ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 17, No. 3Copyright © 1987, Institute for Clinical Science, Inc.

Sinus Histiocytosis M assive Lym phadenopathy Syndrome:

H istogenesis o f the Hepatic Lesion*

R. E. BROW N, M .D. and CYRIL A. D ’CRUZ, M .D.

Department o f Pathology, Cook-Fort Worth Childrens Medical Center,

Fort Worth, TX 76104

ABSTRACT

Sinus histiocytosis massive lym phadenopathy (SHML) syndrome with hepa tic involvem ent, occurring in a seven-year-old black fem ale, is reported . Morphologic characterization of the hepatic lesion is accom­plished utilizing conventional light, fluorescent and electron microscopy, and histochemical techniques and by comparing and contrasting the find­ings with those in cases of familial erythrophagocytic lymphohistiocytosis (FEL) and virus-associated hemophagocytic syndrome (VAHS). The his­tiocytic proliferation in the liver in SHM L differs by showing: (a) an in tra­lobular distribution with portal sparing; (b) m arked steatosis; and (c) lipo­fuscinosis. The aforesaid intralobular distribution and the accompanying hypertrophy and hyperplasia of Kupffer cells, as well as commonalities of steatosis and lipofuscinosis, and, to a lesser extent, erythrophagocytosis and siderosis, suggest a histogenesis from Kupffer cells. The histochemical finding of fatty acid peroxides and both fluorescent microscopic and histo­chemical evidence of lipofuscin inclusions, a by-product of lipid peroxida­tion, in Kupffer cells provide at least a theoretical basis for both erythro­phagocytosis and proliferation eventuating in intralobular histiocytosis.

In troduction

S in u s h is t io c y to s is w ith m ass iv e ly m p h a d e n o p a th y (SH M L) was firs t described as a benign clinicopathological entity by Rosai and Dorfman in 1969.18 The majority of cases (some 80 percent)

* Send reprint requests and correspondence to: R. E. Brown, M .D ., D epartm ent o f Pathology, Cook-Fort Worth Children’s Medical Center, 1400 Cooper, Fort Worth, TX 76104.

occur within the first two decades of life a n d a re c h a ra c te r iz e d c lin ic a lly by lym phadenopathy, fever, leukocytosis, hypergam maglobulinemia, and an accel­e r a t e d e r y th r o c y te s e d im e n ta t io n ra te .18,19,20 Extranodal involvem ent has b een rep o rted in up to 28 p e rc e n t of cases.9,10 Although the liver is a reported site of such involvem ent, inform ation concerning the m orphologic character­ization and histogenesis of the hepatic les io n is S parse .6,8 In a tte m p tin g to

1620091-7370/87/0500-0162 $01.50 © Institute for Clinical Science, Inc.

SHM L SYNDROME: TH E HEPATIC LESION 1 6 3

expand the latter, the light, fluorescent and electron microscopic and histochem- ical features of the histiocytic prolifera­tions in the liver of a patient with SHM L syndrom e are reported; the findings are contrasted with those in cases of familial erythrophagocytic lym phohistiocytosis (FEL)1 and virus-associated hemophago- cytic syndrom e (VAHS)3,15; and a histo­genesis from Kupffer cells is proposed.

Case Report

A seven-year-old black female presented with a three w eek history of recurrent fevers, wheezing, episodes of vomiting and diarrhea, headaches and co n g estio n , and, finally , righ t up per quadrant (abdominal) pain. Her past medical history included treatment for reactive airway disease. Out-patient laboratory find in gs ob ta in ed tw o w eek s prior, revealed both a normal white blood cell count and hemoglobin concentration and 2 + ketonuria. Thera­p eu tic agents ad m in istered during th is period included Accurbron® (a theophylline preparation) and Alupent® (a beta-adrenergic stimulator).

Physical examination at the time of admission to C o ok -F ort W orth C h ild re n ’s M ed ica l C en ter revealed a somewhat dehydrated child with a tem ­perature o f 38.0°C . P ertinent negative findings included absence of lymphadenopathy and organo­megaly. Laboratory data revealed: anemia (hemoglo­bin 7.6 g per dl with expected range for age 11.4 to15.4 g per dl),4 thrombocytopenia (125 x 103 per mm3 with expected range for age 250 to 470 X 103 per mm3); hyperaspartate aminotransferasemia (142 U per L with expected range for age 20 to 45 U per L) and hyperalanine aminotransferasemia (57 U per L with expected range for age of 2 to 15 U per L) associated with eubilirubinemia (total 1.2 mg per dl with expected range for age up to 1.5 mg per dl). An erythrocyte sedim entation rate perform ed on the second day o f admission with the patient’s hematocrit having been raised to 30.6 percent following a trans­fusion o f packed red blood cells was accelerated (62 mm per hour with expected range for age 0 to 13 mm per hour).

Seronegativ ity for antibodies to M ycoplasm a pneumoniae, hepatitis A and B viruses, Epstein-Barr virus and antinuclear antibodies was documented. Similarly, viral and bacterial cultures collectively of urine, blood, stool, throat and bone marrow failed to dem onstrate infectious agents. A bone marrow biopsy revealed plasmacytosis and erythrophagocy- tosis by histiocytes consistent with a hemophagocytic syndrom e. During this first hospital course, she developed overt congestive heart failure which was even tually controlled w ith Lasix® (furosem ide), packed red blood cells, dopamine, fluid control and oxygen.

A second admission within a two week period was occasioned by a history of continuous fever and “two

pillow” orthopnea. Physical examination revealed: a chronically ill appearing child with a temperature of 38.0°C; tender hepatomegaly and nontender spleno­megaly; and palpable submandibular, axillary and inguinal lymph nodes. Laboratory data at this time revealed: anem ia (hem oglobin 5.2 g per dl); mild thrombocytopenia (195 X 103 per mm3); and leuko­cytosis (15.6 X 103 per mm3) with a predominance of neutrophils; a polyclonal gammopathy as evidenced by increased IgG (1,690 m g per dl with expected range for age 633 to 1,280 mg per dl) and IgE (377 U per ml with expected range for age 0 to 211 U per ml) immunoglobulins in the face of normal concentra­tions for age of IgA and IgM immunoglobulins and the absence of an M-band in the concomitant serum protein electrophoregram; and eufibrinogenem ia (380 mg per dl with expected range 200 to 400 mg per dl).

Subsequently, definitive bone marrow, liver, and lymph node biopsies were obtained under general anesthesia. A diagnosis o f reactive plasmacytosis and mild erythrophagocytosis was rendered on the bone marrow biopsy. The excisional lymph node biopsies from both the cervical (neck) region and omentum revealed marked sinus histiocytosis with lymphocy- tophagocytosis and plasmacytosis consistent with SHM L syndrom e.18 The patient was treated conser­vatively with hyperalimentation and transfusions and discharged tw enty days postadm ission in a much improved state.

Approximately two w eeks after discharge, she developed cutaneous lesions, and a punch biopsy of the skin revealed a histiocytic proliferation consistent with extranodal involvem ent by SHM L syndrome.23 At the time of the writing of this manuscript (approxi­m ately 14 months post discharge), the patient is asymptomatic and in a relatively good state o f health.

Materials and Methods

SHML Syndrome

Excisional lymph node biopsies of the cervical (neck) region and om entum as well as an open liver biopsy provided fresh (unfixed) tissues for the histopatho­logic studies in this case. Portions of the cervical lymph node w ere subm itted for culture and cryostat sectioning, respec­tively. Touch im prints w ere made of the cut-surfaces of bo th lym ph nodes and portions of each w ere placed in Carson’s (formalin) fixative for routine light and electron microscopy. The wedge-shaped piece of liver showed m ultiple bu t pin­point-sized, yellowish foci in the fresh state. Touch preparations were made and a portion was subjected to cryostat sec­

164 BROWN AND D'CRUZ

tio n in g . T he re m a in d e r o f th e liv e r biopsy was placed in Carson’s fixative.

The aforesaid cryostat sections of fresh tissue w ere sta ined w ith oil red 0 for lipid; the W inkler-Schultze technique for fatty acid peroxides13 and periodic acid-Schiff hematoxylin (PASH). Cryostat sections of liver fixed in Carson’s w ere treated with 1.0 percent osmium tetrox- ide to dem onstrate lipid. Another por­tion of the Carson’s-fixed liver tissue was post-fixed in 1.0 percent osmium tetrox- ide and processed for electron m icros­copy. Thin sections w ere stained in ura- n y l a c e t a te a n d le a d c i t r a t e a n d examined in a JEO L transmission elec­tron microscope. Representative depar- affinized sections of lym ph node and liver w ere e ither stained with hematoxy- lin-eosin (H and E), Mallory’s procedure for iron, and Fontana-M asson for lipofus- cin or m ounted in phosphate-buffered saline for detection of possible autofluo­rescen ce . T he la t te r was c a rr ie d out using an ep i-illum ination flu o rescen t microscope employing a RG12 + KV418 exciter filter and an OG515 barrier filter. A d d itio n a l s ta in in g te c h n iq u e s p e r ­fo rm ed on deparaffin ized sections of l iv e r in c lu d e d : p e r io d ic a c id -S c h iff hem atoxylin (PASH) with and w ithout diastase pretreatm ent; m ethod of Armed Forces Institu te of Pathology (AFIP) for lipofuscin ; d iam ino silver hydrox ide m ethod for reticu lin fibers; aldehyde- th ionin m ethod for hepatitis B surface antigen; Brow n-H opps Gram stain for b ac te ria ; Z ieh l-N ee lsen for acid fast organisisms and silver-m ethenam ine for fungi.14

E r y t h r o p h a g o c y t ic

Ly m p h o h i s t io c y t o s e s

Biopsy m aterials of liver specim ens from th ree cases of familial erythropha­gocytic lym phohistiocytosis (FEL) and one case of Epstein-Barr virus-associated hemophagocytic syndrome (VAHS) were

available in our files. The histopathologic and histochemical findings in these were com pared and contrasted w ith those in SH M L syndrome.

Results

As noted previously, excisional biop­sies of cervical and om ental lymph nodes revealed m arked expansion of sinuses by a population of reactive histiocytes con­ta in ing ab u n d an t cytoplasm and asso­ciated, on occasion, with intracytoplas- m ic collections of small lym phocytes. Focal plasm acytosis was also p resen t. The perinodal tissues showed striking m ultilocular change in the adipocytes.

A pro liferation of sim ilar appearing histiocytes was ev ident in the liver as m icronodular foci showing both an intra­lobu lar d istrib u tio n and contiguity at their periphery with sinusoidal cells (fig­ures 1 and 2). O ther distinguishing histo­pathologic features of such proliferations included focal hyperem ia and associated congestion and dilatation of sinusoidal sp a ce s . F u r th e r m o r e , in th e la t te r regions, erythrophagocytosis by histio­cy tes was m ore read ily ap p rec ia ted . F in a lly , no m ic ro o rg a n is m s w e re detected in these lesions using the afore­m entioned staining techniques.

Histochem ical and fluorescent micro­scopic studies on histiocytic cells within these foci revealed the following intracy- toplasm ic findings: occasional Schiff’s p o s itiv e /d ia s ta se -re s is ta n t aggregates (figure 3); lipofuscin inclusions as evi­denced by the combination of Fontana- M asson and (Kinyoun’s) carbol fuchsin positivity and appropriate autofluores- cen ce14,21,22 (figure 4); and num erous lipid inclusions that w ere oil red 0 posi­tive (figure 5) and osmiophilic and fre­quently exhibited W inkler-Schultze pos­itivity at their cytosolic interface (figure 6). U ltrastructural counterparts of sev­eral of these histochemical and fluores­c e n t m icro scop ic fin d in g s w e re also

SHML SYNDROME: THE HEPATIC LESION 165

m ■« V;

\ î • ; i . .*y ;■ • : *»v.. ' V . \ *< • * A. •

k

V* *

* * 4

fV*£*3*

V ,

»> <?m

* ' 6FIGURE 1. Low power view of portion of liver lobule (H&E X200) showing a micronodular focus of

relatively pale cells surrounded by trabeculae o f hepatocytes.F ig u r e 2 . H ig h p o w e r v ie w o f su c h m icro n o d u la r fo c i in th e liv e r (H & E x 1000) r ev e a ls a p r e p o n d er a n c e

o f h is t io c y tic c e l ls , s o m e w ith in d e n te d n u c le i an d a b u n d a n t foam y to vacu o lar cy to p la sm .F ig u r e 3. Periodic acid SchifFs (PAS) positive (red) intracytoplasmic aggregates in several histiocytes

within the micronodular foci in the liver (PAS with diastase pretreatment X 1000).F ig u r e 4 . Yellowish-orange autofluorescent inclusions consistent with lipofuscin within histiocytic foci in

the liver. Note bright green autofluorescent erythrocytes within adjacent, congested vascular spaces (depar- affinized, unstained section mounted in phosphate-buffered saline X 1000).

F i g u r e 5 . N u m e r o u s a n iso d im en sio n a l (red) lip id in c lu s io n s o c cu p y th e cy to p la sm o f th e in tra lo b u la r h is t io c y te s in th e liv e r (oil red 0 X 1000).

F ig u r e 6. Indophenol blue synthesis consistent with the presence of fatty acid peroxides evident atperiphery of lipid droplets in hepatic foci using W inkler-Schultze technique (X 1000).

e v id e n t in t r a n s m is s io n e le c t r o n m icrographs of represen tative foci (fig­ures 7 and 8). In comparison with other lymphohistiocytic processes and specifi­

cally cases of F E L and VAHS, obvious differences were found. Such differences related to the microanatomical location of the histiocytic proliferations and the

166 BROWN AND D'CRUZ

FIGURE 7. U ltrastru ctu ra l o v e r v ie w o f c lu sters o f in tra lob u lar h is t io c y tic c e l ls w ith in th e liv e r sh o w in g n u m ero u s lip id (L) a n d o cca sio n a l lip o fu sc in (arrow Lf) in c lu sio n s. A lso n o te ly m p h o c y te in u p p e r r igh t h an d co rn er ( X 3750).

degree of steatosis and lipofuscinosis associated with same. These are summa­rized in table I.

In add ition to the a fo rem en tioned contiguity of sinusoidal cells w ith the in tralobular, m icronodular foci, th ere was som etim es striking proliferation of

K upffer ce lls w h ich a p p e a re d to be expanding and filling the sinusoids and thereby presum ably imposing a physical barrier to the blood flow through same. O n rare occasions, plasm acytosis was noted in association with Kupffer cells. Apart from the morphologic similarity of

SHML SYNDROME: TH E HEPATIC LESION 167

F ig u r e 8. Portions of several histiocytes showing characteristic nuclear indentations. Note numerous, variably sized lipid (L) and occasional lipofuscin (arrow Lf) inclusions and cytoplasmic aggregates o f osmio- philic, granular material (arrowhead Oa). The latter may be contiguous with individual lipid inclusions ( X 12841).

the proliferating Kupffer cells to the his­tiocytes in the micronodules, there were o ther commonalities to include steatosis, lipofuscinosis, and, to a lesser extent, s id e ro s is an d e ry th ro p h a g o c y to s is .

Finally, a positive reaction for fatty acid peroxides using the W inkler-Schultze technique13 was evident in some sinusoi­dal, presum ably Kupffer cells in associa­tion with lipid inclusions.

1 6 8 B RO W N A N D D ’C RU Z

TABLE I

Comparative Findings in the Liver in Erythrophagocytic Syndromes

Sinus Histiocytosis Familial Erythrophagocytic Virus-AssociatedMassive Lymphadenopathy Lymphohistiocytosis Hemophagocytic Syndrome

(SHML) (FEL) (VAHS)

Infiltrate

Erythrophagocytosis

Steatosis

Lipofuscinosis

Intralobular

Kupffer cells Intralobular infiltrates (occasionally)

Intralobular infiltrates (marked)Kupffer cells (moderate) Hepatocytes (occasionally)

Intralobular infiltrates

Portal with periportal extension

Kupffer cells Portal infiltrates (occasionally)

Absent to minimal in portal infiltratesHepatocytes (mild to marked)

Absent in portal infiltrates

Portal with periportal extension

Kupffer cells Portal infiltrates (occasionally)

Absent to minimal in portal infiltrates Hepatocytes (marked)

Absent in portal infiltrates

Discussion

The clinical and laboratory findings of fever, leukocytosis, polyclonal gammopa- thy, and an accelerated erythrocyte sedi­m entation ra te w hen coupled w ith the d e v e lo p m e n t o f a ly m p h a d e n o p a th y show ing charac te ris tic histopathologic fea tu re s e s ta b lish e d th e diagnosis of S H M L synd rom e in th is p a tie n t. In ad d itio n , ex tranodal in v o lv em en t by similar appearing histiocytes was evident in biopsies of h e r skin and liver.

A lth o u g h S H M L sy n d ro m e in th e liver m ust be distinguished from other lymphohistiocytic processes such as F E L and VAHS th a t also show p ro m in e n t erythrophagocytosis, the histopathologi- cal differences, based on the finding in our study, are obvious, and, therefore, m ake this task relatively easy. Specifi­cally, th e h istiocytes in SH M L differ from those in F E L and VAHS by show­ing: (1) an intralobular distribution with portal sparing; (2) m arked steatosis; and (3) lipofuscinosis.

The histogenesis of the hepatic histio­cytic proliferation in SHM L appears to be from Kupffer cells. This conclusion is based on the following: (a) the intralobu­lar distribution of the m icronodular foci; (b) the contiguity of said foci with sinu­

soidal (Kupffer) cells; (c) an accompany­ing h y p e r tro p h y and h y p e rp la s ia of Kupffer cells; and (d) commonalities of stea to sis and lipofuscinosis and , to a lesser extent, of erythrophagocytosis and siderosis.

A lthough it is realized tha t th e etio- pathogenesis of the Kupffer cell prolifer­ation in SHM L may involve some inher­en t hyper-responsiveness on the part of the reticuloendothelial system to normal s t im u l i , t h e p r e s e n t a u th o r s a re in trig u ed by th e possib ility th a t lip id peroxidation may be initiating the pro­cess. The collective evidence for lipid perox idation ’s having occu rred in the proliferating Kupffer cells and/or micro­nodular histiocytic foci includes histo- chem ical, a u to flu o re sce n t and u ltra - s tru c tu ra l foo tp rin ts o f sam e. T hese com prise : th e p re se n c e o f lipofuscin (which is considered to be a by-product of lipid peroxidation, probably 1-amino- 3 -im inopropene derivatives o f m alon- dialdehyde);21,22,23 the finding of SchifFs positive and granular, osmiophilic aggre­gates in the cytoplasm of histiocytes by routine histochem istry and transmission e lectron microscopy, respectively;2,5,21 and the dem onstration of fatty acid p e r­oxides in such cells w ith the W inkler- Schultze technique.13 The elem ents nec­

SHM L SYNDROME: TH E HEPATIC LESION 1 6 9

essary to effect lip id peroxidation are u n sa tu ra te d fatty acids and m olecular oxygen w ith “iro n ” serv ing as a cata­lyst. 17,22,24 In this regard, the presence of siderosis7,24 and of steatosis w ith both g ran u la r, o sm io p h ilic d e n s itie s , and W inkler-Schultze positivity at the cyto­solic interface of individual lipid inclu­sions is noteworthy. Moreover, the acti­vation o f “ scavenger re c e p to rs” 16 in Kupffer cells by products of lipid peroxi­dation m ight possibly also stim ulate their hypertrophy and proliferation.

The resultant narrowing of sinusoidal spaces w ou ld fo rce in tim a te co n tac t b e tw een K upffer cells and circu lating erythrocytes, perhaps leading to peroxi- dative dam age of red cell m em branes and erythrophagocytosis.12

Finally, the relative rarity of extrano- dal hepatic involvem ent in SHM L syn­d rom e suggests th a t a com bination of circumstances m ust be operative for this to becom e manifest in any given individ­ual. In this patient, it is clear that m ulti­ple factors prom oting lipid peroxidation w ere p resen t. For example, free fatty acids for lip id peroxidation appear to have been mobilized from adipose tissue stores as evidenced by the previously described multilocular change in adipo­cytes in biopsy material. Circumstances prom oting this over the course of her ill­ness include a poor caloric intake conse­quen t to episodic vomiting and diarrhea and the administration of potential adi- pokinetic agents including theophylline, dopam ine, and a beta-adrenergic stim u­la to r .11 A d d itio n a lly , fa c ili ta tio n o r potentiation of lipid peroxidation might have occurred as a result of an increased iron load in the form of transfused red blood cells; the use of the diuretic, furo- sem id e ;25 and th e conversion o f 1,3- dim ethylxanthine (theophylline) to 1,3- d im ethylurate.11 The mechanism of the latter is complex and could involve not only the generation of H2Oa and superox­

ide (Oa —) b u t also the reductive release of iron24 from expanded ferritin stores in the Kupffer cells (vide supra).

In summary, it is proposed that lipid peroxidation consequent to an interplay of num erous clinical circumstances and therapeu tic agents may be responsible for stim ulating both erythrophagocytosis and proliferation of Kupffer cells even­tuating in intralobular histiocytosis, the hepatic lesion in SH M L syndrome.

Acknowledgm ent

Thanks are extended to Dr. Louis P. Dehner at the University o f Minnesota for reviewing the histopa- thology and concurring in the diagnosis.

References

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24. T h o m a s , C. E ., M o r e h o u s e , L. A ., and A u s t ,S. D .: Ferritin and superoxide-dependent lipid peroxidation. J. Biol. Chem . 260:3 2 7 5 -3 2 8 0 ,1985.

25. W e n d e l , A. and R e it e r , R . : In v itro assessment o f hepatic lipid peroxidation by m alondialde- hyde or ethane determination. Oxygen Radicals in Chemistry and Biology. Bors, W ., Saran, M., and Tait, D ., eds. Berlin, Walter de Gruyter,1984, pp. 345-349 .