suggests ‘early HCC’ (to these some add a

‘nodule within nodule’ pattern, cytoplasmic basophilia and the features mentioned for well diff HCC

q.v.) – the term ‘early HCC’ is no longer recommended, consider ‘small HCC’ deﬁned as <2cm



d/dg HCA/FNH (see those entities above)

Mesenchymal Hamartoma

Myxoid stroma with PMN and blood vessels

Irregular/branching BD-like structures that may be lined by bland cuboidal epithelium or be unlined

Admixed areas of normal hepatocytes (not seen within d/dg bile duct adenoma – q.v.)

Hepatocellular Carcinoma (HCC)

Clin: cirrhosis/hepatitis/IEM, pain/mass, ±↑AFP (for details and d/dg, see p. 19)

Macro:  cut surface: haemorrhage, necrosis, bile staining, [and background liver disease]

 border: expanding, inﬁltrating, multifocal

 invasion: capsule, BD, veins (portal, hepatic, IVC)

 record: size, n˜o. of nodules, capsule (±), capsular invas

(±), venous invas

(±)

Background liver usu. shows cirrhosis/chronic hepatitis,

Cytology: polygonal cells, well-deﬁned membrane, ↑NCR, round/irregular/hyperchromatic nuclei ±

nuclear pseudoinclusions ± eosinophilic cytoplasmic inclusions

Cytological variants: giant/clear/spindle/oncocytoid ﬁbrolamellar

Patterns: pelioid, clear cell, solid/sclerosing(scirrhous)

, trabecular (trabeculae >3 cells thick, lined

by endothelium ± widely separated or isolated – ‘ﬂoating’), acinar

(may contain cell debris or be

thyroidal with ﬁbrin instead of colloid), giant cell, spindle cell (mets are more common), ﬁbrolamellar,

HCC with lymphoid stroma (T8-rich, plasma cells, follicles and ‘piecemeal necrosis’-like reaction –

good prognosis) and regressing HCC

Sinusoids: CD34 is uniformly +ve ± perisinusoidal ﬁbrosis (capillarisation), Kupffer cells ↓/lost

Grading:  very well diff: PT or vasc. invasion by near normal hepatocytes

 well diff: mitoses <5/10 hpf, plates ≤3 cells thick, ± good retic staining

 mod. diff: mitoses >5/10 hpf, plates >3 cells thick, poor retic staining

For small, well diff HCC, good diagnostic criteria are lacking; features suggesting HCC include:

 ↑cellularity (nuclei per mm

)of≥2x the surrounding non-neoplastic cirrhotic liver

 clear cell change (due to glycogen, water or lipid)

 diffuse and uniform CD34 staining of sinusoidal endothelium

 portal tract or vascular invasion

Fibrolamellar:  younger, no cirrhotic background (.

. better prog. cf. conventional HCC with cir-

rhosis)

sclerosing HCC are considered to be due to compression or chemo/radioRx artefact and not a speciﬁc subtype – more typical HCC

should be present elsewhere otherwise the diagnosis should be reconsidered

the preferred term is pseudoglandular in the liver (so as not to confuse with the liver acinus)

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Liver, Biliary Tract and Pancreas 172

 calciﬁcation and pale bodies (ground glass ﬁbrinogen cf. d/dg HBsAg)

 lamellar ﬁbrosis

 large oncocytic cells, vesicular nucleus and prominent nucleolus

 immuno: CK7 and CK19 +ve (cf. usual type HCC which are mostly −ve)

Features of hepatocellular differentiation

pCEA (and CD10) +ve canaliculi are pathognomonic of hepatocellular differentiation in a tumour

Intracellular bile is pathognomonic of hepatocellular differentiation in a tumour

Mallory hyaline (+ve for ubiquitin, CK & p62) is nearly pathognomonic of hepatocellular

differentiation

Cu/CuBP (rhodanine/Shikata orcein +ve) are nearly pathognomonic of hepatocellular differentiation

DPAS +ve globules (usu. 

AT, albumin or ﬁbrinogen) and AFP are suggestive but not speciﬁc

Hep Par 1 is useful but not speciﬁc (many gastric and some cholangioCA are +ve)

ISH for albumin: +vity occurs in cells with hepatic/hepatoid differentiation – highly speciﬁc

d/dg cholangiocarcinoma

Mucin is −ve in pure HCC (but can be +ve in mixed HCC-cholangioCA)

Features of hepatocellular differentiation are usu. −ve in cholangioCA (esp. if ‘pathognomonic’ – vide

supra)

MOC-31, mCEA, amylase, CK7 and CK19 are +ve in cholangiocarcinoma but −ve in HCC (! some

pseudoglands in HCC may show CK7 +vity but not usu. CK19 unless ﬁbrolamellar variant)

Trabeculae are separated by desmoplastic stroma in cholangiocarcinoma (cf. sinusoids in HCC)

EM: glandular features in cholangiocarcinoma

Other differentials

d/dg NE tumour: NE tumour has smaller cells, inconspicuous nucleoli and prominent vascularity

d/dg clear cell HCC vs. RCC: cytoplasmic +vity for TTF-1 favours HCC (see table 19.1 p. 276)

d/dg HCA, MRN & AAN: (see respective sections above)

d/dg metastasis from 1

◦

hepatoid carcinoma of stomach, lung or ovary

Combined Hepatocellular and Cholangiocarcinoma

There must be both proper glands with mucin and features of hepatocellular differentiation (vide supra)

not based on immuno alone (if just ambiguous immuno = adenocarcinoma NOS)

May be collision-type (most common), admixed or cells of dual differentiation (intermediate cells ±

c-kit +ve)

Prog. is worse than with either HCC or cholangiocarcinoma

Bile Duct Adenoma (Peribiliary Gland Hamartoma) and Bile Duct Adenoﬁbroma

Well-circ., para-PT, subcapsular, many small ducts/ductules in mature ﬁbrous stroma, no bile plugs

Glands have rounded edges, bland cytology and no mitoses or vascular invasion cf. d/dg adenoCA

Admixed inﬂam

cells (lymphocytes, PMN) ± follicles at periphery, ± PTs incorporated at periphery

± Focal mucinous or NE differentiation (d/dg NET), 

AT globules or, rarely, clear cells (d/dg CCC)

Adenoﬁbroma has tubular, branching and cystic spaces ± bile ±apocrine metaplasia (≈ FA of breast)

d/dg metastatic adenoCA: as above; CA may also show the surrounding mass effect triad of

◦

PT oedema

with polymorphs,

◦

atypical bile ductular prolif

◦

focal sinusoidal dilatation

Mucinous Cystic Lesions (Biliary Cystic Lesions)

Simple cysts are usu. unilocular and perihilar with simple bland epithelium

Benign cystadenoma is usu. multilocular [may be large] with simple bland epithelium ±small papillae

Borderline cystadenoma/CIS has polyps or solid areas with cytol. atypia, mitoses, stratiﬁcation

Cystadenocarcinoma: must show stromal invasion by deﬁnition (.

. need extensive sampling to exclude

it) – d/dg cholangiocarcinoma ex cystic BD malformation (more aggressive)

Generally: stroma may be ﬁbrous or (in women) ovarian-like ± focal cyst ulceration/M response

Dysplasia in the Gallbladder and Large Extrahepatic Bile Ducts

Nuclear changes: enlargement (↑with NCR), broadening and hyperchromasia

Loss of polarity ± some cells rising to the surface ± intestinal metaplasia

d/dg reactive:  pseudostratiﬁcation and nuclear elongat

without the above are considered reactive

in biliary epithelium (cf. pancreatic ducts where such changes are considered mild

dysplasia)

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Liver, Biliary Tract and Pancreas 173

 admixed pencil cells favour reactive over dysplasia

 adjacent nuclear inﬂam

ulcerat

favour reactive esp. if not much hyperchromasia

 p53 +vity (–vity means nothing), abrupt transition and mitoses favour dysplasia

Cholangiocarcinoma

Macro: intrahepatic (peripheral or hilar) and extrahepatic (periampullary CA being the most

distal)

Growth patterns:

◦

mass forming (radial mass with well-deﬁned border),

◦

periductal inﬁltration and

◦

intraductal (= CIS – often multifocal, papillary ± stalk invasion or mucinous; dysplasia may extend

into peribiliary glands ! d/dg periductal inﬁltration); types

◦

and

◦

may occur together

Usu. scirrhous adenoCA (mucin +ve) or other (e.g. mucinous, signet ring, ASC, SCC, sarcomatoid)

Arch. is usu. tubulopapillary or cords or small narrow ductules (i.e. ‘cholangiocellular’ type)

Adjacent major bile duct hyperplasia/dysplasia/CIS (! d/dg Pagetoid spread of metastatic carcinoma)

Peribiliary glands may show adenomatoid hyperplasia ± CIS (! d/dg invasive carcinoma)

Immuno: +ve for cytoplasmic mCEA, CA-19.9, CK7, CK19, amylase

d/dg HCC: vide supra, ! hepatocyte bile may be incorporated into the periphery of cholangioCA

d/dg metastatic adenocarcinoma – this may be impossible to differentiate:

 clin. associat

s of cholangioCA (PSC, CIBD, liver ﬂuke, BD malformat

s, Hx of thorotrast,

etc.)

 multifocality in the liver, peritoneal carcinomatosis and ↑ serum CEA occur in both cholan-

gio

CA and some mets – so these features are not helpful

 presence of a likely 1

◦

elsewhere – esp. if it is of a type that has characteristic immuno

 Hep Par 1 +vity is strong evidence against cholangiocarcinoma

 +vity for both CK7 and CK19 favour cholangio

CA but are not absolute (see pp. 14–15)

 perineural invasion or CIS (! not d/dg Pagetoid spread) favour cholangiocarcinoma

d/dg benign malformation/ﬁbrous stricture e.g. on FS – features that favour malignancy incl.:

 ↑ nuclear size, marcronucleoli and pleom. (may not help if very well diff), intracytoplasmic

lumena

 cribriform glands, sharp/jagged gland proﬁles (! some glands of vMC may be angulated)

 cellular debris in the lumen of glands

 perineural or vascular invasion (or LN mets – esp. useful for lower BD tumours with much

desmoplastic stroma and sparse malignant cells .

. consider requesting a local LN sample if

FS)

 cytoplasmic mCEA in cholangiocarcinoma (cf. lumenal surface staining in benign epithelium)

 nuclear p53 +vity (using heat-based antigen retrieval)

d/dg benign intraductal papilloma vs. intraductal cholangioCA: papilloma has low grade cytology and

lacks mitoses/stalk invasion (cholangiocarcinoma may also lack stalk invasion)

d/dg biliary papillomatosis: a synonym for papillary intraductal cholangioCA of the extrahepatic BDs

d/dg adenoma of the extrahepatic BDs vs. intraductal cholangioCA: adenomas have similar

histology to those found elsewhere in the GIT but the lining may be of biliary, pyloric or intestinal

epithelium

Other Tumours/Tumour-like Lesions of the Biliary Tree

Serous cystadenoma: as for pancreatic (not ovarian) counterpart – see p. 177

Granular cell tumour, traumatic neuroma, adenomyoma (! d/dg invasive adenoCA), botryoid RMS

Almost anything else (e.g. melanoma, epithelioid haemangioendothelioma, etc.) can occur but is rare

Lymphomas may be assoc

with a degree of ﬁbrosis incl. P-P linking

Gallbladder

Acute Cholecystitis

An ischaemic dilatation that may be calculous or acalculous (e.g. Salmonella) ± CTD vasculitis

Haemorrhage, oedema, ﬁbrosis, myoﬁbroblasts ± necrosis (gangrene) of the wall ± mucosal ulcerat

some authors do not use ‘cholangioCA’ for extrahepatic BD tumours (which include gall bladder CA). Carcinoma of the ampulla of

Vater are of biliary or intestinal histol. (some call only the former ‘periampullary’)

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Liver, Biliary Tract and Pancreas 174

± Prior chronic cholecystitis may be superimposed

Any PMN are usu. 2

◦

to necrosis/ulcerat

/infection and are not essential for the diagnosis

Effects of Salmonella on the Gallbladder

None (normal histology)

Carcinoma

Mucosal lymphoid polyps +/ follicular cholecystitis

Acute acalculous cholecystitis (vide supra)

Polyps

Adenomyoma usu. occurs at the fundus and glands may surround nerves (! pseudo neural invasion)

Adenomatous: may be tubular, papillary (usu. villous) or tubulopapillary with a range of dysplasia and

be of pyloric, intestinal (≈ colonic adenomas) or biliary cytological type

Low grade pyloric tubular adenomas are distinguished from metaplastic polyp by size >5mm

Biliary types are rare and have ≈ normal biliary epithelium ↑ apical mucin – d/dg pap. hyperplasia in

chronic cholecystitis or cholesterol polyp (stroma ﬁlled with foamy M)

Others: metaplastic (e.g. pseudopyloric), heterotopic, lymphoid, cholesterol and inﬂam

pseudotumour

Flat Dysplasia

See pp. 172–173 for features: if high grade/CIS this may indicate further Rx post cholecystectomy

More likely to be assoc

with invasive CA (cf. adenomas) .

. take more blocks if dysplasia is found

d/dg colonisation of Luschka ducts or Rokitansky-Aschoff sinuses vs. invasive carcinoma

Carcinoma

Associations: old age and gallstones; most occur in the fundus, then body

Spread: direct (e.g. to liver), LN (cystic duct ± beyond), transcoelomic, blood vasc. → distant mets

Usu. adenocarcinoma (pancreatic ductal-like but with less cellular mucin, even if well diff)

Other types of adenoCA: intestinal, colonic, cribriform, mucinous, papillary

Other types of carcinoma: ASC, carcinosarcoma, SCC, CCC, spindle cell, giant cell, SmCC

Well-diff variant: papillary carcinoma (has a predom. intralumenal exophytic growth + invasion)

Poorly diff variants:  signet ring

 spindle cell

 giant cell (pleomorphic giant cells constitute the bulk of the tumour)

 small cell undiff: focal mucin production, no NE markers

 SmCC: as for pulm. SmCC, may be combined with adeno

CA/carcinoid

Neuroendocrine Neoplasia

Paraganglioma, carcinoid and SmCC

Features are as for these tumours elsewhere (see pp. 93–94, pp. 139–140 and p. 279)

Exocrine Pancreas

Normal Histology

The sphincter of Oddi is comprised of longitudinal and circular muscle coats of the main (Wirsung)

pancreatic duct and common bile duct that thicken as they enter the duodenum. The bile duct component

(= sphincter choledochus) is usu. more prominent than the Wirsung duct component

Features near the ampulla of Vater:

 all main ducts have valves of Santorini (long bland papillary folds)

 accessory ducts insinuate through the duodenal musculature – d/dg adenocarcinoma (esp. on

FS): these ducts form lobules encased in deﬁnitely formed ﬁbrous tissue and lack cytological

atypia

Pancreatic ducts have a smooth (non-papillary) lining and an adventitial sheath of bland ﬁbrous tissue

which is esp. prominent in extralobular and larger ducts (the latter having periductal glands)

Pancreatic acini differ from salivary acini in that they have eosinophilic apical cytoplasm, basophilic

basal cytoplasm and lack myoepithelial cells. They contain central pale centroacinar cells

Pancreas divisum: the Wirsung and Santorini duct systems do not fuse. They may drain separately into

the major and minor duodenal papillae.

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Liver, Biliary Tract and Pancreas 175

Acute (Haemorrhagic) Pancreatitis

Ductal damage  alcohol, gallstones/other obstruction

 periductal necrosis, acute inﬂam

± haemorrhage

Vascular insufﬁciency  shock/dehydration/hypothermia

 perilobular necrosis

Secondary changes occurring in either type

Autodigestion → thromboses → infarction and pan-lobular necrosis, haemorrhage

Surrounding fat necrosis ± chemical (± bacterial) peritonitis

Abscess/pseudocyst formation

Autoimmune Pancreatitis (= Lymphoplasmacytic Sclerosing Pancreatitis)

Clin: ↑ serum IgG4 (70 mg/dl), low CBD stricture + pancreatic mass (d/dg carcinoma); Rx =

steroids

Periductal inﬂam

(lymphocytes, plasma cells ± eos., peripheral lymphoid follicles) with epithelial

preservation, ﬁbrosis, obliterative phlebitis with arteriolar preservation, loss of exocrine parenchyma,

no fat necrosis

Multi-organ involvement (salivary glands, GIT, liver, gallbladder, etc.) – ? related to multifocal ﬁ-

brosclerosis

Immuno: plasma cells +ve for IgG4 (>10 per hpf counting 10 hpf) in all affected organs

Chronic Pancreatitis

Histology ∝ cause, stage of evolution and degree of atrophy and may get these changes adjacent to CA

Early changes of perilobular ﬁbrosis ± chronic inﬂam

may cause enhanced lobulation

Later there is ﬁbrosis within (and atrophy of) acini with residual ducts in lobular conﬁguration (i.e.

centrally there are larger, possibly branched, ducts with peripheral smaller ones) – albeit distorted.

Duct lumena may contain Ca

/protein plugs with some aetiologies (! not d/dg necrotic cell debris)

Irregular duct ectasia (‘retention cysts’) ± mucinous metaplasia/hyperplasia/dysplasia (vide infra)

Mucinous (pyloric) metaplasia can occur which may not retain lobular arch. but has benign cytology

(with ﬂattened basal nuclei); if there are mild anomalies of pseudostratiﬁcation, uniform nuclear en-

largement and distinct (but not macro) nucleoli = mucinous hyperplasia; if it also shows focal loss of

polarity, anisonucleosis ±micropapillae =atypical hyperplasia; if extensive loss of polarity/arch./cytol.

atypia (chromatin ± macronucleoli) ±↑mitoses = dysplasia (= CIS if severe)

Other metaplasias include multilayered (‘squamous’), goblet cell, acinar and oncocytic

Advanced atrophy affects ducts as well as acini and results in changes that can mimic carcinoma incl.:

 simulation of partial lumena in atrophic ducts

 islet cell aggregation (d/dg NET vide infra)

 islets extending into fat (d/dg extrapancreatic invasion) d/dg adeno

CA but these cells

 ductuloinsular complexes (endocrine cells apposed to ducts)



are NE, not glandular, and do

 diffuse islets (cords/trabeculae) inﬁltrating around nerves not have malignant cytology

d/dg adenoCA (vide infra): cytology is important, lack of desmoplasia is no help as some CA are not

desmoplastic, presence of a two-duct-type (one benign, one atypical) helps, CEA is −ve in benign

ducts, perineural invasion/sharply angulated ducts (esp. if inﬁltrating muscle/fat) favour malignancy

Other Non-Neoplastic Lesions

Mucinous cyst (developmental/retention)

Inﬂammatory pseudotumour (see p. 310)

Pancreatic pseudocyst: non-epithelial ﬁbroinﬂammatory and granulation tissue lining ± haemor-

rhagic/necrotic contents. d/dg cystic epithelial tumour or GIST (.

. may get a FS)

Lymphoepithelial cyst/lymphoid hyperplasia

Ductal Mucinous Metaplasia, Hyperplasia, PanIN, Dysplasia and CIS

Mucinous metaplasia (pyloric type) has tall apical mucin and bland ﬂat basal nuclei (= PanIN 1A)

Hyperplasia has mild anomalies of pseudostratiﬁcation, uniform nuclear enlargement and distinct (but

not macro) nucleoli; it may also have a papillary arch. (= PanIN 1B)

Atypical hyperplasia also shows focal/partial loss of polarity, up to mod anisonucleosis ±micropapillae

(= PanIN 2)

Dysplasia (= PanIN 3) shows ↑ mitoses and extensive loss of polarity/papillae ± cribriformity and

more severe cytol. abnormalities (incl. chromatin ± macronucleoli); = CIS if the changes are severe

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Ductal Adenocarcinoma

↑N˜o of irregular tubular and ductal structures irregularly distributed in a desmoplastic stroma

Inﬁltration does not respect lobular boundaries and non-neoplastic structures may be entrapped (d/dg

close apposition of islet cells to benign ducts in chronic pancreatitis = ductuloinsular complex)

Carcinomatous inﬁltration of duodenal muscle shows single/sparse atypical glands in between muscle

ﬁbres without well-formed stroma around them

Lumenal anomalies: partial lumens, irregular branching, cribriformity, dirty necrotic contents

Higher grade: poorly-formed glands, less mucus, ↑mitoses, ↑pleomorphism, perineural invasion

Adjacent ducts may show papillary or ﬂat in situ changes (= dysplasia) ± CIS (vide supra)

Immuno: +ve for CK (liver and biliary – i.e. CK8,18,7,19), CEA (benign ducts may be CEA −ve),

EMA, CA-19.9; usu. −ve for pancreatic enzymes (trypsin, amylase) and NE markers; 

AT ±ve

WHO (Kl¨oppel) grading is based on the worst grade present (not the predominant grade):

 the original series (of pancreatic head tumours) used Bouin’s ﬁxation and a very small hpf

 an even more marked correlation was found between nuclear circumference and survival (<24

 did best, >31  did worst) but this measure is not part of the grading system.

Grade 1 (Well diff): well-formed ducts, relatively large (cf. benign ducts) with some microcystic

foci and smaller tubular glands; regular cells with minimal pleomorphism, basal nuclei;

marked mucin production; mitoses <5/10 hpf. Cytoplasm is often clearer cf. normal or mod

diff carcinoma

Grade 2 (Mod diff): predominantly smaller tubular glands with some larger well-formed ducts;

loss of polarity; some prominent nucleoli; variable mucin; mitoses 5–10/10hpf.

Grade 3 (Poorly diff): irregular/poorly formed/compact aggregates of tubules or microglandular

formations ±solid areas/mucoepidermoid foci (larger ducts are rare); marked pleomorphism

and chromatin clumping; minimal mucin; mitoses >10/10hpf

d/dg intraductal papillary hyperplasias/neoplasia/intraductal (Pagetoid) spread of invasive adenoCA

d/dg gangliocytic paraganglioma/hamartoma (p. 179)

d/dg accessory pancreatic ducts that penetrate duodenal muscle: these usu. occur in packets/lobules

within a deﬁnitely formed stroma

d/dg mimics of perineural invasion: closely apposed/perineural islet NE cells in chronic pancreatitis or

true benign glandular perineural and intraneural inclusions

d/dg ductal atrophy in chronic pancreatitis vs. incomplete lumen formation in carcinoma

FS diagnosis of pancreatic ductal adenocarcinoma

Adenocarcinoma is rare under 40 years of age, it should have (at least):

◦

many glands haphazardly distributed and

◦

abnormal duct shapes and cytology (partial lumena, nuclear size variation of ≥ 4:1 and large

irreg. nucleoli)

The surrounding fat should be checked for free, lymphatic or perineural invasion (also look for this in

CBD resection margin FS)

d/dg chronic pancreatitis which:

 shows residua of normal lobules within ﬁbrosis (i.e. respect for lobular architecture that may

manifest as central larger [possibly branched] ducts with smaller ducts around them)

 shows Ca

and protein plugs in ducts (unlike CA which may have dirty necrotic cellular

debris)

 is not mitotically active and does not have dirty necrosis in duct lumena

 may have islet cell remnants apposed to nerves/benign ducts (! not d/dg perineural/

periductal invasion by grade 3 adeno

CA because of the lack glandular structure or high grade

cytology)

 may be impossible on FS due to distortion of entrapped ducts in a small sample (do levels)

d/dg gangliocytic paraganglioma (p. 179)

Intraductal Papillary Mucinous Neoplasms (IPMN)

Predominantly intraductal growth of complex villopapillary fronds in dilated main duct ± tributaries

Benign (intraductal papillary adenoma): mild or no dysplasia

Borderline: moderate dysplasia ± invasion of stalks but not into the surrounding pancreatic stroma

CIS: severe dysplasia ± extraductal invasion (ductal adenocarcinoma NST or mucinous CA)

the stated area of an hpf was 1356 

(= a diameter of 41.6  = 0.0416 mm). Most modern microscopes’ hpf have a diameter

≈ 0.5 mm. Furthermore, it seems that the mitotic count was 2

◦

to the architectural and cytological grade (e.g. grade 1 tumours had,

on average, a mitotic count of <5 per 10 hpf) and a later study showed that cytological and architectural grading was more predictive

than the Ki-67 LI.

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Mucinous Cystic Tumours

FM (rare in men and rare in head of pancreas); curable by resection unless invasive CA is present

Usu. has ovarian-like stroma (unless in men) – not a feature of d/dg ectatic IPMN

Benign: no/mild dysplasia, often ﬂat lining; if not excised may progress to malignant type

Borderline: moderate dysplasia ± papillaroid lining

Malignant: severe dysplasia ± invasion ± mural nodules

(focal changes, needs extensive sampling)

Immuno as for ductal carcinoma but may also have some NE marker + vity ± goblet & Paneth cells

d/dg ectatic IPMN, but cystic tumours are not connected to the main duct system

Serous Cystic Tumours (Microcystic Adenoma and Serous Microcystic Carcinoma)

Microcystic (d/dg acinar cell CA variant) or macro/oligocystic (assoc

with VHL) ± stellate scar

Cysts lined by glycogenated clear cells (unlike serous tumours of the ovary or acinar cell carcinoma)

Bland compact nuclei with small or absent nucleoli (more irregular/larger nuclei in some VHL)

Stroma is composed of vascular dense ﬁbrous bands ± Ca

Usu. benign and amitotic ± focal tufting (malignancy is deﬁned by invasion ± metastases)

Immuno: +ve for CK, EMA, CA-19.9; −ve for CEA

VHL: AD; other assoc

s include: supratentorial haemangioblastoma, granular renal cysts, RCC,

phaeochromocytoma, pancreatic NET, endolymphatic sac tumours, etc.

Atypical Acinar Cell Nodules (Acinar Cell Dysplasia)

Compact aggregates (d/dg islets of Langerhans) of atypical acinar cells

Basophilic type: loss of apical granules with nuclear (± nucleolar) enlargement (↑NCR)

Eosinophilic type: larger cells with loss of basal basophilia and with normal/dark nuclei ±cytoplasmic

vacuoles

Acinar Cell Carcinoma

Usu. late adulthood, poor prog. esp. if >10cm  regardless of histology (except childhood ones)

Macro: solid/cystic, haemorrhagic, ﬂeshy; nodular with nodules separated by thick ﬁbrous septa

Arch.: acinar, microglandular (dilated acini), trabecular, solid; rich vasculature but sparse stroma

Cytology: DPAS +ve granular apical cytoplasm, uniform basal round nucleolated nuclei, clumpy

chromatin

Variable mitoses, usu. >1/10 hpf (more in solid, less in pure acinar variants)

Variant: solid – has less cytoplasm, more mitoses and is more likely to show nucleoli

Variant: acinar cystadenoCA – has many large (mm to cm) cysts (d/dg serous microcystic tumours)

Immuno/stains: +ve for lipase, amylase, trypsin, chymotrypsin, 

AT and CAM5.2; CEA ± ve

d/dg NET vs. solid variant: see p. 178 – also, NE markers are diffusely +ve in NET

d/dg pancreatoblastoma: usu. children, has squamoid nests ± mesenchymal prolif

d/dg solid pseudopapillary CA has myxoid ﬁbrovascular stroma and different immuno (vide infra)

Solid Pseudopapillary (= Solid / Cystic Solid and Papillary Epithelial) Tumour

Young, FM, large partly solid and cystic haemorrhagic/necrotic mass; rarely metastasise

Uniform cells with eosinophilic or vacuolated cytoplasm and rare mitoses/nucleoli (d/dg NET)

Necrosis with blood/myxoid cysts, cholesterol clefts in GC and papillae with loose ﬁbrovascular cores;

there are also solid areas and admixed collections of foam cells ± eosinophilic globules

Immuno: 

AT, vimentin +ve; CK, CEA, CA-19.9 usu. −ve; NSE, CgA and lipase only focal +vity

d/dg NET but lack diffuse CgA +vity and have foamy M, vimentin and 

AT +vity (unlike NET)

Other Tumours

A special type must comprise >50% of the tumour to qualify as that type

Carcinomas with mixed differentiation (e.g. mixed ductal-endocrine or mixed acinar-endocrine): the

minor type should comprise ≥30% of the tumour and both types intimately admixed to qualify

ASC must have ≥30% of the tumour as squamous to qualify, else = NST: NB: the tumour may be

predominantly squamous ! do not misdiagnose as d/dg SCC – take more blocks

Mucinous non-cystic carcinoma (i.e. colloid carcinoma = the usual type mucinous CA [e.g. colonic])

Signet ring carcinoma

Carcinoma with osteoclast-like giant cells: mononuclear elements are pleomorphic ± spindled

Undiff CA (= anaplastic CA): may have pleomorphic giant cells (cf. bland osteoclast-like giant cells)

Clear cell carcinoma (d/dg metastatic RCC/ACC)

similar to the mural nodules seen in ovarian mucinous cystadenocarcinoma (see p. 246)

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Oncocytic carcinoma

Hepatoid carcinoma

Microglandular adenocarcinoma

Endocrine Pancreas

Normal Histology

Islets of Langerhans are CD99 +ve, usu. lack mitoses, may show dilated blood-ﬁlled spaces (peliosis

insulis) and come in two main forms:

(a) diffuse islets: found in the head, predom. PP cell, have an ‘inﬁltrative’ boundary (! d/dg

on FS), form loose trabeculae and gland-like structures and have cells with distinct nucleoli ±

columnar cells

(b) compact islets: found in the dorsal pancreas are well-circ. with compact trabeculae of cells

with typical NE nuclei and a mixture of alpha (glucagon, peripheral), beta (insulin, central), delta

(somatostatin) and PP (very few) cells. Other peptides are usu. found only in tumours (e.g. gastrin)

Diabetes Mellitus

Type I (juvenile onset)

Early: lymphohistiocytic insulitis of the islets of Langerhans

Late: no inﬂam

but loss of -cells

Type II (adult onset)

No inﬂam

, -cells preserved

Amylin amyloid in islets

Well-Differentiated Endocrine Tumours

Risk of malignancy (deﬁned by gross invasion of adjacent organs or mets e.g. to LN, liver or distant)

is related to:

◦

hormone produced (by immuno/EM) – vide infra

◦

tumour size

≥ 2cm 

◦

vascular/perineural invasion (large vessel invasion can be seen as a form of gross invasion)

◦

coagulative tumour cell necrosis

◦

high proliferation (mitoses ≥2/10 hpf or Ki-67 LI ≥2%)

WHO (2004) distinguishes ‘neoplasm’ from ‘carcinoma’ by the presence of extrapancreatic spread and

splits ‘neoplasms’ into ‘benign behaviour’ or ‘uncertain behaviour’ by the presence of any one of

◦

above.

Carcinoid-like cells and arch. (± small nucleoli) ± gland-like formations of columnar NE cells

Admixed ﬁbrous stroma with delicate vessels ± amyloid (e.g. amylin in insulinomas)

Variants: clear cell (esp. in VHL) and oncocytic

Insulinoma (→ hypoglycaemic attacks); >95% are benign

ACTH or PTHrP producing tumour are ≈ always malignant

Glucagonoma (→ diabetes and necrolytic migratory erythema) these are

Somatostatinoma (psammoma bodies and glandular structures)



mostly

Non-functioning

. they may present at a later stage) malignant

gastrinoma (→ ZE syndrome, ± MEN 1) 50 % of

VIPoma (→ Verner-Morrison WDHA syndrome)



these types

GHRH producing tumours are malignant

Other peptides or multihormonal tumours (e.g. PP + other peptides in MEN-1)

EM may be characteristic in some (esp. for granule contents, if immuno is −ve)

Immuno: for characteristic peptide(s) + NE markers (CD56, CD57, chromogranins, synaptophysin,

NSE, PGP 9.5); many pancreatic NET may also be CD99 +ve; CAM5.2 +ve; CK7 is usu. −ve

d/dg solid acinar cell carcinoma: has acinar foci and lacks NE nuclei or ﬁbrous stroma within lobules

d/dg solid pseudopapillary carcinoma (p. 177)

called microadenoma if < 5mm (if ≤ 0.3 mm = ‘large islet’ provided the distribution of peptide-producing cells is normal; a

partial ﬁbrous capsule favours microadenoma)

non-functioning is meant clinically, the cells may be immuno +ve e.g. calcitonin, PP and neurotensin