DIGESTIVE TRACT INVOLVEMENT WITH EXUDATIVE ENTEROPATHY IN LANGERHANS CELL HlSTlOCYTOSlS

Liliane A. Boccon-Gibod, MD, and Hichem A. Krichen, M D 0

Pathology Department, HBpital d’Enfants Armand Trousseau, 75012 Paris,

France

Fetal Pediatr Pathol Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.

Laure M . B. Carlier-Mercier, MD 0 Pediatric Gastro-Enterology and Nutrition Department, HBpital d’Enfants Armand Trousseau, 75012 Paris, France Jean F. Salaun, M D

Department of Hematology and Oncology, H8pital

0

d’Enfants Armand Trousseau, 75012 Paris, France

Jean L. Fontaine, M D

0 Pediatric Gastro-Enterology and Nutrition Department, HBpital d’Enfants Armand Trousseau, 75012 Paris, France

GUY R. Leverger, M D

0

Department of Hematology a n d Oncology,

HBpital d’Enfants Armand Trousseau, 75012 Paris, France

Protein-losing enteropathy was observed in two children with Langerhans ’ cell histiocytosis (LCH). One patient was an infant with congenital cutaneous lesions; the second child had sigmoid and lymph node infiltration. Electron microscopy and immunohistochemistry confirmed, in both, infiltration of duodenum, skin, and liver by LCH. Gastrointestinal involvement by L C H seldom produces prominent clinical manifestations but indicates widespread multisystem disease. Immunohistochemical and/or ultrastructural features allow definitive diagnosis from mucosal biopsy specimens. Review of the literature of gastrointestinal infiltration by L C H emphasizes its poor prognosis, especially when associated with organ dysfunction. 0

KEY WORDS: congenital histiocytosis X; gastrointestinal inuolvement; histiocytosis, Laqerhans’ cell; protein-losing enteropathy.

The authors thank Dr. Ala B. Hamoudi, Department of Pathology, Children’s Hospital, Columbus, Ohio, and Dr. R. M. Egeler, Department of Pediatric Hematology-Oncology, University Hospital of Minnesota, who kindly provided detailed information about cases they had previously published. We also wish to express our gratitude to Mr. Wolfesperger for taking the photographs and to Mrs. J. Elmira and Mr. A. Ilies for their technical assistance with immunohistochemistry and electron microscopy. Address reprint requests to: Professor Liliane A. Boccon-Gibod, Department of Pathology, H8pital d’Enfants Armand Trousseau, 26 avenue du Dr Arnold-Netter, 75571 Paris Cedex 12, France.

Pediatric Pathology, 12515-524, 1992 Copyright 0 1992 by Hemisphere Publishing Corporation

515

516

L. A. BOCCON-OIBOD ET AL.

Fetal Pediatr Pathol Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.

INTRODUCTION Disseminated Langerhans’ cell histiocytosis (LCH) is known to involve lung, liver, skin, bone, lymph nodes, and other sites (1). Gastrointestinal (GI) tract lesions have seldom been described and little has been reported concerning GI symptoms, which only rarely constitute a major clinical problem (210). Isolated case reports have described protein losing enteropathy (3, 9), malabsorption (2, 6), protracted diarrhea (4), and intestinal perforation (7). In fact, histological involvement of the GI tract is not rare in LCH and should more often be investigated by simple diagnostic procedures such as duodenal, colonoscopic or rectal biopsy for better monitoring of diagnosis, stage and prognosis. Our two patients presented with prominent GI tract symptoms. Intestinal and colonic biopsies were useful in assessing the GI tract lesions. Immunophenotyping of the histiocytoses and electron microscopy were used to ensure definitive diagnosis (11) and to distinguish LCH from other histiocytic infiltrations of the GI tract. Both patients had multisystem disease with organ dysfunction (12). Only partial remission was achieved using prednisone and vinblastine, and etoposide (VP- 16) was introduced.

CASE REPORTS Case 1 A 3120-g white male infant was born at 39 weeks of gestation to a healthy 24-year-old, gravida 1, para 1 mother by vaginal delivery after an uneventful pregnancy. There was no family history of hereditary disease. Immediately after birth, the infant was observed to have a generalized rash. The lesions were distributed over the head, neck, trunk, and extremities. There was no hepatosplenomegaly. The eruption was first considered to be infectious and treated with antibiotics. Langerhans’ cell histiocytosis was suspected and was confirmed by cutaneous biopsy on day 12. Protein loss was diagnosed on day 14. The total serum protein was 28 g/L. The albumin/globulin ratio was low, 1.16, because of exudative enteropathy as shown by elevated a,-antitrypsin clearance in the stools: 34 to 40 m1/24 h (normal < 15 m1/24 h). Biopsies of the GI tract revealed smallintestinal involvement by LCH. A histiocytic infiltrate was present in the duodenum, which displayed partial villous atrophy, but gastric and colonic biopsies were normal. The spleen and liver were not enlarged but hyperbilirubinemia (3 1 pmollL) was present; hepatic biopsy revealed involvement. Radiologic examination showed that lungs and bones were not involved. The bone marrow was

Fetal Pediatr Pathol Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.

INTESTINAL LANGERHANS HlSTlOCYTOSlS

517

hypercellular, but morphologic and immunohistochemical study showed that it was not infiltrated by histiocytic cells. The child failed to thrive and developed anemia (hemoglobin 8.4 g/dL) and thrombocytopenia (1 17 X lo’). Total parented nutrition with albumin and blood transfusions were instituted on day 20 and oral prednisone (2 mg/ kg/day) on day 26. Because of a positive liver biopsy at 1 month of age, specific chemotherapy was initiated with vinblastine, 3 mg/m2 intravenously, on a weekly basis. For a short period the cutaneous lesions cleared and there were weight gain, cessation of protein loss, and correction of the blood count abnormalities, but most symptoms soon recurred and the child developed fever and diarrhea. The cutaneous rash and hepatosplenomegaly increased. Etoposide, 100 mg/m2 three times a week, was initiated at 13 weeks but had only a partial and transitory effect, and interferon-a was given at age 15 weeks. Melena appeared at 15% weeks and the infant died at age 17 weeks. At parental request, no postmortem examination was performed.

Case 2 A 16-month-old previously well girl was admitted to Hbpital d’Enfants Armand Trousseau for evaluation of bloody diarrhea, fever, failure to thrive, and a purpuric rash. She had been born at term following an uneventful pregnancy and delivery to a 3 1-year-old, gravida 1, para 1 mother. The father had a minor form of von Willebrand disease, and von Willebrand disease was diagnosed in the baby at age 4 months. Physical examination revealed a pale, febrile, whining child with hepatosplenomegaly (liver and spleen respectively 3 and 4 cm below the costal margin) and polyadenopathy. Purpura with occasional papular lesions was distributed on the trunk. Bloody stools were noted. Laboratory studies included a hematocrit of 33%, hemoglobin 9.1 g/L, white blood cell count 5500 cells mm3, platelet count 136,000, fibrinogen 1.06 g/L. Stool cultures grew Helicobacterjejuni. Total serum protein was 5 1 g/L, aspartate aminotransferase 65 U/ L, alanine aminotransferase 50 U/L. A chest and skeletal radiographic survey was unremarkable. Bone marrow aspirate was hypercellular, with erythroid hyperplasia and 10% histiocytes. No erythrophagocytosis was present. Biopsies from skin, lymph nodes, stomach, duodenum, and sigmoid demonstrated a histiocytic infiltrate typical of LCH. Birbeck granules were identified by electron microscopy. Gastric biopsy displayed no involvement. Thrombocytopenia worsened quickly, to 72,000 cells/mm3, as did other hemostatic factors. Fibrinogen was below 1 g/L. Lymphadenohepatosplenomegaly increased dramatically (the spleen was 10 cm below the costal margin). Fever to 40 OC and melena were present. Therapy with corticosteroids was instituted immediately after diagnosis,

518

L. A. BOCCON-GIBOD ET AL.

Fetal Pediatr Pathol Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.

together with antibiotics for the Helicobacter and transfusion of fresh frozen plasma, von Willebrand factor, and platelets. The child improved dramatically only when the first injection of vinblastine (6 mg/m2) was added to this treatment. Fever disappeared within a day. After 2 months of steroid therapy and eight injections of vinblastine, moderate hepatomegaly and splenomegaly were still present. Liver biopsy revealed sparse Langerhans’ cells within Disse’s space, and etoposide was added to the regimen (100 mg/m2/day X 3 / week, every 3 weeks). This treatment has led to complete remission with only a short follow-up period of 4 months.

PATHOLOGICAL FINDINGS In both patients, skin, liver, and digestive tract were biopsied, and in patient 2 lymph node specimens were also obtained. All were fixed in Bouin’s solution; liver, lymph node, and skin biopsies were fixed in glutaraldehyde for electron microscopic study. Skin, liver, lymph node, stomach, small intestine, and colon specimens were frozen in liquid nitrogen for immunohistochemical demonstration of CD1 and immunophenotyping. Endoscopic biopsy was performed at the level of the second part of the duodenum. Dissecting microscopy showed indistinct furrows. Partial villous atrophy with enlarged villi was present, associated with infiltration of the axis of the villi and the lamina propria by characteristic medium-sized Langerhans’ histiocytes. The pink cytoplasm was abundant, and the nuclei were grooved and lobulated. Nucleoli were small. Mitoses were numerous but cytological atypia was mild. Eosinophils were scarce (Fig. 1). SlOO protein and peanut agglutinin immunostaining showed the Langerhans’ cell infiltrate to be more prominent at the tips of the villi (Fig. 2) and to decrease toward the crypts. The liver was involved in both patients. Langerhans’ cells were almost exclusively infiltrating hepatic sinusoids. No eosinophils were present (Fig. 3 ) . In both cases, SlOO protein helped localize the cells and showed them to be more numerous than first suspected. Although Langerhans’ histiocytes were numerous on semithin sections, Birbeck granules could not be demonstrated in the liver by electron microscopy. Skin lesions were characteristic in both cases. The papillary dermis was infiltrated with large round cells with well-defined pink cytoplasm. The nuclei had the characteristic folding, grooving, and irregular notching. Very few eosinophils were noted. SlOO protein was demonstrated on the normal Langerhans’ cells of the adjacent epidermis and in the pathologic histiocytic infiltrate. Numerous Birbeck granules with round and fuzzy ends were present in the cytoplasm.

Fetal Pediatr Pathol Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.

INTESTINAL LANGERHANS HlSTlOCYTOSlS

519

FIGURE 1. Case 2: duodenal biopsy. The villus is broadened with infiltration of the lamina propria by numerous histiocytes, which have eosinophillic cytoplasm and grooved nuclei. X 400.

DISCUSSION Langerhans' cell histiocytosis with clinically manifest GI tract involvement is rare. In a review of 63 children with LCH managed at the Children's Hospital of Philadelphia from 1970 through 1984 (8), bowel involvement was mentioned in only one child, a neonate who had multiple sites of involvement without organ dysfunction. He responded completely to multiple-agent chemotherapy and was alive with no relapse at 7'/12 years. Gastrointestinal symptoms were not mentioned in three other reviews of disseminated LCH (1315). Review of several major older series (16-19) reveals clinical GI findings in less than 1'j%of all patients. An isolated case of LCH with GI localization but no other organ involvement was reported by Idlibi and Hamoudi (6). Histological involvement of the GI tract in LCH may be more frequent than classical textbook descriptions of this disease would suggest, as shown by

Fetal Pediatr Pathol Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.

520

L. A. BOCCON-GIBOD ET AL.

FIGURE 2. Case 2: duodenal biopsy. Numerous Langerhans’ cells have irregular nuclei (arrow) and SlOO protein in the cytoplasm. S100, X690.

FIGURE 3. Case 1 : liver. There is pericapillary infiltration by round cells, with pale irregular nuclei and striated cytoplasm (arrows), the Gaucher-like pattern. X 300.

Fetal Pediatr Pathol Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.

INTESTINAL LANGERHANS HlSTlOCYTOSlS

521

Keeling and Harries (2). These authors reviewed the files of 12 deceased children with presumed histiocytosis X at Great Ormond Street Hospital and found 7 to have had histiocytic infiltration of the intestinal lamina propria. Only five of these seven children had diarrhea during their illness; two others had extensive GI tract histiocytic infiltrate, one of them from esophagus to ileum, without diarrhea. Fourteen reported cases with pertinent clinical data, including the two reported here, are summarized in Table 1. Duodenal biopsies were positive in 6 of the 14 children. Mild to severe partial villous atrophy was described with Langerhans’ cells irregularly filling the lamina propria, being more numerous in the superficial mucosa and decreasing progressively toward the crypts. Eosinophils were scarce or absent. The surface epithelium was normal in most instances but was ulcerated in cases 9 and 10. Infiltration seldom extended through the muscularis mucosae to the submucosa (case 3). Transmural ileal infiltration with perforation and granulomas consisting in equal proportion of histiocytes and eosinophils may lead to an initial diagnosis of Crohn’s disease, in the absence of extra intestinal manifestations (case 6). Colonic infiltration was not usually investigated during life except by colonoscopy (case 8) or sigmoidoscopy (case 14). Mucosal ulcerations were noted in vivo (case 8) or at postmortem examination (case 4; A. Hamoudi, personal communication about case 5). The crypts may be slightly distorted (case 8), decreased (case 4), or destroyed (case 11). Rectal suction biopsy may unexpectedly demonstrate a histiocytic infiltrate typical of LCH (seen in 4 of the 14 cases). Suction biopsy is a moderately noninvasive method and may be useful when LCH with GI tract involvement is suspected. The immunohistochemical confirmation consists of staining for S 100 protein and peanut lectin binding, characteristic of Langerhans’ histiocytes. Immunophenotyping of Langerhans’ cells on fresh frozen material is unique; they are the only histiocytes to demonstrate CD1 (T6) on the surface (20). This is one of the criteria for definitive diagnosis of LCH, the other being Birbeck granules on electron microscopic examination (1 1). Other antigenic determinants usually present on the Langerhans’ cell surface, CD4 and HLADR, are not specific. Staining for pan T and pan B cells is negative in all lesions (21). Electron microscopy was the original method by which Langerhans’ cells of the skin were linked to histiocytosis X. In 1965, Basset et al. (22, 23) described structures present in pulmonary and osseous lesions of histiocytosis X; these were rod-shaped profiles with a dense central osmiophilic core. The granules may have a saccular dilatation at one end, like a tennis racket, and may be related to the cell membrane. Although the GI tract is not an organ whose dysfunction has been identified as crucial for prognosis (12), most of the patients with digestive tract

Malabsorption Protein-losing enteropathy

Protracted diarrhea

2 mo,’ F 1 d,’ M

4 mo, F

?

Diarrhea ( f bloody), vomiting

Diarrhea, vomiting

6 mo, M

4 mo, M

y, F

Diarrhea

+ melena

Protein-losing enteropathy

14 d,* M

24/12

Diarrhea ( f bloody)

F

3 wk,’ F 1 mo,*

F

Protein-losing enteropathy Bloody diarrhea

Diarrhea, malabsorption Diarrhea, intestinal perforation

9 mo, F 3 Y, F 1 mo,’ ?

10 mo,

Bloody diarrhea

F

4112 mo,

Presentation

Age at diagnosis, sex

DS

D

D

DJJ All intestine especially J DJ,C

GI sites

+ OD I1 + OD I1

+ OD I1 + OD I1

+ OD I1

+ OD I1

MS

MS

+ OD I1

+ OD I1

MS IB

MS MS

MS

MS

MS IB MS IB MS IB

MS

+ OD11 MS + OD I1

MS MS

Staging (8)

Liver

EM CD1 EM CDl

EM CD1

EM EM

EM CDl EM

EM CD1 SlOO PDg

EM

PDg EM

Diagnosis

Alive at

llh

year

Death at 3, 8 months

Death at 10 months

Death at 16 months Death at 4 months

Death at 18 months CD1

Death at 21/~years Alive at 5 years Alive at 7314 years with NED Alive at 2 years

Death at 5112 months

Death at 5 months

Death at 5, 8 months Death at 6 weeks

Follow-up

“Abbreviations:A, appendix; D, duodenum; J, jejunum; R, rectum; C, colon; I, ileum; M, Meckel; S, sigmoid; MS, multisystem; PDg, presumed diagnosis; OD, organ dysfunction; *congenital.

Case (reference)

TABLE 1. Gastrointestinal Involvement in Langerhans’ Cell Histiocytosis“

Fetal Pediatr Pathol Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.

Fetal Pediatr Pathol Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.

INTESTINAL LANGERHANS HlSTlOCYTOSlS

523

involvement have done very poorly. The reported cases (Table 1) all had multisystem disease with organ dysfunction (8). Of eight infants with this form of LCH [group I1 of Raney and D’Angio (8)],only one was alive at 2 years (9). Of four children with multisystem disease without organ dysfunction (group IB), two were alive at 5 and 7’/12 years and the two others died 10 months and 2 years after the diagnosis. Of the 14 cases in Table 1, liver dysfunction was present in 8 and 6 died after a short follow-up. Langerhans’ cell proliferation or infiltration of the sinusoids of the liver has been described by Favara (24) as the most frequent form of liver involvement. This pattern has been described as “Gaucher-like” because of the swollen, pink, sometimes lamellar appearance of the cells, distinctive for histiocytosis X (25). In patients with chronic forms of LCH, findings range from triaditis to fibrosis and cirrhosis (26). Favara proposed that histiocytic infiltration and/or proliferation in portal and intralobular regions with cholangitis led to fibrosis, intrahepatic biliary obstruction, and biliary cirrhosis (24, 27). Cirrhosis may be also a manifestation of an underlying disease (28). Although unusual, cholestasis in L C H has ominous significance (29). Prednisone alone was effective in one child (case S), who did not present with organ dysfunction, but protocols for treatment of multisystem disease include vinblastine. This treatment led to recovery in patient 7, who presented without organ dysfunction (group IB) (8), but was only partially effective in patients 8 and 14, both of whom had organ dysfunction (group 11) (8). It was not effective in patients 2, 3, 9, 12, and 13, all of whom except patient 12 had organ dysfunction, and all of these children eventually died. Etoposide (VP-16) has been especially effective in the treatment of the monocyte/macrophage neoplastic disorders. Its use in resistant or relapsed childhood LCH has been reported (30, 31). Etoposide was used in the two cases reported here and by two other authors (9, 10). In patients 12 and 13 etoposide produced only a partial clinical response. In patients 8 and 14, both of whom relapsed despite vinblastine and prednisone treatment, etoposide led to remission in a 6- and a 4-month follow-up. As these four children all had multisystemic LCH with organ dysfunction, etoposide might be an effective agent and should be considered in this form of the disease, in which prognosis is especially poor.

REFERENCES 1. Broadbent V, Gadner H , Komp DM, Ladisch S. Histiocytosis syndromes in children: Approach to the clinical and laboratory evaluation of children with Langerhans cell histiocytosis. Med Pediatr Oncol 1989; 17:492-5.

2 . Keeling JW, Harries JT. Intestinal malabsorption in infants with histiocytosis X. Arch Dis Child 1973;48:350-4.

Fetal Pediatr Pathol Downloaded from informahealthcare.com by Nyu Medical Center on 11/11/14 For personal use only.

524

L. A. BOCCON-GIBOD E l AL.

3. Tamura T, Umetsu M , Motoya H , Yokoyama S. Congenital Letterer-Siwe disease associated with protein losing enteropathy Eur J Pediatr 1980; 135:77-80. 4. Deprettere A, Aelvoet G, Van Acker KJ, D o c k P. Intractable diarrhea in histiocytosis X. Helv Paediatr Acta 1983;38:291-4. 5. Hyams JS, Haswell JE, Gerber MA, Berman MM. Colonic ulceration in histiocytosis X. J Pediatr Gastroenterol Nutr 1985;4:286-90. 6. Idlibi 0, Hamoudi AB. Primary histiocytosis X of bowel. (Abstract) Pediatr Pathol 1984;2:492. 7. Sutphen JL, Fechner RE. Chronic gastroenteritis in a patient with histiocytosis-X. J Pediatr Gastroenterol Nutr 1986;5:324-8. 8 . Raney RB Jr, D’Angio GJ. Langerhans’ cell histiocytosis (histiocytosis X): Experience at the Children’s Hospital of Philadelphia, 1970-1984. Med Pediatr Oncol 1989; 17:20-8. 9. Egeler RM, Schipper ME, Heymans HS. Gastrointestinal involvement in Langerhans’ cell histiocytosis (histiocytosis X): A clinical report of three cases. Eur J Pediatr 1990;149:325-9. 10. Lee RG, Braziel RM, Stenzel P. Gastrointestinal involvement in Langerhans cell histiocytosis (histiocytosis X): Diagnosis by rectal biopsy. Mod Pathol 1990;3:154-7. 1 1 . Histiocytosis syndromes in children. Writing group of the Histiocyte Society. Lancet 1987;1:208-9. 12. Lahey ME. Prognostic factors in histiocytosis X. Am J Pediatr Hematol Oncol. 1981;3:57-60. 13. Lahey ME, Histiocytosis X: An analysis of prognostic factors. J Pediatr 1975;87:184-9. 14. Nezelof C, Frileux-Herbet F, Cronier-Sachot J. Disseminated histiocytosis X: Analysis of prognostic factors based on a retrospective study of 50 cases. Cancer 1979;44:1824-38. 15. Nesbit ME. Current concepts and treatment of histiocytosis X (Langerhans’ cell histiocytosis). In: VoQte PA, Barret A, Bloom HJ, Lemerle J , Neidhart MK, eds. Cancer in Children: Clinical Management 2nd ed. Vol. 1 . Berlin: Springer-Verlag, 1986;176-84. 16. Oberman HA. Idiopathic histiocytosis. A clinicopathologic study of 40 cases and review of the literature on eosinophilic granuloma of bone, Hand-Schuller-Christian disease, and Letterer-Siwe disease. Pediatrics 1961;28:307-27. 17. Lucaya J. Histiocytosis X. Am J Dis Child 1971;121:289-95. 18. Sims DG. Histiocytosis X. Follow-up of 43 cases. Arch Dis Child 1977;52:433-40. 19. Talbot ML. Histiocytosis X . Am Surg 1974;40:89-96. 20. Ralfkiaer E, Stein H , Plesnes T, Hov-Jensen K, Mason D. In situ immunological characterization of Langerhans’ cells with monoclonal antibodies. Comparison with other dendritic cells in skin and lymph nodes. Virchows Arch [A] 1984;403:401-12. 21. Ornvold K, Ralfkiaer E, Carstensen H. Immunohistochemical study of the abnormal cells in Langerhans cell histiocytosis (histiocytosis X). Virchows Arch [A] 1990;416:403-10. 22. Basset F, Turiaf J. Electron microscopic identification of probable viral particles in pulmonary histiocytosis X granulomas. (In French) C R Acad Sci (Paris) 1965;261:3701. 23. Basset F, Nezelof C, Mallet R, Turiaf J. Repeated identification of viral-like particles in another form of histiocytosis X: Eosinophilic granuloma of bone. (In French) C R Acad Sci (Paris) 1965;261:5719. 24. Favara BE. The pathology of “histiocytosis.” Am J Pediatr Hematol Oncol 1981;3:45-56. 25. Landing BH. Lymphohistiocytosis in childhood. Pathologic comparison with fatal Letterer-Siwe disease (disseminated visceral histiocytosis X). Perspect Pediatr Pathol 1987;9:48-74. 26. Heyn RM, Hamoudi A, Newton WA J . Pretreatment liver biopsy in 20 children with histiocytosis X: A clinicopathologic correlation. Med Pediatr Oncol 1990; 18:110-8. 27. Favara BE, McCarthy RC, Mierau GW: Histiocytosis X. Hum Pathol 1983;14:663-76. 28. Pirovino M, Jeanneret C, Lang R H , Luisier J, Bianchi L, Spichtin H . Liver cirrhosis in histiocytosis X . Liver 1988;8:293-8. 29. Leblanc A, Hadchouel M, Jehan P, Odisvre M , Alagille D. Obstructive jaundice in children with histiocytosis X. Gastroenterology 1981 $0: 134-9. 30. Ceci A, de Terlizzi M , Colella R,et al. Etoposide in recurrent childhood Langerhans’ cell histiocytosis: An Italian cooperative study. Cancer 1988;62:2528-31. 31. Broadbent V, Pritchard J, Yeomans E. Etoposide (VP 16) in the treatment of multisystem Langerhans cell histiocytosis (histiocytosis X). Med Pediatr Oncol 1989;17:97-100. Received July 15, 1991 Revision accepted January 6, 1992

Digestive tract involvement with exudative enteropathy in Langerhans cell histiocytosis.

Protein-losing enteropathy was observed in two children with Langerhans' cell histiocytosis (LCH). One patient was an infant with congenital cutaneous...
1MB Sizes 0 Downloads 0 Views