Chemotherapy-induced Sinusoidal Injury (CSI) score: a novel histologic assessment of chemotherapy-related hepatic sinusoidal injury in patients with colorectal liver metastasis

Abstract

BackgroundPreoperative neoadjuvant therapy for colorectal liver metastases (CRLM) is increasing in use and can lead to chemotherapy-induced damage to sinusoidal integrity, namely sinusoidal obstruction syndrome (SOS). SOS has been associated with an increased need for intraoperative blood transfusions, increased length of hospitalization post-surgery, decreased tumor response, and a shorter overall survival after resection due to liver insufficiency. It is critical for clinicians and pathologists to be aware of this type of liver injury, and for pathologists to include the status of the background, non-neoplastic liver parenchyma in their pathology reports. In this study, expression of CD34 by sinusoidal endothelial cells (SECs), increased expression of smooth muscle actin (SMA) by hepatic stellate cells (HSCs), and aberrant expression of glutamine synthetase (GS) by noncentrizonal hepatocytes were semiquantitatively evaluated in liver resection or biopsy specimens from patients with CRLM to determine their diagnostic value for assessing chemotherapy-induced sinusoidal injury (CSI).MethodsThe expression of each marker was compared among 22 patients with CRLM with histologically evident SOS (SOS+) and 8 patients with CRLM who had not undergone chemotherapy. Each case was given a histologic grade using the sinusoidal obstruction syndrome index score (SOS-I) to assess the likelihood of SOS. Cases were also given an immunohistochemical grade using the total CSI score calculated as the sum of CD34, SMA, and GS scores.ResultsAbnormal staining patterns for CD34 and SMA were significantly more frequent and extensive in SOS+ cases than in the controls (81.8% vs. 25%, P < 0.01; 72.7% vs. 25%, P = 0.03). Aberrant GS expression in midzonal and periportal hepatocytes was only observed in SOS+ cases (31.8% vs. 0%), but this difference did not reach statistical significance. The CSI score was significantly higher in the SOS+ cases when compared to controls (P < 0.01), and was associated with a higher SOS histologic grade (P = 0.02).ConclusionsThe CSI score, calculated using an immunohistochemical panel consisting of CD34, SMA, and GS, may serve as an objective marker of chemotherapy-induced sinusoidal injury and could help diagnose this peculiar form of liver injury.

Nodular Regenerative Hyperplasia Associated With Immune Checkpoint Blockade

“…(3) Aberrant CD34 expression has been used as a measure of severity of oxaliplatin-induced liver injury and sinusoidal obstruction syndrome. (4) In our case, the sinusoidal expression pattern of CD34 suggests a similar mechanism to oxaliplatin-induced endothelial damage. Regardless of the mechanism of drug-induced liver injury, immune-related adverse events with PD-1 inhibitors are highly idiosyncratic and necessitate an individualized approach to management.…”

“…The commonly used chemotherapeutic, oxaliplatin, is linked with sinusoidal obstruction syndrome and NRH, whereby increased expression of the endothelial cell marker, CD34, is associated with a loss of fenestrae in the sinusoidal endothelium, a process known as sinusoidal capillarization . Aberrant CD34 expression has been used as a measure of severity of oxaliplatin‐induced liver injury and sinusoidal obstruction syndrome . In our case, the sinusoidal expression pattern of CD34 suggests a similar mechanism to oxaliplatin‐induced endothelial damage.…”

Risk Factors for Development of and Progression of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome

“…Several studies have demonstrated early diagnosis or prediction of VOD/SOS with this method, before the appearance of conventional clinical criteria [74][75][76]. Other proposed methods involve the multifactorial, or panel, scoring approach for early diagnosis or prediction of VOD/SOS with the use of ultrasound [77][78][79][80]. Independent predictors of VOD/SOS that may enhance ultrasound diagnosis include gallbladder wall thickening and paraumbilical vein blood flow [78,80].…”

“…Independent predictors of VOD/SOS that may enhance ultrasound diagnosis include gallbladder wall thickening and paraumbilical vein blood flow [78,80]. Proposed methods aimed at diagnosis or prediction specifically of chemotherapy-induced VOD/SOS include a score consisting of expression of CD34 cells, increased levels of smooth muscle actin, and aberrant expression of glutamine synthetase [79]. The use of contrast-enhanced computed tomography also has been suggested to detect multiple factors such as clover-like sign, peripheral distribution of heterogeneity, increased spleen volume, and hepatic parenchyma, which were found to be independent predictors of VOD/SOS via this method [77,81,82].…”

Current topics in liver surgery

“…This difference may reflect the hepatic venous pressure gradient and parenchymal stiffness, and the increasing rate of SOS is associated with morbidity after liver resection. Rate of increase in splenic volume and decrease in platelet count are predictive of SOS . Reportedly, 75% of patients who received adjuvant chemotherapy had increased splenic volume and 40% of patients did not recover after discontinuation of chemotherapy .…”