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

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Liver, Biliary Tract and Pancreas 159

 paracetamol: sharply deﬁned perivenular necrosis with little inﬂam

 mixed hepatitic/cholestatic picture with duct damage (e.g. ﬂucloxacillin/paraquat)

Alcohol: perivenular ballooning with PMN (cf. lymphocytes) ± Mallory hyaline/steatosis/ﬁbrosis

Biliary disease:  may show granulomas in PBC (but ! d/dg IVDA)

 relative lack of lobular disease

 CuBP (black dots with orcein or blue dots with a Victoria blue stain)

 greater ductular proliferation ± ductopaenia with relative lack of cholestasis

 CPC (autoAbs, etc.)

◦

cholestasis: liver cell damage conﬁned to cholestatic areas, lack of spotty necrosis

AIH: hard to distinguish from acute hepatitis (esp. HAV) .

. need CPC (auto/viral Abs, etc.)

Chronic hepatitis/cirrhosis: distinguish bridging/conﬂuent necrosis from ﬁbrosis (vide infra)

Features Favouring Necrosis cf. Fibrosis

Other assoc

features of acute hepatitis

Elastic is absent (elastic takes time to develop so is a sign of chronicity)

Residual hepatocyte plate structure is preserved (although collapsed) on reticulin stain

Stroma is more haemorrhagic with more M (! don’t confuse ceroid M for hepatocytes)

Bile ductular proliferation and PMN

Chronic Viral Hepatitis

General Points

Def

of chronic hepatitis: continuing clinicopathological disease for ≥6 months

 excludes PBC, PSC, 

AT deﬁciency and Wilson’s disease.

 usu. due to viruses, autoimmunity and drugs

Traditional classiﬁcation into CAH, CPH and CLH is no longer used because all may co-exist and the

difference depends on interface activity whereas other factors (conﬂuent necrosis, ﬁbrosis, etc.) may

be more signiﬁcant – hence the current vogue for histological grading and staging schemes

‘Activity’ has two aspects: interface and lobular.

Portal Inﬂammation and Interface Activity

Predominantly T4 cells and some plasma cells (T8 cells at the advancing front of interface hepati-

tis/activity)

Interface activity = spill-over of inﬂam

beyond the PT limiting plate (± hepatocyte apoptosis) with

lymphocytes closely adhered to (peripolesis) or apparently within (emperipolesis) hepatocytes. It is

helpful to see lymphocytes at the hepatocyte-hepatocyte interface (otherwise it could just be sinusoidal

inﬁltration)

Hepatitic damage to bile ducts ± portal phlebitis (cf. the central phlebitis in acute hepatitis)

It is no longer necessary to see dead/dying hepatocytes to diagnose interface activity

Lobular Activity

Focal spotty necrosis: this term includes perivenular parenchymal inﬂam

or acute-type necrosis – not

just apoptoses (Councilman bodies), although these are also included

Conﬂuent necrosis: may be linking +/ bridging (C-C +/ P-C but only P-C is used in the Ishak grade)

±hepatitic rosettes (surrounded by inﬂam

/connective tissue and usu. lack a lumen cf. d/dg cholestatic

rosettes that may also show a connection to bile ductules, contain bile and stain for biliary CK)

Viral Co-Infection

HBV: if serology +ve for HBV with tissue immuno −ve for HBsAg, suspect co-HCV or co-HDV

HIV and HBV: a higher % progress to chronicity but they show lower histological activity. May get

‘reactivation’ lobular hepatitis in severe AIDS, even if +ve for HBsAb (may even get FCH)

HIV and HCV: synergistic – both the HIV and HCV pursue a worse course (incl. ↑ risk of HCC)

Hepatitis B (HBV)

Ground glass hepatocytes (eccentric nucleus ±clear rim around the ground glass cytoplasmic inclusion

cf. d/dg oncocytic change) ± lymphocyte emperipolesis

does not include inﬂam

cells only in the sinusoids; ! exclude cross-cuts of inﬂamed PT septa

HBV is the only one out of A, B, C, D, E that is a DNA virus

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Liver, Biliary Tract and Pancreas 160

Sanded nuclei (core Ag or HDV), ↑ anisonucleosis ± large cell dysplasia (q.v.)

↑ Replication (and ↑ histological activity unless immunosuppressed) if immuno shows:

◦

membranous staining for HBsAg (not just cytoplasmic)

◦

HBcAg +vity (esp. if there is cytoplasmic staining)

90% of cases become e&sAg−ve, Ab +ve: this indicates protective Ab virus elimination

10% of cases become e&sAg+ve, Ab −ve: this indicates chronic hepatitis (active)

50% of chronic hepatitics seroconvert to eAg −ve, Ab +ve (assoc

with clinical and histological

exacerbation) to become chronic carriers

mutants:

◦

pre-core: eAg not expressed, eAb +ve despite ongoing replication and active disease

◦

sAg: vaccine resistant

Hepatitis C (HCV)

Bx changes do not correlate with clinical/biochemical severity .

. Bx gives independent information

Lymphoid follicles (1

◦

or 2

◦

– germinal centres are esp. characteristic) ± hepatitic BD damage

Mild-moderate steatosis (macro and microvesicular)

Sinusoidal lymphocytes (d/dg EBV)

Synergistic with OH: suggest OH if severe fat or pericellular/venular ﬁbrosis or ballooning and PMN

Fe in Kupffer ∝ poor response to Rx; Fe in parenchyma:

◦

PCT

◦

cirrhosis

◦

haemochromatosis

Granulomas (PT or lobular) – but not assoc

with chronic ductopaenia and not causing BD destruct

Extrahepatic effects: cryoglobulinaemia, GN

,Sj¨ogren’s; PAN, LP, PCT, lymphoma (low grade B-cell

e.g. LPL, MZL and MALTomas incl. hepatic/salivary 1

◦

– not TCL or HL), autoAb e.g. ALKM,

anti-thyroid, ANA (a false +ve due to cross-reactivity with HCV Ags) and antiphospholipid (but usu.

without the TMA of antiphospholipid Ab syndrome)

Hepatitis D (Delta Agent, HDV)

Co-infection/super-infectionwith HBV is assoc

with active/fulminant disease (recurrent acute hepatitis

is characteristic), cirrhosis and HCC; may see periportal morule cells (multivacuolated hepatocytes)

Immuno (nuclear +vity for delta agent) is more reliable than serology

Inhibits HBV replication →

◦

HBV immuno can become −ve,

◦

↓ mortality in Tx patients

Chronic HDV may have an ALKM-3 AIH component

The Modiﬁed Histological Activity Index (HAI) for Chronic Hepatitis – Table 12.1

! Sub-capsular/peri-hilar biopsies show unrepresentative accentuation of ﬁbrosis +/ necrosis

The Royal College of Physicians/BSG categories for HCV hepatitis

Mild: stage ≤ 2 AND either  combined grade ≤3/18

or  A grade ≤ 1

AND C grade ≤ 1 AND B grade = 0(D grade = any)

Moderate: stage 3–5 AND/OR combined grade >3/18

Cirrhotic: stage = 6 (any grade)

Differential Diagnosis of Chronic Viral Hepatitis

Acute hepatitis A: interface activity and plasma cells ++ can give impression of AIH or chronic viral

hepatitis .

. look for lobular changes and CPC

AIH:  serology, plasma cells ++, interface ++ with rosetting, parenchymal collapse

 ! HCV can give false +ve ANA

 ! an AIH component may accompany hepatitis B, C and D

 ! d/dg drug-induced AIH-like disease

Metabolic:  

AT deﬁciency: DPAS +ve globules (! exclude concomitant viral infection)

 Wilson’s disease: Mallory hyaline, fat, Cu, broad vascular ﬁbrous septa

Drug-induced: viral-type chronic hepatitis is rare but can occur (e.g. with -methyldopa – but AIH-like

chronic hepatitis is commoner with this drug)

PBC: early lesions difﬁcult to distinguish from HCV which may show bile duct damage and loss. Later:

◦

granulomatous BD destruct

;

◦

ductular prolif

◦

chronic cholestasis periportal/septally

PSC, PBC and other biliary diseases: deposition of Cu/CuBP at an early stage of liver disease favours

a biliary disease (but any cause of end-stage liver disease can cause CuBP to accumulate)

membranoproliferative or ADP (both may be due to cryoglobulins)

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Liver, Biliary Tract and Pancreas 161

TABLE 12.1 Grade and stage in heptatitis

SCORE ACTIVITY

INFLAMMATORY CONFLUENT FIBROSIS

INFILTRATE NECROSIS

WITHIN SEPTA & (% of acini

PORTALTRACTS Interface Lobular (foci with confluent

(% of septa/ per x10 necrosis in

(% of septa/PTs af fected) PTs af fected) objective)

a zonal pattern) (% of PTs expanded)

D Grade A Grade C Grade B Grade Stage

0 none none none none none

1 mild (in ≤ 100%) focal & <50% ≤1 focal (not zonal)

†

<50% ± short septa

‡

2 moderate (in ≤ 100%) focal & >50% 2–4 <50% (zone 3 only) >50% ± short septa

3 100%, some with continuous 5–10 >50% (zone 3 only) >50% & occ. P-P links

a severe inﬁltrate around <50%

4 100%, all with a continuous >10 occasional bridging marked linking/bridging

severe inﬁltrate around >50% to zone 1 (P-C) (P-P +/ P-C)

5 multiple P-C bridges as for score 4 plus

occasional nodules



6 ≥ 1 acinus shows zonal cirrhosis (even if

necrosis in all 3 zones only probable)

This grading & staging system is a modiﬁcation of Knodell’s HAI & is based on Ishak K, Baptista A, Bianchi L, et al.

JHepatol(1995); 22:696-9

i.e. focal inﬂam

/apoptosis/‘lytic’ cell dropout. Focal inﬂam

does not include diffuse sinusoidal inﬁltration by inﬂam

cells. It is ‘interface’-type inﬂam

but in a pericentral location.

†

i.e. contiguous groups of hepatocytes are necrotic (not apoptotic) but without a clear zonal pattern (d/dg HSV or TB).

‡

septa due to interface activity tend to be curved, cellular & stain for retic but not type I collagen until mature.



this is sometimes called ‘incomplete cirrhosis’ which, here, appears to mean ‘not quite fully cirrhotic’ rather than the

more tightly deﬁned entity of incomplete septal cirrhosis (q.v.).

! Avoid overcalling cirrhosis due to artefactual Bx fragmentation.

Leukaemia/lymphoma: no true piecemeal necrosis; lymphoid cells may look ‘clonal’/‘pure culture’

(i.e. not mixed inﬂam

); some claim scarring is absent while others describe possible ﬁbrosis incl. P-P

linking

Autoimmune Hepatitis (AIH)

Type 1: classic lupoid CAH: ANA/ASGP-R/ANCA, assoc

with other system autoimmunity

Type 2: idiopathic in children (in adults it is usu. due to HCV = Type 2b), ALKM-1, ALC

Type 3: assoc

with SLP auto-Abs (also called SLA), no other system autoimmunity

Type 4: assoc

with anti F-actin smooth muscle Abs (ASMA)

↑ Globulinaemia and autoAbs (>1:80 adult or 1:20 child) though some may be −ve at presentation

and many auto-Abs e.g. ANA or ASMA are not speciﬁc to AIH so other features must be present

Plasma cells ++, interface hepatitis ++, ± cholestasis/bile duct damage; in acute AIH there is also

severe lobular plasma cell-rich inﬂam

± giant cells and ballooning

± Central necrosis ± bridging, ± acute/fulminant hepatitis (d/dg HAV) esp. in childhood type 2 AIH

Zone 3 variant: centrilobular necroinﬂam

, usu. with plasma cell clusters ± congest

± PT inﬂam

d/dg AMA −ve PBC: in AIH inﬂam

is more uniform and intense, shows lobular activity and lacks

typical PBC duct damage

d/dg zone 3 variant vs. venous outﬂow obstruction

‘Probable AIH’(→trial of steroids) if:

◦

mild changes or

◦

lack typical Abs or

◦

other possible aetiological factors are present

Overlap Syndromes

Steroid-responsive cholangiopathic autoimmune hepatitides (! long-term steroids may worsen PBC)

Mixed AIH/PSC: uncommon, often in children

Mixed AIH/PBC

◦

AMA −ve, ANA/ASMA +ve and the inﬂam

has some PBC-like features or

◦

AMA +ve with AIH-type inﬂam

◦

clinically, any patient with ≥ 2 features of AIH and ≥ 2 features of PBC

AMA -ve types are sometimes called ‘autoimmune cholangiopathy’ or ‘immunocholangitis’.

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Liver, Biliary Tract and Pancreas 162

Intrahepatic Bile Ducts

Cholestasis

Perivenular canalicular bilirubinostasis (seen in acute hepatitis, drugs, ischaemia, post-op, etc.)

Cholestatic liver cell rosettes (usu. have a lumen and are surrounded by other hepatocytes)

Biliary interface activity (biliary piecemeal necrosis):

 is the main clue to diagnosing a 1

◦

biliary disorder (obstructive, inﬂam

, etc.)

 is deﬁned by three features:

◦

cholate stasis,

◦

ductular react

◦

ﬁbroplasia

◦

Cholate Stasis:

 feathery degeneration of periportal hepatocytes which acquire Cu and CK7/19 +vity

 later bilirubin and Mallory hyaline (in zone 1) also accumulate ± xanthomatous M

◦

Ductular Reaction:

 proliferation of ductules and neocholangioles at the limiting plate

 ± PMN due to irritant effect of bile (not seen in other causes of ductular proliferation e.g.

infection, alcohol, venous outﬂow obstruction or isolated ductular hyperplasia)

◦

Fibroplasia: accompanies the ductular reaction and is loose/oedematous and at the periphery

of the PT/septum (→ clear ‘halo’ effect around septa/PTs)

Biliary cirrhosis: monolobular arch. (i.e. retained central venule ± ‘jig-saw’ parenchyma), clear halo

around septa, lots of zone 1 Cu/CuBP and loose lamellar ﬁbrosis in the septa suggest a biliary origin

Vanishing Bile Duct Syndrome

Adequacy of sampling

10 PTs are needed (some say 20) to diagnose ductopaenia by the 50% rule (i.e. ≥50% of PT arteries

are unaccompanied by a BD). Also, sig. BD loss is present if <80% of PTs have a BD

However there is evidence that, for BD loss to be statistically signiﬁcant, the minimal % BD loss

required varies with the n˜o. of PTs in the Bx e.g. for a Bx with 4 PTs you need 100% loss, for 8 PTs

you need ≥75% loss, etc. (see Tadrous and Goldin, 1997)

(Sub)acute BD loss

Acute cholestasis with little or no biliary interface activity

Causes incl. GVHD, liver Tx rejection, some drugs, treated HL

Chronic BD loss

Little cholestasis but prominent biliary interface activity → cirrhosis

Causes incl. PBC, PSC/SSC, liver Tx rejection, sarcoid, ischaemia, some drugs and infections

Septal/large duct disease

PSC and childhood extrahepatic biliary atresia may cause ductopaenia

Other causes

Idiopathic adulthood ductopaenia (diagnosis of exclusion, some are progressive like PSC/PBC)

Infantile/childhood:  syndromic e.g. Alagille, Zellweger, 

AT ↓, CF, Down’s, etc.

 non-syndromic e.g. PFIC (cholestasis, cholate stasis, inﬂam

and cirrhosis),

d/dg BRIC (canalicular cholestasis only)

Staging of PBC and PSC

In a Bx, report the highest stage present (not the predominant stage). Some recommend using the HAI

I changes conﬁned to the PT

II interface activity (chronic inﬂam

and biliary) ± short radiating septa

III scarring, incl. signiﬁcant septa or P-P linkage (‘biliary ﬁbrosis’)

IV biliary cirrhosis

Primary Biliary Cirrhosis (PBC)

Clin.: FM (9:1), anti-M2 AMA +ve in >95%, ± Sj¨ogren’s, PSS, coeliac, etc.

Early:  mixed chronic inﬂam

inﬁltrate in PT (predom. lymphoid) with granulomas =‘ﬂorid bile

 small BD epithelial damage and regeneration, intraepithelial lymphocytes



duct lesion’

 patchy changes (! sampling may result in non-speciﬁc PT inﬂam

only)

ductular prolif

(often lumenless) is seen in many conditions with limiting plate hepatocyte damage

isolated ductular hyperplasia (i.e. with no other lesion) is a cause of prolonged ↑ in ALT +/  GT

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Liver, Biliary Tract and Pancreas 163

Medium term:  vestigial CK7/19 or PAS +ve elements

 condensation of ﬁbrous tissue



where BDs used to be

 lymphoid aggregates ± foamy M

Late:  progressive BD loss (the smaller the duct the more likely it is to be lost)

 biliary interface activity

 biliary cirrhosis and cholestasis

Other:  mild lobular inﬂam

incl. sinusoid lymphocytosis ± small granulomas

 lymphocytic interface hepatitis ± occ. plasma cells and the odd germinal centre (d/dg

viral/AIH)

 ± Councilman bodies (some say that hepatocyte damage or other sig. lobular activity is

not typical of PBC and should suggest a superimposed process or an overlap syndrome)

d/dg: sarcoid (vs. AMA −ve PBC) granulomas are not targeted at BDs, may cluster and are ≈ bare

d/dg: drugs, PSC, viral or AIH, HL and any cause of vanishing BDs

Primary Sclerosing Cholangitis (PSC)

Clin.: M>F, ± colonic CIBD, pancreatitis, multifocal ﬁbrosclerosis, osteopaenia, cholangioCA

Radiol: abnormal MRI cholangiogram or ERCP (otherwise = ‘small duct PSC’)

Macro: normal → dilated irregular ducts → segmental/hemi cirrhosis (i.e. more uneven cf. PBC)

Largest BDs:  periduct ﬁbrosis extending to fat, prolif

of periductal glands

 severe (mainly lymphoplasmacytic) inﬂam

(! d/dg severe hepatitis)

 ulceration (± acute inﬂam

and bilirubin impregnation) ± dysplasia

Large BDs:  tortuosity ± mixed inﬂam

± follicles ± interface activity (biliary ± AIH-like)

 d/dg PBC but PSC has:  less inﬂam

but more oedema

 sparse/no intraepithelial lymphocytes/granulomas

 concentric lamellar (‘onion skin’) and hyaline ﬁbrosis

 nodular scarring ± adjacent parenchymal collapse

 larger ducts also involved

 ± cholangitis

 earlier cholestasis

Small BDs:  BDs vanish (replaced by a hyaline/ﬁbrous scar)

 PT arteries appear to proliferate (due to tortuosity 2

◦

to PT ﬁbrous shrinkage)

Gallbladder: l.p. lymphocytic + plasma cell inﬂam

(esp. if diffuse and acalculous) ± ﬁbrosclerotic

vasc. changes

d/dg SSC (HIV, post-op ischaemia, mastocytosis, HX, etc.): can’t distinguish from PSC by histol.

d/dg: PBC and any other cause of vanishing bile duct syndrome (q.v.)

d/dg extrahepaticor large duct obstruction (q.v.) from anycause incl. PSC (they may coexist)or recurrent

suppurative cholangitis (healing → ﬁbrous scar replaces duct) due to Clonorchis/ascarids

Dubin-Johnson Syndrome

Variably-sized lipofuscin-like granules in (predom. zone 3) hepatocytes but no cholestasis

Caroli Disease and Syndrome

Clin.: disease is sporadic, no portal HT; syndrome (=disease +congenital hepatic ﬁbrosis) is usu. AR

Dilated bile ducts (upto 2cm ) with thickened walls and marked chronic inﬂam

Lining: BD epithelium (bland or reactive atypia or dysplasia) or denuded with bile encrustation ± M

± Surrounding small duct proliferation: d/dg atresia (q.v.)

Assoc

with autosomal recessive polycystic kidney disease, choledochal cyst(s) and cholangioCA

d/dg biliary ectasias 2

◦

to PSC

Congenital Hepatic Fibrosis

Usu. AR (but AD occurs) ± Caroli disease ± portal HT, cholangitis, cholangioCA, polycystic kidney

disease (AR and AD types), TS, Meckel-Gruber and many more syndromes

Liver carved up into irregular islands (‘jig-saw’) by ﬁbrous tissue

Elongated irregular BD-like structures at the limiting plate and separate BDs centrally within the septa

No cholestasis or sig. inﬂam

unless complicated by ascending cholangitis (or Caroli)

± Mallory hyaline but no sig. lobular activity/necrosis

Assoc

with malformation of intrahepatic portal vein branches (may be small/absent)

d/dg cirrhosis: this has regenerative nodules ± inﬂam

/necrosis

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Liver, Biliary Tract and Pancreas 164

Alagille’s Syndrome (Arteriohepatic Dysplasia)

Sporadic/AD, dysmorphic baby, CVS anomalies, ± portal HT

Canalicular cholestasis ± hepatocellular giant cells, biliary interface activity and evidence of biliary

epithelial damage (lymphocytes, PMN, ± lumenal ﬁbro/epithelial obliteration)

Chronic BD loss (for def

see ‘Vanishing Bile Duct Syndrome’, p. 162)

von Meyenburg Complexes (vMC or Bile Duct Hamartoma)

Para-PT, usu. <5mm, ± multiple; assoc

with cavernous haemangioma, cholangioCA, ADPCKD

Round with irregular (branched, angulated, ectatic) and inter-connected ducts in cellular ﬁbrous stroma

Cytology: bland, ± inﬂam

atypia if intralumenal PMN, ± bile plugs, ± intralumenal mucin (rare

and not intracellular as in d/dg adeno

CA or BD adenoma) or amorphous eosinophilic proteinaceous

secretions

Immuno: mCEA has a lumenal pattern (cf. cytoplasmic in adenocarcinoma)

d/dg adenocarcinoma: good circumscription, bland cytology, bile plugs, vMC gland architecture and

lack of intracellular mucin all favour vMC

d/dg multiple vMC vs. congenital hepatic ﬁbrosis: use CPC

d/dg BD adenoma (q.v.) is bigger with less stroma, smaller (and more packed) ducts and no bile plugs

Extrahepatic and Large Bile Ducts

Large Duct Obstruction in Neonates (Extrahepatic Biliary Atresia)

Early: PT oedema, BD (and ductular) prolif

± PMN ± inspissated bile (d/dg sepsis q.v.)

Lobules may show cholestasis (esp. zone 3) ± a few zone 1 multinucleated hepatocyte GC

Later: BD loss progressing to 2

◦

biliary cirrhosis (see section on Cholestasis, p. 162)

Obliterated extrahepatic duct(s) show ﬁbrosis ± chronic inﬂam

± residual epithelial cells

FS during Kasai procedure:

 are there genuine BDs (cf. para-scar blind saccules)?

 BD lumen of ≥100–200 

 at the proximal resection margin sug-

gests likely success (else the procedure may be abandoned)

d/dg incl. many things (so deﬁnitive diagnosis should not be solely histological):

 neonatal hepatitis: atresia has ductular prolif

, sig. PT ﬁbrosis, less retic collapse/lobular

disarray, fewer GC (and these tend to be in zone 1 cf. widespread) and more cholestasis

 prolonged TPN (≥3 weeks) and obstructive choledochal cyst show similar histology .

. need

CPC

 some cases of CMV or 

AT↓ or other IEM

Large Duct Obstruction in Adults

Early changes: zone 3 cholestasis with enlarged Kupffer cells, PT oedema

Later in PT: mixed inﬂam

incl. PMN ±eos., ±concentric BD ﬁbrosis (d/dg PSC, which may coexist)

Later in lobules: feathery degeneration and mild changes reactive to bile: apoptosis, mitosis and inﬂam

≈ Speciﬁc changes (helpful in the d/dg but not always present):

 para-PT lobular bile infarcts: a bile infarct is an area of pale/foamy/rounded/pyknotic or dead

hepatocytes (! d/dg M) and ﬁbrin ± bile-staining

 PT bile extravasates with M response ± giant cells

 marginal bile ductular prolif

with the ductules orientated ≈ parallel to the limiting plate

If untreated → cholate stasis → 2

◦

biliary cirrhosis

d/dg drug reaction (if eos. prom.): obstruction rarely shows bland cholestasis without ductular prolif

d/dg alcohol (ASH) (if PMN prom.): OH has more lobular activity (incl. PMN, Mallory and steatosis)

d/dg acute hepatitis: necrosis (without bile infarcts) with bridging favours hepatitis

d/dg ductular prolif

of cholate stasis: biliary piecemeal necrosis has more irregular ductules, many

without lumena and not arranged ≈ parallel to the limiting plate (as may occur in marginal prolif

)

d/dg space occupying lesions may show similar changes but with sinusoid dilatation

d/dg TPN can also be a mimic in adults but more commonly it shows steatosis and less/no PT changes

d/dg sepsis and 2

◦

ascending cholangitis (q.v.)

d/dg autoimmune pancreatitis: plasma cells in liver are +ve for IgG4 and patients have ↑ serum IgG4

The lesions of ADPCKD are thought to arise by dilatation of vMCs and peribiliary glands.

some say it makes no difference if ducts are found at FS or what their  is - the procedure may still work. Others say that a total

lumenal area (of all hilar ducts) ≥ 100000 m

is a good prognostic.

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Liver, Biliary Tract and Pancreas 165

HIV Cholangiopathy (= AIDS Cholangiopathy)

Occurs in late HIV with low CD4 count

Due to Cryptosporidium/microsporidium/CMV infection

MRI, ERCP and histology are all similar to that seen in PSC (q.v.)

Liver Transplant Pathology

FS of Potential Donor Liver

Exclude contraindications to Tx: severe macrovesicular steatosis, neoplasia or chronic hepatitis

Mild portal triaditis is acceptable provided there is no clinical/serological evidence of viral disease

Reperfusion Injury (e.g. in the Baseline Bx at

hour)

Cholestasis (intrahepatocyte and canalicular) lasts a few weeks

Ballooning without necrosis is also transitory

Mild focal endothelialitis is acceptable without implying rejection

± Lipopeliosis (fatty expansion of sinusoids) may occur in steatotic transplants

Tiny foci of hepatocyte necrosis ± local PMN (usu. resolve within days)

Widespread PMN or zones 1&3 necrosis with subcapsular accentuation is a poor prognostic

Transplant Rejection

Hyperacute (humoural) rejection

Occurs hours to 1 week after Tx

Early: sinusoid engorgement, ﬁbrin, PMN, Ig and C3

Later: extensive zone 3 haemorrhagic coagulative necrosis

Acute rejection

Occurs in the ﬁrst 2 months (after Tx or after reduction in immunosuppression); requires ≥2 of:

◦

venular endothelialitis (predom. PT but, if severe, extends to zone 3 necrosis ± regenerat

congest

)

◦

mixed PT inﬂam

(eos., lymphocytes [usu. T8], blasts, M, plasma cells, PMN) ±interface if

severe

◦

BD epithelial vacuolation/regenerative atypia ± lymphocytes +/ PMN (! d/dg ascending

cholangitis)

± Arterial endothelialitis/ﬁbrinoid indicate severe rejection and

± Zone 3 necroinﬂam

not 2

◦

to venular endothelialitis



↑ risk of chronic rejection

Atypical acute rejection has zone 3 necroinﬂam

, congestion ± dropout but no sig. PT anomaly

In early rejection PT inﬂam

is predominantly lymphocytic, other cells (esp. eos.) ↑ with severity

Immunosuppression Rx quickly removes endothelialitis and decreases eos. and mononuclear cells .

if Rx started prior to initial Bx look for BD epithelial damage and be wary of grading severity

Grade (via the Banff Rejection Activity Index – see Bibliography and www.tpis.upmc.edu)

 ≥ moderate rejection (i.e. RAI ≥6 or inﬁltrate expanding most PTs) requires additional Rx

 only grade if rejection is the predominant cause of the abnormalities

 only grade if Bx is adequate: ≥5 PTs available, ≥2 H&E sections at each of ≥2 levels

d/dg: recurrent viral hepatitis (esp. HCV): HCV chronic hepatitis occurs >4 months post Tx and is

favoured by high serum HCV RNA, predominantly lymphocytic inﬂam

, ↑ interface, ↑ ﬁbrosis, sig.

lobular activity (steatosis, sinusoidal dilatat

, necroinﬂam

, etc.) and lack of venular endothelialitis. If

features are equivocal, consider simultaneous HCV and rejection.

d/dg other causes of endothelialitis e.g. severe HCV (i.e. endothelialitis alone is not proof of reject

)

d/dg: other causes of zone 3 necroinﬂam

: reperfusion injury, chronic reject

, viral hepatitis, AIH,

calcineurin inhibitors, vasc. occlusion (any vessel) and idiopathic chronic hepatitis

Chronic rejection

Occurs ≥ 60 days (post Tx or reduction in immunosuppression)

Medium and larger arteries: prolif and obliterative endarteritis with foam cells → ischaemia (q.v.)

PT early changes:

 cytologically atypical BD atrophy (nuclei: irregular distribution, drop-out, ↑ size and hy-

perchromasia; cytoplasm: eosinophilia and syncytia) with ↓ inﬂam

inﬁltrate as rejection

progresses

 mild BD loss (≥50% of PTs have a BD) and mild PT artery loss (≥75% of PTs have an

arteriole)

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Liver, Biliary Tract and Pancreas 166

PT late: marked BD loss (<50% of PTs have a BD), PT artery loss (<75% of PTs have one)

Zone 3 early: necroinﬂam

(± pigment M, cell dropout and mild ﬁbrosis)

Zone 3 late: ballooning, cholestasis, severe ﬁbrosis ± foam cells in sinusoids/smaller vessels

d/dg recurrent chronic biliary disease (PBC/PSC): rejection has ↓inﬂam

in PT, no ﬂorid BD granulo-

mas, no ductular prolif

or PT ﬁbrous expansion. PSC/PBC usu. recur late (≥ 1 year)

d/dg: other causes of zone 3 necroinﬂammation or vanishing BD syndrome (vide supra)

Idiopathic chronic hepatitis

Occurs >1 year post Tx, ↓ endothelialitis, ↓ BD damage, ↑ interface, ↑ zone 3 spotty necrosis

Not obviously viral, AIH or drug-related. (? is a form of delayed acute reject

)

Recurrent and De Novo Disease in the Graft

Most look similar to the disease in the native liver but may be modiﬁed by immunosuppression

PSC must be distinguished from chronic rejection (vide supra) and ischaemic SSC (which usu. presents

<6 months post Tx unlike recurrent PSC)

Infection post Liver Tx:

Opportunistic (e.g. CMV): look for mini-microabscesses (PMN aggregates) +/ granulomas

Fibrosing Cholestatic Hepatitis (FCH) may occur in the 1

few months of recurrent HBV/HCV with

widespread viral immunopositivity. It shows:

◦

PT ductular reaction with ﬁne reticular ﬁbrosis,

◦

ﬂorid

hepatocyte ballooning but minimal inﬂam

◦

cholestasis.

New/recurrent HBV: usual acute/chronic hepatitis (± more aggressive) or steatosis +/ FCH

New/recurrent HCV: usual histology (±ductular reaction/conﬂuent necrosis) or predominantly lobular

apoptoses with mild PT changes or FCH

Other Post Tx Complications

Vascular thromboses can lead to infarcts (usu. in the 1

2 weeks post Tx)–!exclude d/dg fungi

SSC/biliary anastomotic obstruction (cholestasis + ductular reaction + PT oedema and PMN)

Drug effects incl. cholestasis +/ zone 3 necrosis/ﬁbrosis – d/dg acute rejection/ischaemia

PTLD may present as a mass lesion or as PT inﬁltrates d/dg acute rejection inﬁltrate (which is EBV &

HHV8 −ve)

Graft vs. Host Disease (GVHD)

Due to foreign lymphocytes from BMTx, non-irradiated blood or solid organs (e.g. SI or liver Tx).

Maternal lymphocytes can produce similar pathology in the immunocompromised fetus

Clin.: changes occur in the liver (jaundice and cholestatic LFTs), skin & gut (and, if chronic, also in

LN, muscle, lung, lacrimal & salivary glands)

month: lobular focal inﬂam

, focal necrosis and Councilman bodies (d/dg viral hepatitis, CMV, etc.

– but these usu. have less BD damage cf. GVHD)

month:  PT lymphocytes (T8 and CD56 +ve NK cells) – mild (cf. liver Tx reject

)

 BD atypia (incl. stratiﬁcat

, hyperchromasia, vacuolat

and ↑NCR), distort

and loss

 parenchymal bilirubinostasis without biliary interface activity

month: BD loss, PT ﬁbrosis, endothelialitis (≈diagnostic if present, in the absence of other causes)

Longer term: ± connective tissue plugs in veins, ± 2

◦

biliary cirrhosis (clin./radiol. d/dg SSC)

Other BMTx assoc

disease: viral hepatitis, transfusion siderosis, VOD, NRH, infection, PTLD

Sepsis and Infections

Sepsis

Cholangiolitis lenta: periportal cholangioles dilated with bile plugs with PMN in +/ around them

 without suppurative cholangitis = sepsis

 with suppurative cholangitis = ascending cholangitis (q.v.) or toxic shock syndrome

Any bile plug may be a sign of sepsis, the larger the plug (from canaliculus to portal tract bile duct) the

stronger the association

Other features: steatosis, perivenular necrosis, microabscesses, clumps of cocci and PMN

Ascending Cholangitis (Suppurative Cholangitis)

◦

to obstruct

, bacteria, helminthes (Clonorchis, ascarid or schistosomal), opportunistic infect

, etc.

Affects the smaller (portal tract) bile ducts; large ducts may look normal

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Liver, Biliary Tract and Pancreas 167

More PMN (cf. biliary irritation alone) and PMN aggregates within BD walls and lumens

± Bacterial colonies ± PT abscesses ± portal pyelephlebitis/thrombosis ± cholangiolitis lenta

± Lobular changes: PMN in sinusoids; parenchymal necrosis

Some Speciﬁc Causative Organisms

Salmonella (Typhoid)

Sinusoid lymphocytosis,

Kupffer cell hyperplasia, erythrophagocytosis

Granulomas that may necrotise (but no Langhans giant cells)

Microvesicular steatosis

Brucella

Kupffer cell hyperplasia ± focal hepatocyte necrosis

Granulomas (anything from microgranulomas to tuberculoid type)

Coxiella burnetii (Q-Fever)

Fibrin-ring granuloma (small, PMN, M, ring of ﬁbrin) are typical but non-speciﬁc (see ‘Drugs’)

Non-speciﬁc granulomas, foci of necrosis, steatosis, inﬂam

and ﬁbrosis ± cirrhosis

Listeria

Viral hepatitis-like

Microabscesses with Gram +ve rods

Granulomas

Francisella tularensis (Tularaemia)

Granulomas may be indistinguishable from TB or sarcoid

Bartonella

Cat scratch granulomas i.e. irregular shape with periph palisaded M and central PMN/necrosis

Bacillary peliosis hepatis is the equivalent to bacillary angiomatosis (see p. 319) and not the bland blood

ﬁlled cystic dilatations of ordinary peliosis hepatis (this may also occur with infections, be idiopathic

or be assoc

with drugs, cachexia, Tx (liver/renal), asphyxia and tumours)

HIV (and AIDS)

May get a mild lobular hepatitis upon seroconversion ± sinusoidal lymphocytosis (d/dg EBV)

Children may show a giant cell hepatitis or a GVHD-like picture with lobular and PT lymphocytes

Hepatocyte and Kupffer cell Fe (± EMH) is usu. 2

◦

to transfusions/haemolysis

Reaction to opportunists may be suppressed and microbes may roam free within the sinusoids .

. should

always stain for opportunists (DPAS, ZN ± Grocott/CMV immuno)

Peliosis hepatis (ordinary and bacillary types)

Tumours: HCC (due to HCV), 1

◦

DLBCL, 2

◦

HL, KS (d/dg bacillary angiomatosis/peliosis), etc.

Vide supra for association with HBV/HCV and cholangiopathy; vide infra for drug reactions

Other viruses (EBV, CMV, etc.)

See ‘Acute Hepatitis’ (p. 158) and ‘Infection post Liver Tx’, (p. 166).

Drugs/Iatrogenic

Generalities (with examples)

Clin.: usu. subside on removing the drug (or persist if taken for >6 months) & relapse if restarted

Eosinophils – but ! these may be present in small N˜os in other things e.g. AIH, HCV, etc.

Zone 3 cholestasis alone [‘bland cholestasis’] (anabolic steroids, oral contraceptives, [pregnancy])

Cholestatic hepatitis [zone 3 bile, lobular inﬂam

, ±eos] (phenothiazines, Augmentin



, erythromycin)

Cholestatic acute hepatitis [≈ d/dg HAV-type with necrosis] (halothane, isoniazid )

Ascending cholangitis (phenothiazines, allopurinol)

Vanishing bile ducts ± PBC-like (ﬂucloxacillin, paraquat, ibuprofen, erythromycin, phenothiazines)

SSC (ischaemia, post-op/post liver Tx, intra-arterial ﬂoxuridine)

Granulomas esp. if atypical, of NST (d/dg idiopathic or 2

◦

to lymphoma) or accompanied by eos. Some

speciﬁc types are linked to drugs (e.g. ﬁbrin-ring granuloma with allopurinol d/dg Q-fever, HL, viruses,

CTD, leishmaniasis, Toxoplasma, etc. and lipogranulomas with oral mineral oils – usu. para central

venules cf. d/dg steatohepatitic ones)

Chronic hepatitis (-methyldopa, zidovudine-like anti-retrovirals, isoniazid, nitrofurantoin, aspirin)

AIH-like, type 1 (ANA +ve, ASMA −ve) (minocycline, -methyldopa)

d/dg of lymphocytes in dilated sinusoids include: typhoid, EBV (infectious mononucleosis), HCV, HIV, malaria (tropical

splenomegaly syndrome) and CLL.

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Liver, Biliary Tract and Pancreas 168

Macrovesicular steatosis (OH, cortisone, oestrogens, methotrexate)

Microvesicular steatosis (i.v. tetracyclines)

Mixed steatosis (microvesicular and macrovesicular) ±giant mitochondria (2

◦

to mitochondrial damage

due to OH, valproate, antivirals e.g. zidovudine and Reye’s syndrome initiated by salicylates)

NASH (TPN, oestrogens & tamoxifen, nifedipine, didanozine, amiodarone, cortisone)

Fibrosis/cirrhosis (OH, vitamin A, methotrexate)

Zone 1 necrosis [d/dg PET] (cocaine, phosphorus, ferric sulphate, aﬂatoxin & other toxins)

Zone 2 necrosis [d/dg VHF] (frusemide)

Zone 3 necrosis [coagulative necrosis ± ductular prolif

] (cocaine, paracetamol – aggravated by OH,

CCl

)

Veno-occlusive disease (chemo/radioRx, bush teas, OH may cause veno-occlusion)

Hepatic vein thrombosis → Budd-Chiari (prolonged progesterone e.g. OCP, pregnancy)

Peliosis hepatis (azathioprine, tamoxifen)

Siderosis (ribavirin causes haemolysis hepatocyte and Kupffer cell Fe, OH may cause haemolysis)

Lamellar inclusion phospholipidosis (co-trimoxazole, amiodarone)

Neoplasia (oestrogens, androgens, vinyl chloride monomer, aﬂatoxin, thorotrast, post-Tx/immuno-

suppression)

Methotrexate

Damage ∝ dose, interval, cumulative dose, OH, obesity, diabetes, reason for Rx (psoriasis > RhA)

Nuclear hyperchromasia, glycogenation and anisonucleosis

Steatosis, ballooning, necrosis

Fibrosis → micronodular cirrhosis (cirrhosis is rare with cumulative dose <1.5g)

PT show a mixed inﬁltrate (lymphocytes, M, PMN)

Grading is via the classiﬁcation of Roenigk et al., 1982 – see table 12.2

TABLE 12.2 Grading methotrexate liver damage

Nuclear Liver cell Portal

Grade Steatosis variability necrosis inflam

Fibrosis

I none/mild mild none mild none

II moderate/ moderate/ moderate/ moderate/ none or mild PT expansion without

severe severe severe severe septa or limiting plate disruption

IIIa any any any any mild with septa

IIIb any any any any moderate to severe with septa

IV any any any any cirrhosis

Vascular Disorders

General Features of Ischaemia

Zone 3 accentuated changes ± patchy/sharp demarcation depending on cause

Cholestasis, ballooning, hepatocyte atrophy or dropout of hepatocyte clusters

If more chronic: perivenular and pericellular ﬁbrosis ± cirrhosis (! d/dg alcohol)

If severe and acute: infarction (coagulative ± haemorrhagic necrosis)

Portal Vein Thrombosis

Large portal vein (Virchow’s triad: alterat

in endothelium/ﬂow/coagulat

) e.g. MPD, sepsis, tumour

Small portal vein: local PT disease (e.g. cirrhosis, schistosomiasis, hepatitis, PBC, PSC, vasculitis,

sarcoid)

Maybe2

◦

to systemic venous HT (e.g. Budd-Chiari syndrome/VOD, CCF)

May be idiopathic (small vein obliteration is particularly marked)

Veins: large – thromboses/recanalisation; small – obliterat

/dilatat

(to give ‘ectopic’ PT veins)

Acute thrombosis → (pseudo)infarct of Zahn (= a wedge of congest

& atrophy) ±↑apoptoses

Other: partial atrophy of lobe, partial nodular transformation, NRH or no histological abnormality

If portal vein thrombosis extends to occlude splenic vein ostium → venous bowel infarction

Portal Hypertension

Many causes or idiopathic, Bx may be normal or show variable anomalies:

Perisinusoidal sclerosis, dilated (‘ectopic’) PT veins or ﬁbrotic PT with small, inconspicuous veins

Incomplete septal cirrhosis +/ NRH

↑ Visibility and dilatation of PT lymphatics