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Unusual manifestation of Erdheim-Chester disease

Unusual manifestation of Erdheim-Chester disease Background: Erdheim-Chester disease (ECD) is a rare multisystem non-Langerhans cell histiocytosis that is characterized histologically by xanthogranulomatous infiltrates and radiologically by symmetrical sclerosis of long bones. The xanthomatous process is characterized by prominent foamy histiocytes staining positive for CD68, occasionally for PS100 and negative for S100 and CD1a. Gastroenterological involvement is exceedingly rare. Case Presentation: This case report describes the case of a 69-year-old man who presented otherwise well to the gastroenterology department with unspecific abdominal symptoms, nausea, vomiting and weight loss. ECD involving the gastrointestinal tract was confirmed clinically, radiologically and histologically. Conclusion: Gastroenterological manifestation of ECD is rare but should be considered in the differential diagnosis in patients presenting with evidence of multi-organ disease and typical radiological features of Erdheim-Chester disease elsewhere. Background Physical examination revealed that he was febrile (38.8C Erdheim-Chester Disease (ECD) is a rare multisystem °) and appeared cachexic but with no peripheral stigmata histiocytosis characterized by the xanthomatous or of chronic liver disease. His abdominal examination xanthogranulomatous infiltration of tissues with histio- revealed hepatomegaly but no other organomegaly, per cytes, surrounded by fibrosis. The disease can affect rectal examination was unremarkable. His cardiopulmon- multiple organs systems, but gastrointestinal involve- ary examinations were unremarkable apart from bilateral ment, is exceedingly rare. We describe here the case of pitting edema up to his ankles. Peripheral blood analysis a 69-year old man with ECD who presented to the gas- revealed an anaemia of chronic disease with hemoglobin troenterology department with unspecific abdominal of 108 g/L (norm - male 130 - 175 g/L), serum iron symptoms, nausea, vomiting and weight loss. 2 μmol/L (norm 10 - 30 μmol/L), transferrin 1.4 g/L (2 - 3.5 g/L), transferrin saturation 6% (norm 16 - 50%) and Case presentation ferritin 354 μg/L (norm 20 - 500 μg/L). Consistent with a A previously fit and well 69-year-old man was admitted systemic illness the c-reactive protein was increased to 208 to the gastroenterology department with a short one mg/L (norm < 5 mg/L) but multiple urine and blood cul- month history of lethargy, decreased appetite, persistent tures were negative for bacterial infection. Normal serum vomiting, significant weight loss of six kilograms over 1 electrolytes and creatinine of 83 μmol/L (norm 50 - month and a dry cough. He denied abdominal pain, hae- 120 μmol/L). Liver function test was normal apart from a marked hypoalbuminaemia of 28 g/L (norm 35 - 50 g/L). matemesis, dysphagia and a change in bowel habit and described no cardiac, respiratory, neurological symptoms Protein electrophoresis, Vitamin B12, folate, and thyroid or bone pain. His past medical history includes appen- functions were normal. Chest X-ray showed interstitial dectomy and total hip joint replacement. At the time of infiltration involving both lung bases. Lung function test admission, he was not on any regular medication. was consistent with a restrictive lung disease (FVC 3.33 L (73%), FEV1 2.49 L (72%), FEV1/FVC 75% and decreased in diffusion capacity (DLCO 17.81 ml/min/mmHg). Ultra- * Correspondence: [email protected] sound of the abdomen confirmed a 19 cm hepatomegaly, Gastroenterology Unit, Southern District Health Board, Dunedin, New Zealand with normal liver texture and no evidence of a mass lesion. Full list of author information is available at the end of the article © 2011 Pan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Pan et al. BMC Gastroenterology 2011, 11:77 Page 2 of 5 http://www.biomedcentral.com/1471-230X/11/77 Due to ongoing vomiting and weight loss, a gastroscopy was performed with no significant pathology. Computer tomography (CT) of the chest showed peri-aortic tissue infiltration creating the appearance of “coated aorta” (Figure 1) as well as thickening of the interlobular septa in both lungs (Figure 2). The infiltration processes also involved the pulmonary vessels, pericardium, lung par- enchyma and the oesophagus. CT of the abdomen showed hypo-attenuated homogenous tissue infiltration with weak contrast enhancement in the renal fossa. Symmetric and bilateral infiltration of the peri-renal, anterior and poster- ior para-renal spaces gave the appearance of “hairy kidney” (Figure 3). Inferior vena cava, aorta and mesentery were also involved. These findings were seen as consistent with a possible diagnosis of Erdheim-Chester Disease (ECD) [1-3]. A CT guided biopsy of the retroperitoneal space and a Figure 2 Imaging of the lung with interstitial thickening of the bone marrow aspiration were performed which were interlobular septa. inconclusive, consistent with reactive inflammatory pro- cesses. To confirm the diagnosis of ECD a laparotomy was performed to obtain tissue for diagnostic purposes. the findings allowed a diagnosis of severe multi-organ Operative findings revealed an infiltrating process invol- ECD [1]. ving the liver, omentum and small bowel mesentery. Subsequent magnetic resonance imaging (MRI) Biopsies were taken from the liver (Figure 4), the omen- (Figure 7) of the whole body showed an increased mar- tum (Figure 5) and mesenteric lymph nodes (Figure 6). row signal in the distal femur and proximal tibia consis- Histological examination of the tissue showed xantho- tent with ECD [4]. Due to further rapid decline, the matous infiltration involving the liver, omentum and patient was started on total parenteral nutrition, IV surrounding the lymph nodes. The xanthomatous pro- hydrocortisone at 1 g once daily for 2 days, then 500 cess was characterized by prominent foamy histiocytes, mg once daily for 8 days before changing to oral predni- admixed with occasional giant cells and chronic inflam- sone at 100 mg (1 mg/kg/day) for a week. The predni- matory cells. Immunohistochemical stains revealed that sone dose was then tapered down to 30 mg once daily. these cells were positive for CD68 and negative for S100 Although the patient’s appetite improved after the initia- and CD1a. There was no evidence of malignancy and tion of steroid treatment, hypoalbuminaemia persisted and thrombocytopenia developed. One month after initiation of treatment the patient died of respiratory failure. Figure 3 Axial view shows bilateral and symmetric peri-renal infiltration. Irregular bands present along posterior parts of peri- renal infiltration gives the appearance of “hairy kidney”. The Figure 1 Axial view of the chest shows presence of peri-aortic posterior margin of the pancreas is indistinct due to the infiltrate in and oesophageal infiltration. the retroperitoneum. Pan et al. BMC Gastroenterology 2011, 11:77 Page 3 of 5 http://www.biomedcentral.com/1471-230X/11/77 Figure 6 Biopsy of mesenteric lymph nodes showed evidence of perinodal histiocytic infiltrate. Figure 4 Histology of the liver showed a predominantly histiocytic (foamy histiocytes) infiltrate. foamy histiocytes nested among polymorphic granuloma and fibrosis or xanthogranulomatosis with CD68-positive Conclusion and CD1a-negative immunohistochemical staining. (2) Erdheim-Chester Disease (ECD) is a rare multisystem Typical skeletal findings with a) radiographs showing bilat- non-Langerhans cell histiocytosis first described by eral and symmetric osteosclerosis of the diaphyseal and Jakob Erdheim and William Chester in 1930 [5] and metaphyseal regions in the bones and/or b) symmetric since then approximately 400 cases have been reported and abnormally increased labeling of the distal ends of the [6]. It is characterized by the xanthomatous or xantho- long bones of the lower limbs, and sometimes the upper granulomatous infiltration of tissues with foamy histio- limbs, on 99Tc bone scintigraphies. cytes, surrounded by fibrosis. The aetiology of the There are typical radiological and pathological features disease remains unknown. The disease can affect multi- which can lead to the diagnosis, but the clinical spectrum ple organs systems, including musculoskeletal, central shows a broad variation, ranging from asymptomatic tis- nervous, cardiac, pulmonary and renal systems. Gastro- sue infiltration to fulminant multisystem organ failure. intestinal involvement, despite being seen more often in Bone pain is the most common presenting symptom other histiocytoses [7], is exceedingly rare and to our of ECD mainly affecting the legs, especially knees and knowledge there are 2 case reports regarding involve- ment of the liver and biliary system [4,8]. Two criteria, of which one should be fulfilled, were pro- posed by Veyssier-Belot [1] in 1996 as a requirement for the diagnosis of ECD. (1) Typical histological findings with Figure 7 MRI scan showed an increased marrow signal in the Figure 5 Biopsy of omentum showed histiocytic infiltrate. distal femur and proximal tibia. Pan et al. BMC Gastroenterology 2011, 11:77 Page 4 of 5 http://www.biomedcentral.com/1471-230X/11/77 ankles and has been reported in 47-86% of patients presenting of ECD, he remained asymptomatic from his with ECD [1,9-12]. About half of all patients have extra- skeletal lesions. Other features of ECD demonstrated in skeletal manifestations including retroperitoneal fibrosis, our patient include retroperitoneal, cardiovascular and orbital infiltration, interstitial lung disease [2,13], bilat- respiratory involvement. eral adrenal involvement [14], testis infiltration [15], Various therapies for ECD have been proposed, breast, central nervous [9,16,17] and/or cardiovascular including corticosteroids [1], multiple chemotherapeutic regimes including vinblastine, vincristine, cyclospho- system [18]. Other general symptoms such as fever, sphamide, doxorubicin [1], cladribine [1,21-23], radio- weight loss and weakness can also occur. therapy [19,24], cyclosporine and alpha interferon [1]. Retroperitoneal involvement is secondary to infiltra- tion of the fat and surrounding structures by histiocytes The latter treatment has gained some attention recently and associated fibrosis. This process can lead to peri- with the initial report of a durable response in three renal and/or ureteral obstruction causing renal impair- patients [25]. This was followed by a series report of ment. This is reported to occur in 29-59% of patients treatment with interferon-alpha in eight patients with with ECD [1,19]. Erdheim-Chester infiltration is distin- variable response. While treatment with interferon-alpha guished from retroperitoneal fibrosis principally by its is promising, mechanisms of action are still largely many foamy histiocytes, lack of plasma cells, and lack of unkown [26]. Prognosis of the disease depends largely vasculitis [20]. on the extent and distribution of the extra-skeletal, in The cardiovascular manifestations of ECD have been particular cardio-vascular [26] and central nervous sys- known to exist since the disease was first described; this tem [6] involvement. Based on these results it was sug- occurs in about 40% of the patients with peri-aortic “fibro- gested by the authors that interferon-alpha is considered sis” as the most frequent cardiovascular involvement. as a first-line treatment for patients with ECD but a Other manifestations include heart failure, valvular dys- 40% mortality in the first 40 months after diagnosis has function, reno-vascular hypertension and pericarditis [18]. still to be accepted [26]. It was previously thought that only about 20% of patients In summary, we describe the case of a 69-year-old man have lung involvement however, a recent study reported who presented to the gastroenterological department clinical and/or radiological pulmonary involvement in up with unspecific symptoms of fever, fatigue, decreased to 59% of patients [2]. Usually patients present with dys- appetite, persistent vomiting and weight loss. He had pnea or a dry cough [2]. Most patients have mediastinal clinical, radiological and histological features consistent with gastrointestinal involvement of ECD. He also infiltration, diffuse interstitial infiltrates and pleural and/or demonstrated the involvement of skeletal, retroperito- interlobar septal thickening best seen on high-resolution CT [3]. Characteristic lung histopathology includes the neal, cardiovascular, and respiratory system. He fulfilled accumulation of histiocytes with variable amounts of fibro- the two criteria proposed by Veyssier-Belot in 1996 for sis and a variable lymphoplasmacytic infiltrate in a lym- the diagnosis of Erdheim-Chester disease. Although a phangitic distribution [13]. bone scan was not performed, the MRI STIR showed an The involvement of liver, pancreas, mesentery and increased marrow signal in the distal femur and proximal gastrointestinal tract is extremely rare [8,4]. The diagno- tibia. Even though bone pain is the most commonly pre- sis of ECD in our patient was challenging as he pre- senting symptom in ECD, apart from general unspecific sented with unspecific symptoms such as a decrease in symptoms, our patient did not show any evidence of appetite, persistent vomiting, weight loss and fever. He bone pain. Despite the multiple extra-skeletal manifesta- had features of malnutrition with cachexia, peripheral tions seen radiologically, gastroenterological manifesta- oedema secondary to hypoalbuminaemia. Evidence of tion of ECD is rare but should be considered in the both hepatic and mesenteric involvement of ECD was differential diagnosis in patients presenting with evidence present, with operative findings of liver, omentum and of multi-organ disease and typical radiological features of small bowel mesentery infiltration. Liver biopsy showed Erdheim-Chester disease elsewhere. xanthomatous infiltration with prominent foamy histio- cytes positive for CD68 and negative for S100 and Acknowledgements CD1a. Biopsies also confirmed the involvement of Written consent was obtained from the patient for publication of study. mesenteric lymph nodes and the omentum. It was inter- Special thanks to Dr Michael Lau, Pathologist, Southern Community Laboratories, Dunedin for his provision of histology slides. esting to see that a normal liver function test does not preclude the involvement of the liver by histiocytic infil- Author details tration in ECD. Our patient also showed features consis- Gastroenterology Unit, Southern District Health Board, Dunedin, New Zealand. Department of Radiology, Southern District Health Board, Dunedin, tent with skeletal involvement with MRI demonstrating New Zealand. Department of Medicine, University of Otago, Dunedin, New increased marrow signal in the distal femur and proxi- Zealand. mal tibia. Although bone pain is the most common Pan et al. BMC Gastroenterology 2011, 11:77 Page 5 of 5 http://www.biomedcentral.com/1471-230X/11/77 Authors’ contributions 15. Sheu S, Wenzel R, Kersting C, Merten R, Otterbach F, Schmid KW: Erdheim- Chester disease: case report with multisystemic manifestations including AP was involved in the treatment of the patient, consulted the literature and testes, thyroid, and lymph nodes and a review of literature. J Clin Pathol drafted the manuscript. MS and RL participated in the design of the study 2004, 57:1225-1228. and analysis of the results. MS, corresponding author was supervising the 16. Wright R, Hermann R, Parisi J: Neurological manifestations of Erdheim- study, conducted the literature review and assisted in the writing of the Chester disease. J Neurol Neurosurg Psychiatry 1999, 66:6672-75. manuscript. All authors read and approved the manuscript. 17. Caparrios-Lefebvre D, Pruvo JP, Remy M, Wallaert B, Petit H: Neuroradiological aspects of Chester-Erdheim disease. Am J Neuroradiol Authors’ information 1995, 16:735-740. Dr Pan is an advanced trainee in gastroenterology and general medicine at 18. Haroche J, Amoura Z, Dion E, Wechsler B, Costedoat-Chalumeau N, the Dunedin Hospital, Southern District Health Board, New Zealand. Cacoub P, Isnard R, Généreau T, Wechsler J, Weber N, Graef C, Cluzel P, Competing interests Grenier P, Piette JC: Cardiovascular involvement, an overlooked feature of The authors declare that they have no competing interests. Erdheim-Chester disease report of 6 new cases and a literature review. Medicine (Baltimore) 2004, 6:371-92. Received: 21 March 2011 Accepted: 22 June 2011 19. Mascalchi M, Nencini P, Nistri M, Sarti C, Santoni R: Failure of radiation Published: 22 June 2011 therapy for brain involvement in Erdheim Chester disease. J Neurooncol 2002, 59:169-172. 20. Eble J, Rosenberg A, Young R: Retroperitoneal xanthogranuloma in a References patient with Erdheim-Chester disease. Am J Surg Pathol 1994, 18:843-8. 1. Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, Wechsler J, Brun B, 21. Serratrice J, Granel B, De Roux C, Pellissier JF, Swiader L, Bartoli JM, Remy M, Wallaert B, Petit H, Grimaldi A, Wechsler B, Godeau P: Erdheim- Disdier P, Weiller PJ: “Coated aorta": a new sign of Erdheim-Chester Chester disease. Clinical and radiologic characteristics of 59 cases. disease. J Rheumatol 2000, 27:1550-1553. Medicine 1996, 75:157-169. 22. Sheidow TG, Nicolle DA, Heathcote JG: Erdheim-Chester disease: two 2. Arnaud L, Pierre I, Beigelman-Aubry C, Capron F, Brun AL, Rigolet A, cases of orbital involvement. Eye 2000, 14(Pt 4):606-612. Girerd X, Weber N, Piette JC, Grenier PA, Amoura Z, Haroche J: Pulmonary 23. Myra C, Sloper L, Tighe PJ, McIntosh RS, Stevens SE, Gregson RH, Sokal M, involvement in Erdheim-Chester disease: a single-center study of thirty- Haynes AP, Powell RJ: Treatment of Erdheim-Chester disease with four patients and a review of the literature. Arthritis Rheum 2010, cladribine: a rational approach. Br J Ophthalmol 2004, 88:844-847. 62:3504-12. 24. Matsui K, Nagata Y, Hiraoka : Radiotherapy for Erdheim-Chester disease. 3. Brun AL, Touitou-Gottenberg D, Haroche J, Toledano D, Cluzel P, Int J Clin Oncol 2007, 3:238-4. Beigelman-Aubry C, Piette JC, Amoura Z, Grenier PA: Erdheim-Chester 25. Braiteh F, Boxrud C, Esmaeli B, Kurzrock R: Successful treatment of disease: CT findings of thoracic involvement. Eur Radiol 2010, 20:2579-87. Erdheim-Chester disease, a non-Langerhans-cell histiocytosis, with 4. Gundling F, Nerlich A, Heitland W, Schepp W: Biliary manifestation of interferon-alpha. Blood 2005, 106:2992-4. Erdheim-Chester disease mimicking Klatskin’s carcinoma. Am J 26. Haroche J, Amoura Z, Trad SG, Wechsler B, Cluzel P, Grenier PA, Piette JC: Gastroenterol 2007, 102:452-4. Variability in the efficacy of interferon-alpha in Erdheim-Chester disease 5. Chester W: Über lipoid Granulomatose. Virchows Arch Pathol Anat 1930, by patient and site of involvement: results in eight patients. Arthritis 279:561-602. Rheum 2006, 54:3330-6. 6. Arnaud L, Hervier B, Néel A, Hamidou MA, Kahn JE, Wechsler B, Pérez- Pastor G, Blomberg B, Fuzibet JG, Dubourguet F, Marinho A, Magnette C, Pre-publication history Noel V, Pavic M, Casper J, Beucher AB, Costedoat-Chalumeau N, Aaron L, The pre-publication history for this paper can be accessed here: Salvatierra J, Graux C, Cacoub P, Delcey V, Dechant C, Bindi P, Herbaut C, http://www.biomedcentral.com/1471-230X/11/77/prepub Graziani G, Amoura Z, Haroche J: CNS involvement and treatment with interferon-α are independent prognostic factors in Erdheim-Chester doi:10.1186/1471-230X-11-77 disease: a multicenter survival analysis of 53 patients. Blood 2011, Cite this article as: Pan et al.: Unusual manifestation of Erdheim-Chester 117:2778-82. disease. BMC Gastroenterology 2011 11:77. 7. Singhi AD, Montgomery EA: Gastrointestinal tract langerhans cell histiocytosis: A clinicopathologic study of 12 patients. Am J Surg Pathol 2011, 35:305-10. 8. Gupta A, Aman K, Al-Babtain M, Al-Wazzan H, Morouf R: Multisystem Erdheim-Chester disease; a unique presentation with liver and axial skeletal involvement. Br J Haematol 2007, 138:280. 9. Lachenal F, Cotton F, Desmurs-Clavel H, Haroche J, Taillia H, Magy N, Hamidou M, Salvatierra J, Piette JC, Vital-Durand D, Rousset H: Neurological manifestations and neuroradiological presentation of Erdheim-Chester disease: report of 6 cases and systemic review of the literature. J Neurol 2006, 253:1267-1277. 10. Franzius C, Sciuk J, Bremer C, Kempkes M, Schober O: Determination of extent and activity with radionuclide imaging in Erdheim-Chester disease. Clin Nucl Med 1999, 24:252-255. 11. Sandrock D, Merino MJ, Scheffknetch B, Neumann RD: Scintigraphic Submit your next manuscript to BioMed Central findings and follow up in Erdheim-Chester disease. Eur J Nuclear Med and take full advantage of: 1990, 16:55-60. 12. Dion E, Graef C, Miquel A, Haroche J, Wechsler B, Amoura Z, Zeitoun D, Grenier PA, Piette JC, Laredo JD: Bone involvement in Erdheim-Chester • Convenient online submission disease: imaging findings including periostitis and partial epiphyseal • Thorough peer review involvement. Radiology 2006, 238:632-9. 13. Allen T, Chevez-Barrios P, Shetlar D, Cagle PT: Pulmonary and ophthalmic • No space constraints or color figure charges involvement with Erdheim-Chester disease a case report and review of • Immediate publication on acceptance the literature. Arch Pathol Lab Med 2004, 128:1428-31. • Inclusion in PubMed, CAS, Scopus and Google Scholar 14. Haroche J, Amoura Z, Touraine P, Seilhean D, Graef C, Birmelé B, Wechsler B, Cluzel P, Grenier PA, Piette JC: Bilateral adrenal infiltration in • Research which is freely available for redistribution Erdheim-Chester disease. Report of seven cases and literature review. J Clin Endocrinol Metab 2007, 6:2007-12. 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Unusual manifestation of Erdheim-Chester disease

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Copyright © 2011 by Pan et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Gastroenterology; Internal Medicine; Hepatology
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Abstract

Background: Erdheim-Chester disease (ECD) is a rare multisystem non-Langerhans cell histiocytosis that is characterized histologically by xanthogranulomatous infiltrates and radiologically by symmetrical sclerosis of long bones. The xanthomatous process is characterized by prominent foamy histiocytes staining positive for CD68, occasionally for PS100 and negative for S100 and CD1a. Gastroenterological involvement is exceedingly rare. Case Presentation: This case report describes the case of a 69-year-old man who presented otherwise well to the gastroenterology department with unspecific abdominal symptoms, nausea, vomiting and weight loss. ECD involving the gastrointestinal tract was confirmed clinically, radiologically and histologically. Conclusion: Gastroenterological manifestation of ECD is rare but should be considered in the differential diagnosis in patients presenting with evidence of multi-organ disease and typical radiological features of Erdheim-Chester disease elsewhere. Background Physical examination revealed that he was febrile (38.8C Erdheim-Chester Disease (ECD) is a rare multisystem °) and appeared cachexic but with no peripheral stigmata histiocytosis characterized by the xanthomatous or of chronic liver disease. His abdominal examination xanthogranulomatous infiltration of tissues with histio- revealed hepatomegaly but no other organomegaly, per cytes, surrounded by fibrosis. The disease can affect rectal examination was unremarkable. His cardiopulmon- multiple organs systems, but gastrointestinal involve- ary examinations were unremarkable apart from bilateral ment, is exceedingly rare. We describe here the case of pitting edema up to his ankles. Peripheral blood analysis a 69-year old man with ECD who presented to the gas- revealed an anaemia of chronic disease with hemoglobin troenterology department with unspecific abdominal of 108 g/L (norm - male 130 - 175 g/L), serum iron symptoms, nausea, vomiting and weight loss. 2 μmol/L (norm 10 - 30 μmol/L), transferrin 1.4 g/L (2 - 3.5 g/L), transferrin saturation 6% (norm 16 - 50%) and Case presentation ferritin 354 μg/L (norm 20 - 500 μg/L). Consistent with a A previously fit and well 69-year-old man was admitted systemic illness the c-reactive protein was increased to 208 to the gastroenterology department with a short one mg/L (norm < 5 mg/L) but multiple urine and blood cul- month history of lethargy, decreased appetite, persistent tures were negative for bacterial infection. Normal serum vomiting, significant weight loss of six kilograms over 1 electrolytes and creatinine of 83 μmol/L (norm 50 - month and a dry cough. He denied abdominal pain, hae- 120 μmol/L). Liver function test was normal apart from a marked hypoalbuminaemia of 28 g/L (norm 35 - 50 g/L). matemesis, dysphagia and a change in bowel habit and described no cardiac, respiratory, neurological symptoms Protein electrophoresis, Vitamin B12, folate, and thyroid or bone pain. His past medical history includes appen- functions were normal. Chest X-ray showed interstitial dectomy and total hip joint replacement. At the time of infiltration involving both lung bases. Lung function test admission, he was not on any regular medication. was consistent with a restrictive lung disease (FVC 3.33 L (73%), FEV1 2.49 L (72%), FEV1/FVC 75% and decreased in diffusion capacity (DLCO 17.81 ml/min/mmHg). Ultra- * Correspondence: [email protected] sound of the abdomen confirmed a 19 cm hepatomegaly, Gastroenterology Unit, Southern District Health Board, Dunedin, New Zealand with normal liver texture and no evidence of a mass lesion. Full list of author information is available at the end of the article © 2011 Pan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Pan et al. BMC Gastroenterology 2011, 11:77 Page 2 of 5 http://www.biomedcentral.com/1471-230X/11/77 Due to ongoing vomiting and weight loss, a gastroscopy was performed with no significant pathology. Computer tomography (CT) of the chest showed peri-aortic tissue infiltration creating the appearance of “coated aorta” (Figure 1) as well as thickening of the interlobular septa in both lungs (Figure 2). The infiltration processes also involved the pulmonary vessels, pericardium, lung par- enchyma and the oesophagus. CT of the abdomen showed hypo-attenuated homogenous tissue infiltration with weak contrast enhancement in the renal fossa. Symmetric and bilateral infiltration of the peri-renal, anterior and poster- ior para-renal spaces gave the appearance of “hairy kidney” (Figure 3). Inferior vena cava, aorta and mesentery were also involved. These findings were seen as consistent with a possible diagnosis of Erdheim-Chester Disease (ECD) [1-3]. A CT guided biopsy of the retroperitoneal space and a Figure 2 Imaging of the lung with interstitial thickening of the bone marrow aspiration were performed which were interlobular septa. inconclusive, consistent with reactive inflammatory pro- cesses. To confirm the diagnosis of ECD a laparotomy was performed to obtain tissue for diagnostic purposes. the findings allowed a diagnosis of severe multi-organ Operative findings revealed an infiltrating process invol- ECD [1]. ving the liver, omentum and small bowel mesentery. Subsequent magnetic resonance imaging (MRI) Biopsies were taken from the liver (Figure 4), the omen- (Figure 7) of the whole body showed an increased mar- tum (Figure 5) and mesenteric lymph nodes (Figure 6). row signal in the distal femur and proximal tibia consis- Histological examination of the tissue showed xantho- tent with ECD [4]. Due to further rapid decline, the matous infiltration involving the liver, omentum and patient was started on total parenteral nutrition, IV surrounding the lymph nodes. The xanthomatous pro- hydrocortisone at 1 g once daily for 2 days, then 500 cess was characterized by prominent foamy histiocytes, mg once daily for 8 days before changing to oral predni- admixed with occasional giant cells and chronic inflam- sone at 100 mg (1 mg/kg/day) for a week. The predni- matory cells. Immunohistochemical stains revealed that sone dose was then tapered down to 30 mg once daily. these cells were positive for CD68 and negative for S100 Although the patient’s appetite improved after the initia- and CD1a. There was no evidence of malignancy and tion of steroid treatment, hypoalbuminaemia persisted and thrombocytopenia developed. One month after initiation of treatment the patient died of respiratory failure. Figure 3 Axial view shows bilateral and symmetric peri-renal infiltration. Irregular bands present along posterior parts of peri- renal infiltration gives the appearance of “hairy kidney”. The Figure 1 Axial view of the chest shows presence of peri-aortic posterior margin of the pancreas is indistinct due to the infiltrate in and oesophageal infiltration. the retroperitoneum. Pan et al. BMC Gastroenterology 2011, 11:77 Page 3 of 5 http://www.biomedcentral.com/1471-230X/11/77 Figure 6 Biopsy of mesenteric lymph nodes showed evidence of perinodal histiocytic infiltrate. Figure 4 Histology of the liver showed a predominantly histiocytic (foamy histiocytes) infiltrate. foamy histiocytes nested among polymorphic granuloma and fibrosis or xanthogranulomatosis with CD68-positive Conclusion and CD1a-negative immunohistochemical staining. (2) Erdheim-Chester Disease (ECD) is a rare multisystem Typical skeletal findings with a) radiographs showing bilat- non-Langerhans cell histiocytosis first described by eral and symmetric osteosclerosis of the diaphyseal and Jakob Erdheim and William Chester in 1930 [5] and metaphyseal regions in the bones and/or b) symmetric since then approximately 400 cases have been reported and abnormally increased labeling of the distal ends of the [6]. It is characterized by the xanthomatous or xantho- long bones of the lower limbs, and sometimes the upper granulomatous infiltration of tissues with foamy histio- limbs, on 99Tc bone scintigraphies. cytes, surrounded by fibrosis. The aetiology of the There are typical radiological and pathological features disease remains unknown. The disease can affect multi- which can lead to the diagnosis, but the clinical spectrum ple organs systems, including musculoskeletal, central shows a broad variation, ranging from asymptomatic tis- nervous, cardiac, pulmonary and renal systems. Gastro- sue infiltration to fulminant multisystem organ failure. intestinal involvement, despite being seen more often in Bone pain is the most common presenting symptom other histiocytoses [7], is exceedingly rare and to our of ECD mainly affecting the legs, especially knees and knowledge there are 2 case reports regarding involve- ment of the liver and biliary system [4,8]. Two criteria, of which one should be fulfilled, were pro- posed by Veyssier-Belot [1] in 1996 as a requirement for the diagnosis of ECD. (1) Typical histological findings with Figure 7 MRI scan showed an increased marrow signal in the Figure 5 Biopsy of omentum showed histiocytic infiltrate. distal femur and proximal tibia. Pan et al. BMC Gastroenterology 2011, 11:77 Page 4 of 5 http://www.biomedcentral.com/1471-230X/11/77 ankles and has been reported in 47-86% of patients presenting of ECD, he remained asymptomatic from his with ECD [1,9-12]. About half of all patients have extra- skeletal lesions. Other features of ECD demonstrated in skeletal manifestations including retroperitoneal fibrosis, our patient include retroperitoneal, cardiovascular and orbital infiltration, interstitial lung disease [2,13], bilat- respiratory involvement. eral adrenal involvement [14], testis infiltration [15], Various therapies for ECD have been proposed, breast, central nervous [9,16,17] and/or cardiovascular including corticosteroids [1], multiple chemotherapeutic regimes including vinblastine, vincristine, cyclospho- system [18]. Other general symptoms such as fever, sphamide, doxorubicin [1], cladribine [1,21-23], radio- weight loss and weakness can also occur. therapy [19,24], cyclosporine and alpha interferon [1]. Retroperitoneal involvement is secondary to infiltra- tion of the fat and surrounding structures by histiocytes The latter treatment has gained some attention recently and associated fibrosis. This process can lead to peri- with the initial report of a durable response in three renal and/or ureteral obstruction causing renal impair- patients [25]. This was followed by a series report of ment. This is reported to occur in 29-59% of patients treatment with interferon-alpha in eight patients with with ECD [1,19]. Erdheim-Chester infiltration is distin- variable response. While treatment with interferon-alpha guished from retroperitoneal fibrosis principally by its is promising, mechanisms of action are still largely many foamy histiocytes, lack of plasma cells, and lack of unkown [26]. Prognosis of the disease depends largely vasculitis [20]. on the extent and distribution of the extra-skeletal, in The cardiovascular manifestations of ECD have been particular cardio-vascular [26] and central nervous sys- known to exist since the disease was first described; this tem [6] involvement. Based on these results it was sug- occurs in about 40% of the patients with peri-aortic “fibro- gested by the authors that interferon-alpha is considered sis” as the most frequent cardiovascular involvement. as a first-line treatment for patients with ECD but a Other manifestations include heart failure, valvular dys- 40% mortality in the first 40 months after diagnosis has function, reno-vascular hypertension and pericarditis [18]. still to be accepted [26]. It was previously thought that only about 20% of patients In summary, we describe the case of a 69-year-old man have lung involvement however, a recent study reported who presented to the gastroenterological department clinical and/or radiological pulmonary involvement in up with unspecific symptoms of fever, fatigue, decreased to 59% of patients [2]. Usually patients present with dys- appetite, persistent vomiting and weight loss. He had pnea or a dry cough [2]. Most patients have mediastinal clinical, radiological and histological features consistent with gastrointestinal involvement of ECD. He also infiltration, diffuse interstitial infiltrates and pleural and/or demonstrated the involvement of skeletal, retroperito- interlobar septal thickening best seen on high-resolution CT [3]. Characteristic lung histopathology includes the neal, cardiovascular, and respiratory system. He fulfilled accumulation of histiocytes with variable amounts of fibro- the two criteria proposed by Veyssier-Belot in 1996 for sis and a variable lymphoplasmacytic infiltrate in a lym- the diagnosis of Erdheim-Chester disease. Although a phangitic distribution [13]. bone scan was not performed, the MRI STIR showed an The involvement of liver, pancreas, mesentery and increased marrow signal in the distal femur and proximal gastrointestinal tract is extremely rare [8,4]. The diagno- tibia. Even though bone pain is the most commonly pre- sis of ECD in our patient was challenging as he pre- senting symptom in ECD, apart from general unspecific sented with unspecific symptoms such as a decrease in symptoms, our patient did not show any evidence of appetite, persistent vomiting, weight loss and fever. He bone pain. Despite the multiple extra-skeletal manifesta- had features of malnutrition with cachexia, peripheral tions seen radiologically, gastroenterological manifesta- oedema secondary to hypoalbuminaemia. Evidence of tion of ECD is rare but should be considered in the both hepatic and mesenteric involvement of ECD was differential diagnosis in patients presenting with evidence present, with operative findings of liver, omentum and of multi-organ disease and typical radiological features of small bowel mesentery infiltration. Liver biopsy showed Erdheim-Chester disease elsewhere. xanthomatous infiltration with prominent foamy histio- cytes positive for CD68 and negative for S100 and Acknowledgements CD1a. Biopsies also confirmed the involvement of Written consent was obtained from the patient for publication of study. mesenteric lymph nodes and the omentum. It was inter- Special thanks to Dr Michael Lau, Pathologist, Southern Community Laboratories, Dunedin for his provision of histology slides. esting to see that a normal liver function test does not preclude the involvement of the liver by histiocytic infil- Author details tration in ECD. Our patient also showed features consis- Gastroenterology Unit, Southern District Health Board, Dunedin, New Zealand. Department of Radiology, Southern District Health Board, Dunedin, tent with skeletal involvement with MRI demonstrating New Zealand. Department of Medicine, University of Otago, Dunedin, New increased marrow signal in the distal femur and proxi- Zealand. mal tibia. Although bone pain is the most common Pan et al. BMC Gastroenterology 2011, 11:77 Page 5 of 5 http://www.biomedcentral.com/1471-230X/11/77 Authors’ contributions 15. Sheu S, Wenzel R, Kersting C, Merten R, Otterbach F, Schmid KW: Erdheim- Chester disease: case report with multisystemic manifestations including AP was involved in the treatment of the patient, consulted the literature and testes, thyroid, and lymph nodes and a review of literature. J Clin Pathol drafted the manuscript. MS and RL participated in the design of the study 2004, 57:1225-1228. and analysis of the results. MS, corresponding author was supervising the 16. Wright R, Hermann R, Parisi J: Neurological manifestations of Erdheim- study, conducted the literature review and assisted in the writing of the Chester disease. J Neurol Neurosurg Psychiatry 1999, 66:6672-75. manuscript. All authors read and approved the manuscript. 17. Caparrios-Lefebvre D, Pruvo JP, Remy M, Wallaert B, Petit H: Neuroradiological aspects of Chester-Erdheim disease. Am J Neuroradiol Authors’ information 1995, 16:735-740. Dr Pan is an advanced trainee in gastroenterology and general medicine at 18. Haroche J, Amoura Z, Dion E, Wechsler B, Costedoat-Chalumeau N, the Dunedin Hospital, Southern District Health Board, New Zealand. Cacoub P, Isnard R, Généreau T, Wechsler J, Weber N, Graef C, Cluzel P, Competing interests Grenier P, Piette JC: Cardiovascular involvement, an overlooked feature of The authors declare that they have no competing interests. Erdheim-Chester disease report of 6 new cases and a literature review. Medicine (Baltimore) 2004, 6:371-92. Received: 21 March 2011 Accepted: 22 June 2011 19. Mascalchi M, Nencini P, Nistri M, Sarti C, Santoni R: Failure of radiation Published: 22 June 2011 therapy for brain involvement in Erdheim Chester disease. 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