Is Hepatectomy Justified for BRAF Mutant Colorectal Liver Metastases?: A Multi-institutional Analysis of 1497 Patients.

OBJECTIVE: To analyze clinical outcomes and prognostic variables of patients undergoing hepatic resection for BRAF mutant (BRAF-mut) colorectal liver metastases (CRLM). BACKGROUND: Outcomes following hepatectomy for BRAF-mut CRLM have not been well studied. METHODS: All patients who underwent hepatectomy for CRLM with complete resection and known BRAF status during 2001 to 2016 at 3 high-volume centers were analyzed. RESULTS: Of 4124 patients who underwent hepatectomy for CRLM, 1497 had complete resection and known BRAF status. Thirty-five (2%) patients were BRAF-mut, with 71% of V600E mutation. Compared with BRAF wild-type (BRAF-wt), BRAF-mut patients were older, more commonly presented with higher ASA scores, synchronous, multiple and smaller CRLM, underwent more major hepatectomies, but had less extrahepatic disease. Median overall survival (OS) was 81 months for BRAF-wt and 40 months for BRAF-mut patients (P < 0.001). Median recurrence-free survival (RFS) was 22 and 10 months for BRAF-wt and BRAF-mut patients (P < 0.001). For BRAF-mut, factors associated with worse OS were node-positive primary tumor, carcinoembryonic antigen (CEA) >200 µg/L, and clinical risk score (CRS) ≥4. Factors associated with worse RFS were node-positive primary tumor, ≥4 CRLM, and positive hepatic margin. V600E mutations were not associated with worse OS or RFS. A case-control matching analysis on prognostic clinicopathologic factors confirmed shorter OS (P < 0.001) and RFS (P < 0.001) in BRAF-mut. CONCLUSIONS: Patients with resectable BRAF-mut CRLM are rare among patients selected for surgery and more commonly present with multiple synchronous tumors. BRAF mutation is associated with worse prognosis; however, long-term survival is possible and associated with node-negative primary tumors, CEA ≤ 200 µg/L and CRS < 4.

The accuracy of pre-operative imaging in the management of hepatic cysts.

BACKGROUND: Biliary cystic tumours (BCT) [biliary cystadenoma (BCA) and cystadenocarcinoma (BCAC)] warrant complete resection. Simple liver cysts (SLC) require fenestration when symptomatic. Distinguishing between BCT and atypical SLC with pre-operative imaging is not well studied. METHODS: All patients undergoing surgery for a pre-operative suspected SLC or BCT between 1992 and 2014 were included. Peri-operative data were retrospectively reviewed. A blind radiological review of pre-operative imaging was performed. RESULTS: Ninety-four patients underwent fenestration (n = 54) or complete excision (n = 40). Final pathology was SLC (n = 74), BCA (n = 15), BCAC (n = 2) and other primary malignancies (n = 3). A frozen section (FS) was performed in 36 patients, impacting management in 10 (27.8%) by avoiding (n = 1) or mandating a liver resection (n = 9). Frozen section results were always concordant with final pathology. Upon blind review, a solitary lesion, suspicious intracystic component, septation and biliary dilatation were associated with BCT (P < 0.05). Diagnostic sensitivity was high (87.5-100%) but specificity was poor (43.1-53.4%). The diagnostic value of imaging was most accurate when negative for BCT (negative predictive value: 92.5-100%). CONCLUSION: Radiological assessment of hepatic cysts is relatively inaccurate as SLC frequently present with concerning features. In the absence of a strong suspicion of malignancy, fenestration and FS should be considered prior to a complete resection.

Detailed pathologic characteristics of the primary colorectal tumor independently predict outcome after hepatectomy for metastases.

INTRODUCTION: Outcome after hepatic resection for colorectal cancer liver metastases (CRLM) is heterogeneous and accurate predictors of survival are lacking. This study analyzes the prognostic relevance of pathologic details of the primary colorectal tumor in patients undergoing hepatic resection for CRLM. METHODS: Retrospective review of a prospective database identified patients who underwent resection for CRLM. Clinicopathological variables were investigated and their association with outcome was analyzed. RESULTS: From 1997-2007, 1,004 patients underwent hepatic resection for CRLM. The median follow-up was 59 months with a 5-year survival of 47%. Univariate analysis identified nine factors associated with poor survival; three of these related to the primary tumor: lymphovascular invasion (LVI, p<0.0001), perineural invasion (p=0.005), and degree of regional lymph node involvement (N0 vs. N1 vs. N2, p<0.0001). Multivariate analysis identified seven factors associated with poor survival, two of which related to the primary tumor: LVI (hazard ratio (HR) 1.3, 95% confidence interval (CI) 1.06-1.64, p=0.01) and degree of regional lymph node involvement [N1 (HR 1.3, 95% CI 1.04-1.69, p=0.02) vs. N2 (HR 1.7, 95% CI 1.27-2.21, p<0.0005)]. A significant decrease in survival along the spectrum of patients ranging from LVI negative/N0 to LVI positive/N2 was present. Patients who were LVI-positive/N2 had a median survival of 40 months compared with 74 months for patients who were LVI-negative/NO (p<0.0001). CONCLUSIONS: Histopathologic details of the primary colorectal tumor, particularly LVI and the detailed assessment of the degree of lymph node involvement, are strong predictors of survival. Future biomarker studies should consider exploring factors related to the primary colorectal tumor.

Patterns of recurrence after ablation of colorectal cancer liver metastases.

PURPOSE: To determine the local recurrence rate and factors associated with recurrence after intraoperative ablation of colorectal cancer liver metastases. METHODS: A retrospective analysis of a prospectively maintained database was performed for patients who underwent ablation of a hepatic colorectal cancer metastasis in the operating room from April 1996 to March 2010. Kaplan-Meier survival curves and Cox models were used to determine recurrence rates and assess significance. RESULTS: Ablation was performed in 10% (n = 158 patients) of all cases during the study period. Seventy-eight percent were performed in conjunction with a liver resection. Of the 315 tumors ablated, most tumors were ≤ 1 cm in maximum diameter (53%). Radiofrequency ablation was used to treat most of the tumors (70%). Thirty-six tumors (11%) had local recurrence as part of their recurrence pattern. Disease recurred in the liver or systemically after 212 tumors (67%) were ablated. On univariate analysis, tumor size greater than 1 cm was associated with a significantly increased risk of local recurrence (hazard ratio 2.3, 95% confidence interval 1.2-4.5, P = 0.013). The 2 year ablation zone recurrence-free survival was 92% for tumors ≤ 1 cm compared to 81% for tumors >1 cm. On multivariate analysis, tumor size of >1 cm, lack of postoperative chemotherapy, and use of cryotherapy were significantly associated with a higher local recurrence rate. CONCLUSIONS: Intraoperative ablation appears to be highly effective treatment for hepatic colorectal tumors ≤ 1 cm.

Outcome of metastatic GIST in the era before tyrosine kinase inhibitors.

BACKGROUND: Treatment of metastatic GIST with imatinib mesylate results in a 2-year survival of approximately 72%. The outcome of patients with metastatic GIST not treated with tyrosine kinase inhibitors is not well defined. METHODS: One hundred nineteen patients with metastatic GIST diagnosed prior to July 1, 1998 (approximately 2 years prior to the use of imatinib for GIST) were identified from an institutional database of patients with pathologically confirmed GIST. Mutational analysis was performed in cases with available tissue. The log rank test and Cox regression models were used to assess prognostic factors. RESULTS: Median survival was 19 months with a 41% 2-year survival and a 25% 5-year survival. Resection of metastatic GIST was performed in 81 patients (68%), while 50 (42%) received conventional chemotherapy. Twelve patients (10%) were eventually started on imatinib. Primary tumor size <10 cm, <5 mitoses/50 HPF in the primary tumor, epithelioid morphology, longer disease-free interval, and surgical resection were independent predictors of improved survival on multivariate analysis. Mutational status did not predict outcome. In patients who underwent resection, the 2 year survival was 53%, and negative microscopic margins also independently predicted improved survival. CONCLUSIONS: Treatment with imatinib appears to improve 2-year survival of metastatic GIST by approximately 20% when compared to surgery alone. The combination of imatinib and surgery for the treatment of metastatic GIST therefore warrants investigation.