THE MICHIGAN SOCIETY OF

PATHOLOGISTS

presents

A SEMINAR on

PEDIATRIC PATHOLOGY moderated by

Jay Bomtloin, M.D. Director, Deportment of Anatomic Pathology

William Beaumont Hos.pitol and

A Joseph Brough, M.O. Acting Oirecror of labofororie.s.

Chifdren"s Hospital of Michigan and

Kathleen P. Heidelberger, M.D. Assistant Ptofauor of Pothofogy

The University of Michigan

Saturday, October 19, 1974 Tho Uni ... ersity of Michigan Medico! School

Ann Arbor, Michigan

TIUi MtCillCAN SOC ltT'f Of

PNI't!OLOCISTS

A SEMlNAR Oft

PEDlATRlC PATHOLOGY cOdtn.ted by

Jny lhH'n tttc1n, M.D . IHT.t'.ct o r , OepllTCIIICIOt Of ,\ n <J. tomic P!lthOLO~.)'

William BcDumunl Hospiral ••4

A. Joseph Brough, M.D. Actbg: Dtr«.tor of Laboratoriee Children's Ho•p1ul of Mic;higan

•nd Kathleen P. lltidolbergcr • .x.o.

Anil;tQnt. P:rofciHtor of Pat bolog.y The Univeutcy of NichiS:i •'

•• Saturday, October 19. 1974

Tht: University of Hichls.:m MecHe:U Stbool Ann Arbor, Kichigen

CASE I

An etgh~-ye~r-old ~~~~ female in£•nt, the

pro4 uet o£ A fu!l·t~.-. uncomplicatd &Oiil.•

oc. l on nnd dol.i VlH')', becumn j aundiced {It

31~ ceo days. Phyele4l ex~~~tlon ia

hOtrpl tal showed gert\u.aUuO Lcterua . LJb­

OI'3C.Or y exa;lllinat.lOnl tncluded hemogLobin

1 1.. 0 gm% : 1-.'BC 14,300/'ll'ell (25~ sc.gmc.nt.cd

110\itroph!ls, $X b:uuS fc:mPs. 53% lympho•

cyte• . i% ao~yte4 ~4 l ll eas1nophJle) ,

~daquste pl3tel et•, recfculoc7L~ count

6.1X; btU r ubin: t oCftl G. O cgcn~ . d i r ect:

rr~c:.tion l. i mgsn%, ud ne ucobilinogon Mt­

ot1v~. £s:pl oratory l4p4tOt01%1)· :md ci'IO­

lan&lo~r~pby vert per{o~d.

CAS£ 11 (Case A73-137 Pontt~e c~. Hoap.)

A 1200 ga. 11-day-old tnfenc vas cyanotic

ac. b irth . Th~ i nfnnt 1.Hspl .:aycd spont.:ln•

•'Ollll but '-'C."lk rcspil"r~tlons . Clinlenl d {(I­

KftU~l& o( hyali ne ~br~ne disease va• Qade

•M tb.e. infant vat pbc:td on 100% oxystn

vlo teepl cator. Chc•t x-ray on da y or

binh was repor ted •• •uly (mini ma l)

hyolJn~ metthrLLne dhuse. La~oracory

ltudlu s~ J>H'"6.96: p02

=2S ~:

p002•12 MIIIHg. Tht- ptl and Po

2 rett~.-<t:ltted

Lov. Chest x-ray on the sev-enth day tt•

V<Hll<!J a diff use , b .l lllit(l.rol g canular jHttt•

ern a.od on t-t-.c :linch d.ay coarse alveoler

ln(Lltrate bilater31ly. Tbe infant dled

on chc (:hwentb day.

CASE 111

A 6--yeoc-old male wHb DQ\.-n' 6 &yQdrOIDO vu

hotpit:al iz~d heeauu of bemateOOEisi& nnd

t nt'y 40t()ols. PhysSelll axom.ination dt ....

do•od a gr·eat-ly diltA.n<led a!>doeen v1th

hep.atte. nnd $plcnle ~rger.ent, u:aaho

a1cit~•, ~nd dilac•d auperficial vein1 .

llc W('ll mildly fln t:mic: t ho SC!I:Ull bilirub:l n

waa o.a - ~.5 ms/dl and t he SGOT 55 unitt.

Serua ~o~na. nit-rosen va• l& =&/dl. IDent­

geno&rama confirced the prc$~nce of eao­

phli .. l varices. Excretory urograms lilhowed

no1'1Ml renal outltno8 tuld ret ent ion ot con­

craat =aterial ~~thin .cdullary cysta.

Porc•J venogr~ d~n.trated distortion of

tho Lntrahcp3tie. v~eculeture, and a porto-

CASE lll (Coo't)

covol anast~sts v~t performed . Hit rt­

sponuf! to surgcC'y ,.,, poor , and he expired

2 J /2 conths later.

Stucl1u of the p~ronte and six aiblln,ce

dt=on,trotcd tbnt four aiaters (3Set 27,

22 , 19 ~nd 16) had oxcrctory urogram3 ln­

tCI"I,rcto4 as sh.owin~ "~:tedullary spons:o

kidney. •• Cortteal C)'iiiU we.re ;sls<J c!eaorr­

atrat~ in the elden. Uver $eo2nto ehovod

abnormolit1es in throe of t he four s1et4r• .

nnd tho youngest l1ad abnormal hep<\ti<: flm ...

ction and biopsy evtd~nee of cOnAenitaJ

hepatic fibr0$1S v1th cholan$iti&.

~

A 4-ye~r-old ~hite a1rl born ~iter a non., I

geltttion and del ivery ~nd vei ghing 8 lb•· ·

6 ot . , developed hepatomegaly and pa! pnblc

a.xilbey and io.gui.od lyeph nodes at aa•

l& ..onths-. Sbe had rKdV~ her OPT and

unt WC1 t4); vlch1n u ot-1N\-l ll1i11ts. A llllllc

stbltng ~as alive ~nd w~lL, b~t a prev1o~s

r ... le sibling died at asc 14 ~ntba fro.

dO<JJ.y progressive c.hrontc. pneu::aoniti&.

llxt:ltnacion of the pac1tn t showed a nor rool

chcwc x-ray vith a norrM L t hymic shado~o~ ot

.:aa• 4 weks and at 1 110nchs. She exhiJ:I.o.

Urd lntens:tcce.n.t leukopeniA (2SOO...S000/-3

),

p~r•1fttenc eosinophilia and intermittent

~ (Coo' t )

ly.phopenia (4C0-3000/ .. 3) .

At aau 24 wont ha s he oxper:ienced r~!Jit: llted

llJ) I,t'C>des o£ upper r u p1rator y 1nfee t ion,

prosreasing t o ehroate pneumonitis nt ego

SO oonths. B. i nflu•naae, r$eUd~naa •P· ·

t . ~CtU a nd Klebstell4 ~p. wel:'e c u ltu-red

f ront the sputu.tll a t V4riOut; times. 1'horc

was progres~~ve d~lerjoration despite

creau.eoL vi th ~ntlbiotice and ster tod•.

At aa~ 40 con~hs sb~ devtloped chronte

obe t r uc t i vu airvay d laQoa~. Lahoraco ry ciC­

B~inseiona shoved a nor&41 l eukocyte count

aDd ruoct:ioo, total protUo 8.4 s::;;s%

Cal~ 4.3; globuJln 4.1) , lgC 182S acet ,

[gA 74 cgu%, tSM 1312 ~31% , IgE 23 ~6% j

~ (Coo ' t )

Co.pltccnt (C3) 180 -&•% . Alpha- 1-Antll~Jp­

tltn 3~5 mg.s%. normal rauo o f T and ll

lyutl)hocytes. The SehJck t est wa~ pofit1ve.

l n vltro r~$ponsc of lynphocyteB to attm•

ulntlon vith PRA aM allosene.ic: c:~Jl• va•

mnrkodly decr eased . Th~r~ vas oo de l1y~d

hypcracnsltiv;l.ty l'UJ>0•' 8o to SK/ sn, Cnnd­

ida, PPD .:tnd DNCB . VtJ&inal c:u lr.\ttCR yf(!)d­

ed C.odid3 albic:ane, Ca~c:l~ ~nd phoa­

phorOU$ and thyroid func:~on testa ~re

wJ th tn no ntal llmiu.

A thyllllc hottetransplont• t1on was perfONil(td

at a,ge 43 ::.ooths. There vas io.!U.sl urk~

clJntcol b rpr:ovem.ent, olthough ehoeat x-ray

findill$1f did not r egrou . Lvmnhocvtf'! !'l rt'-

'

~ (con'c)

8p0n.ded to !'UA in v1tro. n.ere vae a weak

r~aponse t o Candid~ •ftd DKCB ~ktn testtn;.

Cot>tnbtl po$itive homolytic ancmU dcvtUoped

PulconQry symptoe~ p~ogTessed and eb~ ex­

pired lu p~!.o~~rr (altura at age 4.

A four-•eek•old blQck fe.ale lnf•nt, the

p roduct of a t hird ful1-c:~r;a uncomp<Llcoto¢

Q~atotion ilnd d QUVOI!'y ...,(IS adl!U.t ted ..., tth '

ona-~eek history ot peroic ious e=c•1• •nd

•bdo.iwal distention. Pos1tJve phyetcaJ

!tndlngs consi8tod of amall sbotty btl~t­

o ral ce rvica l l ymph node~. a grade 11/VI

Ry$tOlic murmur hcord ovnr the entire pre­

c.ordiua, Ui.!l"ked abdozUo.al di&tentJon abel a

1 lvor palpable J J/2 iocbc:s bclov the

d8ht costal :md loh cot•C;l-1. marg;tns . l.{lb·

or{ltory ex<ut~inationa :tncJ 1.1ded bemo&lobi n

11.2 gm%. RBC ).4 :111ion/mm3, YBC 18. 700/

:::al (9% se:pented neutrophil.s, 91 band

foroa, 77% lymphocytes, S% eosinophi l l) ,

CASt Y (C<Int 'd)

adequate plat~et5, re~!culocy~c count

).6X , moderate anil'top..-.~kiloc:ytosi.a , b1Ji •

rubtn 0.4 mgm% total , SCOT 100 uni ca .

phoRphorus 4.9 agm%, total procein 4.8 ca1

(al~ ).1; glo~lin 1.7). \lt~ 2.8 ~24

hl)ura . X- rays of th~ cheRt and long bon~•

we r o 1dt hin norm<Jl J.:bllts. tVP s hovod no

abnormal ities aside rrom marked enlargo­

.. nt of t he liver. A percut~~ous ne•4le

liv4r biopsy vas perroreed .

~

An 11- ycar-old vhita boy W3S ~tt~d for

"orkup or "chronle rer111l disease11• 11 1:1 h.1d

boon wt'll un t il th<: pas t year ~he-n t hq

par4t:nt s not e d tnc:renin& letb:irg:y ami wcak.­

n•••· which reached a peak about: seven

mOnth• prior to thte 11d•ission vhen he

became p.:ale and so ~o>ol•k he '"as unabl.:t to

t unc t1on oorm.1.U.y. llo had severe ane.tr~tn.

and the parent.s wero told that. the chiJd

had "aeve.re renal dlat••e". MonU,ly traq­

aru~Uon.!l dtd not Improve his physical eou­

d ~tion s o be wns rc Perrod for furtl1er d Jng­

noata and tteatl:lent,

the only c.u. co:pla!At vas- occ:.asionaJ

enur~de. 'there wot no family hi.uory oC

~ (Co<~t'd)

ren.'ll diaease.

P. E.: Short stature for age.

Pal e, wasted boy wit h

blood prU98Ut6 140/104.

Decrea•ecl -.aKJ(! .str~­

gth aod dovo..lop:en t.

II011p1ttl course c;onahtt!d Clf ••ork-up con ...

rH·m~•\g chr:ooic renol diJJe.ose, with vomit.­

il'IG• t vitc.hjng, disorte.nu.lioa., aod var1-

ablt blood press~~e l•vela. Slgn!il~anl

blood a tudles included: Kr 6 .4 mBq/l.; co2

:

8 efl!q /1.; Crea tinine: 15.3 e.g%; BUN 26 l ag%

and decreased Hgb; red &nd white cella w~ro

found in urine. Uri~t lptcific gravity

rAnJJ,Cd bet...,een 1.007 nnd 1 .010.

CASE VI (Coat'd)

lVPt Soall kiOncy& vlth nan-vln~llaatlon

wi t h 90% Hypaque . T reftttwnt ... •as &VJ>iiOrL­

tvo , lnc tudlnS low protein d iet. <Jnt l h)'liM­

tenttvo d~ugs, bl ood trnns{U$ [ons, and

perlton~,l dialy5is ovtr che next alx

month~ u~t11 rtghl ncphrectoay and ~adavcr

r:Ct13 1 trnnspltl.nt wtWil J)trforu.~d. Even t"'

u1.11Ly , rennl fallurc c:m•ued. Kypert~nulon

pro&reaaed aod tho chUd d.ted thre!! yun

tattr. vitb intraer3ntel hesorrba&es.

S.l.lda J.G from bis OWl\ kidney JJt j)O'Jt UIOti!CO

oJC{lflliftll t ton .

CA.SB Vll

A oiat•yesr•old whitt boy v~s ftrst adott­

tcd nt tJ&e tvenry-rhteC! mo•lths wft:h ll b Jt•­

tory of :tncermitl~nt. (uvea· up ro 1{)}• b\.1''"'

glnnin& ln t-be neonatal perlod. He 1:1hort ly

thutaft~r uhlbitd lnl•raiuent t'hinorr­

h~a 4 nd coush. Stoola ,,,.~Ye frequent and

foul i'I!IO.llin£:, ocet~o ton a L.ly conta~n_i nR

bLood. Wd&hc g.aln .,..;,u rct~rdcd. but dc:,­

volo,.ent ~o·ilS othc:rvl•o nor.Jl, The 1r

.e4Sate family history vas aon- contrib­

utory. lnitial physical examination

ahO':td a ...,eight" of 21. S lbs •• and bi•

lattt41 rhonehl. Cb~tt k-r~y $~ed

dl!fu•c e-phyG~l~ chant~ vith t04T&en­

tn& o£ tM ccntrtll lung Mt'kin.&s extend ..

CA-'t VII {Cont' d)

in,S lnt.o the tid- port ioa of the lung

Uddt. Laboratory e.xnalnnt LOI'I~.: Jncluded

0 ht.moalob!n of 12.6 amX. wnr. count

14,100/e3 (36% :-:~~ntecl n.eut:-ophi.ls,

151 band !o~, 46% l,.,hoeyte&, 21 aono­

eytcs ~nd 1% co6inophilJ), adequate plat•·

lets land nogat iva udnolysls . Follow~ ng

tecocment vi th antibioticft , t he pa tient

v«~• d l•charged and foUoved ln che Pul­

.onary Clinic. Be ••• rtadoitted on

1}evcr(l l occasions . Our lflg hls ninth

year, ho developed p(ogr~tsive nasal ob­

$truct1on and vas admitted for polypect-

CASE Vltl

Jbi1 6-day-old eale vAa adai£ted fro•

another hospi t.;,l [or a workup o : posslblt

conaon l to l hctt r t d:IHCfllli! fl lld also for f ur­

ther genet ic study o£ mu Lt. j p I ~: congt'nlttd

ano.-.. .1 lt'&·

Xhe patient did vell until t he 13th d•Y of

ho•pitd~lt~t1on when M wflfl febrile, hn.d

a toehycardia <and d-htttndu-c! :tbdomen vtth

d.e<n-lted bcr.;e1 souncb - one 8.,'( ...-~s

,grouLJ blood)' . lad.,. onema showed trr­

esulnrity of the mucota ond decr~ased

cu.L:Lbor ausgcs t ina &l.lbAUeos~l he.bOrrh•a•

or enterocolitis. [n~tt41 t~~tment val

•upportive vitb good ro~lt$ for four

CASE V1tt (Con't)

4aye . at vhicb t~ he began voai~ins.

3Gdll passed b l oody ltOOlS flr.d <.lg._"lin hnt.l

obdOflltnn L d i.sten t: Lon , Scvcrnl hou~s

httr the child vas taken to su~gc~;y fol"

nbdoetftAl ~xploratJon.

CASI! IX

lbe P<)tll"Dt. an 8-,.a~Jd girl . bad be~n

under •t\ldi· bec::<auae of ret3n:lcd dcvt>lo,.­

mc" t rrom t.he age of opprox:lnlatal y one

yeer. Initial phyatc•l examination had

Jthown dtspropo:-tionau d~velopeent of tht

head .and tnmk. gtv ln$ the t::pre.MJOrt of

fln onJurged he.:sd, a!thougl. me;tsure.mentt~

were normaL l'hc br.i4ge of t he nose ... •nM

lov: there ~ere no eorntal opac.ities.

Tbc utreatue... \;'ere fl.bOrt and d~oe. f ll'liJt~U

thie~oned and fusifQrm. &oentgenos~aa•

l howod bone changes typtctal of Autl te'r­

llur-l or ' s 6yndrome. Sevcr(ll uamina t ion•

of tbo uti06 ~ere nesettve !or oucopoly­

saechulde!'l. a lthouah th~ urtne Cld conuJn

f~SP. lX (Cont•d)

an tnc.nued a:IIOUnt: a( ga.lac:t0$e.. Stud:IC!•

ot Cell c:.ult.ure& deiiN'Jnatr~h .. od il high UP""

tAkel t1 f 11u l.ph1'1Cc t h1'1t "''01 inc:orporat~d i n­

to n tJm;,lll mucopol)'aac.ch.nide. Cella wcro

devoid of ~ta-8~lactol1daae. ~t ita coo­

untrAthm in t.bc culture mediUlll vas hfch.

She 6UfCer(!.d from r requent respira t ory

tract infecdons and: c:na.lna.ll y . .,.as found

to have .oderate protelnurJ• and ptttfna

edema of the legij . Th6 liver ~nd splctn

vere both enlarged. She e:xp:l;r~d at home ,

spptrrcntly I rom rer,;urronL rcspiracory

Jn!ectloo.

~ (CUnL'd)

Post.ortc• ex~cation disclosed s evere

grovth retardatton (body length 67 em,

¢hOt1t eirc::umterence t.S em). The msxilat')'

gin&l\ln \I'OS ~~~o'llrkedly hypertrophied, and

the ton&u~ app~red to be la~ae. Costo­

chondral junct ion$ vere b~~dcd, and there

was gibbus 7 i;m in len~;th from »10

t o L2

.

Tho cxtrc;Uths ~ere .shott #.nd the hands

cla~likQ. fbe heart v~• enlarged vith

thlcteni~ and defo~ity ot gitral and

c·ticuspi4 valves. lnfllt('t~tes of foam

cellt vere identified in the renal glom•

erult, vplenic capsulet, Gtrioventricular

valves and tbywus.

tUCHIGAN SOCIETY OF PATHOLOGISTS 19 October 1974

Symposium on Pediatric Pathology

DIAGNOSES

Case 1. Hepatitis in alpha1-antitrypsin deficiency

Case 2. Bronchopulmonary dysplasia

Case 3 Infantile polycystic disease -congenital hepatic fibrosis

Case 4. Combined immunodeficiency disease

Case 5. Hepatic neuroblastoma

Case 6. 14edullary cystic disease

Case 7. Nasal polyps (fibrocystic disease)

Case 8. Necrotizing enterocolitis

Case 9. !-cell disease

l.O'f

Brough

Heidelberger

Bernstein

Brough

Heidelberger

Bernstein

Brough

Heidelberger

Bernstein

CASE Ill

HEPATIC CHOLESTASIS IN A1 ANTI-TRYPSIN DEFICIENCY

Conjugated hyperbilirubinemia in early infancy provides a diagnostic challenge which may not be resolved by clint.' ,1 and biochemical evaluation. The majority of cases are examples of either hepatitis or atresia of the extra-hepatic bile ducts for which liver biopsy is a reliable tool in t heir differentiation. The absence of significant inflammation and/or a paucity of bile ducts should alert one to the possibility of other disorders of heredofamilial or metabolic type . A pr ime example is alpha1 anti-trypsin deficiency, a disorder characterized metabolically by a marked decrease in serum alphal anti-trypsin the major component of alpha! globulin faction. At least 11 allelic genes are recognized, of which to date only the Pi ZZ variant is recognized as being associated with clinical disease. The previously dichotomous clinical expression of pan-acinar obstructive emphysema in young adults and juvenile cirrhosis is not expanded from the observation of more recent cases to include a host of diverse and variable expressions which include transient neonatal conjugated hyperbilirubinemia, juvenile c irrhosis with or without associated obstructive emphysema, adults with obstructive emphysema, with or without associated cirrhosis and hepatocarcinoma, and lastly children and adults without clinically manifest disease. On morphologic grounds , the diagnosis may be achieved by the presence of characteristic pigment deposits, largely within periportal hepatocytes, which are diastase resistant PAS positive and characteristically stained with PTAH and Massone Trichrome technique. Addi­tionally, specific fluoresce with fluorecein labeled anti-human alpha! anti- trypsin demonstrate deposits in the same distribution and electron microscopy shows an accumulation of fibri l lar mate r ial within the rough endoplasmic reticulum.

References: Brough, A. J . and Bernstein, J .: Conjugated hyperbilirubinemia in early infancy. Human Pathology 5:507-516 , 1974 . Sharp, H.L.: Alphal anti-trypsin deficiency. Hosp . Prac . 83-96, May, 1971. Aagenaes, 0., et 'al: Neon'atal cholestasis i n alp hal anti- trypsin deficient children. Act a Pediat . Scand. 61:632-642, 1972. Berg, N.O. and Eriksson, S.: Liver disease in adults with alpha1 anti­trypsin deficiency. N.E.J.M. 287:1264-1267, 1972. Glascow, J.F.T., et al: Alpha1 anti-trypsin deficiency in association with both cirrhosis and chronic obstruct ive lung disease in two sibs. Am. J . Med. 54 :181-194 , 1973.

t

MICHIGAN SOCIETY OF PATHOLOGrSTS - PEDIATRIC PATHOLOGY SE1UNAR

CASE 2. TABLE r3 Pulmonary Pathology in 74 Infants Following Oxygen Ther apy

Pulmonary reaction

HY.C! 1i n!l rr.cir.brane disease Exudative & early reparative re~ctiQn

Reparative fibropro-1 iterative reaction

No.

34

27

13

SELECTED REFERENCES

Survival time

3 hr. 2-1/2 dats

2-8-l/2 days

5-1/£-135 days

Respirator therapy

3-60 hours

34 hr.-8-1/2 days

5-1/2-135 days

Pulmonary pathologic findings and sequelae

Hyaline Exudative Prolifer- Inter-membranes ative stitial

reaction react~on fibrosis

100. 35.3

77.7 100. 77.7 44.4

23.0 69.2 100. 84.6

(%) Oblitera- · cystic

Emphysema tive bronchi- bronchi-olitis olectas~s

33.3 11.1 11. 1

76.9 38.4 23.0

1. Northway, W.H., Jr.; Rosan, R.C., and Parker, O.Y.: Pulmonary disease following respi rator therapy of hyaline mem­brane disease. New Eng. J.Med. 276:357, 1967.

2. Boat, T.F.; Klei~§rman, J.I.; Favaroff, A.A., and Matthews, L.W.: Toxic effects of oxygen in cul tured and human neonatal respiratory epithelium. Pediat. Res. 7:607-615, 1973.

3. Anderson W.R.; Strickland, M.S.; Tsai, S.H., and Haglin, J.J.: Light microscopic and ultrastructural study of the adverse effects of oxygen therapy in the neonate lung. Am.J.Path. 73:727-748, 1973. (Good pictures and table)

4. Tsai, S. H.; Anderson, \~.R.; Strickl and, t1.B., and Pliego, M.: BPOassociated with oxygen therapy i n infants with RDS. Radiology 105:107-112, 1972.

5. LeMarre: Residuali!lulmonary abnormalities in survivors of idiopathic respiratory distress syndrome. Am. Rev. Respir. Dis. lOB:56-61 , 1973.

6. Outerbridge, E.loJ.; tlogrady, M.B., Beaudry, P.H., and Stern, L.: Idiopathic ROS. Recurrent respiratory illness in survivors. Am. J. Dis. Child. 123:99-104, 1972.

7. Hodgman, J.E.; Mikity, V.G.; Totter, 0., and Cleland, R.S.: Chronic respiratory distress in the premature infant. Wilson-Mikity syndrome. Pediatrics 44:179-195, 1969.

8. Mikity, V.G., and Taber, P.: Complications in the treatment of the ROS. Pediat. Clin.N.Am. 20:419-431, 1973.

MICHIGAN SOCIETY OF PATHOLOGISTS PEDIATRIC PATHOLOGY SEMINAR

CASES 3 and 6 DIFFERENTIAL DIAGNOSIS OF RENAL MEDULLARY CYSTS A. Infantile Polycystic Disease

1. Medul lary tubular ectasia (R) 2. Congenital hepatic fibrosis (R)

B. Medullary Cystic Disease Complex 1. Medullary cystic disease (D,S) 2. Familial juvenile nephronophthisis (R) 3. Renal-retinal dysplasia (R)

a. Leber's optic atrophy b. Christie L~ken's syndrome c. Retinitis pigmentosa d. Laurence-Moon-Biedl-Bardet syndrome e. Alstrom's syndrome

C. Medullary Sponge Kidney (S?) D. Medul l ary Necros.is (A) E. Pyelogenic Cyst (A)

Selected References

D Autosomal dominant inheritance R Autosomal recessive inheritance S Sporadic mutation A Acquired lesion

1. Bernstein, J.: Heratlitary disorders of the kidney. 1. Par·enchymal defects and malformations. In: Perspectives in ,Pediatric Pathology, Eds. R. P.Bolande and H. Rosenberg. Year Book Medical Publishers, Chicago, Vol. 1, 1973.

2. Ekstrom, T., ~ 21·: Hedullary Sponge Ki dney. Stockholm, Almquist and Wickse 11 1959.

3. Gardner, K.D.: Evolution of clinical signs in adult onset cystic disease of the renal medulla. Ann. Int. Med. 74:47, 1971.

4. Giselson, ' N, et al.: Renal medullary cystic disease or familial juvenile nephronophthisiS:a renal tubular disease. Am.J.Med. 48:174, 1970.

5. Goldstein, 'J.L., and Fialkow, P.J.: The Alstrom syndrome. Medicine §£.:53, 1973. 6. Pascal, R.R.: Hedullary cystic disease of the kidney. Am.J.Clin.Path. 59 :659,

1973. 7. Senior, B.: Familial renal - ret4nal dysplasia . Am.J.Ois.Child. 125:442, 1973.

NEUTROPHILIC LEUKOCYTE

*Absolute count *N.B.T. Phagocytosis Chemotaxis Bacteriocidal capacity

REFERENCE!

HUMORAL

*Serum electrophoresis *Immunoelectrophoresis *A1 AT Secretory lgA Complement *lsoagglucinins *Torch, RSV, PI

C.F. H.l.

Schick Test

LN Biopsy

LYMPHOCYTE

*Absolute Count PHA PWM Con-A Candida SK/SD *Delayed

1\ypersenti vi ty Candida SK/SD

MLC MIF

DNCB

E & EAC Rosettes Immunofluorescence

IgM, G, A Transfer factor E. H. ADA *X-ray

AUTOIMMUNE

*Coombs *ANF Anti-lgA Anti-IgG Anti-DNA

Stiehm, E. Richard and Fulginiti, Vincent A. 1 Immunologic Disorders in Infants and Children. W.B . Saunders Co. , 1973.

Case 5 STAGING: l

MICHIGAN SOCIETY OF PATHOLOGISTS PEDIATRIC PATHOLOGY SEIHNAR

I . Tumor ·confined to organ or structure of origin. II. Tumor extending in continuity beyond structure of origin, but not crossing

midline. Homolateral regional lymph nodes may be involved . III. Tumors extending in continuity beyond midline. Regional lymph nodes may be

involved bilaterally. IV. Remote disease involving skeleton, organs, soft tissue, or distant lymph

node groups. IVS. Patients otherwise I or II, but with remote disease confined only to one or

more of the following sites: l i ver, skin or bone marrow (without bone metastasis on skeletal survey) .

(

PRQ~~6JlT~C FACTORS IN SURVIVAL: 2 I. Age at diagnosis 2. Location of primary 3. Presence or absence and location of metastasis 4, Total vs subtotal excis·ion 5. Lymphocyte counts at diagno§is 4 6. Microscopic differentiation ' 7. Tumor immugity5 8. Stage IV S

Selected References 1. Evans, A.E. , O'Angio, G.J . , and Randolph, J.: A proposed staging for children

with neuroblastoma. Cancer 27:374-378, 1971. 2. Swank, R.L., II.; Fetterman, G·.H.; Sieber, W.K. , and Kiesewetter, W.B.: Prog­

nostic factors in neuroblastoma. Ann.Surg. 174:428-435, 1971. 3. Bechwith, J:e·., andJ~artin; R.F.: Observations on the histoP,athology of .neuro­

blastomas. J.P_~diat. Surg. 1:106-110, 1962. 4. Mahinen, J.: Microscopic patterns as a guide to prognosis .of neuroblastoma in

childhood. Cancer 29:1637-1646 , 1972. 5. Hel l strom, K.E., and Hellstrom, I.: Immunity to neuroblastomas and melanomas.

Ann.Rev. Med. 23:19-38, 1972. 6. O'Angio, G.J.; Evans, A.E., and Koop, C.E. : Special problems of widespread

neuroblastoma with a favorable prognosis . Lancet 1:1046-1049, 1971 7. Evans, A.e .. : Treatment of neuroblastoma . Cancer 30:1595-1599, 1972. 8. Young, L.W.; Rubin, P., and Hansen, R.E. : The extra- adrenal neuroblastoma:

High radiocurability and diagnostic accuracy. Am.J.Roentg.,Rad.Ther., Nucl. t~ed. 108:75-gl, 1970.

9. Turkel, S.B., and Itabashi, H.H. : The natural history of neuroblastic cells in the fetal adrenal gland. Am.J.Path. 76:225-243, 1974.

10. Everson, T.C., and ccile, W.H.: Spontaneous Regression of Cancer . Philadelphia, Saunders, 1966, Chapt. 3.

11. Voute, P.A. ; Wadman, S.K. , and VanPotten, H.J.: Congenital neuroblastoma. Symptoms ·in mother during pregnancy. Clin. Pediat. (Philadelphia) 9:206-207, 1970. -

12 . Griffin, M.E. , and .Bolande, R.P. : Familial neuroblastoma with regression and maturation to ganglioneuroma. Pediatrics 43:377-382, 1969.

CASE 117

NASAL POLYPS IN CYSTIC FIBROSIS

While the existence of nasal polyps has been recognized for 2000 years, their pathogenesis is still widely debatable. Various factors including intolerance to drugs such as aspirin, vasomotor imbalance, carbohydrate dysmetabolism, inflammation and mechanical obstruction have been incriminated, it is now recognized that cystic fibrosis is a common cause of nasal polyps in childhood although polyps as such are rare in this age group. While it is reported that nasal polyps in patients with cystic fibrosis have no specific characteristics, personal observations indicate that the diagnosis may be strongly suspected when excessive changes of "mucosis", as frequently seen in other areas of the respiratory and gastrointestinal tract of C.F . patients, are encountered. The importance of t his is emphasized by the fact that nasal polyposis may precede the development of pulmonary symptoms in approximately 15 per cent of cases.

References : Lanoff, G., Daddono, A., and Johnson, E.: study. Ann. Allergy 31:551-554, 1973.

Nasal polyps in children: a 10-year

Schwachman, H. , Kulzzycid, L.L., and Mueller, H.D.: with cystic fibrosis. Am. J. Dis. Child. 102:768-9,

Nasal polyposis in patients 1961.

Case 8

fUCHIGAN SOCIETY OF PATHOLOGISTS PEDIATRIC PATHOLOGY SEMINAR

CLINICAL SIGNS: 1. Vomiti ng 2. Abdominal distension 3. Gastrointestinal bleeding and/or diarrhea 4. Pneumatosis intestinalis 5. Lethargy 6 . Apnea 7. Jaundice (~)

ASSOCIATED FACTORS: 1. Prematurity (usually) 2. Hypoxia (frequently RDS) 3. Hypotension 4. Exchange transfusion

CAUSES : (Theories, some new, some old, few discarded) 1. Bi rth trauma 2. Congenital defects of bowel wall 3. Respiratory acidosis (many with RDS) 4. Umbilical vessel catheters 5. Sepsis (any source) 6. Feeding practices 7. Loca 1 i zed Sh~1artzman reaction 8 . Endotoxin and lysosome factors

AUTOPSY FINDIIlGS ( 13/13) 3 NNE: Ileum 5

Ileum, cecum, ascending colon 3 Ascending colon 2 Cecum, duodenum, each 1

OTHER: Jejunum, stomach and esophagus 1

Pulmonary atelectasis 13 Intracerebral hemorrhage 8 Petechiae 8 Peritonitis (all perforated) 7 Pulmonary hemorrhage 5

SELECTED REFERENCES: 1. ToulouKian, R.J .: Ischemic gastroenterocolitis in infants: Clinical aspects and

thoughts on its etiology. Conn.fled. 37:229-234, 1973. 2. Robach, S.A. , et al.: Necrotizing enterocolitis: Emerging entity in regional

infant intensive care faci lity. Arch.Surg. 109:314-319, 1974. 3. Hopkins, G.B. ; Gould, V.E. ; Stevenson, I. K.~nd Oliver, T.K.: Necrotizing

enterocolitis in pr~mature infants . Am.J.Dis.Child. 120:229-232, 1970 4. Fetterman, G.H.: Neonatal necrotizing enterocolitis.--old pitfall or new problem?

Pediatr ics 48:345-348 , 1971. 5. Hermann, R.~: Perforation of the colon from necrotizing colitis in the newborn.

Report of a survival alid' a·:new etiologic concept. Pediatric Surg. 58:436-441, 1965.

6. Editorial (with references): Neonatal peritonitis and exchange transfusion. Brit. r~ed. J. 1:340-341, 1968.

fHCHIGAN SOCIETY OF PATHOLOGISTS PEDIATRIC PATHOLOGY SEMINAP.

Case 9. DIFFERENTIAL DIAGNOSIS OF GLOMERULAR FOAl>! CELLS A. Epithelial foam cells

*1. Fabry's diseasel,2 2. Generalized GM1 gangliosidosis3 3. I-cell disease 4

**4. Alpert's disease5 B. f4esangi a 1 foam ce 11 s

*1. Familial lecithin7cholestrol acyltransferase (LCAT) deficiencl #2. Gaucher's disease 3. Hyperglycemia

a. Hyperlipoproteinemia, type III8 b. Hyperlipoproteinemia

10type Iv9

c. Hypertriglyceridemia 11 **d. Idiopathic nephrofic syndrome e. Hepatic cirrhosisl2

4. Niemann-Pick disease9 **5. Hemolytic-uremic syndrome

Notes: *Associated with renal insufficiency #Associated with severe proteinuria

**Occasional, incidental finding in primary renal disease

Selected References 1. Jensen, E.: On the pathology of angiokeratoma corporis diffusum (Fabry). Acta

pathol. microbial. scand. 68:313, 1966. 2. Pabico, R., et 21.: Renal pathologic lesions and functional alterations in a

man with Fabry's disease. Am.J.Med. 55:415, 1973. 3. Scott,C.R.,et 21.:Familial neurovisceral lipidosis. J . Pediat. 11:357, 1967. 4. Gilbert, E.,~t 21·= I-cell disease, mucolipidosis II. Z kinderheilk 114:259,

1973. 5. Krickstein, H. , et ll·: Renal pathology in hereditary nephritis with deafness.

Arch.Path. 82:506, 1966. 6. Hovig, T., and Gjone, E.: Familial plasma lecithin: cholesterol acyltransferas~

(LCAT) deficiency. Acta pathol . microbial. scand. 81A:681, 1973. 7. de Brito, T., et al.: Glomerular involvement in Gaucher's disease. Arch.Path.

95:1, 1973. --

8. Amatruda, J.!·l., et ll· : Type III hyperlipoproteinemia. Arch.Path. 98:51, 1974. 9. Rosenmann, E. , and Aviram, A.: Glomerular involvement in storage diseases.

J . Pathol. J.ll.:61, 1972. 10. McKenzie, I.F.C., and Kincaid-Smit~. P.: Foam cells in the renal glomerulus .

J. Pathol. 97:151, 1972. 11. Allen, A. C.: The Kidney. Ne~J York, Grune & Stratton, 1962, 2nd ed., p. 269. 12. Bloodworth, J.M.B., and Sommers, S.l.: "Cirrhostic glomerulosclerosis," a renal

lesion associated with hepatic cirrhosis. Lab. Invest. 8:962, 1959.

Original Contribution

CONJUGATED HYPER­BILIRUBINEMIA IN EARLY INFANCY A Reassessment of Liver Biopsy

A.j(ISejlh Brmtgh., M.D.,* (Ill(/ jay Bernstein, M.D.t

Abstract

Liver biopsy pnwicles a re liable toni for difreremialiu~ biliary obstmction from hepalocdl ular disease in the cv;duation or co.yug-ateci h yp~t·bilirubinemia in newborns and ynu ng infants. In 158 cases with adequalc clinical follnw·up there were 10 mi.diagnoses (6.3 pet· cent). Critical retrospective review of the m:nerial indiancd that the rate of ciTOI' could be red uced u>lcss thau5 per ccnL Diagnostic errors stem moSL often from .. over-reading" mild or moderate de­grees of bile duct hyperplasia in hepatiti,. ~larked bile duct proliferation may also obscure the ltisrologic appearance of alpha1·antitrypsiu dcfiLiency. A Jack of bile dueL prolil'cnuion in bil iaq' aLrcsia w.ill nlso tcsult iu tnisdiagnOsis, bw iL is a rare finrling. ltl evaluating lt cpa10ccllular d isease. the histopath(>Jogist should be alert 10 a paucity of inn·ahcpatic bile ducts, which might be a sign or abnormalities in bile salt metabolism, and to a-lack of inflammation, wh ich might signal metabolic di~ase ratl1er than hepatitis.

Obstructi ve jaundice: in c;al'ly infan<:y poses tn ;til a diagnostic challcugc 1 hat too often cannot be resolved by clinical and biochemical evaluation. l.i\'CI' biopsy, either pcrcuraneous or open, has been previously shown to us to afford a high de­gree of reliability in dilferemiating jaundice due to anatomic obstruction of tile extrahepatic bile ducts fmm that due tel hcparocellulat' aocl other nonobstruc· tive lesiuns.' The importt<nce of idemifyiug the hepatic lesion in a nt~dlc biopsy lies in spal'ing an infam with hepatocellular disca>e the t'isk inherent in :mesthesia and surget-y. T he purpose of thi~ discussion is 10 review cenain diagnoslic t;rrors and to

define some of the pit.f~tlls of bistopatho· logic diagnosis.

CLINICAL MATERIAL

To date, since 19fi7, 2 18 biopsies have been performed in 181 cases. lJl 158 there were suflicicnt follow-up data, based OJI

ctinlcal course and ou tcome. to confirm the biopsy diagnosi;; 23 f>atients were lost 10 follow-up. r n the groupofl58 confirmed c_~~s there were 195 specimens. 98 per· cutaneous needle and 97 open wedge biopsies. Se,•e•-al patients had uatdcrgone two biopsies, an init ial needle biopsy

"t\)!iisuuH Prof(.':Ssnr of t•:uholngy, Wayne State:- UniH:Isity Sc:hool of Medicine. Aslloci;ue l'a~holo· j:i,t. <:hildl·en's I l<»pital uf ~lichig;m, Ot.-troit, Mit.hig;m.

t Dircnnr, Dcparunem e>IJ\nUtumic l'athology. \\'illianl8~aumunl Hospital. KopiOOlk, ~Jkh.igan. 507

508

HUMAN p,\THOLOGY- VOLUME 5. N UMBER 5 Stpttmb<r 1974

TABLE 1. 0JHCJNA1, Uuwsv DIA(~NOSI~s IN J58 CAsts WiTH AottQ.UA1"& fOLLO\"·Ln> DA'rA

Anatomic No ,.obnructiV:e Le&iolu Oltttrudion llcpotiliJ Otlm,.

Female Whi(C :!3 12 Blnck !3 12

M ale While 26 27 Black 9 22 Ori('ntJil 1

82 73 :s *One nlpha, ·antitrypsin dcfkicnq. one bilc-u<:itl

abnorn1ttli1y. one _ABO hemoly1ic disease.

interpreted as showiug extrahepatic biliary obstruction and 1 hen an open bi· opsy ~t Lhe time of lapat'OLomy. Biopsy Willi

perf(mned as eaHy as six days and <lll late as 40 weel<.s, with an ave rage of 8.5 wee ks. The patient population an d initial biopsy diagnosc.s in the con firmed casc.s are -shown in Table I. The figures show a 3: I predominance of whites in the bi li<u·y a1re~i~l group and no nu.:ial predilection in hepatitis, dara in accord '''ilh our previous repo rL; the racial distribution in_t)le patic nL population continues as before, approxi· mately equal black and white admissions.' Males continue to show a 2 : I predomi · nancc in the hepat ilis group.

ln tCrpre wl'ion of the biopsyspedmc ns l'aS Cal'l'icd Otll Without knol'lcdge of the clinical data, using bile duct prolifet·arion in all visible portal a reas as the sole cri·

terio11 of extrahepatic obstru<:tion. Focal bile duct p roliferation was discounted. Collation with the bioch emical. surgic:al. radiologic. a nd subsequent clinical da1a has revealed 12 errors in ren cases (fable 2). These were nine cases of he patocellular disease ct·t•tmeously diagnosed as ana1omk obstruction and one cx~mple of biliary atresia misdiaf:,'llosed as ltepatiris. Ex· amplc.s of' choledochal cyst and obstructing plugs of t.he extrahepatic ducts are in­cluded in the group of "anato mic obstruc· lion;" the histoparholob>ic changes in the liver are similar, as ate Lhe implications for thcl";ll)eutic surgical i1aerventjon.

PITFALLS OF HISTOLOGIC DIAGNOSIS

T h e histopathologic dill'eremiation or anatomic ducLal obstntctio n from tlle h epawccllular disease< ca using conjugated h yperbilirubinemia in the newborn and young infa nt rests on the recognition of certain inu<~hepatic changes secondary to the obstt·uction. The presence o•· abs~nce uf hepawcellular giant cell transfot'rnation a nd inflammatory cell inliiLnllion is of no b efp In 1his h:g-.ud . si nce these char• ctcr· isric changes of hepati tis :~rc: also frequent accompaniments of both bili:~ry atresia and choled(>chal cyst. The pt·esence of hilc plugging: in por ta l areas is a lso unreliable, since it has been found with some fre­quency in hepatitis. The single, most t·eliable criterion has been portal duaal

TABLE 2. o ... c~OSTIC ERROI<S

ToJt•• •I OrJ'ginal Rftlicw Ullimatt Cdtt A&e BioJis1• Dictnoxis Diagt1oais Diagnosis

10 ..... 0 OMtrua ion othtmruon Probo>M• hcp;uitis 2 4 \O,l k.. N Obstruction ~tr'l.•cliou PCK..~it,c hcp0titis, pos~ibl

biliiU')~duodcnal fistub 3 4 wk. C) OhstJ'U(tion Ohsll'llt liun Hcp:1tiLis ~ 3 wk. N Olmn•rtio•• Hcpl•lh is Htpatil i~ 5 2 wk. N OhstJ'••ctjon Ucp:ui1j11 Hcp:uitl,) 6 4 1110. 0 Obstl'llelidn O b.\ 11 UCi ion J)ro00b1e hepa1i1is 7 8 ,,.~:,_. 0 Ob~1ruaiou Otxtn.terion Alpha,•:anticrypsiu

drfkiency 8 8 wk. 0 Ohsrructiun Of>51rUCliOU Alph:•1·a.rrlitrypsin

tldicic:nc.:y ~ I mo. N Ob,truc:tion Hopr••hi" 1-iep:~ r itis

10 3 mo. N ll~p:uil i.s Hep:-mti~ 1\iliar')' llll't:.!>ia

,.0 • upen wedge. N = JH:r c:utaneous needle.

CONJUGATED HYPERBILIRUIHNEM!'A-BR0U<:H. BtJ>><sretN

Figure J. Typical-c;::s.amptc nf 1 he hcpntkc·h:mges associ:Hed with biliary ~u;resi::- i 1l ~IU ejght week ol.d inf~m. f hc culm'gcd t>ortaJ nre-.ts corm•ill ~ul iw.:tcascd I IUtnbcr of hypcrpl<tstit i111tcrcmuu:<:1ing hilc duqs an'cl •• light iMilo·:ue of in flamm::nory cells. The enlarged duct in the center of the pon al Mt;~ appea.rs 10 be 1 he iniCFiobul:u­duct; cluC1ule-s <at lht: pt:ripht:ry uf 1 ht: p<,•rtal ~trdl :Ire also increased. OccaSi(Jn:il pli1g:; of ii1spiss::.ucd bile can be "-'elL Blood \'(~scls an: rclmJw,:.l~ iuconsplcuuus. but t.>•mphatic..o; nre dilme cl. There is :1lso mild hep~•lQ<:elluJ:n chang e. (Hcmatoxyliu <md eosin slaw . X I ~U.)

proli ferati~nl ,· a finding cotnmon 1.0 extra~ hepatic bilia ry atresia. to cho ledochal cyst, and 10 obstl'Uctiou of the common bile duct by p lugs of i nspissatcd secretion. T he dlaracLeristic histolOgic draoge in o ur e.xperience h;is been a prolifci·ati('Jn 9 r hxperplasia o f the inr.erl<.lbul"r ducts, leading to an elong<lt.ed and t.onuous ap­peanrnc:e with intet·connccting segmencs in the plane of a single section (fig. !). The structures appc~ar. ~herefore, 1.0 I'Cpl'esenl. ~13ttened cisterns. freq_uenLiy SUIT Ounding the porllll blood vessels. We have not been able lO make a clea.l' d istinctioo bet ween ductal and ductul;u· h yperplasia, although one or 1he othc.r n1ay predo,minate jn a given case. Ductul.es at !'he peripheries of the portal areas ;1re a lso characteristiotll y hyperplastic and conuuu nicate irreg ularly with the d ucts. Bile duct pro life ration is t)'pically seen in all porwl areas. and a f<)Cal or irregular dislribution suggeS~s that ~xtrahepatic obstruction might nor be pz·escm.

Diagnostic error has resulted, there­fore, u:om lhe misioteq>rctation of d ut tal abnoz·ma lities - from the .. over-reac;ling" o [ bile d uct pm li.feration i.n ~hildren shown subsequemly to recover from their jaun­dice. and from ilS '\mder·rcading;~• in chi I· dren shown subseguenLly to have biliar)' tran obstt'uction. T he second pt·oblem

has been infrequent; the fi rst, the most conHllOn cause of histopathologic error.

n.ile Duel Prolijeratio11 in Nonob#r·uclive Liver Disease

An errol!leous diagnosis ofbj liary tract nbstructiott was based on Lhc presence -of ducral hyperplasia in n ine instances. All nine inl~tnts have re<:overed from their jaundice. Two siblings (cases 1 and 8} had alpha,-am itrypsin ddidenq•. The othet·s a·re regarded. as hiving had hepatitis. Two of the nine (t<•ses I and 2) were cited in the earlier t·epon.•

T he seven patiems· with heRatitis un­detwcnt biopS)~ bt.tween tW() wCeks and t'our months o( age. the majority al one month or less. T he age distribu Lion, wirh an average of approximately six weeks. differs only slightly from that of the en Lire group. Four infants initially underwenl percutane­o us biopsy. Two (cases 4 and 9) were lhen sul~ected to surgical exploration (hal demonsu'ated p;ztenGy of the· extt ahepatic ducts; a third (case 5) was rega rdtd clinically as h;lving hep~tit is and ex­ploratimi was not per formed. lnthe fotlrth (case 2) the z·e were at laparotlnn y no idcntifial:ile bi le, duct~. and chola ngiog-raphy cou ld nor be carried our; biliary. 509

510

HU,\1,\N I'ATHOI.OGY- V(H.l!ME ~. NU~·I BER !i &JJI<mber /'f74

Tigu('C 2. Bile dll<.:l proiH(t)'~tiou ~md bc:>pathis mi.sdk•s-no~(·d ~ll' obnt·uction. Oper:ni,,e chol;mgingr:tph}' tlcmonslrdlt:cl p~ltt:nl bile ducts. Ca!'i.c I. (1-Jc:mawxylin and eosin st:dn. X 270.)

drainage fro111 the region of the porta hepatis resulted in permanen t tle~tring of u,e jaun dice. but ~;xrrahep<~tic bi li;~i·y du,ts have never beeo visualized, The precise nature of Lhe case remains unsdl\red. af1d it is still canicd a, a d iagnos~ic e rror.' The initial biopsy -in th<·! other tln·ee cases was obLaioed surgically at the time o[ biliary exP.Ioration. C:lwlangiog raphy de.mons11·ated patency of the cxu-abcpati<: biliary tree in two patien ts (c.1se~ I and$), who became anicteric postopet·miMely and liave t'emalned so (Fig. 2}. The last parient (Gase 6) in this group unde rwe nL ~urgical e~-ploration at four months. whfn chol~n-

gi<>graphy failed to demonstrate by reu·o· grade filling struciurcs abo\~t the junction ·of o.h~ common hepatic and cystic ducts. Toe child nonetheless became anicteric shonly after operation and has renutined so fol' more than four years (Fig. 3).

1-lisLOiogic review of the biopsies in these sel'en cases led w redassific:ation of three, in which we felt that our own diag· nostic criteria had tlOt been adequately fulfi lled and in which a diagnosis of ob· su·uctio n should have not been n1~1de on ini tial examit1ati()n. The ductal and ·dtrct'u­la r l1yperplasia \,·as neither of a q uality nor of a quaJltity compar~tb1e to thm. .seen i-n

"figure~- M:trkerl d ucml:tr pt·o li fct·;uion inu;!rpn~w-d ;,~ ~>:trah.::p;uic nh:;trttt:ti<m in :i cll ild \\'ho:;cjaundicc de<! red rollowing exploration and ChOian.g·iog'i''a))h)'· Op.:·rU0\1C chuiMgio({;r<lphr h:ld nliled l(l demon.str:tte I he hepatic ducts. The patient is alive :md well more th:m four yc:-ers :•t'lcr opcr:mon. C:.se 6. (Hcrnar.oxrlin and <."Ul)in St:ti 11. X 3(1().)

COI'..Jlf(;A I f:L) HYI'[RBILIRl,;Bl)I(MlA - IIRot:cll, BtR:<>Ttl~

Pigm·e <I, ~IMl>:ed hilc: duct pmlife1.1t111H in ·• c:h~o' o t ltom ozyg,mu :J iph.• ,· :•m •n·~p!oi ll cldidc:nc} wbdiaJo;· uo.st:d 1h l•ili;u'' ohsmu:tiun. C:L'ie S. ( l-l<:mtll(JMiut .utd eosin sr.ain. X IUH.)

' 'erilicd ca.1cs of biliary atresiJ "' other· fornlS or an:uomic obstnlctioo. Some: dc:­gree of bile duct proliferatjon was. how· ever. p!'C'SctH in all. and in I he rmUoril)' i1 cuu ld 1101 be difl-'erentiated even 1 et ro­spectivd)' from 1he truly obSII'UCLivc ksiur1 (Figs. 2, 3). We nn1~t admit, 1.hcreforc, 1hnr. fincl illb'S rCg"arck d as d wracteristir of ob:;Lrucliou , including marked hi1\; duct proli!'er:ttion .-ith l ymphan giectasia and with intrad uctal and inrraductular bile plug>. will be encountered in some cai<:S of hepawcellular disease. We have also learned that c'-aluation of bile ducr pm· liferation sh<)u ld not be done on rhc basis

of !-richrome stained sections, in which bile ducts arc tincwrially distincr and tend 10

be overlr pmmincm or emphasized. A misdiotJ:.,'llOsis of obsLruction beotuse

of marked bile ducr proliferation and bile p lu gging was 1·c nd crcd in (\"0 cases of homOZ)'g'ous al ph H1-:.tn tilrypsin deJid cJJt.:y (casos 7 and 8). T his genetically determined abnonnalitT hns been recognized by Sharp and his collea~;ucs' • w be associate<l with earl)· infantilt: co•!iu!(ated h )•pcrbili· rubinernia and I he f r cquem developrnelll of fatal child hood cirrhosis. Light micro~· copy of hep;nic biopsies has shown ltcpadtis~ like changes. often with gia ltl cdl

51 I

512

H UMAN PATHOLOGY- VO!.LIA!Jo 5, c\IUoiHIEil ·5 Sr/JIIIm6rr 11/;-l

ct'anSfo1·mation. A distinctive feature l•as been the prc~ence of inLracellular1 dias-­tnse-nondigcslib1c , PAS-posiLivc deposit$ tha1 have been sJ1 own by speci h.c im muno­lluoresaence and elecrron microscopy to l)e accumulations of aiJlha,-a lllitr)'Jhin residlng in the e ndopla$mic re tic:ulum. O ur e xperie nce \dth 1hese 1w0 l'n isdiag·­nosed cases and ;mnLher QJlC in whit;h cbe coudilioo was: recogoized histologically indicates a lso the freque.m prescltce of bile duct proliferation (Fig. 4) a nd is ~imila r to the observatio ns rece ntly re ported by Poner aJld colleagues." !\!though the ductal prolife-ratio n was as:;oci<ued wi1 h bole plugging (Fig. 5) and· was sufficient in d e.gree tO suggest the d.iagnosis.o f anatoni ic obst..r uclion, rctrospe~tive evaluation :>ug­geste.d rhar the pmlifenuiqn was pre· dominant ly ductuJar and that duct al proliferati6n was m ild. T his difl'<:>rence and the presence of inLracyt<lplasmic. PAS­posilive granules .emlb.led us to make t-he correct diagnosis in th e th ird case.

Lack of Bile Duct Prolifer·atiou in Biliary Atresia '

On only one O(cas ion (qse I 0) has Lhc lack of bile duct ptoliferarion led t,JS ro the ern.)neoO$ d iag·nosis of hcpatiLis in a C<~\e subsequen~y shown Lo be biliary atresia. In a pen:utaneows biopsy per­fo rmed aL Lhree mom hs of age, the ponal areas were ntinhnally t!nlargcd aud the

bile dut~s difficult r.o ido:nLify (Fi~. 6). T he biopsy specimen oon tain.ed six portal areas and was regarded as adequate. l nA<t.rn· nHHion and _giant cdltransfon natiott wc:rc rhough• to he: compat ib le \\1iLh h cpatit.i.s. N9 e .x-lrtthc pa tic bile d ucrs were idenli­fiable at la parotomy. however. and post­morLem e xamina tion atone ye-a1·confinned Lhe d iagnosis n r1 ext rahep~ltj<; biliar y arresia. 0Jl!.ly tiny disconlinuous remmm.ts of rhe extrahepatk ducts could be found. at1d there \,·as no <:omrnu nication with intra· hepatic ducts at the pona hepatis . .'vl icro· scc)opic <::xaminaLioo showed d isJon io n and apparenc scarring 1hat were in~erprel,ed as eesid11a or Clli i iJfl~tmffiatory pr()cess leading to desu·ucLion o f t.he dueL~. The intYahe.palic dut;ts, however, now -had a mo re lypic;ll configuration of biliary alt'esia - bile duct:;tl and """'ked ductular proli fe rat:io n (Fig. i).

D1FFERENTIAL DIAGN OSIS m· CONJUGATED H YPERBILIRUBI·

NEMIA IN EARLY INFANCY

The cmph~si~ in o ur previous SL,ttdy wa:5 10 rtj lfe re nl iate hepa1 ic Je~ions due tO an::tromic extr~t hepatic ljjlia ry obstr uc,ion ti·om those of hepatocellula•· d isease, the hu ~er designated simply as 1'he patitis.'1

l As already noted , we Tecog;nized several fonl1S o f extrahepatic obst.ruct.ion , all as· sociated with simil<.tr aiLerati(m$ wiLhitt the

Hgure 6. ltt llf\tl\nHtlioo. g-iu!H cdl uiuhfol'lumion. ~t.nd l~td of siguifi<:mtl bile dun prolifcnuiou in biliary alrt\sla uti.sdiagnost:d a:; hcpat.ids. Case 10. (Hematoxylin anrl eosin uain. X 270.)

CO'\j l:GA TE.O H YI'E:RBII .IIW Ill '\EM IA -II ROUCH , Br•«STWI

Figure i. l)ufl.ll .md dltc ud:u proliferation " ·itl1 bile ph1ggu1g in JMhllllutlt•m 11\{'t );J>t.'<iruco. ttioc: mouth.s ;after OTIJ!lll .. l hif•1~\ (..A-.r II)_ ( llcmiUOX\Iin ;md t,.'():'lll)(Uirl )( II fl.)

liver. and we h"'·c not been able to dis­lin!,'llish an10ng them by liver biopsy. L iver biopsy in chulcduchal cyst. for example, clltH'acteri~ticall >, s hows as much inHcun· malion a nd g·i:mc celln•tmsfonnatidn as Lhc biopsy in bi I i:n•y a ll'<"ia. !\It hough " ' rcsia is by fal' lht: musl <..:OIIHtton condition. ac .. cuu m i ng· ff>t' pcl'lm ps 95 pe1· celll of (,b.slruc:l ivc Clh iiOI'IIIII Iit ics. these other possibi lities mus t I)C: kept in mind.

Hcp~Hocellular diseases constitute a hroadc1 sp.:cmun <lf abnormality. and the differential di<~gnosis has accordinglr be­come mote complex . \\'e ha\e come: LO

expect a relath cl) good prognosis in "neo-

natal hepati tis." It has become mon.> important. therefore, lO recognize mela­bo1ic ahnorn'l:tHties that carr}' a poorer long t t:J' Ill pr•o« •gnosis because ()f persistence or the undel'iying disease, even though Lhc j:unulice lllll )' initiall y clear. T he term "hc(Jillilis" p·r·opcrly comprises those co n· dition> with hcpatm:ellular damage and iuthtr ntu :nion. It also includes a numbcrvf' infcc:ti<,us t:(II JdiLions associated with focal or Lonal necrosis, l'or examplef neona1al listeriosi-s, the reroh"llition of ,,1hich is im­porwnt bccau >e of the efficacy of prompt antibiotic therapy. The presence or ab­sence o f giant cell tran.~formarion is of

Figun:o 8. \bwttf~ ••f Jl<lln .• r bilt- ttuas. ~·c.:aUt'Clmtr<~.hcpaiK: •tr-cda. h'ilh ntgtiqihle irlll~nltll31iou dtld lac k of fihtcN!t nt .;1 c .1~ uf •'IJ•tt•lltUtl bile ~It mctabn lisnl. ( HtmaiOX\ h•' Jllfl ~·hul ' I :lin. X j00 ) 513

5 14

IIUMA!\ PATHOLOGY- VOLU~IE 5 . :'\UMB£R .> Sr(JI<mlxr IY74

li ttle hel p, for it may or rnay not be presem in any of the con ditions un der consideration, but the absence of an iufl;unmatory cell rcspv 11se should aler t the patholo~ist to the pus.1ibility of metabolic disease. The most important to t•ccognize is. perha ps, g-.tlactosemia, for remedial dietar y measures can he insti­tuted to prevem further dssue damage. An important due is the presence of mru·ked fatty infilu-ation, which is not ordinarily a feature of neonatal hepariris. It should be noted parenthetica lly that the clinical diagnosis of galactosemia will be missed if the laborator y uses only a glucose oxidase test instead of a no nspecilic reducin g test for tll'inalysis.

Another clue to possible metabolic disease is a de ficiency of intrahepatic bile ducts {Fig. 8). Among those conditions listed under 1.he heading of "paucit)' of intrahepatic bile ducu" are several syn­dromes seem ingly related to abnormali­ties of bile salt metabolism. The nosology of this group is far from clear , for th e clittlcal dlfferentcs cmpha.~i?.ccl in a num­ber <)f reports may or may not establish genetic heterogeneity.•-•• T he picture is confused still fu rther by desr.riptions of d uctal o r ductular J>I'Oiiferation in some cases and hypoplasia or deficiency in othen;. It seems likely thai. this group en­compasses, wholly or partially, cases p1•eviously reponed as intrahepatic atresia and a• biliary hypopla,ia (imrd- and ex tra­hepatic}. We do not propose at the presen t time to sort out these "cholestatic syn­dromes."" which are listed in T able 3, bm only to remind Lhc hist.opathologist that the find ing of a paud ty or int rahe patic

T ABLES. CHOt.J!.S'TATIC S\'NDRO){ES

Jntnlo6u/ar su,ouctl lnjfammatiou

lnl l'~ lu~:pat.ic biliary Absent nr Abseru to ;urc11ia or dimi11i$hccJ sHght hypoplasia~'-"

l•urahc1>atic Varinble; . Absentot' d •oleswsis'""'':. u.sunlly slight

dimirlhiH:d Byler'$. di$ea.o;e1*· tr Normal Abscnr Hereditar)' Diminh•hed or AbsenL

lvmphedrmat•·•• pmlifer"'Ait:d 8LIC' acid Dimiobhed or A.J.nem

deficiency"' normal

TABLE 4. D1Ft£RL,"I"lAL D tAC!"IOSI\

o. CONJUCA'I't:O HYP£.R.BII .. JRORI~'f'MI•\ IN .EARLY l KFANCV

I. f.lcp~•l i lis of infectious o rig in (iialll cell hepatitis of pl'(-sumcd

\'ir~t «'>rigin l~ubcll "'. c-rtomegalo\1irus Coxsadie,•irus, echovirus,

••ml•ssh e hep.,tic -necrosis"' 1-tct"pej'irus. ,'a.J"io:lla To:<opla.smosi:s f..ucs.IUteriosis. tul:x!rculosis t l~patiti.l assoc:ia1ed antigen

Z. Riti.aty obst.ruction txcr.ahepatic :atresia r~xtl"'.a.hcp~tic stcnoSi$ and

elaoledochal G)"Sl l)ilc Jdug spnlro r'n.e Tumors ( IH:pt~ toma. bile dun sn• com:-a) Filn'OC')'lltic diK·ase and mecot1iuan ll..:us

3. '1'oxic" hcp~aLiUs &psi' and coliform pyel6nephl'itis DJilrrllC:a lntolinal obMtuction (ileum) 11u.-101pcutic hyperalimcnt:uioo

4. llemol)1.ic disease Et}·thmbla.nosis fct.ali.<i

:\. llercdofamtlial :.md met:tbolic: diS(:l~C Familial gi~mt-<dl hepatiti!> :md

bllinry m:resia 1'1'iil•)my E l)C)wn's ~rndromc, !cprech:. • •n i~m Zcllwegcr·'s srndnJir\e

("hiliar)' drsgencs.is .. ) Dubin·JohJ\sOli djst:ase,

Rotor'.ssyndrome Wilson's disease Alpha,-antiarypsin deficiency "'ldiupathjc neonatal hemoc:hrocnatosU .. fibroqscic. disease lndi.m thildhood cirrhosis <.:~•lac:to:lemi-a, frtactO!emia, t)'•'O:Iinemi;l :-lit.:mann .. l'ick disease. Gaucher':~ disease WOimon's disease. glycogen~!~ IV Cl•ulcsllllic syndromc.-s

J':nar.:ity of imrahepmlc bilh•ry duels Uilc saiL disorder?

Familial hepalOSlealosis

dueLS may p1-esage chronic disease despite init ial amelioration of the hyperbili.-ubi­nem ia. The diagnosis depends uhimatcly o n other laboratory tests.

T he diffe re ntial diagnosis of coayu­gat cd hype rbilirubin emia has become le n{,'lhy a nd complex. Most of the con­ditions ca nnot be diagnosed specilically by liver biopsy, but certain diseases can be sus peered or su ggested for funhcr evalua­tion. A cun-em list, without embellishment, is pt-o,·id~>d in Table 4: we make no claim fot· its com plereness or for irs permanence.

CON.J UGATED l·IYPF.RBILIRU Ll l NJ::MJA - BROUGH, Lle~<NSTETN

DISCUSSION

\'le have shown that liver biopsy is a valuable au c:l reliable cool in the evaluation of neonatal or early inf'amile conjugated hyperbilirubinemia. The percentage of error in our surgical pathology reports, in a series of 158 cases over " pel'iod of 18 years, has been on ly (l.3 per cent when the clinical follow-up and outcome in t.-ach case are used as the JCSI< of those diag­noses. In a subsequent •·cview of the slides. undertaken without knowledge o r the clinical data 0 1' outcomes. several diagnoses w~re clearly in error by histologic criteria, and the percentage of diagnostic mistakes could be reduced up to 4.4 per cellt. T hat figure stands up exu·emdy well in com­parison lviLh 1he rate of error erJC<>untet·ed •vith any uth~r diagnostic technique. It also indicates that a 20 per cent error" is exces­sive. We believe a lso, despite the possi­bility of common etiologies,"· 23 that the pattern o r obstruction. once established. is ch:tracteronic and that the histopathologic distinction between hcpll_!itis and biliary obstruction is valid. The im portltncc of ~1t:curacy in eva1uaLi11g per·clatancous needle biopsies lies in sparing the child unnecessary surgery with its inherent ri•ks. Furthermore, the surgical approach cur­rently advoc:tted for biliary atresia involves reseclion of the entire exu·a· hepatic biliary tract or its remains along the hepatodundenal ligamem. "" ir­•·evocablc procedure." When doubt about tl1c diagnosis P'"·sists. lapan>tomy with wedge biopsy and operat ive cholanb>io­graphy can reduce th~ rate of error to slightly more Limn I per cent, but it must be emphasized that cholangiography of small dueLs can be unsuccessful lllld that sur{,>ical exploration and inspection are subject to considerable f:tllibility.

Our principal difficulty w<~s caused by the occasional occul'I'Cnte of bile duct proliferaLion in bepaLitis; its prcscn,:e is not, therefore, "specific" for bilia•·y tract obstruction. We can speculate that bile duct prolifcra~ion in hepatitis results from trnnsicnL or segmental clmlll\Jgiolar it~jury with resu ltam, perhaps temporary, obstruction. If neonatal hepatiti• and biliary atresia do indeed have common etiologies. biopsies may show both hepato­cellular and cholangiolar injury. T his seems to be t.he case in biliary atresia with

hepatocdlu Jar damage and giam cell transformation. It should be noted that cl1()langiolal' damage and bile duct pro­lifel-ation have been observed in the congenital o·ubella syndrome. a condition that may also be associated with giant cell hepatitis.••

The association of bile duct prolifera­tion with hepatocellular injury in certain metabolic and hereditary disordet•s is more difficult to unde1-sl:\nd. There is, for example, t'll ob\'ious basis for ductal hyperplasia in Zellwege•··s syndrome, un­less. like the hepatic lesion of ]1blycystic disease. it represents intl'insic maldcl'elop­ment. We cannot account fo1· L11c occur­rence of such marked ductal h)•pc•·plasia in our cases of alpha1-antitrypsin de­ficiency; significant obstruction seems unlikely. since the patients b'=me anictelic sbot·tly after laparotomy :11 which the surge01·1 ·'Rushed" the extrahepatic ducts with srtline~ We must be prepared, L11en. to accept some degree of bile duct proliferation in hepatitis or with hepato­cellular injury. recognizing that it will at times be severe enough to confuse the diagnosis and will be o r a frequency suf­ficient to introduce a r~lativelr lo"· r.ne of di~gnostic error.

Our ob$ervations and views are some-what ar variance with statements dlat itlterlobular ducts in biliary atresia are characteristically hypoplastic.'" The lack of bile duct proliferation in a case of biliar)' atresia, in which biopsy was .perfo•·med a t Lhree months. is unique in our experience. The infant was not subjected to biopsy too early in the course of disease: at three momhs the lesion is usually well estab­lished and easily diagnosed. T he fJresence of proliferative changes at postmortem examination~ nine 1nonths Jater. indicates 10 us that 1 he customar)' rt.~ponse was de-layed and t bat we were n<>t looking at a d ifferen t type of lesion. l'erhaps tJ1c initi.al d;nnage 0 1" pathologic proce~ was "active" at the time of the biopsy and the respon~ible agent caused hepatocellu-lar, cholangiolar, and ductal damage simultaneously. T he damaged intr:~hepatic ducts had possibly not yet responded by proliferating. Is this the nature of uni-versal intra- and extrahepatic au-esia? l'erhaps, if simultaneous injury 10 intra­hepatic and extrahepatic ducts can t:ause widespread ductal lysis and disappearance. 515

516

H UMAN PAT HOL.OGY - VQl.U ME 5. NUMilE il fj Srpimllb<f !9'J./

Possibly later examination of such cases w<?uld show tbe typical response. Is this 1.he natun' of extrahepat ic "b~liary hy po· plasia"? Probably not. for in ,l,he patients rcp<>rtcd as having the condition·, the intra­hept•tk ducts are few in numbea~ and remain so; the -p-atients are~ often several years older and the clinical cou rses are pro.wict<,d."' T he dinicaJ descripticms of "biliary hypoplasia" are reminiscent o f "irurahepa tic aLTesia," and we suspect thar such cases may evemually be liste.d within the "paucity ufimrahepa tit bilc duct" com­plex and that soinc of i.hem will he.~ shown to nave abnormalities of bile salt metabo· lism.

ACKNOWLEDO~ffiN'f

T he authors wish to thank Dr. !. ~f. Ratner apd Dr . .J. J. ~\-Iolnar. Department of Rathology, Bronx Municipal Hospillll Center and Albert Einste in College o f Medicine, for providing and ~ llowing us ro use sections of 1J1e liver· biopsy i.n case I 0, which had been seen originally in <:on· sulta rion.

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1 J97:4.

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2·L Kotsai. ti.J.. KiruurJ.. S .. Asala mt. Y .. Suzu.ki, II.. 'raira, Y .• and Ohashi, E.: Surgical trcatincm of bilia•·}' attes.ia. J. Pe.d. Sl1rg . • .J:665. 1968.

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ChiMren's l:lospilal ~r'"Michigarl 390.1 n eaubi'cu t1ecroit. Michigan 4820 J (Dr . Brough)