Published online October 9, 2006
PEDIATRICS Vol. 118 No. 5 November 2006, pp. e1593-e1599 (doi:10.1542/peds.2006-0708)

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hait, E. Articles by Fox, V. L. Search for Related Content PubMed PubMed Citation Articles by Hait, E. Articles by Fox, V. L. Related Collections Gastrointestinal Tract Social Bookmarking                         What's this?

EXPERIENCE & REASON

Gastrointestinal Tract Involvement in Langerhans Cell Histiocytosis: Case Report and Literature Review

Elizabeth Hait, MD, MPH^a, Marilyn Liang, MD^b, Barbara Degar, MD^c, Jonathan Glickman, MD, PhD^d and Victor L. Fox, MD^a

^a Divisions of Gastroenterology and Nutrition
^b Dermatology
^c Hematology and Oncology
^d Pathology, Children's Hospital Boston, Dana Farber Cancer Institute, and Harvard Medical School, Boston, Massachusetts

ABSTRACT

Digestive tract involvement in Langerhans cell histiocytosis is exceedingly rare. We report a case of Langerhans cell histiocytosis in an otherwise thriving neonate presenting with hematochezia, anemia, and rash. We also review the few cases of Langerhans cell histiocytosis with gastrointestinal involvement reported in the English-language medical literature. Although gastrointestinal involvement can range in severity from mild to life-threatening, its presence may be indicative of multisystemic disease, and aggressive treatment should be considered.

---

Key Words: Langerhans cells histiocytosis • colitis

Abbreviations: LCH, Langerhans cell histiocytosis

Gastrointestinal involvement in Langerhans cell histiocytosis (LCH) is rare and usually associated with severe systemic illness. We report a case of LCH in an otherwise thriving neonate presenting with hematochezia, anemia, and rash. We also review the few cases of LCH with gastrointestinal involvement reported in the English-language medical literature between 1966 and 2004.

LCH is a rare disease characterized by proliferation and accumulation of dendritic cells with features of epidermal Langerhans cells. It is a challenging disease with a wide clinical spectrum, ranging from a spontaneously regressing skin rash to a potentially fatal multiorgan system disorder.^1,2 It occurs in all age groups, but its peak incidence is in young children aged between 1 and 4 years. The annual pediatric incidence of LCH is estimated to be between 2 and 5 cases per million per year.³ The morbidity and prognosis of LCH depend on the extent of disease and the presence of visceral organ dysfunction. LCH most commonly involves bone and skin but may involve nearly any site or organ.^1,2

The etiology of LCH is obscure. Molecular studies have demonstrated clonal cell proliferation. However, LCH has not been considered a malignant disorder because of the frequent occurrence of spontaneous remissions and the absence of aneuploidy or karyotypic abnormalities in lesional cells.^3,4 LCH is currently thought to represent a cytokine-mediated reactive cellular proliferation. To date, no studies have identified an immunologic or viral etiology.

CASE REPORT

A 1-month-old triplet girl born at 36 weeks' gestation presented with a persistent rash and intermittent mild rectal bleeding. The rash initially erupted on the second day of life and included pinpoint white pustules on an erythematous base involving the face, chest, back, and extremities but concentrated in the inguinal folds. Test results of scrapings from the lesions were negative for bacterial, viral, and fungal cultures as well as polymerase chain reaction analysis for herpes simplex virus. The patient's parents reported intermittent passage of stool with streaks of blood and mucous over the preceding few days, and passage of a maroon-colored guaiac-positive stool was witnessed by her pediatrician. The infant was otherwise acting well, had no fever, vomiting, or irritability, and was gaining appropriate weight. There were no ill contacts or animal exposures. She was a trizygotic triplet resulting from an in vitro fertilization conception and was delivered by elective cesarean section at 36 weeks' gestation after an uncomplicated pregnancy. Her triplet sisters were healthy. The child's father and several paternal aunts and uncles had psoriasis. A blood count measurement performed in the pediatrician's office revealed a hematocrit level of 22%, and the infant was admitted to the hospital for additional evaluation.

On physical examination, the infant appeared vigorous with moderate tachycardia but otherwise normal vital signs. Diffuse red-brown petechial macules and papules, variably ulcerated, and overlying pustules were found on the skin, mostly concentrated in intertriginous areas (Fig 1). One pustule was located on the anal margin, and 2 ulcerated lesions were present in the right inguinal fold. In addition, her scalp had hyperkeratotic scale. Results of the general physical examination were otherwise unremarkable. There were no oral lesions, lymphadenopathy, or dysmorphic features. Her abdomen was soft, nontender, and nondistended, with normal bowel sounds and without hepatosplenomegaly or masses. The diaper contained seedy green-colored stool with guaiac-positive streaks of mucous and blood.

View larger version (53K): [in this window] [in a new window]   FIGURE 1 Red-brown petechial macules and papules on the chest and abdomen.

 
Her white blood cell count was 12329/µL (31% neutrophils, 47% lymphocytes, 2% atypical lymphocytes, 13% monocytes, 6% eosinophils). The hematocrit level was 26.8% and the platelet count was 482000/µL. The reticulocyte count was 10.2%. Serum electrolytes, alanine aminotransferase, aspartate transferase, serum urea nitrogen, creatinine, and albumin levels and coagulation studies were all within reference ranges. A radionuclide scan for Meckel diverticulum was negative.

Allergic colitis caused by cow milk protein was suspected, and the grossly bloody stools improved after 2 days of hospital admission with a diet restricted to an elemental, amino acid–based formula. A skin biopsy taken from one of the ulcerated inguinal lesions revealed a histiocytic infiltrate that stained positive for CD1a, CD45, and S100, consistent with LCH. These results prompted a flexible sigmoidoscopy, which revealed a diffuse pattern of fine mucosal nodules with subtle central ulceration (Fig 2). Rectosigmoid biopsy specimens showed mild-to-moderate active colitis with neutrophilic cryptitis and crypt abscesses (Fig 3). There was also a nodular diffuse infiltrate of intermediate-sized cells with irregular nuclei, vesicular chromatin, and indistinct nucleoli, which stained positive for CD1a and S100, confirming involvement with LCH (Fig 4). Results from a skeletal survey, chest radiograph, and bone scan were negative. A bone marrow biopsy revealed no features of histiocytosis.

View larger version (133K): [in this window] [in a new window]   FIGURE 2 Sigmoidoscopic appearance of Langerhans cell histiocytosis showing mucosal nodules with subtle central ulceration.

 

View larger version (121K): [in this window] [in a new window]   FIGURE 3 A, Photomicrograph of the rectal mucosal biopsy showing mild-to-moderate active colitis with dense hypercellularity of the lamina propria and crypt abscesses (hematoxylin/eosin, original magnification: x100). B, Photomicrograph of the rectal mucosal biopsy at high power showing nodular diffuse infiltrate of intermediate-sized cells with irregular nuclei, vesicular chromatin, and indistinct nucleoli (hematoxylin/eosin, original magnification: x400).

 

View larger version (116K): [in this window] [in a new window]   FIGURE 4 Immunohistochemistry staining of rectal mucosal biopsy revealing CD1a+ cellular infiltrate.

 
Hematochezia recurred within 3 days, accompanied by a drop in hematocrit to 19% despite continued use of an elemental formula. After a red blood cell transfusion, systemic chemotherapy was initiated with prednisone and vinblastine. The skin rash and rectal bleeding rapidly resolved.

Weekly vinblastine plus continuous oral prednisone was continued for 6 weeks and then tapered to vinblastine every 3 weeks with pulse steroids. During the vinblastine taper, the infant developed irritability, feeding intolerance, recurrence of rash, and guaiac-positive stools. Colonoscopy to the terminal ileum was grossly and histologically normal. An upper gastrointestinal endoscopy revealed multiple small ulcers in the stomach, and biopsies showed infiltration with LCH. Recurrent disease was controlled with resumption of high-dose steroids, weekly vinblastine, and daily mercaptopurine. The disease was subsequently well controlled for 6 months with the addition of weekly low-dose methotrexate to a regimen of daily mercaptopurine, alternate-week vinblastine, and pulse steroids. Multiple minor infections including central line infections, upper respiratory tract infections, and a varicella exposure prompted an interruption of her treatment regimen. She relapsed again at 13 months of age, this time with hematologic, liver, and spleen involvement. She decompensated rapidly and was intubated for several months with respiratory failure. She was to be treated with stem cell transplantation but, unfortunately, died from presumed sepsis 1 day before stem cell infusion.

LITERATURE REVIEW

A Medline (PubMed, MDConsult) literature search was performed using the key words "Langerhans cell histiocytosis," "colitis," and "gastrointestinal tract" for articles published between 1966 and 2004. Twenty-four cases of gastrointestinal involvement in LCH were identified. One case was excluded because of insufficient details about the nature of the gastrointestinal involvement and the methodology of diagnostic testing.⁵ A second case was excluded because it described an adult patient (a 76-year-old woman with ileal Crohn disease who subsequently developed LCH with extensive infiltration of the small bowel).⁶ The clinical presentation, gastrointestinal symptoms and findings, and outcomes after treatment were summarized from the remaining 22 patients (Table 1).

View this table: [in this window] [in a new window]   TABLE 1 Summary of Reported Cases of Langerhans Cell Histiocytosis With Gastrointestinal Tract Involvement From 1966 to 2004

 
Clinical Features
Fifty-five percent (12 patients) were male, similar to the percentage found in cases of LCH without gastrointestinal involvement.² The mean age at diagnosis was 6 months (range: birth to 36 months).

The gastrointestinal symptoms were preceded by or associated with the characteristic LCH rash in 86% (19) of the patients. Eighteen percent (4 patients) had hepatic dysfunction, 23% (5 patients) had bony involvement, and 14% (3 patients) had pulmonary involvement at presentation.

The gastrointestinal symptoms were manifest as hematochezia (59% [13 patients]), nonbloody diarrhea (18% [4 patients]), perianal fistulas (4% [1 patient]), and constipation (9% [2 patients]). Hematochezia was only described in ill infants with multiorgan disease. Seventy-seven percent (17) of the patients had hypoproteinemia.

Diagnostic Testing
There was no uniformity with respect to diagnostic testing. Sixty-eight percent (15) of the patients had skin biopsies that were positive for LCH. Pathologic evidence of LCH was found in biopsies of liver in 14% (3 patients), gingiva in 9% (2 patients), and lymph nodes in 4% (1 patient). Not all case reports specified whether immunohistochemistry was performed.

Gastrointestinal involvement was diagnosed by endoscopic biopsy in 91% (20) of the patients. Of the patients who underwent esophagogastroduodenoscopy, 86% (12 of 14) had histologic evidence of LCH in the duodenum. Of these 14 patients, 8 had lower gastrointestinal symptoms (hematochezia, diarrhea). Only 7 patients had documented gastric biopsies, but 100% (7 of 7) of the gastric biopsies were positive for LCH. Rectal, sigmoid, or colonic biopsies were obtained from 64% (14) of the patients. All but 1 of these patients had histologic evidence of LCH. One patient, case 14, had positive duodenal biopsies, but colonic biopsies were negative for LCH. This patient had no lower gastrointestinal symptoms.

Treatment and Outcome
Treatment efficacy and outcomes could not be compared, because each patient was treated with a different chemotherapy regimen and the duration of follow-up varied. One patient ultimately underwent autologous bone marrow transplantation but died after 13 months of treatment (case 13). Whether the patient died as a result of transplant-related complications or recurrence of LCH was not clarified. Fifty-nine percent (13) of the patients died within 1 years of diagnosis, whereas 18% (4) of the patients achieved complete remission that was sustained for at least several years. Eighteen percent (4) of the patients had <2 years of follow-up reported, so it is difficult to know if these children had sustained remission. On the basis of this series, it is unclear to what extent age of onset, severity of symptoms, or timing of treatment contributed to outcome.

DISCUSSION

In this article we describe a thriving infant with a skin rash and mild hematochezia who was diagnosed with systemic LCH. We reviewed the medical literature and were only able to identify a total of 22 pediatric cases of well-defined LCH with gastrointestinal tract involvement over a nearly 40-year period. Digestive tract involvement in LCH is exceedingly rare. The French Langerhans Cell Histiocytosis Study Group conducted a retrospective study of all patients diagnosed with LCH in 6 French pediatric centers between 1983 and 1994.¹⁶ Only 9 (2.6%) of the 348 patients exhibited gastrointestinal symptoms, including 4 patients with hematochezia. Among 63 patients diagnosed with LCH at the Children's Hospital of Philadelphia between 1970 and 1984, only 1 child (1.6%) exhibited bowel involvement.⁵

Patients with LCH with digestive tract involvement tend to present at a very young age. Although LCH in general may present at any age, >50% of cases are diagnosed between the ages of 1 and 15 years.¹ This is in contrast to the patients with LCH with gastrointestinal involvement; the majority of reported patients (86%) presented under 1 year of age, and 95% of the patients presented before 18 months of age.

Gastrointestinal involvement in LCH may manifest as hematochezia, constipation, or diarrhea and can range in severity from mild to life-threatening. The gastrointestinal symptoms were preceded by or associated with the characteristic LCH rash in 86% of the patients. Most duodenal biopsies (86%) demonstrated histologic evidence of LCH, even in patients who were not experiencing upper gastrointestinal tract symptoms. Although only 6 patients had documented gastric biopsies, all 6 demonstrated histologic changes consistent with LCH. Therefore, we suggest that gastric and duodenal biopsies be considered in the initial LCH-staging studies in patients with no other evidence of systemic disease.

Gastrointestinal involvement in LCH likely should be treated as a multisystemic disease irrespective of the patient's clinical status. At her initial presentation, our patient was clinically well and had no other evidence of disseminated disease. All of the other reported children with LCH and hematochezia were in critical condition at the time of presentation. Therefore, this case highlights that any gastrointestinal involvement in patients with LCH may be indicative of aggressive multisystemic disease.

It is apparent that the prognosis of LCH with gastrointestinal involvement is relatively poor. Fifty-nine percent (13) of the patients died within 1 years of diagnosis, whereas only 14% (3) of the patients achieved complete remission. This is in stark contrast to LCH mortality rates in general, which have a 7% mortality rate for single-system disease and a 40% mortality rate for multiorgan disease.^16,17 It remains unclear if age of onset, severity of symptoms, or timing of treatment contributes to outcome.

This literature review supports the conclusions of the French Langerhans Cell Histiocytosis Study Group that any gastrointestinal involvement with LCH warrants aggressive evaluation and treatment. Endoscopic assessment of both the upper (gastroduodenal) and lower (distal colon) gastrointestinal tract with multiple mucosal biopsies is essential for accurate staging of this disease. Although gastrointestinal involvement is rare in LCH, if it is detected aggressive systemic therapy is clearly indicated, and optimal treatment regimens that might result in a durable long-term remission or cure deserve additional study for this highly fatal condition.

FOOTNOTES

Accepted May 26, 2006.

Address correspondence to Victor L. Fox, MD, Children's Hospital, Boston, Division of Gastroenterology and Nutrition, 300 Longwood Ave, Boston, MA 02115. E-mail: victor.fox{at}childrens.harvard.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

REFERENCES

1. Egeler RM, D'Angio GJ. Langerhans cell histiocytosis. J Pediatr. 1995;127 :1 –11[CrossRef][Web of Science][Medline]
2. Peter CL, Egeler RM, Arceci RJ, Pritchard J. The Nikolas Symposia and histiocytosis. Nat Rev Cancer. 2005;5 :488 –494[CrossRef][Web of Science][Medline]
3. Bhatia S, Nesbit ME Jr, Egeler RM, Buckley JD, Mertens A, Robinson LL. Epidemiologic study of Langerhans cell histiocytosis in children. J Pediatr. 1997;130 :774 –783[Web of Science][Medline]
4. Willman CL, McClain KL. An update on clonality, cytokines, and viral etiology in Langerhans cell histiocytosis. Hematol Oncol Clin North Am. 1998;12 :407 –416[CrossRef][Web of Science][Medline]
5. 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 –28[Web of Science][Medline]
6. Lee-Elliott C, Alexander J, Gould A, Talbot R, Snook JA. Langerhan's cell histiocytosis complicating small bowel Crohn's disease. Gut. 1996;38 :296 –298[Abstract/Free Full Text]
7. Sabri M, Davie J, Orlando S, Di Lorenzo C, Ranganathan S. Gastrointestinal presentation of Langerhans cell histiocytosis in a child with perianal skin tags: a case report. J Pediatr Gastroenterol Nutr. 2004;39 :564 –566[Web of Science][Medline]
8. Choi SW, Bangaru BS, Wu CD, Finlay JL. Gastrointestinal involvement in disseminated Langerhans cell histiocytosis (LCH) with durable complete response to 2-chlorodeoxyadenosine and high-dose cytarabine. J Pediatr Hematol Oncol. 2003;25 :503 –506[CrossRef][Web of Science][Medline]
9. Usmani GN, Westra SJ, Younes S. Case 13–2003: a 14-month-old boy with hepatomegaly, perianal lesions, and a bony lump on the forehead. N Engl J Med. 2003;348 :1692 –1701[Free Full Text]
10. Geissmann F, Thomas C, Emile JF, et al. Digestive tract involvement in Langerhans cell histiocytosis: the French Langerhans Cell Histiocytosis Study Group. J Pediatr. 1996;129 :836 –845[CrossRef][Web of Science][Medline]
11. Boccon-Gibod LA, Krichen HA, Carlier-Mercier LM, Salaun JF, Fontaine JL, Leverger GR. Digestive tract involvement with exudative enteropathy in Langerhans cell histiocytosis. Pediatr Pathol. 1992;12 :515 –524[Web of Science][Medline]
12. Patel BJ, Chippendal AJ, Gupta SC. Case report: small bowel histiocytosis X. Clin Radiol. 1991;44 :62 –63[CrossRef][Web of Science][Medline]
13. Egeler RM, Schipper MEI, Heymans HAS. Gastrointestinal involvement in Langerhans' cell histiocytosis (histiocytosis X): a clinical report of three cases. Eur J Pediatr. 1990;149 :325 –329[CrossRef][Web of Science][Medline]
14. Lee RG, Braziel RM, Stenzel P. Gastrointestinal involvement in Langerhans cell histiocytosis (histiocytosis X): diagnosis by rectal biopsy. Mod Pathol. 1990;3 :154 –157[Web of Science][Medline]
15. Hyams JS, Haswell JE, Gerber MA, Berman MM. Colonic ulceration in histiocytosis X. J Pediatr Gastroenterol Nutr. 1985;4 :286 –290[Web of Science][Medline]
16. The French Langerhans' Cell Histiocytosis Study Group. A multicentre retrospective survey of Langerhans' cell histiocytosis: 348 cases observed between 1983 and 1993. Arch Dis Child. 1996;75 :17 –24[Abstract/Free Full Text]
17. Braier J, Chantada G, Rosso D, et al. Langerhans cell histiocytosis: retrospective evaluation of 123 patients at a single institution. Pediatr Hematol Oncol. 1999;16 :377 –385[CrossRef][Web of Science][Medline]

---

PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

CiteULike    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				K Windebank and V Nanduri Langerhans cell histiocytosis Arch. Dis. Child., November 1, 2009; 94(11): 904 - 908. [Abstract] [Full Text] [PDF]

				E. T. Park, S.-i. Suh, H. Y. Seol, Y. H. Lee, H. S. Seo, and B. K. Shin Sonography of Biopsy-Proven Langerhans Cell Histiocytosis in Lymph Nodes of the Neck J. Ultrasound Med., April 1, 2009; 28(4): 519 - 525. [Abstract] [Full Text] [PDF]

				A. H. Grifo Langerhans Cell Histiocytosis in Children Journal of Pediatric Oncology Nursing, January 1, 2009; 26(1): 41 - 47. [Abstract] [PDF]

				S. Schmidt, G. Eich, A. Geoffray, S. Hanquinet, P. Waibel, R. Wolf, I. Letovanec, L. Alamo-Maestre, and F. Gudinchet Extraosseous Langerhans Cell Histiocytosis in Children RadioGraphics, May 1, 2008; 28(3): 707 - 726. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hait, E. Articles by Fox, V. L. Search for Related Content PubMed PubMed Citation Articles by Hait, E. Articles by Fox, V. L. Related Collections Gastrointestinal Tract Social Bookmarking                         What's this?