CLINICAL OBSERVATIONS IN HEPATOLOGY Diagnosis of Sinusoidal Obstruction Syndrome by Positron Emission Tomography/Computed Tomography: Report of Two Cases Treated by Defibrotide Mathieu Gauthe,1 Laurence Bozec,2 and Pierre Bedossa3 Sinusoidal obstruction syndrome (SOS) is a potentially fatal liver injury that mainly occurs after myeloablative chemotherapy. We report two cases of SOS investigated by 18F-fluorodeoxyglucose positron emission tomography/computed tomography and treated with defibrotide. (HEPATOLOGY 2014;60:1789-1791)
S
inusoidal obstruction syndrome (SOS) generally occurs within 3 weeks after myeloablative chemotherapy.1,2 The reported incidence ranges from 5% to 70% depending on the conditioning regimen and risk factors such as previous exposure to cytotoxic agents.1,2 We report two patients with SOS treated with defibrotide in whom 18F-fluorodeoxyglucose positron emission tomography / computed tomography (FDGPET/CT) demonstrated interesting findings.
Case Reports Case 1 A 36-year-old man with brain tumor previously treated with chemotherapy followed by hematopoietic stem cell transplantation (HSCT) was investigated 2 months later by PET/CT scan, which revealed numerous disseminated lesions with increased FDG uptake in the liver corresponding to multiple hypodense lesions on CT, suggestive of metastases (standardized uptake Abbreviations: FDG-PET/CT, 18F-fluorodeoxyglucose positron emission tomography / computed tomography; HSCT, hematopoietic stem cell transplantation; SOS, sinusoidal obstruction syndrome; SUV, standardized uptake value; TJLB, transjugular liver biopsy. e decine Nucl e aire, Department of From the 1Institut Curie, Service de M Nuclear Medicine, Saint-Cloud, France; 2Institut Curie, Service d’Oncologie e partment M e dicale, Department of Medical Oncology, Saint-Cloud, France; 3D d’Anatomie Pathologique Beaujon-Bichat, Inserm U773, Universit e ParisDiderot, H^ opital Beaujon, Clichy, France. Received October 28, 2013; accepted March 13, 2014. Address reprint requests to: Mathieu Gauth e , Institut Curie, Service de M e decine Nucle aire, 35 rue Dailly, Saint-Cloud, F-92210, France. E-mail: [email protected]; fax: 133147113378. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27132 Potential conflict of interest: Nothing to report.
value [SUV] peak 5 2.7) (Fig. 1A). Clinical examination was normal. Laboratory work-up showed thrombocytopenia and slightly elevated transaminases (Table 1). Transjugular liver biopsy (TJLB) revealed SOS with moderate injury of sinusoidal endothelium and dilatation of the sinusoids, no hepatocyte necrosis, and only mild fibrin deposition in hepatic venules. Treatment with defibrotide was initiated, according to the protocol recommended by our national multidisciplinary meeting for vascular disorders of the liver: defibrotide is available through a strictly regulated compassionate-use program. Once approved, treatment is authorized for 2 weeks at a dose of 6.25 mg per kg body weight, with the possibility to apply for longer use if treatment is effective. No improvement of laboratory parameters was observed after 1 month of treatment. Follow-up PET/ CT did not demonstrate any significant changes (Fig. 1B). Defibrotide was stopped and transaminases remained stable and slightly elevated. Thrombocytopenia did not improve and was attributed to chemotherapy-induced dysmyelopoiesis. The patient died from brain herniation due to progression of the primary tumor 3 months after completion of defibrotide therapy. Case 2 A 51-year-old man with a Hodgkin’s lymphoma presented with dyspnea and jaundice 2 weeks after HSCT. Clinical examination revealed significant hepatomegaly and anasarca. Laboratory work-up showed marked elevation of transaminases and bilirubin, thrombocytopenia and decreased clotting factors (Table 1). PET/CT showed diffusely increased hepatic activity (SUV peak 5 3.3) (Fig. 1C). TJLB demonstrated SOS with severe destruction of sinusoidal endothelium, dilatation of the sinusoids 1789
1790
ET AL. GAUTHE
HEPATOLOGY, November 2014
Fig. 1. PET (maximum intensity projection images) focused on the abdomen showing disseminated FDG hot spots in the liver before defibrotide (A) with no significant improvement after defibrotide (B) in case 1 (top); and diffusely increased hepatic activity before defibrotide (C) with complete normalization after defibrotide (D) in case 2 (bottom).
Table 1. Comparison of Clinical, Laboratory, and Histologic Findings Between the Two Cases Case 1
Case 2
Previous chemotherapy
2 cycles of carboplatin and etoposide
HSCT conditioning regimen Clinical examination Laboratory parameters AST/ALT (N: 6-40 IU/L) Bilirubin (N150,000/L) Prothrombin time (N>70%) Proconvertin (FVII) (N>70%) Histology Sinusoidal endothelium Dilatation of sinusoids Appearance of hepatocytes Hepatic venules
High-dose thiotepa Normal
4 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) 4 cycles of docosahexaenoic acid-oxaliplatin High-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) Dyspnea, Jaundice, Hepatomegaly, Generalized edema
2-3xULN Normal 16,000/L 100% Normal
20xULN 190 micromol/l 16,000/L 40% 22%
Moderate alteration Moderate dilatation Normal Mild fibrin deposition
Severe destruction Major dilatation Severe necrosis Obliterated
ET AL. GAUTHE
HEPATOLOGY, Vol. 60, No. 5, 2014
Fig. 2. Transjugular liver biopsy from patient 2 showing dilated sinusoids (black arrow). Hematoxylin-eosin-safran staining (magnification 34).
(Fig. 2), hepatocyte necrosis, and obliterated hepatic venules. Treatment with defibrotide was initiated. Liver FDG uptake returned to normal after 1 month of treatment (SUV peak 5 2.4, Fig. 1D), associated with complete clinical recovery and normalization of laboratory parameters.
Discussion SOS should be suspected in postmyeloablative chemotherapy patients who develop hepatomegaly, jaundice, and weight gain.1,2 While 70% of patients with mild/moderate SOS recover spontaneously, severe SOS usually leads to multiorgan failure and is associated with a high mortality rate.1 No specific treatment for SOS is currently available. Defibrotide is an antithrombotic agent reported to improve symptoms and signs of SOS in 42% of patients.3 The diagnosis of SOS is established by liver biopsy, with histologic findings including endothelial cell damage, dilatation of the sinusoids, hepatocyte necrosis, and collagen deposition in the sinusoids, with subsequent liver fibrosis.4 In hepatocytes, FDG is taken up by surface glucose transporter-2 expressed by the sinusoidal endothelium. The prevailing hypothesis of SOS pathophysiology focuses on damage to the hepatic ven-
1791
ular and sinusoidal endothelium as an initial event that activates the coagulation cascade. The venular and sinusoidal lumen is reduced due to concentric subendothelial zone edema.1,5 We suggest that PET findings in the liver could be explained by trapping of FDG in dilated sinusoids; FDG cannot enter hepatocytes due to destruction of the sinusoidal endothelium. An inflammatory reaction is a less likely hypothesis, as no inflammatory cells were observed on liver biopsy. Interestingly, patient 2 presented more severe clinical features and histologic findings, but obtained complete recovery in response to treatment, while patient 1 had no significant clinical findings, only moderate damage on liver biopsy, and derived no benefit from treatment. Differences in sinusoidal injuries may be predictive of response to defibrotide, but this aspect requires further investigation. In conclusion, FDG-PET/CT imaging may be a useful tool to assess the prognosis of SOS and the therapeutic efficacy of defibrotide, but further data need to be generated and validated by larger studies.
References 1. Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol 2012;18:1851-1860. 2. Carreras E, Bertz H, Arcese W, Vernant JP, Tomas JF, Hagglund H, et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the European Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood 1998;92:3599-3604. 3. Richardson PG, Elias AD, Krishnan A, Wheeler C, Nath R, Hoppensteadt D, et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood 1998;92:737-744. 4. Richardson P, Guinan E. The pathology, diagnosis, and treatment of hepatic veno-occlusive disease: current status and novel approaches. Br J Haematol 1999;107:485-493. 5. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 1995;85:3005-3020.
S
inusoidal obstruction syndrome (SOS) generally occurs within 3 weeks after myeloablative chemotherapy.1,2 The reported incidence ranges from 5% to 70% depending on the conditioning regimen and risk factors such as previous exposure to cytotoxic agents.1,2 We report two patients with SOS treated with defibrotide in whom 18F-fluorodeoxyglucose positron emission tomography / computed tomography (FDGPET/CT) demonstrated interesting findings.
Case Reports Case 1 A 36-year-old man with brain tumor previously treated with chemotherapy followed by hematopoietic stem cell transplantation (HSCT) was investigated 2 months later by PET/CT scan, which revealed numerous disseminated lesions with increased FDG uptake in the liver corresponding to multiple hypodense lesions on CT, suggestive of metastases (standardized uptake Abbreviations: FDG-PET/CT, 18F-fluorodeoxyglucose positron emission tomography / computed tomography; HSCT, hematopoietic stem cell transplantation; SOS, sinusoidal obstruction syndrome; SUV, standardized uptake value; TJLB, transjugular liver biopsy. e decine Nucl e aire, Department of From the 1Institut Curie, Service de M Nuclear Medicine, Saint-Cloud, France; 2Institut Curie, Service d’Oncologie e partment M e dicale, Department of Medical Oncology, Saint-Cloud, France; 3D d’Anatomie Pathologique Beaujon-Bichat, Inserm U773, Universit e ParisDiderot, H^ opital Beaujon, Clichy, France. Received October 28, 2013; accepted March 13, 2014. Address reprint requests to: Mathieu Gauth e , Institut Curie, Service de M e decine Nucle aire, 35 rue Dailly, Saint-Cloud, F-92210, France. E-mail: [email protected]; fax: 133147113378. C 2014 by the American Association for the Study of Liver Diseases. Copyright V View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27132 Potential conflict of interest: Nothing to report.
value [SUV] peak 5 2.7) (Fig. 1A). Clinical examination was normal. Laboratory work-up showed thrombocytopenia and slightly elevated transaminases (Table 1). Transjugular liver biopsy (TJLB) revealed SOS with moderate injury of sinusoidal endothelium and dilatation of the sinusoids, no hepatocyte necrosis, and only mild fibrin deposition in hepatic venules. Treatment with defibrotide was initiated, according to the protocol recommended by our national multidisciplinary meeting for vascular disorders of the liver: defibrotide is available through a strictly regulated compassionate-use program. Once approved, treatment is authorized for 2 weeks at a dose of 6.25 mg per kg body weight, with the possibility to apply for longer use if treatment is effective. No improvement of laboratory parameters was observed after 1 month of treatment. Follow-up PET/ CT did not demonstrate any significant changes (Fig. 1B). Defibrotide was stopped and transaminases remained stable and slightly elevated. Thrombocytopenia did not improve and was attributed to chemotherapy-induced dysmyelopoiesis. The patient died from brain herniation due to progression of the primary tumor 3 months after completion of defibrotide therapy. Case 2 A 51-year-old man with a Hodgkin’s lymphoma presented with dyspnea and jaundice 2 weeks after HSCT. Clinical examination revealed significant hepatomegaly and anasarca. Laboratory work-up showed marked elevation of transaminases and bilirubin, thrombocytopenia and decreased clotting factors (Table 1). PET/CT showed diffusely increased hepatic activity (SUV peak 5 3.3) (Fig. 1C). TJLB demonstrated SOS with severe destruction of sinusoidal endothelium, dilatation of the sinusoids 1789
1790
ET AL. GAUTHE
HEPATOLOGY, November 2014
Fig. 1. PET (maximum intensity projection images) focused on the abdomen showing disseminated FDG hot spots in the liver before defibrotide (A) with no significant improvement after defibrotide (B) in case 1 (top); and diffusely increased hepatic activity before defibrotide (C) with complete normalization after defibrotide (D) in case 2 (bottom).
Table 1. Comparison of Clinical, Laboratory, and Histologic Findings Between the Two Cases Case 1
Case 2
Previous chemotherapy
2 cycles of carboplatin and etoposide
HSCT conditioning regimen Clinical examination Laboratory parameters AST/ALT (N: 6-40 IU/L) Bilirubin (N150,000/L) Prothrombin time (N>70%) Proconvertin (FVII) (N>70%) Histology Sinusoidal endothelium Dilatation of sinusoids Appearance of hepatocytes Hepatic venules
High-dose thiotepa Normal
4 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) 4 cycles of docosahexaenoic acid-oxaliplatin High-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) Dyspnea, Jaundice, Hepatomegaly, Generalized edema
2-3xULN Normal 16,000/L 100% Normal
20xULN 190 micromol/l 16,000/L 40% 22%
Moderate alteration Moderate dilatation Normal Mild fibrin deposition
Severe destruction Major dilatation Severe necrosis Obliterated
ET AL. GAUTHE
HEPATOLOGY, Vol. 60, No. 5, 2014
Fig. 2. Transjugular liver biopsy from patient 2 showing dilated sinusoids (black arrow). Hematoxylin-eosin-safran staining (magnification 34).
(Fig. 2), hepatocyte necrosis, and obliterated hepatic venules. Treatment with defibrotide was initiated. Liver FDG uptake returned to normal after 1 month of treatment (SUV peak 5 2.4, Fig. 1D), associated with complete clinical recovery and normalization of laboratory parameters.
Discussion SOS should be suspected in postmyeloablative chemotherapy patients who develop hepatomegaly, jaundice, and weight gain.1,2 While 70% of patients with mild/moderate SOS recover spontaneously, severe SOS usually leads to multiorgan failure and is associated with a high mortality rate.1 No specific treatment for SOS is currently available. Defibrotide is an antithrombotic agent reported to improve symptoms and signs of SOS in 42% of patients.3 The diagnosis of SOS is established by liver biopsy, with histologic findings including endothelial cell damage, dilatation of the sinusoids, hepatocyte necrosis, and collagen deposition in the sinusoids, with subsequent liver fibrosis.4 In hepatocytes, FDG is taken up by surface glucose transporter-2 expressed by the sinusoidal endothelium. The prevailing hypothesis of SOS pathophysiology focuses on damage to the hepatic ven-
1791
ular and sinusoidal endothelium as an initial event that activates the coagulation cascade. The venular and sinusoidal lumen is reduced due to concentric subendothelial zone edema.1,5 We suggest that PET findings in the liver could be explained by trapping of FDG in dilated sinusoids; FDG cannot enter hepatocytes due to destruction of the sinusoidal endothelium. An inflammatory reaction is a less likely hypothesis, as no inflammatory cells were observed on liver biopsy. Interestingly, patient 2 presented more severe clinical features and histologic findings, but obtained complete recovery in response to treatment, while patient 1 had no significant clinical findings, only moderate damage on liver biopsy, and derived no benefit from treatment. Differences in sinusoidal injuries may be predictive of response to defibrotide, but this aspect requires further investigation. In conclusion, FDG-PET/CT imaging may be a useful tool to assess the prognosis of SOS and the therapeutic efficacy of defibrotide, but further data need to be generated and validated by larger studies.
References 1. Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol 2012;18:1851-1860. 2. Carreras E, Bertz H, Arcese W, Vernant JP, Tomas JF, Hagglund H, et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the European Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood 1998;92:3599-3604. 3. Richardson PG, Elias AD, Krishnan A, Wheeler C, Nath R, Hoppensteadt D, et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood 1998;92:737-744. 4. Richardson P, Guinan E. The pathology, diagnosis, and treatment of hepatic veno-occlusive disease: current status and novel approaches. Br J Haematol 1999;107:485-493. 5. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 1995;85:3005-3020.
