Case Reports in Medicine Figure 2: Overview of the intra-operatively obtained liver specimen (Case 2) in which the liver has a disturbed architecture with nodular appearance of liver parenchyma (white arrows) characteristic of nodular regenerative hyperplasia. Areas with sinusoidal congestion are also present (black arrow). Hematoxylin and eosin, original magniﬁcation 50x. Figure 3: Detail of the intra-operative liver specimen (Case 2) showing nodular regenerative hyperplasia in which a regenerative nodule (white arrow) is bordered by irregular aligned small-sized hepatic trabeculae (black arrows). Hematoxylin and eosin, original magniﬁcation 100x. the CLMs by nonanatomical wedge resections followed by an uneventful clinical course. Histopathologic examination of intra-operative liver specimen showed signs consistent with NRH again. Eighteen months later, another recurrent CLM was resected from segment IVb after which the clinical course was uneventful. No neoadjuvant chemotherapy was administered prior to surgery this time as the CLM was deemed resectable without the need for downsizing by means of chemotherapy. Histopathologic examination of the nontumorous liver did not reveal signs for NRH anymore. However, some areas of the nontumorous liver did still show minimal sinusoidal congestion. 3 3. Discussion Chemotherapy is an essential element in the multimodal approach of CLMs. However, chemotherapy consisting of either irinotecan or oxaliplatin has been associated with the development of histologic lesions in the nontumorous liver that are related to post-resectional complications [2, 5, 6]. Irinotecan has been shown to induce hepatic inﬂammation classiﬁed as chemotherapy-associated steatohepatitis which is associated with increased 90-day mortality after liver surgery [5, 8]. Oxaliplatin is related to vascular lesions classiﬁed as sinusoidal obstruction syndrome (SOS) and, sporadically, also to NRH [3, 4, 6, 9, 10]. Recently, Nakano et al. showed a signiﬁcant association between the presence of vascular lesions in the nontumorous liver secondary to oxali- platin and increased morbidity after major hemihepatectomy [6]. NRH of the liver is characterized by the diﬀuse presence of regenerative nodules made up of hyperplastic hepatocytes less than 3 mm in diameter without ﬁbrous septa [11]. The liver parenchyma between the nodules contains atrophic hepatocytes and shows signs of sinusoidal dilatation and congestion (Figures 2 and 3). Usually, these lesions are cli- nically asymptomatic but they can be associated with portal hypertension, splenomegaly, and bleeding from oesophageal varices [12]. Liver function is usually preserved in patients suﬀering from NRH, although slight increases in alka- line phosphatase or aspatate aminotransferase might be noticed. The parenchymal injury characteristic of NRH originates from a heterogeneous perfusion of the liver secondary to obliterative lesions in either the portal vein or hepatic sinusoids [11, 13]. Oxaliplatin-based chemotherapy has a toxic eﬀect on sinusoidal endothelial cells resulting in sinusoidal dilatation, congestion, and obstruction. Depletion of sinusoidal glutathione and activation of matrix me- talloproteinases by oxaliplatin have been postulated as pathogenic factors in the development of these sinusoidal lesions [13]. Furthermore, it has been hypothesized that the sinusoidal lesions impair hepatic regeneration [4, 14] and aggravate portal pressure. The extent of reversibility of these lesions is still uncertain; patients undergoing repeat resection because of recurrent CLMs still showed sinusoidal dilatation or (progressive) ﬁbrosis [4]. On the other hand, a longer time interval between neoadjuvant chemotherapy and surgical resection seemed to decrease the incidence of sinusoidal injury [6]. It is imperative to recognize the presence of SOS or NRH prior to hemihepatectomy. The diagnostic value of a preoperative liver biopsy seems to be minimal because of sampling error resulting in a high false-negative result rate and therefore, suspicion is merely based on the patient’s history, preoperative liver function, and intra-operative macroscopic aspect. In this respect, 4 factors independently associated with sinusoidal injury have been identiﬁed [6]. These include female gender, administration of 6 or more cycles of oxaliplatin-based chemotherapy, abnormal value of preoperative aspartate aminotransferase (>36 IU/L), and indocyanine green retention rate at 15 minutes of >10%.