Archives of Disease in Childhood, 1988, 63, 423-426

Isolated pulmonary histiocytosisH P McDOWELL, P I MACFARLANE, AND J MARTIN

Department of Haematology and Oncology, Royal Liverpool Children's Hospital, Alder Hey, Liverpool

SUMMARY Pulmonary disease in the 'histiocytosis syndromes' is not uncommon. Isolatedpulmonary histiocytosis, however, is rarely diagnosed. We describe three patients with thiscondition, with ages ranging from 3 weeks to 91/2 years, in whom there was no evidence of diseasein any other organ. Their presentation, treatment, and clinical progress over three years of followup are discussed.

Pulmonary histiocytosis most commonly occurs aspart of multisystem disease by histiocytosis X.Disease limited to the lung is reco-gnised as a causeof interstitial lung disease in adults but has not beenextensively reported in children.We report here three cases of isolated pulmonary

histiocytosis and describe their clinical course in thethree years since diagnosis.

Case reports

Case 1. A 2 month old boy presented with aclinically diagnosed bronchopneumonia. Persistentcough and breathlessness were accompanied bypoor feeding, vomiting, and weight loss. On exam-ination he was tachypnoeic, not cyanosed, butcrepitations were audible over both lung fields. Achest radiograph showed soft hazy infiltrativechanges in both lungs, which were more noticeableon the left (fig 1). He was treated with antibioticsand chest physiotherapy with some resolution in hissymptoms. At 4 months of age he had a furtherexacerbation of breathlessness that was accompa-nied by wheezing and cyanosis. A further chestradiograph showed asymmetrical fine reticular infil-tration of the left lung. Isotope lung scanningshowed normal perfusion, but diminished ventila-tion in the right lung. Histological examination of aspecimen from an open lung biopsy of the left lowerlobe showed diffuse proliferation of histiocytesbetween alveoli and around terminal bronchioles;this was compatible with a diagnosis of pulmonaryhistiocytosis X.

After a course of treatment with vinblastine,prednisolone, and etoposide (VP16) there was adefinite improvement. Steroids were continued untilthe age of 15 months. At 3 years of age he remainsfree of symptoms and is on no treatment. Clinically

he has some chest overinflation with sternal promin-ence, and his height and weight are following the50th and 10th centiles, respectively. The most recentchest radiograph showed reticular shadowing inboth lung fields in the upper and mid zones.Histiocytosis has not developed at any other organsite.

Case 2. A 3 week old girl first presented with a twoday history of cough, breathlessness, and slowfeeding. She was feverish and had signs of respira-tory distress with widespread crepitations andwheezes over both lungs. The rest of the examina-tion was normal. A chest radiograph showed patchyshadowing in the right upper zone and antibiotics

Fig 1 Chest radiograph ofcase 1, aged 2 months at thetime ofpresentation, showing soft hazy infiltrative changes,most noticeable in the left lung.

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424 McDowell, Macfarlane, and Martin*

were prescribed for what was thought to be broncho-pneumonia. Her condition improved but she wasreadmitted two weeks later with a similar illness andthis was followed by a further six episodes warrantingadmissions during the first 13 months of life. Therewas severe failure to thrive with an appreciable falloff in weight. Medication including inhaled 12agonist bronchodilators, anticholinergic agents,antibiotics, and corticosteroids failed to show anyimprovement in her condition. Extensive investiga-tions were performed; sweat chloride analysis andserum immunoglobulins gave normal results as didbronchography and a contrast oesophagogram.Serial chest radiographs showed widespread infiltra-tive changes and fine nodular shadows mainly in theupper and midzones of the left lung (fig 2). Isotopelung scanning showed mismatching with a greaterdiminution in ventilation than perfusion to theseareas. At 11 months of age an open lung biopsyspecimen showed infiltration of peribronchiolar andinteralveolar walls by proliferating histiocytes. Fullevaluation including bone marrow aspirate examina-tion, plain radiograph skeletal survey, and isotopebone scan did not show evidence of histiocytosis atany other site. Treatment with prednisolone andvinblastine was given, but no improvement occurreduntil etoposide was substituted for vinblastine.There was then a noticeable improvement of res-piratory symptoms and growth.At 3 years 7 months of age, when clinically her

symptoms were well controlled, a respiratory arrestoccurred at home and the child was brought into

Fig 2 Chest radiograph ofcase 2, showing widespreadinfiltrative changes and nodular shadows in the left lung.

hospital dead. At postmortem examination thefindings showed pulmonary histiocytosis. Bothupper lobes contained small emphysematous cystsbeneath the pleural surface and numerous smallyellow nodules. These nodules showed the histolo-gical features of histiocytosis X.

Case 3. A boy, aged 9/2 years, was referred becausehe had had a recurrent cough for four months thathad been unresponsive to inhaled 132 agonist bron-chodilator treatment. Physical examination wasnormal and initial chest radiograph showed onlyminimal perihilar streaking. Symptoms persistedand after a further three months the radiological

Fig 3 Chest radiographs ofcase 3: (a) at presentationshowing perihilar streaking and (b) three years later: thisshows the progression to fibrotic changes with partial lobarcollapse and granularity in the right midzone.

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features had progressed to extensive perihilar andparatracheal streaky infiltrative changes accom-panied by loss of lung volume (fig 3a). On chestausculation crepitations were present over bothlungs, but there was no wheezing. Peak expiratoryflow rate was 67% predicted for height, and did notimprove significantly after inhaled bronchodilators.Further pulmonary function tests showed a re-duction in vital capacity (45% predicted), more sothan functional residual capacity (78% predicted,measured by helium dilution). This reductionoccurred at the expense of increased residualvolume so that the ratio of residual volume to totallung capacity was increased (38%). The ratio offorced expiratory volume in one second to forcedvital capacity was normal (85%). This reflects arestrictive defect with evidence of gas trapping.Isotope lung scanning showed patchy decreasedventilation to the left base but normal perfusion. Asa consequence of this mismatching he washypoxaemic at rest (PaO2 7.9 kPa). An open lungbiopsy specimen showed infiltration of peribron-chiolar tissue and alveolar walls by histiocytes andplasma cells. He has remained well with minimalrespiratory symptoms, and there is no disease in anyother organ system in the three years since diagnosis.Despite absence of symptoms and physical signs hispulmonary histiocytosis has progressed radiologi-cally with more noticeable perihilar streaking andfibrotic changes leading to partial right lower lobecollapse (fig 3b). There are no clinical or electro-cardiographic signs of pulmonary hypertension.

Discussion

Histiocytosis limited to the lung as described inthese three cases is a rare cause of interstitial lungdisease in childhood. The entity, histiocytosis X,encompasses an overlapping group of disorders thatshare the common histological features of prolifera-tion of atypical histiocytes, but each disorder haswidely different patterns of organ disease and avariable prognosis ranging from excellent to lethal.2The lungs are affected in 50% of children who havemultisystem disease3 but much of what is knownabout isolated lung histiocytosis is based on theexperience in adult practice of a relatively benign,frequently self limiting cause of interstitialpneumonitis in the young or middle aged.' Revortsof 'primary pulmonary histiocytosis' in children andadults5 have included patients with histiocytosisdisease at other organ sites outside the lung. To our

knowledge there have been only three previousreports in children of lung histiocytosis X as the soleorgan to be affected.f8Two of the children reported here presented early

Isolated pulmonary histiocytosis 425

in infancy with failure to thrive and persistentbreathlessness. Both infants had presentations sug-gestive of alternative diagnoses and their initialchest radiographs were not typical of interstitial lungdisease. Only later in the clinical course did nodularor reticular shadows become apparent, and thesewere accompanied by prominent perihilar streaking.The usual radiographic features of primary pul-

monary histiocytosis in adult patients are fine orcoarse reticular or nodular infiltrates in the upperand midzones with notable sparing of the costophre-nic angles.9 If the disease progresses small cysts orbullae appear and eventually there is fibrosis and'honeycombing'.1 Hilar lymphadenopathy is un-usual. The radiological features of primary pulmon-ary histiocytosis are not specific enough to make thediagnosis in adult practice, and our experience inchildren would support this. Investigations, otherthan lung biopsy, were not of diagnostic value butare necessary to exclude important alternativediagnoses. Pulmonary function testing in adults hasshown variable patterns but the most consistentabnormality has been depression of diffusion cap-acity reflecting disease of the alveolar capillaryvasculature.1 Isotope ventilation/perfusion scanningin two of our patients gave considerably abnormalresults though certainly not specifically diagnosticfor histiocytosis. In general ventilation was moreimpaired than perfusion, and the areas affectedwere more extensive than shown radiologically.Isotope scanning of this type may be of value inserially following affected children as it is apparentthat clinical symptoms, signs, and radiologicalappearances do not necessarily parallel one another.Gallium 67 isotope scanning has been unhelpful inadult patients.'10The histology of histiocytosis in the lung is not

essentially different between primary pulmonaryhistiocytosis and the disseminated disease. Thelungs contain yellow or grey nodules and subpleuralcysts, which are predominantly in the upper lobesand vary in size from 1 mm to 1-5 cm. The nodulescontain mainly atypical histiocytes (Langerhanscells) and eosinophils with few lymphocytes. Thisinfiltrate is mainly peribronchiolar but is alsopresent in the alveolar wall and around small vesselsand capillaries. Langerhans cells are not normallypresent in the alveolar wall and rarely present in thebronchilar wall of the adult lung.9 Electron micros-copy of Langerhans cells shows characteristic cyto-plasmic organelles (Birbeck granules). On diseaseprogression affected areas are replaced by fibroustissue leaving characteristic stellate shaped scars.

It is now thought that histiocytosis X is a non-malignant proliferative disorder of the Langerhanscell system, and that histiocytes share numerous

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426 McDowell, Macfarlane, and Martin

morphological and biological features withmacrophages. The Langerhans cell system can beregarded as a subpopulation of the mononuclear cellsystem and is closely allayed to T cell populationsand the lymphocytic immune system.'1 12 Identifi-cation of Langerhan cells containing Birbeckgranules can now be performed using the mono-clonal antibody OKT6 and antibody to S100protein.Such is the apparent rarity of isolated pulmonary

histiocytosis in children that it is likely that only themost severe or fatal cases will be reported, thereforeconclusions about clinical features, treatment re-sponse, and natural history must be viewed withcaution. In our experience there is an initial phase ofprominent respiratory symptoms (and growth fai-lure in infants) but radiological features are nottypically nodular or reticular until later. After avariable period the symptoms improve considerablybut radiological signs of the disease do not show anyresolution and may even show a progression.The cause of death in case 2 at the age of 3 years 7

months is unexplained by postmortem findings.Despite extensive pulmonary disease with cystformation she appeared to have been symptom freefor some while. We speculate that she sufferedcatastrophic pneumothoraces from rupture of asubpleural cyst; this is a complication of pulmonaryhistiocytosis occurring in up to 10% of adult cases.5

Unlike histiocytosis limited to other single organsites where the prognosis is usually good, theprognosis for primary pulmonary histiocytosis inchildhood is, at best, unpredictable. Based oncurrent available information no strong recom-mendations can be made for the treatment ofprimary pulmonary histiocytosis, although a ther-

apeutic trial of steroids in symptomatic patients isjustified.

References

Prophet D. Primary pulmonary histiocytosis X. Clin Chest Med1982;3:643-53.

2 Grundy P, Ellis R. Histiocytosis X: a review of the etiology,pathology, staging and therapy. Med Pediatr Oncol 1986;14:45-50.

3 Nesbit ME. Current concepts and treatment of histiocytosis(Langerhans cell histiocytosis). In: Voute PA, Barrett A,Bloom HJG, Lemerle J, eds. Cancer in children; clinicalmanagement Berlin: Springer-Verlag, 1986:176-84.

4 Nondahl SR, Finlay JL, Farrell PM, Warner TF, Hong R.A cases report and literature review of "primary" pulmonaryhistiocytosis X of childhood. Med Pediatr Oncol 1986;14:57-62.

5 Friedman PJ, Liebow AA, Sokoloff J. Eosinophilic granulomaof lung: clinical aspects of primary pulmonary histiocytosis in theadult. Medicine (Baltimore) 1981;6:385-96.

6 Hambleton G, Gad A, Godfrey S. Pulmonary eosinophilicgranuloma in a child. Arch Dis Child 1976;51:805-7.

7 Aftimos S, Nasser V, Najjar S. Primary pulmonary histiocytosisin an infant. Am J Dis Child 1974;128:851-2.

8 Berlow ME, Markarian B, Heitzman R, Raasch BN. Diffusepulmonary disease in a 2½/2 year old child. JAMA 1982;248:875-6.Colby TV, Lomard C. Histiocytosis X in the lung. Hum Pathol1983;14:847-56.

10 Crystal RG, Bitterman PB, Rennard SI, Hance AJ, Keogh BA.Interstitial lung diseases of unknown cause. N Engl J Med1984;310:235-44.

" Nezelof C. Histiocytosis X. An histological and histogeneticstudy. Perspect Pediatr Pathol 1979;5:153-78.

12 Favara BE. The pathology of "histiocytosis". Am J PediatrHematol Oncol 1981;3:45-56.

13 Histiocyte Society. Histiocytosis syndromes in children. Lancet1987;i:208-9.

Correspondence to Dr HP McDowell, Department of Haema-tology and Oncology, Royal Liverpool Children's Hospital, AlderHey, Eaton Road, Liverpool L12 2QB.

Accepted 10 November 1987

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histiocytosis.Isolated pulmonary

H P McDowell, P I Macfarlane and J Martin

doi: 10.1136/adc.63.4.4231988 63: 423-426 Arch Dis Child 

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