Hand Sücheler crhistian desease

LETTERER-SIWE DISEASE BY A. A. MAcKELVIE, F.R.C.S.Ed., and W. WALLACE PARK*, M.B. From the Stirling Royal Infirmary and the Royal College of Physicians Laboratory, Edinburgh (RECEIVED FOR PUBLICATION JUNE 22, 1949.) * The term Letterer-Siwe disease was applied by been mentioned as a possible aid to diagnosis. To Abt and Denenholz (1936) to a condition first judge from reported cases, and certainly from the described in detail by Letterer (1924) and later findings in our own case, the histolo

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  LETTERER-SIWE DISEASE BY A. A. MAcKELVIE, F.R.C.S.Ed., and W. WALLACE PARK*, M.B. From the Stirling Royal Infirmary and the Royal Collegeof Physicians Laboratory, Edinburgh (RECEIVED FORPUBLICATION JUNE 22, 1949.) The term Letterer-Siwe disease was applied by Abt and Denenholz (1936)to a condition first described indetail by Letterer (1924) and later recognized bySiwe (1933) as a well defined clinico- pathological syndrome. Letterer-Siwe disease is an illness of infants, almost invariably fatal, and of unknown aetiology. The main clinical features are an age incidence fromtwo months to two years; an indefinite onset with no specific symptomatology; a febrile course lasting for a few weeks ora few months to death; generalized enlargement of the lymph nodes, enlargementof the spleen, and often of the liver as well; a haemorrhagic tendency, commonly producinga purpuricor ecchymotic skin rash most marked shortly before death; hypochromic anaemia, sometimes severe; destructive lesionsin bone, commonly in the skull, rarely, if ever, in the bones of the hands and feet, but often occurringelsewhere in the skeleton, e.g. in the ribs,pelvis, humerus, femur,and may be clinically silent or associated withpain and tender- ness, with or without overlying soft tissue swelling; sometimes mottling of the lung fields on x-ray examination; less commonly, secondary bacterial infection, such as otitis media or anginaof the throat, and leucocytosis; no apparent hereditaryor familial incidence. The characteristic patho- logical feature is excessive hyperplasia of the reticulo-endothelial tissue throughout the body, particularly in the spleen, lymph nodes, and skin. Of the nine patients with Letterer-Siwe disease whose case-reports were analysed by Abt andDenenholz (1936), all had splenomegaly,a petechial and ecchymotic skin eruption, a moderate con- tinued fever, and moderate to severe secondary anaemia, and all but one showed enlargement of the lymph nodes. Therewere alterationsin the bone marrow cytology in eight of the patients (no details given in the remaining case) mainly in the form of proliferation of large,pale, histiocytic cells. Four of the patients showed lesionsin bone. The most helpfulfactor in reaching a correct diagnosis would be the knowledge that sucha recognized syndrome existed. Biopsy of tissue from the spleen, bonemarrow, orofa lymph node has * Working with agrant from the British Empire Cancer Campaign. been mentioned as a possible aid to diagnosis. To judgefrom reported cases, and certainly from the findings in our own case, the histological picture is not so specific that Letterer-Siwe disease can be diagnosed outright from biopsy. A biopsy of the three tissues could indicate reticulum cell over- growth, and tothat extent confirma clinical diagnosis of Letterer-Siwe disease, but biopsy ofa lymph nodewould probably alwaysbe the most useful. Much more than biopsyof the spleen or bone marrow it offers to the pathologist the chance of being able to exclude some of the otherconditions which may cause generalized lymph node enlarge- ment.Conditions whichhave been mentioned as entering into the differential diagnosisinclude aleukaemic leukaemia, Hodgkin's disease and lymphosarcoma, generalized osteitis fibrosa, a local boneneoplasm or a metastasizing neoplasm with spread to bones, tuberculous disease ofbone, myelomatosis, generalized xanthomatosis, 'von Jaksch's anaemia ', and typhoid fever. Since the article by Abt andDenenholz at leastfive other examples of theLetterer-Siwe disease complex have been described by Freud, Grossman,andDragutsky (1941), Wallgren (1940) two cases, Gross and Jacox (1942), Jaffe and Lichtenstein (1944). This makes a total of 14 so far reported, but itis quite clearthat many other examples were reported earlier under different names, for instance non-lipoid histiocytosis, reticulo-endotheliosis, or aleukaemic reticulosis, before their identity was realized. The name given to the disease by Oberling andGuerin (1934), 'acute reticulosis of infants,' is in many ways preferable to its present eponymous title. Letterer-Siwe disease is now considered to be only one variant of a basic granulomatoid disorder which appears on otheroccasions as 'infective ' reticulo-endotheliosis, Hand - Schuller - Christian disease, and eosinophilic granuloma ofbone. Transitional stages between these more dist nctive forms of thedisorder are relatively common. Jaffe and Lichtenstein (1944), for example, con- sidered thatthe case described by Hand, which led to theassociation of his name with those of Schuller and Christ an in the name Hand-Schiller-Christian disease, was more probably an example of Letterer- Siwe disease. 93  ARCHIVES OF DISEASE IN CHILDHOOD Amongst the nine cases accepted by Abt and Denenholz as examples of Letterer-Siwe disease was one of a series of four (Case No. 4) described by Gittins (1933) inhis study of 'Anaemia and Reticulo- Endotheliosis.' Apart from this we have not found anyexamples of Letterer-Siwe disease reported in the British literature, and our casereport appears to be the first account in this country of Letterer-Siwe diseasesince the disease was recognized as a cinico-patho- logical entity. Case Report Baby A.W., a girl, aged 7 months, was seen on June 3, 1947, at the Outpatient Departmentof Stirling Royal Infirmary. Except for a history of possible whooping cough at the age of 14 weeks, the child hadhad no illnessuntil four weeks before, when a swelling appeared behind the left ear. This swelling had been incised and treated as an abscess two weeks previously at another hospital where an otologist had reported that there wasno middle-ear or mastoid disease. Three weeks before being seen at Stirling the child haddeveloped a rash on the anterior thoracic and abdominal walls. She was fretful andwas not gaining weight. Therewas no apparent pain and no history of diarrhoea. Examination showed a pale child with a soft swelling, not redbut tender, above the left mastoid area. Over the swell- ing was a smallhealed incision. The left upper cervical lymph nodes were slightly enlarged. No other lymph node enlarge- mentwas found,nor any enlargement of the liver or spleen. Over the anterior aspect of the lower thorax and upper abdomen there was a scaly, macular, petechial rash. The Wassermann reaction was negative, as was that of both parents. X-rayexaminationof 94  LETTERER-SIWE DISEASE the left mastoid area showed no bone abnormality, but the plates were not very satisfactory. The child was admitted to hospital onJune 7, 1947. It was then found that a small firm swelling 1y cellular tissue. The dark areasare ctions of eosinophil leucocytes. x 80. had developed in the upper outer area of the left orbit. X-ray plates showed an area of bone erosion (Fig. 1). On June 21, 1947, the mastoid swelling was opened, and the soft, greyish tissue curetted out was sentfor pathological examination. This first biopsyspecimen was received at the Royal College of Physicians Laboratory, Edinburgh, a few days later. It consisted of threesmall fragments of soft grey tissue. Microscopically the tissue was highly cellular and without trace oforganized anatomical structure. There was a background of moderately small, uniform cells, sometimes in loose masses, sometimes forming cellular sheets, and much extravasatedblood. Here and there were small, well defined blood vessels. The tissue was widely infiltrated with polymorpho- nuclearleucocytes of which many were eosinophils. Therewere also many lymphocytes,a few plasma cells, and an occasional non-specific multinucleated giant cell. The appearanceswere not diagnostic and indicated asubacute or chronic inflammatory process with some patchy fibroblastic activity. On this occasion no special significance was attached to theeosinophil leucocytes. Penicillin (50,000 units three-hourly) therapy was begun on June 23. The swelling above the left eye was larger. By July 10 the mass behind theear was somewhat smaller, but an abscess had appeared in the neck below the ear. Penicillin (3,900,000 units) had been given. On July 17 it was noted thatthe swelling in the left orbit had increasedgreatly, was fluctuant, and was causing strabismus. X-ray examination showed an increase in the area of bone erosion (Fig. 2). Two days later the orbital swelling was curetted, and a specimen of similar soft grey tissue with small yellow and red areas was again sent for examination. This second biopsy specimen consisted of many small irregular fragments of softtissue and, as in the first specimen,microscopic examination showed a mass of highly cellular, haemorrhagic tissue but there were three main differences: (a) The pre- dominant cells were better preserved and slightly larger, with more cytoplasm and a more regular nuclear outline. Though still not specific the appearances were now those of proliferating reticulum cells. An occasional(reticulum) cell was inmitosis.(b) Eosinophil polymorphonuclear leucocytes were numerous and prominent, forming many large dense aggregations (Figs. 3 and 4). No cells couldbe distinguished with certainty as eosinophil myelocytes. (c) Multinucleated giant cells were more numerous, still without diagnostic features but not unlike osteoclasts (Fig. 5). Appear- ances otherwise were much the same as before: a small amount of fibroblastic proliferation, many lymphocytes, comparatively few neutrophil ' poly- morphs,' and occasional plasma cells. The disease process appeared to be of the nature of a reticulum cell or histiocytic overgrowthwith accompanying inflammatory changes, predominantly as an eosinophil reaction. It brought to mind the so-called eosinophilic granuloma of bone, and this diagnosis was suggested as the most likely. There were no histologicalfindings to suggest neuro- blastoma or Wilm's tumour. FIG. 4.-High-power viewof the same area as in Fig. 3. The dark cells are intenselyeosinophilic. The less hyperchromatic cells are of reticulum cell type. x 350. 95  ARCHIVES OF DISEASE IN CHILDHOOD X-rayexamination on Aug. 8, 1947, showed a further area of bone erosion in the occipito-parietal region. PERIEPHiRAL BLOOD EXAMINATION: Total red blood count, 4,480,000per c.mm. Totalwhite blood count, 25,800per c.mm. Neutrophil polymorphs 50°O = 12,900 per c.mm. Eosinophil polymorphs 40' = 1,032 per c.mm. Basophil polymorphs nil Large lymphocytes 4%o= 1,032 per c.mm. Small lymphocytes 400h = 10,320per c.mm. Monocytes 20° = 516 per c.mm. Individual erythrocytes and leucocytes showedno abnormalities. No primitive cells were seen. The figures indicated a general leucocytosis and a slight absolute eosinophilia. BioPsY OF STERNAL BONE MARROw. The material consisted of cellulartissue with cells of the erythroid and granular series present in average normal proportion.Erythropoiesis was normoblastic and no megaloblasts were seen. Eosinophilmyelocytes were a little more numerous than usual. Mega- karyocytes were plentiful. Therewere noabnormal cells, and no indication of any leukaemic process, myeloma, orother neoplasm. BLOOD CHEMISTRY: Blood cholesterol, 118 mg. 00. Blood phosphorus, 3 5 mg. 00. X-ray examination of all bones on Aug. 9, 1947, showed areas of irregular absorption and erosion in the left iliac bone, the left mastoid and orbitalregions, and in the occipito-parietal region (Fig. 6). FIG. 5.-Multinucleated giant-cells. x 30. An irregular pyrexia had continued since admis- sion to hospital, and the general conditionof the patient had deteriorated steadily. The petechial rash spread up the left side of the neck and head, and there was slight enlargement of the lymph nodesof both sides of the neck. No treatment, including the full courseof penicillin, had producedany improvement. The baby died on Aug. 12, 1947. A full post-mortem examination was made by Dr. W. P. Weir of the Western Infirmary, Glasgow, FIG. 6.-Irregular erosion and absorption in the left iliac bone. who is reporting his findings in a separate article in preparation. He has kindlyallowed us to make use of his notes. The macroscopic findings included enlargement of the spleen, areas of tumour-like growth in the left vertex, left mastoid region, and in the wing of the left ilium, but no gross abnormality in the lungs, thymus, mediastinal, andabdominal lymph nodes. Microscopically, abnormal reticulum cell pro- liferation, focal and diffuse, couldbe seen in the lymph nodes, lungs, skin, oneof the lesions in bone, and especially in the spleen. Besides this, some areas of the lesions in bone still retained the appear- ances of eosinophilic granuloma. It was not until the tissues obtained at necropsy were examiined microscopically, and the findings, together with the clinical data, compared with previous accounts in the literature, that Letterer-Siwe disease was diagnosed. Seen in retrospect the clinico-patho- logical syndrome presented by this patient was an almost typical example of the condition. Discussio Mallory (1942) and Jaffe and Lichtenstein (1944) havegiven full descriptions and discussions of Letterer-Siwe disease and its relationship to the group of reticulo-endothelioses, Schiller-Christian disease, and eosinophilic granuloma of bone, and only a short outline of current views will be given here. Abt and Denenholz (1936) made six categories of thedisorders of the reticulo-endothelial system. 96
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