EuropeanJournal of

Eur J Pediatr (1990) 149 : 325-329

Pediatrics

9 Springer-Veriag 1990

Gastrointestinal involvement in Langerhans' cell histiocytosis (Histiocytosis X): a clinical report of three cases R. M. Egeler 1, M. E. I. Schipper 2, and H. S. A . Heymans 3

1Department of Paediatric Gastroenterology and Nutrition and 2Department of Pathology, University Hospital of Amsterdam, Emma Kinderziekenhnis/Kinder AMC, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands 3Department of Paediatrics, University Hospital of Groningen, Groningen, The Netherlands

Abstract. The gastrointestinal tract may be involved in Langerhans' cell histiocytosis, either as part of a generalized disease or as a separate primary entitiy. Three patients with gastrointestinal involvement are described. One patient presented with a history of prolonged vomiting and diarrhoea with blood and mucus. In this case the diagnosis was based on colonic biopsies. Gastrointestinal tract involvement and its investigation in the diagnosis of Langerhans' cell histiocytosis are discussed. Key words: Langerhans' cell histiocytosis (Histiocytosis X) Gastrointestinal involvement

Introduction

Histiocytosis X is a collective name introduced by Lichtenstein [12] in 1953 to integrate a group of diseases previously known as Hand-Schfiller-Christian disease, Letterer-Siwe disease and eosinophilic granuloma of bone. Histiocytosis is an inflammatory proliferative process which is the common feature in the various pathological expressions of the disease. Nezelof et al. [14] described histiocytosis X as a local proliferation and in some cases dissemination of Langerhans histiocytes. The Langerhans cell, a phagocytic epidermal dendritic cell is considered to be the major lesional cell in this type of histiocytic disorder. It derives from the monocyte that develops a surface antigenic determinant identified by the monoclonal antibody T6. Transformation of monocytes to Langerhans cells take place in perivascular areas of the superficial dermis and continues in the epidermis where some T6 positive macrophages develop Birbeck granules, the ultrastructural marker of the Langerhans cell [4]. Therefore it has been suggested to use the name Langerhans' cell histiocytosis [17], for this disease entity. Recently The Writing Group of the Histiocyte Society recommended a new classification in three classes for all histiocytosis syndromes in children as a standard for diagnosis, patient management and research [21]. In "Class I" the diagnosis Langerhans' cell histiocytosis is based on histogenetic criteria, whereas histiocytoses of mononuclear phagocytes Offprint requests to: R. M. Egeler

other than Langerhans cells were classified as "Class II" and malignant histiocytic disorders as "Class III". This international group of pathologists in the Histiocyte Society [21] has also established confidence levels for diagnosis. "Presumptive diagnosis" is warranted when the diagnosis is made solely on the basis of examining conventionally processed tissue revealing lesions consistent with those defined in the literature. A higher level of diagnostic confidence, simply called "diagnosis", is justified when these findings are supplemented by the presence of at least two of the following characteristics: positive stain for S-100 protein, ATPase, alphaD-mannosidase or peanut lectin binding. The "definitive diagnosis" requires the presence of Birbeck granules in lesional cells, detected by electron microscopy or the demonstration of T6 antigenic determinants on the surface of lesional cells. Despite extensive literature on the clinical presentation of Langerhans' cell histiocytosis, little has been reported concerning gastrointestinal symptoms [10, 13, 15]. The gastrointestinal tract may be involved either as a part of a generalized disease, or as a separate entity, i.e. primary gastrointestinal Langerhans' cell histiocytosis [3, 6-8, 16, 18, 19]. Three cases with severe gastrointestinal involvement diagnosed as Langerhans' cell histiocytosis are described. In the first case, which presented with vomiting and persisting diarrhoea, the diagnosis was based primarily on colonic biopsies. A brief review of the literature on gastrointestinal involvement and its clinical presentation is also given.

Clinical cases Case I

A 6-month-old white boy was admitted to the paediatric department of the University Hospital of Amsterdam with a 1 month history of chonic gastroenteritis. He was born at term following an uneventful pregnancy and delivery as the first child to a Brazilian mother and an American father. In the first 5 months, development was normal. A t the age of 5 months, his parents took him to Brazil for a family visit. After 1 week he became ill and started vomiting and passing blood-stained diarrhoea. He was admitted

326

Fig. 1. (HE-staining, 25 x) Colonic mucous membrane with slightly distorted crypts. In the lamina propria a cellular infiltrate is present, composed of many large histiocytes, lymphocytes and eosinophils. The epithelial surface is intact

Fig. 2. (HE-staining, 100 x) The multiple aggregates of large polygonal histiocytes with irregular shaped nuclei, surrounded by lymphocytes and eosinophils, are highly suggestive of a Langerhans' cell histiocytosis, subsequently confirmed by electron microscopy

to a local hospital. It is reported that physical examination revealed no abnormalities, and stool cultures were negative. Treatment with cotrimoxazol was started, but diarrhoea and vomiting persisted. He was referred to another hospital for further diagnosis and treatment, which consisted of total parenteral nutrition and i.v. gentamycin. As a proximal small bowel obstruction was suspected, a gastroduodenoscopy was performed showing haemorrhagic ulcerations in the proximal part of the duodenum, suggesting Crohn disease. No biopsies were taken. Despite antibiotics and parenteral nutrition, diarrhoea and vomiting continued and his clinical condition deteriorated. No pathological micro-organism could be isolated from blood or stools. The parents preferred to return to Holland, where the boy was admitted to hospital immediately upon arrival. The 6month-old child was in a poor clinical condition; very pale and with generalized oedema. He had profuse diarrhoea.

Laboratory investigations revealed severe anaemia and hypoproteinaemia. No micro-organism could be isolated. By means of a Cr51C13-test [20] a severe protein-losing enteropathy could be established. Despite different antibiotic regimens, his clinical condition further deteriorated, and the diarrhoea with blood and mucus persisted. To exclude a pseudomembraneous enterocolitis a bedside coloscopy was perfomed using a flexible Olympus P10 endoscope (Tokyo, Japan). Swollen mucosal tissue with multiple haemorrhagic erosions could be seen and several biopsies were taken. The tissue specimens were fixed in 4% buffered formalin and prepared for light microscopy. In general the colonic mucous membrane showed a normal architecture. Locally the crypts were somewhat distorted (Fig. 1). The epithelial lining of the crypts was intact and the number of goblet cells was slightly diminished. The characteristic pattern of a pseudomembraneous enterocolitis was not seen. The main

327 abnormalities were to be seen in the stromal component namely a striking amount of histiocytes with abundant polygonal cytoplasm and a central nucleus, without atypia (Fig. 2). There was a slight inflammatory infiltrate composed of lymphocytes and a few eosinophils without neutrophil granulocytes. Granuloma-like structures were not present. Special staining procedures for micro-organisms were negative. The light microscopical examination suggested a histiocytosis, localized in the colonic mucous membrane. In order to classify the histiocytic cells immunohistologically, immunoperoxidase staining for alpha 1-antitrypsin, lysozyme and S-100 were performed on paraffin sections. These proved to be positive. Since positive staining for alpha-l-antitrypsin and lysozyme can be due to the presence of macrophages and because no further immunophenotyping with monoclonal antibodies was possible (no fresh frozen biopsies were available) electron microscopy was perfomed on the formalin fixed and paraffin embedded tissue specimens of the colonic mucosa in order to confirm the diagnosis of Langerhans' cell histiocytosis with gastrointestinal tract manifestation. The histiocytes showed structures defined as Birbeck granules. In the following weeks hepatosplenomegaly developed and dermatological lesions consisting of small brownish papules containing central petechiae appeared mainly on the buttocks. Incubation of a fresh frozen skin biopsy with peroxidase-labelled monoclonal antibodies for T4 and Langerhans cells (OKT6, Orthoclone, Beerse, Belgium) showed positive reading on histiocytes, confirming the diagnosis Langerhans' cell histiocytosis. Thus the light microscopical, immunohistological and electron microscopical evidence of a Langerhans' cell histiocytosis localised in the gastro-intestinal tract and the skin was confirmed ("definitive diagnosis"). Supportive therapy consisting of total parenteral nutrition, transfusion of packed cells and 20% albumin flee frozen plasma every other day, was combined with a chemotherapeutical treatment consisting of arabine-cytosine, vincristine and prednisone. Although the clinical course was complicated by septic episodes, our patient steadily improved. He was discharged from our hospital in full remission and in good health after 3 months of treatment. He was further treated with chemotherapy for 1 full year. However, 2 months after stopping the chemotherapy he was re-admitted because of a relapse of the disease, Langerhans' cell histiocytosis in his lungs, proven by demonstrating Birbeck granules on electron microscopy. Again a chemotherapy regimen consisting arabine-cytosine, vincristine, etoposide (VP-16) and prednisone was started. A remission was quickly attained and the latest check up showed a healthy 2-year-old boy.

Case 2

A boy, healthy until 4 months of age, was admitted to a local hospital, because of failure to thrive. He had also developed a scaly maculopapular rash involving scalp, trunk, groin and buttocks. Laboratory evaluation revealed mild anaemia and hypoproteinaemia. After developing a severe gastro-enteritis with vomiting and mucous diarrhoea, the patient was referred to the University Children's Hospital, Utrecht. Biopsy specimens were taken from lesions on the back, scalp and the duodenum.

Histological examination revealed a dense infiltrate of histiocytes. Especially the histiocytes in the gastrointestinal tract biopsies showed a marked pleomorphism and nuclear atypia with some mitoses. The mucous membrane showed ulceration. The diagnosis "histiocytosis" was made on the presence of many histiocytes in ulcerative gastrointestinal tract lesions. In the skin the histiocytes were localised on the dermal-epidermal junction and infiltrating between the epithelial cells. Pleomorphism and nuclear atypia were not present in these biopsies. Immunophenotyping performed on a fresh frozen skin biopsy was positve for OKT6 (Langerhans' cells) and OKT4 (T helper inducer lympocytes). Also electron microscopy showed Birbeck granules in many histiocytes. These two additional pathological findings confirmed the diagnosis of Langerhans' cell histiocytosis with gastrointestinal involvement. Due to the fact that the disease was considered to be generalized with a life-threatening condition, chemotherapy, combining arabine-cytosine, vincristine and prednisoue, was started. Total parenteral nutrition and 20% albumin infusions were given as supportive therapy. After 1 year of treatment with many complications he was still in a very bad condition, but due to a difficult family situation the treatment could not be given on regular basis. Further therapy was refused after 12 months and he died at the age of 18 months. Autopsy was not performed.

Case 3

A 10-month-old girl was admitted to the University Hospital of Nijmegen because of vomiting, failure to thrive and slight eczema with small petechiae in the eruptions since the age of 6 months. Laboratory investigations revealed hypoproteinaemia caused by protein losing enteropathy as proven by CrSi-labelled albumin [20]. Radiological studies demonstrated an irregularity of the mucosa of the whole duodenum and the proximal jejunum. Gastroduodenoscopy revealed a picture of severe duodenitis. Histological examination of the duodenum-jejunum biopsies showed a dense inflammatory infiltrate and ulcerations of the mucous membrane without specifictiy. Treatment with salazosulphapyridine and prednisone was initiated as Morbus Crohn was suspected. Large quantities of 20% albumin were necessary to maintain a reasonable colloid osmotic pressure. Despite this therapy hepatosplenomegaly developed and as her condition deteriorated an explorative laparotomy was performed revealing severe inflammation of the distal part of the duodenum and proximal part of the jejunum, as well as many mesenteric lymph noduli. A mesenteric lymph node and a Meckel diverticulum were resected. These two tissue specimens demonstrated a large amount of histiocytes. Especially the histiocytes in the sinuses of the lymph node contained atypical, hyperchromatic and pleomorph nuclei, strongly suggesting a histiocytosis. The many histiocytes in the Meckel diverticulum were scattered through out the mucous membrane. The normal architecture was entirely preserved. These histiocytes showed no atypia or mitoses. Granulomas were not found and there was a normal number of eosinophils. The only abnormal finding was the remarkable proliferation of large pale histiocytes. After a skin biopsy and revision of the duodenum and jejunum biopsies, the "presumptive diagnosis" Langerhans'

328 Table 1. Incidence of organ involvement

Number of patients Bone lesions Skin lesions Hepatomegaly Splenomegaly Pulmonary problems Adenopathy Diabetes insipidus

Lahey [10]

Nezelof et al. [15] Nesbit [13]

69 57 (82%) 42 (61%) 30 (43%) 30 (43%) 35 (51%) not available 20 (29%)

50 41 (82%) 40 (80%) 18 (36%) 15 (30%) 30 (60%) 23 (46%) 20 (40%)

24 24 (100%) 21 (87%) 17 (71%) 6 (25%) 13 (54%) 10 (42%) 6 (25%)

cell histiocytosis was made. Despite high doses of chemotherapy, combining cyclophosphamide and prednisone, the patients condition deteriorated. She died at the age of 16 months. Now 9 years later, electron microscopy was performed on the 1% glutaraldehyde fixed and frozen tissue specimens of duodenum and jejunum. Birbeck granules were found allowing the "definitive diagnosis" of Langerhans' cell histiocytosis of the gastrointestinal tract.

Discussion

Although the exact incidence of Langerhans' cell histiocytosis is not known, it has been estimated at 1 per 200000 children each year in the United States [5]. Although spontaneous healing [2] and remission [1] of multi-system Langerhans' cell histiocytosis has been published, there is agreement that age, number or organs involved and presence of organ dysfunction are important unfavourable prognostic factors [11]. A Southwest Oncology Group Study [9] even gives a 50% mortality rate in children younger than 2 years of age with multi-system soft tissue disease with organ dysfunction. Primarily supporting therapy has to be given, but careful consideration of starting chemotherapy or other dangerous treatment regimens should be made for those patients which have a life-threatening disorder. Much has been written concerning the clinical aspects of the disseminated forms of Langerhans' cell histiocytosis [10, 13, 15], summarized in Table 1. The results were based entirely on information derived from the history, physical examination and available laboratory investigations. Gastrointestinal symptoms are not mentioned in any of these reviews. Hyams et al. [6] reported clinical gastrointestinal findings in less than 1% of all patients based on a review of four major series of case reports (involving 145 patients). That primary Langerhans' cell histiocytosis of bowel with no other organ involvement is unusual was emphasized by Idlibi and Hamoudi [7]. A child aged 9 months was presented with diarrhoea and malabsorption syndrome. Multiple biopsies from duodenum, jejunum and rectum showed either an inflammatory process and/or lesions suggestive of granulomatous disease of bowel. Finally, at the age of 2.5 years when she developed a skin rash, a skin biopsy demonstrated Langerhans' cell histiocytosis. The diagnosis was confirmed by S 100 protein immunoperoxidase stain, although Birbeck granules were not seen in the ultrastructural study of the bowel lesions. Keeling and Harries [8], were confronted with a child with in-

testinal malabsoption due to histocytic infiltration in the entire small intestine, with marked nuclear pleomorphism and many mitotic figures in the histiocytes; normal architecture was lost. Those authors retrospectively reviewed another 11 fatal cases in which histological material from the gastrointestinal tract was available. In that small group histiocytic infiltration of the gastrointestinal tract was discovered in 5 cases. In those days (1973) the diagnosis Langerhans' cell histiocytosis was made solely on histological criteria. Tamura et al. [19] presented a case of congenital LettererSiwe disease, confirmed by electron microscopy of a histiocyte in a skin biopsy, associated with protein losing enteropathy. At autopsy they not only found massive infiltration of histiocytes in several organs, but also severe infiltration of the intestine, especially the jejunum. Intractable diarrhoea as a major symptom of Langerhans' cell histiocytosis has been described by Deprettere et al. [3]. Autopsy revealed an extensive histiocytic infiltration of duodenum, jejunum, colon and other organs. On electron microscopic examination of the intestinal and dermal biopsy, Birbeck granules were observed in the histiocytes. Hyams et al. [6] reported a child with blood-stained diarrhoea as the main symptom alongside hepatosplenomegaly and pneumonia. At autopsy many organs were infiltrated by histiocytes and the distal ileum, appendix and colon showed diffuse mucosal ulceration due to histocytic infiltration of the submucosa and lamina propria. Although the gastrointestinal histiocyte involvement was only based on histological criteria, the diagnosis Langerhans' cell histiocytosis was confirmed by immunochemistry and ultrastructural studies on splenic- and lymph node autopsy tissue and on lung- and liver autopsy tissue respectively. A benign proliferative disorder of Langerhans' cell histiocytes of the stomach has been published by Nihei et al. [16]. A 47-year-old woman, who underwent subtotal gastrectomy following a clinical diagnosis of scirrhous carcinoma, proved to have Langerhans' cell histiocytosis localized to the lamina propria of the stomach by light and electron microscopy as well as by immunohistochemistry. The similarity of gastrointestinal Langerhans' cell histiocytosis to Crohn disease was described by Sutphen and Fechner [18] in a case of a 5-year-old girl who presented at 18 months of age with an ileal perforation and radiological evidence of segmental intestinal narrowing. Because of persistent mild chronic intestinal symptoms a review of the histological examination of the removed intestine was performed, showing mixed histiocytic and eosinophilic infiltration characteristic of Langerhans' cell histiocytosis. A "definitive diagnosis" could not be made because biopsies of stomach and duodenum did not show Birbeck granules on electron microscopy. There is no information about immunopathological studies on the tissue. In only two [3, 16] of these seven studies were the gastrointestinal symptoms clearly associated with involvement by histiocytes proven to be Langerhans cells based on ultrastructural and immunohistochemical characteristics. In the other cases [6-8, 18, 19] the gastrointestinal symptoms were associated with involvement of histiocytes defined on histological criteria. The importance and clinical consequences of the gastrointestinal tract involvement have been stressed in these seven studies. In conclusion, we presume that the frequency of gastrointestinal symptoms is underestimated, because of their aspecifictiy, especially in children. Presentation of gastrointesti-

329 nal symptoms may be related to the site and degree of gastroenterological involvement. The clinical symptoms of histiocytic infiltration of the stomach included abdominal pain with signs of intestinal obstruction, nausea, vomiting and diarrhoea. In the small intestine, the ileum is most frequently affected, leading to vomiting, diarrhoea, protein-losing enteropathy and even malabsorption. I n v o l v e m e n t of the colon my give rise to diarrhoea with or without blood, depending on the degree of cell-infiltration disrupting the mucous m e m b r a n e . A l t h o u g h involvement of gastrointestinal tracts, with clinical symptoms like diarrhoea and vomiting seems unusual in the disseminated form of Langerhans' cell histiocytosis we have presented three patients with these features as demonstrating symptoms of Langerhans' cell histiocytosis. A l t h o u g h others [6] have already m e n t i o n e d the value of multiple colonic biopsies, our first patient is the first to our knowledge in which Langerhans' cell histiocytosis was histopathologically diagnosed on colonic biopsies taken during coloscopy.

Acknowledgements. We are grateful to Dr. M. Bruin, and Dr. J. P. M. B6kkerink, for permission to publish details of the cases 2 and 3, as well as the departments Pathological Anatomy of the University Children's Hospital Utrecht (Professor J.A.M.van Unnik) and of the University Hospital Nijmegen (Professor G. P. Vooijs) for allowing us to use material for the cases 2 and 3. We thank Professor P. A. Vofite, for his critical and valuable comments, and Simone Majoor and Corrie van den Berg for secreterial assistance.

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Received February 2, 1988 ! Accepted May 10, 1989