Sinusoidal 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 (FDG-PET/CT) demonstrated interesting findings.
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)
18F-fluorodeoxyglucose positron emission tomography / computed tomography
hematopoietic stem cell transplantation
sinusoidal obstruction syndrome
standardized uptake value
transjugular liver biopsy
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 value [SUV] peak = 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.
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 = 3.3) (Fig. 1C). TJLB demonstrated SOS with severe destruction of sinusoidal endothelium, dilatation of the sinusoids (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 = 2.4, Fig. 1D), associated with complete clinical recovery and normalization of laboratory parameters.
|Case 1||Case 2|
|Previous chemotherapy||2 cycles of carboplatin and etoposide||4 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD)|
|4 cycles of docosahexaenoic acid-oxaliplatin|
|HSCT conditioning regimen||High-dose thiotepa||High-dose carmustine, etoposide, cytarabine, and melphalan (BEAM)|
|Clinical examination||Normal||Dyspnea, Jaundice, Hepatomegaly, Generalized edema|
|AST/ALT (N: 6-40 IU/L)||2-3xULN||20xULN|
|Bilirubin (N<17)||Normal||190 micromol/l|
|Prothrombin time (N>70%)||100%||40%|
|Proconvertin (FVII) (N>70%)||Normal||22%|
|Sinusoidal endothelium||Moderate alteration||Severe destruction|
|Dilatation of sinusoids||Moderate dilatation||Major dilatation|
|Appearance of hepatocytes||Normal||Severe necrosis|
|Hepatic venules||Mild fibrin deposition||Obliterated|
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. 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.
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. 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 venular 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.