Chemotherapy-induced liver injury in metastatic colorectal cancer: about 48 cases

Neoadjuvant chemotherapy of colorectal liver metastases can induce hepatotoxicity in noncancerous liver. The aim of the present study was to describe the chemotherapy-induced major changes in the hepatic parenchyma and their prognostic impact. We undertook a retrospective study of 48 cases of colorectal liver metastases treated with neoadjuvant therapy followed by liver resection. These cases were collected at the Pathology Department of Mongi Slim Hospital over a 2-year period (July 2015-February 2018). Our series consisted of 27 men and 21 women with a sex-ratio (M/F = 1.28). The average age of our patients was 57.68 years old with extremes ranging from 30 to 75 years old. All patients received chemotherapy with FOLFOX. From a total of 48 operative specimens examined, we found 24 cases (50%) of non-systematized steatosis, grade 1 sinusoidal obstruction syndrome (n = 12) and grade 2 sinusoidal obstruction syndrome (n = 12), regenerative nodular hyperplasia (n = 3), portal and/or lobular inflammatory infiltrate (n = 6). In three cases, no abnormalities were reported in the liver parenchyma. Surgical margins were < 1 mm in seven cases and were invaded in four cases. Preoperative chemotherapy is associated with regimen-specific liver injury. The presence of such an injury may have a negative impact on the functional reserve of the liver, thereby increasing the risk of surgical morbidity and mortality.


Introduction
Liver metastasis is the most common complication of colorectal cancer and approximately 50% of patients develop colorectal liver metastases (CLM) during the course of their disease [1,2]. It is universally accepted that patients with inoperable disease should be treated, where possible, with aggressive chemotherapy with a view to downstaging disease such that curative surgery can be offered [3]. Preoperative chemotherapy is associated with regimen-specific liver injury. The presence of such an injury may have a negative impact on the functional reserve of the liver, thereby increasing the risk of surgical morbidity and mortality. In this paper, we report our experience with liver metastases over the past three years. Our aim was to describe the chemotherapy-induced major changes in the hepatic parenchyma and their prognostic impact. Eighty-four patients met the inclusion criteria which were the following: hepatectomy for documented CLM, no underlying chronic liver disease (nonalcoholic, hepatitis B or C virus, or autoimmune chronic liver disease or genetic haemochromatosis) and with sufficient non-tumorous liver parenchyma for pathologic analysis. All patients received preoperative systemic chemotherapy.

Methods
Preoperative evaluation: All patients underwent a preoperative evaluation including an abdominal and thoracic CT scan. Patients were considered for hepatectomy if all detected tumors could be removed completely with grossly negative surgical margins and a safe liver remnant volume.

Indication and regimens of systemic chemotherapy:
In resectable patients, indication for preoperative chemotherapy was to downsize the tumors preoperatively in view of a function-sparing resection or to ensure negative margins and to assess tumor's response to chemotherapy. The patients with nonresectable CLM at presentation received "induction" chemotherapy which aimed at downsizing the CLM to switch the patients from a "non-resectable" status to a "resectable" status. Systemic chemotherapy was administered before hepatic surgery in all cases. The chemotherapeutic agents used were 5-FU, 5-FU with leucovorin and oxaliplatin (FOLFOX).
Pathologic analysis: All slides, which were originally prepared from formalin-fixed and paraffin-embedded tissues, were reviewed.
Representative slides of non-tumorous hepatic tissue located as far as possible from the tumor were selected for the study. The morphological analyses were performed using slides stained with hematoxylin and eosin and Masson trichrome stain. The slides were examined by a single pathologist with hepatobiliary expertise.
Hepatic steatosis was classified into 3 grades: less than or equal to 30%, between 30% and 60% and greater than 60%.

Discussion
The most commonly used CLM chemotherapy regimens include oxaliplatin (OX) plus 5-fluorouracil (5-FU) and leucovorin (FOLFOX) and irinotecan plus 5-FU and leucovorin (FOLFIRI). As chemotherapy is often administered prior to hepatic resection, adverse effects on the background liver parenchyma of CLM patients are increasingly recognized [4][5][6]. which may be associated with liver cell plate atrophy. In severe cases, it can also be associated with perisinusoidal fibrosis, NRH, obstruction of centrilobular veins and peliotic change [12]. In our series, there were 23 cases of sinusoidal dilatation including grade I SOS (n = 1), grade II SOS (n = 12) and grade III SOS (n = 10).
Perisinusoidal fibrosis was minimal in one (2%) case and moderate in one (2%) case. Recent meta-analysis studies have demonstrated that the nature of preoperative chemotherapy liver injury is a regimen-specific phenomenon [13]. For example, OX-based regimens are associated with sinusoidal injury, whereas irinotecanbased regimens are associated with steatohepatitis. In the context of liver surgery, chemotherapy-induced liver injury could increase the risks of intra-and postoperative complications and postoperative liver insufficiency [14]. Sinusoidal obstruction syndrome may also Page number not for citation purposes 4 compromise liver regeneration in patients undergoing hepatectomy [15]. Therefore, both pathologists and clinicians should be aware of this syndrome as it has a relatively high prevalence and may affect patient outcomes. Nodular regenerative hyperplasia, a diffuse parenchymal reactive process, has been reported in 15% of patients receiving preoperative 5-FU-based chemotherapy for metastatic colorectal metastases [16]. Nodular regenerative hyperplasia is characterized by an ill-defined parenchymal nodularity formed by alternating areas of expanding nodules of hyperplastic hepatocytes with sinusoidal congestion and compression of peripheral parenchyma and central veins. The pathogenesis of NRH, which appears to develop within weeks of the completion of chemotherapy, is unknown, although it is believed to be related to a modification of the intrahepatic blood flow. However, no morphologic vascular alteration has been reported in that setting [16]. In our series, nodular regenerative hyperplasia was observed in 3 (6%) patients.

Conclusion
In conclusion, most chemotherapeutic agents used for the management of CLM are associated with various histological patterns of liver injury but the incidence and pathogenesis are not well established. Concerns regarding chemotherapy-associated hepatotoxicity may negatively impact the ability to offer potentially curative therapy or increase morbidity in some patients. Although previously the domain of the oncologist, it is becoming increasingly important that the surgeon is aware of the mechanism of action and hepatotoxicity of these agents in order to predict and anticipate potential problems when the patient comes to surgery [17].
What is known about this topic  Most chemotherapeutic agents used for the management of CLM are associated with various histological patterns of liver injury, but the incidence and pathogenesis are not well established;  Concerns regarding chemotherapy-associated hepatotoxicity may negatively impact the ability to offer potentially curative therapy or increase morbidity in some patients.

What this study adds
 This is the first Tunisian study that describes the chemotherapy-induced major changes in the hepatic parenchyma and their prognostic impact in a Tunisian population.