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Journal of Digestive Diseases 2015; 16; 159–163
doi: 10.1111/1751-2980.12189
Case report
Eosinophilic pseudotumor of the liver: Report of six cases and review of literature Dan Ying ZHANG,* Shu Qiang WENG,* Ling DONG*# & Xi Zhong SHEN*# *Department of Gastroenterology, Zhongshan Hospital, Fudan University, #Shanghai Institute of Liver Diseases, Key Laboratory of Medical Molecule Virology, Ministry of Education and Health, Shanghai, China
INTRODUCTION Langerhans cell histiocytosis (LCH) was first described as an eosinophilic granuloma of bone, characterized by Langerhans cell infiltration in a single or multiple viscera of human beings.1–3 In 1953 it was grouped alongside Hand–Schüller–Christian disease, Letterer– Siwe disease and eosinophilic pseudotumor, in the knowledge that abnormal Langerhans cells are the basic pathological characteristics of the three entities.1,4 Eosinophilic pseudotumor, or eosinophilic granuloma, is the most common and benign form of LCH. The incidence of eosinophilic pseudotumors is approximately 3–4 per million.5 This disease has been found in the endoskeletal system as well as skin and other organs such as the lungs, liver, bile duct and even the bladder.6 The involvement of LCH in the liver is extremely rare. In this article, we reported the clinicopathological and immunohistochemical features and the outcomes of six cases with eosinophilic pseudotumor together with a review of literature. CASE REPORT Six patients including three men and three women aged from 32 to 64 years (mean 45.5 years) with eosinophilic pseudotumor of the liver were treated in the Department of Gastroenterology, Zhongshan Hospital, Fudan University (Shanghai, China) during a Correspondence to: Ling DONG, Department of Gastroenterology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200032, China. Email: [email protected] Conflict of interest: None. © 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
10-year period from 2001 to 2010. The diagnosis was confirmed by histopathology and immunohistochemistry in all cases. Of the six patients, 4 (66.6%) were asymptomatic, one (16.7%) reported upper abdominal discomfort and the other one complained of asthenia and anorexia for 2 months with fever (38°C) and chills. None of the patients had any other clinical manifestations such as ascites, jaundice, weight loss, weakness, chest distress or extrahepatic involvement of the bone, lungs or spleen. Laboratory and imaging examination Routine blood examination after the patients’ admission showed a significant decrease in lymphocyte and monocyte counts in all patients. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and γ-glutamyltranspeptidase (γ-GT) levels were elevated in one of the six patients, while bilirubin, lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) levels were within the normal ranges. α-fetoprotein (AFP), carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were all negative in the six patients. Autoantibodies including antinuclear antibody (ANA), antibodies to extractable nuclear antigens (ENAs) and anti-neutrophil cytoplasmic antibodies (ANCAs) were all negative. Antibodies to parasites were detected in one patient, in whom serum immunoglobulin G (IgG) to cysticercosis was positive but IgG to liver fluke was negative. All the six patients presented similar abnormalities on abdominal ultrasonography and computed tomography (CT), including solitary or multiple nodular lesions of low densities. Abdominal magnetic resonance imaging (MRI) showed low signal in T1-weighted and high signal in T2-weighted images
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Journal of Digestive Diseases 2015; 16; 159–163
Figure 1. Magnetic resonance imaging (MRI) findings of eosinophilic pseudotumor. (a) Multiple low-density lesions on T1-weight images. (b) Peripheral enhancement on the portal vein phase in dynamic MRI. (c) Slightly high signal on T2-weight images.
Figure 2. Histological findings of eosinophilic pseudotumor showing infiltration of large, dysplastic and histiocytic cells with relatively small nuclei eosinophils and lymphocytes (arrows, HE stain, ×400).
in three patients (Fig. 1). Multiple abnormalities, possibly of infectious origin, were observed in the liver, including neoplastic lesions with hemangioma at the right lobe of liver and splenomegaly. Enhanced MRI images showed abnormal peripheral enhancement, indicating probable infectious disease. Pathological and immunohistochemical evaluation Hepatic lobectomy was performed in four patients, and ultrasound-guided biopsy was performed in the other two patients. The sizes of hepatic eosinophilic pseudotumor ranged from 2 to 5 cm in diameter. All patients were diagnosed based on histopathological and immunohistochemical evaluation. Extensive eosinophilic infiltration was observed in all the specimens of the six patients (Fig. 2). Histopathology revealed a number of folding nuclei of histiocytes and eosinophils. Multinucleated cells were widely dispersed among histiocytes. Immunohistochemical stain was positive for vimentin, CD68, CD-1a and S100, which confirmed the diagnosis of LCH (Fig. 3). Treatment and follow-up Four of the six patients received hepatic lobectomy, and were followed up for a mean duration of 3 years. At the last follow-up visit, all four patients were in a good condition without any evidence of recurrence. In
Figure 3. Immunohistochemical stain for CD68, CD-1a and S100 shows strong positivity, confirming the diagnosis of Langerhans cell histiocytosis. (a) CD68 (×100), (b) CD68 (×400), (c) CD-1a (×100), (d) CD-1a (×400), (e) S100 (×100), (f) S100 (×400).
the other two patients, one left our hospital without receiving any treatments, and two years later he received hepatic lobectomy in another hospital because of an increasingly enlarged hepatic mass. And the other patient who complained of upper abdominal discomfort had been treated with antibiotics before hospitalization but her symptoms were not relieved. She was diagnosed with eosinophilic pseudotumor after liver biopsy in our hospital. But as the diagnosis of eosinophilic granuloma from parasitic infection could not be completely ruled out, praziquantel (25 mg/kg thrice daily) was administered. A 6-month follow-up showed that her lesions were enlarged, leading to the diagnosis of LCH rather than parasitic infection. DISCUSSION Many diseases could result in liver eosinophilic granuloma, including LCH, parasitic infections and other infections. The current terminology of LCH was proposed in the mid-1980s by the Histiocyte Society in Los Angeles.7 However, the etiology of histiocytosis mostly remains unknown at present. Suspected causative agents include infectious agents and
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2015; 16; 159–163 immunodysfunction that give rise to abnormal proliferation of histiocytes. Related lymphocyte infiltration, cytokines and genetic factors have also been reported to be associated with the pathogenesis of eosinophilic pseudotumors in visceral organs.8–13 One pediatric study14 reported a rate of liver involvement of 15.6% in 217 cases. The published literatures contain only two small series of adult liver LCH10,15 and isolated cases. The clinical presentations of LCH are variable. The symptoms and signs depend upon the site of the granuloma in some patients, but most of the patients are asymptomatic. In our study, 4 (66.6%) patients were asymptomatic while the other two reported upper abdominal discomfort or asthenia with anorexia and fever. Ultrasound, CT and MRI are the currently available modalities to gather important diagnostic information for the diagnosis of eosinophilic pseudotumors. CT usually depicts extensively low density in the liver and MRI shows low density on T1-weighted images together with slightly high intensity on T2-weighted images. It is difficult to diagnose eosinophilic pseudotumors in the liver by imaging studies alone, pathological and immunohistochemical evidence remains the gold standard for the diagnosis of eosinophilic pseudotumors. Histopathological findings may present as destructive granulomatous lesions with lymphocyte and histiocyte infiltration, and immunohistochemistry can further help to establish the diagnosis. CD68, CD-1a and S100 were all positive in all our patients. CD68 was positive in some histiocytes, and CD-1a and S100 immunostain highlighted an increased number of Langerhans cells. S100 proteins are a family of low-molecular-weight proteins that are normally present in cells derived from the neural crest, chondrocytes, adipocytes, myoepithelial cells, macrophages, Langerhans cells, and so on. CD1 antigens are expressed on cortical thymocytes, but not on mature T cells. The presence of CD1 antigens is often used to identify some kinds of thymomas and malignancies arising from T-cell precursors. CD1a is the most specific marker for Langerhans cells. Only with positive CD-1a and S100 stain in epithelioid cells can the diagnosis of LCH be made. Some studies16–18 have shown that the administration of anti-CD1 monoclonal antibodies could be delivered to the site of disease activity in LCH patients. A differential diagnoses of eosinophilic pseudotumors in the liver include but are not limited to
Hepatic eosinophilic pseudotumor
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epithelioid hemangioendothelioma (EHE),19 inflammatory pseudotumor,20,21 angiomyolipoma,22 segmental atrophy of the liver,23 hepatic hydatidosis and cysticerciasis. EHE is a unique vascular tumor with multiple nodules or large masses of low densities on CT. It is sometimes easier to diagnose vascular tumors using contrast-enhanced CT, especially for some tumor nodules showing marginal enhancement during the arterial phase.24 Immunostain for vascular markers VIII, CD34 and CD31 is also positive in EHE. Inflammatory pseudotumor of the liver is another rare non-malignant entity. Sakai et al.25 reported that this disease could be diagnosed by a typical extravasation of contrast material in the fibrous tissue during the delayed phase of CT scan. SMA and vimentin are usually positive, whereas desmin, CD34 and S100 proteins as well as anaplastic lymphoma kinase are negative.21 Hepatic angiomyolipoma is a benign mesenchymal neoplasm made up of a mixture of thick-walled vessels, fat and myoid cells.26 Immunohistochemical stain is usually positive for melanocytic (HMB-45) and SMA markers.27 Pseudotumors in the liver can result from segmental atrophy of the liver and are associated with focal vascular injury in the liver, presenting as thickened vessels, biliary cysts and elastotic changes in the subcapsular space. Hydatid disease caused by cestode is parasitic infection by Echinococcus spp. Diagnosis of hydatid disease is best on the CT scan where cyst wall calcification and infection can be made out.28 Hepatic visceral larva migrans should be borne in mind when a patient presents with fever and hepatomegaly with persistent eosinophilia. The choice of treatment for eosinophilic neoplasia of the liver is to alleviate the symptoms, if any, in order to prevent complications. The treatment strategies depend on the patients’ age and the size of the pseudotumors. Narrow-band ultraviolet B has been attempted as a treatment option for cutaneous LCH that is proven successful.13 Treatments for pulmonary LCH include cigarette-smoking cessation,29,30 the use of steroids31 and lung transplantation32. LCH can be treated effectively with methotrexate monotherapy, etoposide monotherapy or etoposide in combination with vincristine and prednisolone when organs are involved. However, in many large-sample-sized trials, the data on the treatment for liver LCH are lacking. Sclerosing cholangitis complicating with LCH can lead to end-stage liver diseases, for which liver transplantation may be a favourable option.33,34 It has been reported that survival in children following liver transplantation for LCH-related liver disease is excellent.35
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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Four of our six patients were treated with hepatic lobectomy, and none chose liver transplantation. As early treatment can improve the prognosis of liver LCH, an early diagnosis is of primary importance. As eosinophilic pseudotumor of the liver is rare, it is often misdiagnosed or never diagnosed. A thorough imaging examination and immunohistological panel can help the clinicians to differentiate it from other lesions. Treatment with hepatic lobectomy provides favourable outcomes in our case series. ACKNOWLEDGMENTS We thank Bao Jian PAN for his assistance on the analysis of the pathological and immunohistochemical studies. This study was supported by the National Natural Science Foundation of China (No. 81000968), the Doctoral Fund of Ministry of Education of China (No. 20120071110058) and the National Clinical Key Special Subject of China. REFERENCES 1 Lichtenstein L. Histiocytosis X; integration of eosinophilic granuloma of bone, Letterer–Siwe disease, and Schüller–Christian disease as related manifestations of a single nosologic entity. AMA Arch Pathol 1953; 56: 84–102. 2 The Writing Group of the Histiocyte Society. Histiocytosis syndromes in children. Lancet 1987; 1: 208–9. 3 Favara BE, Feller AC, Pauli M et al.; The WHO Committee on Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Contemporary classification of histiocytic disorders. Med Pediatr Oncol 1997; 29: 157–66. 4 Herzog KM, Tubbs RR. Langerhans cell histiocytosis. Adv Anat Pathol 1998; 5: 347–58. 5 Velez-Yanguas MC, Warrier RP. Langerhans’ cell histiocytosis. Orthop Clin North Am 1996; 27: 615–23. 6 Siegal G, Luntz M, Duchmann H et al. Pathology forum. Quiz case 1. Langerhans cell histocytosis (LCH). Arch Otolaryngol Head Neck Surg 2001; 127: 78. 7 Alessi DM, Maceri D. Histiocytosis X of the head and neck in a pediatric population. Arch Otolaryngol Head Neck Surg 1992; 118: 945–8. 8 Loh JK, Su YF, Hwang SL, Chai CY, Howng SL, Lieu AS. Eosinophilic granuloma of the occipital bone in an adult: a case report. Kaohsiung J Med Sci 2011; 27: 76–9. 9 Sampathkumar S, Younger C, Cramer H, Chalasani N, Skierczynski PA. Langerhans’ cell histiocytosis involving the pituitary, thyroid, lung, and liver. Endocr Pract 2002; 8: 217–21. 10 Kaplan KJ, Goodman ZD, Ishak KG. Liver involvement in Langerhans’ cell histiocytosis: a study of nine cases. Mod Pathol 1999; 12: 370–8. 11 Guthery SL, Heubi JE. Liver involvement in childhood histiocytic syndromes. Curr Opin Gastroenterol 2001; 17: 474–8.
Journal of Digestive Diseases 2015; 16; 159–163 12 Aricò M, Girschikofsky M, Généreau T et al. Langerhans cell histiocytosis in adults. Report from the International Registry of the Histiocyte Society. Eur J Cancer 2003; 39: 2341–8. 13 Aihara M, Hasegawa T, Okuyama Y, Hiruma M, Ikeda S. Langerhans cell histiocytosis treated with narrow-band ultraviolet B. J Dermatol 2011; 38: 151–4. 14 Yag˘ci B, Varan A, Cag˘lar M et al. Langerhans cell histiocytosis: retrospective analysis of 217 cases in a single center. Pediatr Hematol Oncol 2008; 25: 399–408. 15 Favara BE. Histopathology of the liver in histiocytosis syndromes. Pediatr Pathol Lab Med 1996; 16: 413–33. 16 Stockschlaeder M, Sucker C. Adult Langerhans cell histiocytosis. Eur J Haematol 2006; 76: 363–8. 17 Kenn W, Eck M, Allolio B et al. Erdheim–Chester disease: evidence for a disease entity different from Langerhans cell histiocytosis? Three cases with detailed radiological and immunohistochemical analysis. Hum Pathol 2000; 31: 734–9. 18 Kelly KM, Beverley PC, Chu AC et al. Successful in vivo immunolocalization of Langerhans cell histiocytosis with use of a monoclonal antibody, NA1/34. J Pediatr 1994; 125: 717–22. 19 Mehrabi A, Kashfi A, Fonouni H et al. Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy. Cancer 2006; 107: 2108–21. 20 Singhi AD, Maklouf HR, Mehrotra AK et al. Segmental atrophy of the liver: a distinctive pseudotumor of the liver with variable histologic appearances. Am J Surg Pathol 2011; 35: 364–71. 21 Sari A, Tunakan M, Ünsal B et al. Inflammatory pseudotumor of the liver diagnosed by needle biopsy: report of three cases (one with neuroendocrine tumor of the rectum and lung). Turk J Gastroenterol 2010; 21: 308–12. 22 Shi H, Cao D, Wei L, Sun L, Guo A. Inflammatory angiomyolipomas of the liver: a clinicopathologic and immunohistochemical analysis of 5 cases. Ann Diagn Pathol 2010; 14: 240–6. 23 Lory J, Schweizer W, Blumgart LH, Zimmermann A. The pathology of the atrophy/hypertrophy complex (AHC) of the liver. A light microscopic and immunohistochemical study. Histol Histopathol 1994; 9: 541–54. 24 Fulcher AS, Sterling RK. Hepatic neoplasms: computed tomography and magnetic resonance features. J Clin Gastroenterol 2002; 34: 463–71. 25 Sakai M, Ikeda H, Suzuki N et al. Inflammatory pseudotumor of the liver: case report and review of the literature. J Pediatr Surg 2001; 36: 663–6. 26 Parfitt JR, Bella AJ, Izawa JI, Wehrli BM. Malignant neoplasm of perivascular epithelioid cells of the liver. Arch Pathol Lab Med 2006; 130: 1219–22. 27 Petrolla AA, Xin W. Hepatic angiomyolipoma. Arch Pathol Lab Med 2008; 132: 1679–82. 28 Pedrosa I, Saiz A, Arrazola J, Ferreirós J, Pedrosa CS. Hydatid disease: radiologic and pathologic features and complications. Radiographics 2000; 20: 795–817. 29 Mogulkoc N, Veral A, Bishop PW, Bayindir U, Pickering CA, Egan JJ. Pulmonary Langerhans’ cell histiocytosis: radiologic resolution following smoking cessation. Chest 1999; 115: 1452–5. 30 Morimoto T, Matsumura T, Kitaichi M. Rapid remission of pulmonary eosinophilic granuloma in a young male patient after cessation of smoking. J Jpn Respir Soc 1999; 37: 140–5 (in Japanese).
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2015; 16; 159–163 31 Schönfeld N, Frank W, Wenig S et al. Clinical and radiologic features, lung function and therapeutic results in pulmonary histiocytosis X. Respiration 1993; 60: 38–44. 32 Dauriat G, Mal H, Thabut G et al. Lung transplantation for pulmonary Langerhans’ cell histiocytosis: a multicenter analysis. Transplantation 2006; 81: 746–50. 33 Zandi P, Panis Y, Debray D, Bernard O, Houssin D. Pediatric liver transplantation for Langerhans’ cell histiocytosis. Hepatology 1995; 21: 129–33.
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34 Griffiths W, Davies S, Gibbs P, Thillainayagam A, Alexander G. Liver transplantation in an adult with sclerosing cholangitis due to Langerhans cell histiocytosis. J Hepatol 2006; 44: 829–31. 35 Newell KA, Alonso EM, Kelly SM, Rubin CM, Thistlethwaite JR, Jr, Whitington PF. Association between liver transplantation for Langerhans cell histiocytosis, rejection, and development of posttransplant lymphoproliferative disease in children. J Pediatr 1997; 131: 98–104.
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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Journal of Digestive Diseases 2015; 16; 159–163
doi: 10.1111/1751-2980.12189
Case report
Eosinophilic pseudotumor of the liver: Report of six cases and review of literature Dan Ying ZHANG,* Shu Qiang WENG,* Ling DONG*# & Xi Zhong SHEN*# *Department of Gastroenterology, Zhongshan Hospital, Fudan University, #Shanghai Institute of Liver Diseases, Key Laboratory of Medical Molecule Virology, Ministry of Education and Health, Shanghai, China
INTRODUCTION Langerhans cell histiocytosis (LCH) was first described as an eosinophilic granuloma of bone, characterized by Langerhans cell infiltration in a single or multiple viscera of human beings.1–3 In 1953 it was grouped alongside Hand–Schüller–Christian disease, Letterer– Siwe disease and eosinophilic pseudotumor, in the knowledge that abnormal Langerhans cells are the basic pathological characteristics of the three entities.1,4 Eosinophilic pseudotumor, or eosinophilic granuloma, is the most common and benign form of LCH. The incidence of eosinophilic pseudotumors is approximately 3–4 per million.5 This disease has been found in the endoskeletal system as well as skin and other organs such as the lungs, liver, bile duct and even the bladder.6 The involvement of LCH in the liver is extremely rare. In this article, we reported the clinicopathological and immunohistochemical features and the outcomes of six cases with eosinophilic pseudotumor together with a review of literature. CASE REPORT Six patients including three men and three women aged from 32 to 64 years (mean 45.5 years) with eosinophilic pseudotumor of the liver were treated in the Department of Gastroenterology, Zhongshan Hospital, Fudan University (Shanghai, China) during a Correspondence to: Ling DONG, Department of Gastroenterology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai 200032, China. Email: [email protected] Conflict of interest: None. © 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
10-year period from 2001 to 2010. The diagnosis was confirmed by histopathology and immunohistochemistry in all cases. Of the six patients, 4 (66.6%) were asymptomatic, one (16.7%) reported upper abdominal discomfort and the other one complained of asthenia and anorexia for 2 months with fever (38°C) and chills. None of the patients had any other clinical manifestations such as ascites, jaundice, weight loss, weakness, chest distress or extrahepatic involvement of the bone, lungs or spleen. Laboratory and imaging examination Routine blood examination after the patients’ admission showed a significant decrease in lymphocyte and monocyte counts in all patients. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and γ-glutamyltranspeptidase (γ-GT) levels were elevated in one of the six patients, while bilirubin, lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) levels were within the normal ranges. α-fetoprotein (AFP), carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were all negative in the six patients. Autoantibodies including antinuclear antibody (ANA), antibodies to extractable nuclear antigens (ENAs) and anti-neutrophil cytoplasmic antibodies (ANCAs) were all negative. Antibodies to parasites were detected in one patient, in whom serum immunoglobulin G (IgG) to cysticercosis was positive but IgG to liver fluke was negative. All the six patients presented similar abnormalities on abdominal ultrasonography and computed tomography (CT), including solitary or multiple nodular lesions of low densities. Abdominal magnetic resonance imaging (MRI) showed low signal in T1-weighted and high signal in T2-weighted images
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Journal of Digestive Diseases 2015; 16; 159–163
Figure 1. Magnetic resonance imaging (MRI) findings of eosinophilic pseudotumor. (a) Multiple low-density lesions on T1-weight images. (b) Peripheral enhancement on the portal vein phase in dynamic MRI. (c) Slightly high signal on T2-weight images.
Figure 2. Histological findings of eosinophilic pseudotumor showing infiltration of large, dysplastic and histiocytic cells with relatively small nuclei eosinophils and lymphocytes (arrows, HE stain, ×400).
in three patients (Fig. 1). Multiple abnormalities, possibly of infectious origin, were observed in the liver, including neoplastic lesions with hemangioma at the right lobe of liver and splenomegaly. Enhanced MRI images showed abnormal peripheral enhancement, indicating probable infectious disease. Pathological and immunohistochemical evaluation Hepatic lobectomy was performed in four patients, and ultrasound-guided biopsy was performed in the other two patients. The sizes of hepatic eosinophilic pseudotumor ranged from 2 to 5 cm in diameter. All patients were diagnosed based on histopathological and immunohistochemical evaluation. Extensive eosinophilic infiltration was observed in all the specimens of the six patients (Fig. 2). Histopathology revealed a number of folding nuclei of histiocytes and eosinophils. Multinucleated cells were widely dispersed among histiocytes. Immunohistochemical stain was positive for vimentin, CD68, CD-1a and S100, which confirmed the diagnosis of LCH (Fig. 3). Treatment and follow-up Four of the six patients received hepatic lobectomy, and were followed up for a mean duration of 3 years. At the last follow-up visit, all four patients were in a good condition without any evidence of recurrence. In
Figure 3. Immunohistochemical stain for CD68, CD-1a and S100 shows strong positivity, confirming the diagnosis of Langerhans cell histiocytosis. (a) CD68 (×100), (b) CD68 (×400), (c) CD-1a (×100), (d) CD-1a (×400), (e) S100 (×100), (f) S100 (×400).
the other two patients, one left our hospital without receiving any treatments, and two years later he received hepatic lobectomy in another hospital because of an increasingly enlarged hepatic mass. And the other patient who complained of upper abdominal discomfort had been treated with antibiotics before hospitalization but her symptoms were not relieved. She was diagnosed with eosinophilic pseudotumor after liver biopsy in our hospital. But as the diagnosis of eosinophilic granuloma from parasitic infection could not be completely ruled out, praziquantel (25 mg/kg thrice daily) was administered. A 6-month follow-up showed that her lesions were enlarged, leading to the diagnosis of LCH rather than parasitic infection. DISCUSSION Many diseases could result in liver eosinophilic granuloma, including LCH, parasitic infections and other infections. The current terminology of LCH was proposed in the mid-1980s by the Histiocyte Society in Los Angeles.7 However, the etiology of histiocytosis mostly remains unknown at present. Suspected causative agents include infectious agents and
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2015; 16; 159–163 immunodysfunction that give rise to abnormal proliferation of histiocytes. Related lymphocyte infiltration, cytokines and genetic factors have also been reported to be associated with the pathogenesis of eosinophilic pseudotumors in visceral organs.8–13 One pediatric study14 reported a rate of liver involvement of 15.6% in 217 cases. The published literatures contain only two small series of adult liver LCH10,15 and isolated cases. The clinical presentations of LCH are variable. The symptoms and signs depend upon the site of the granuloma in some patients, but most of the patients are asymptomatic. In our study, 4 (66.6%) patients were asymptomatic while the other two reported upper abdominal discomfort or asthenia with anorexia and fever. Ultrasound, CT and MRI are the currently available modalities to gather important diagnostic information for the diagnosis of eosinophilic pseudotumors. CT usually depicts extensively low density in the liver and MRI shows low density on T1-weighted images together with slightly high intensity on T2-weighted images. It is difficult to diagnose eosinophilic pseudotumors in the liver by imaging studies alone, pathological and immunohistochemical evidence remains the gold standard for the diagnosis of eosinophilic pseudotumors. Histopathological findings may present as destructive granulomatous lesions with lymphocyte and histiocyte infiltration, and immunohistochemistry can further help to establish the diagnosis. CD68, CD-1a and S100 were all positive in all our patients. CD68 was positive in some histiocytes, and CD-1a and S100 immunostain highlighted an increased number of Langerhans cells. S100 proteins are a family of low-molecular-weight proteins that are normally present in cells derived from the neural crest, chondrocytes, adipocytes, myoepithelial cells, macrophages, Langerhans cells, and so on. CD1 antigens are expressed on cortical thymocytes, but not on mature T cells. The presence of CD1 antigens is often used to identify some kinds of thymomas and malignancies arising from T-cell precursors. CD1a is the most specific marker for Langerhans cells. Only with positive CD-1a and S100 stain in epithelioid cells can the diagnosis of LCH be made. Some studies16–18 have shown that the administration of anti-CD1 monoclonal antibodies could be delivered to the site of disease activity in LCH patients. A differential diagnoses of eosinophilic pseudotumors in the liver include but are not limited to
Hepatic eosinophilic pseudotumor
161
epithelioid hemangioendothelioma (EHE),19 inflammatory pseudotumor,20,21 angiomyolipoma,22 segmental atrophy of the liver,23 hepatic hydatidosis and cysticerciasis. EHE is a unique vascular tumor with multiple nodules or large masses of low densities on CT. It is sometimes easier to diagnose vascular tumors using contrast-enhanced CT, especially for some tumor nodules showing marginal enhancement during the arterial phase.24 Immunostain for vascular markers VIII, CD34 and CD31 is also positive in EHE. Inflammatory pseudotumor of the liver is another rare non-malignant entity. Sakai et al.25 reported that this disease could be diagnosed by a typical extravasation of contrast material in the fibrous tissue during the delayed phase of CT scan. SMA and vimentin are usually positive, whereas desmin, CD34 and S100 proteins as well as anaplastic lymphoma kinase are negative.21 Hepatic angiomyolipoma is a benign mesenchymal neoplasm made up of a mixture of thick-walled vessels, fat and myoid cells.26 Immunohistochemical stain is usually positive for melanocytic (HMB-45) and SMA markers.27 Pseudotumors in the liver can result from segmental atrophy of the liver and are associated with focal vascular injury in the liver, presenting as thickened vessels, biliary cysts and elastotic changes in the subcapsular space. Hydatid disease caused by cestode is parasitic infection by Echinococcus spp. Diagnosis of hydatid disease is best on the CT scan where cyst wall calcification and infection can be made out.28 Hepatic visceral larva migrans should be borne in mind when a patient presents with fever and hepatomegaly with persistent eosinophilia. The choice of treatment for eosinophilic neoplasia of the liver is to alleviate the symptoms, if any, in order to prevent complications. The treatment strategies depend on the patients’ age and the size of the pseudotumors. Narrow-band ultraviolet B has been attempted as a treatment option for cutaneous LCH that is proven successful.13 Treatments for pulmonary LCH include cigarette-smoking cessation,29,30 the use of steroids31 and lung transplantation32. LCH can be treated effectively with methotrexate monotherapy, etoposide monotherapy or etoposide in combination with vincristine and prednisolone when organs are involved. However, in many large-sample-sized trials, the data on the treatment for liver LCH are lacking. Sclerosing cholangitis complicating with LCH can lead to end-stage liver diseases, for which liver transplantation may be a favourable option.33,34 It has been reported that survival in children following liver transplantation for LCH-related liver disease is excellent.35
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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Four of our six patients were treated with hepatic lobectomy, and none chose liver transplantation. As early treatment can improve the prognosis of liver LCH, an early diagnosis is of primary importance. As eosinophilic pseudotumor of the liver is rare, it is often misdiagnosed or never diagnosed. A thorough imaging examination and immunohistological panel can help the clinicians to differentiate it from other lesions. Treatment with hepatic lobectomy provides favourable outcomes in our case series. ACKNOWLEDGMENTS We thank Bao Jian PAN for his assistance on the analysis of the pathological and immunohistochemical studies. This study was supported by the National Natural Science Foundation of China (No. 81000968), the Doctoral Fund of Ministry of Education of China (No. 20120071110058) and the National Clinical Key Special Subject of China. REFERENCES 1 Lichtenstein L. Histiocytosis X; integration of eosinophilic granuloma of bone, Letterer–Siwe disease, and Schüller–Christian disease as related manifestations of a single nosologic entity. AMA Arch Pathol 1953; 56: 84–102. 2 The Writing Group of the Histiocyte Society. Histiocytosis syndromes in children. Lancet 1987; 1: 208–9. 3 Favara BE, Feller AC, Pauli M et al.; The WHO Committee on Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Contemporary classification of histiocytic disorders. Med Pediatr Oncol 1997; 29: 157–66. 4 Herzog KM, Tubbs RR. Langerhans cell histiocytosis. Adv Anat Pathol 1998; 5: 347–58. 5 Velez-Yanguas MC, Warrier RP. Langerhans’ cell histiocytosis. Orthop Clin North Am 1996; 27: 615–23. 6 Siegal G, Luntz M, Duchmann H et al. Pathology forum. Quiz case 1. Langerhans cell histocytosis (LCH). Arch Otolaryngol Head Neck Surg 2001; 127: 78. 7 Alessi DM, Maceri D. Histiocytosis X of the head and neck in a pediatric population. Arch Otolaryngol Head Neck Surg 1992; 118: 945–8. 8 Loh JK, Su YF, Hwang SL, Chai CY, Howng SL, Lieu AS. Eosinophilic granuloma of the occipital bone in an adult: a case report. Kaohsiung J Med Sci 2011; 27: 76–9. 9 Sampathkumar S, Younger C, Cramer H, Chalasani N, Skierczynski PA. Langerhans’ cell histiocytosis involving the pituitary, thyroid, lung, and liver. Endocr Pract 2002; 8: 217–21. 10 Kaplan KJ, Goodman ZD, Ishak KG. Liver involvement in Langerhans’ cell histiocytosis: a study of nine cases. Mod Pathol 1999; 12: 370–8. 11 Guthery SL, Heubi JE. Liver involvement in childhood histiocytic syndromes. Curr Opin Gastroenterol 2001; 17: 474–8.
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