Histopathologic patterns as markers of prognosis in patients undergoing hepatectomy for colorectal cancer liver metastases – Pushing growth as an independent risk factor for decreased survival

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Abstract

Introduction

Liver resection combined with neoadjuvant chemotherapy (NAC) has reported notable results in patients with colorectal liver metastases (CRLM). Tumoral response to NAC is associated with specific histopathologic patterns with prognostic implications. The main objective of this study was to evaluate the influence of pathological findings on overall survival (OS), disease-free survival (DFS) and liver recurrence-free survival (LRFS).

Patients and methods

Analysis of clinical and outcome data from 110 patients who underwent first CRLM resection between January 2010 and July 2013. Blinded pathological review of histological material of several parameters: resection margin, tumor regression grade (TRG), tumor thickness at the tumor-normal interface (TTNI) and the growth pattern (GP).

Results

The median survival following hepatic resection was 52 months and 3- and 5- year Kaplan-Meier estimates were 69 and 48%, respectively. Seventy-four patients developed recurrent disease. Oxaliplatin-based chemotherapy was significantly associated with a pushing GP. A positive resection margin was an independent predictor of decreased DFS (p = 0.018) but not of decreased OS. LRFS was strongly reduced by the absence of histologic tumor response (p = 0.018). The pushing pattern had an adverse impact on both OS (p = 0.007) and DFS (p = 0.004) on multivariate analysis.

Conclusion

The prognostic value of histopathological features in patients who underwent CRLM's resection is undeniable. The pushing GP was related with worse prognosis. Further studies are required to clarify the biological mechanisms underlying these findings in order to enhance a more personalized and efficient treatment of these patients.

Introduction

Yearly, 1.2 million new cases of colorectal cancer (CRC) are diagnosed worldwide and around 50% of them will develop liver metastases [1]. Hepatic resection remains the most efficient treatment for these patients; however, a strategy combining surgery with neoadjuvant chemotherapy (NAC) has gained wide acceptance. Furthermore, some of those patients have initially unresectable metastases which can be resected after down-staging with conversion chemotherapy [2], [3], [4].

Several clinical variables have been identified as valuable predictors of recurrence and survival [5], [6].

Current research is focused on finding pathological indicators which may influence treatment response. The role of surgical margin on patients' outcome after colorectal liver metastases (CRLM) resection has been thoroughly investigated [7] and is still subject of debate [8], [9], [10]. Recently, new pathologic markers of prognosis have been described. Dipen Maru et al. [11] established a pathologic predictor of survival: the tumor thickness at the tumor-normal interface (TTNI); and Rubbia-Brant et al. [12] documented a pathological tumor regression grade (TRG) system for CRLMs according to the extent of fibrosis and the amount of residual tumor cells.

In 2001, Vermeulen et al. [13] carried out one of the most interesting studies in this area and described three histological CRLM growth patterns (GP) with different angiogenic and invasive potential.

Apart from the prediction of response to chemotherapy, these pathologic patterns can also reflect important tumor-host interactions, as spontaneous necrosis of tumor metastases has been described [14].

The primary purpose of this study was to estimate the value of pathological findings as prognostic factors, analyzing their impact on overall survival (OS), disease-free survival (DFS) and liver recurrence-free survival (LRFS). Secondarily, to evaluate the influence of NAC and clinical parameters on patient's outcome.

Section snippets

Study design

The present study reviews clinical and pathological data from a total of 142 patients who underwent hepatic resection for CRLM from January 2010 to July 2013 at our surgical department.

Demographic and clinical information were collected from patients' medical records. Six of these patients had insufficient clinical data and were excluded. Another six patients were not included due to inadequate histological material. Patients undergoing rehepatectomies (20 patients) were also excluded. The

Overall, disease-free and liver recurrence-free survival

After a median follow-up period of 31.7 months (range 0–72 months), 74 patients (67%) developed recurrent disease while the remaining 36 patients (33%) were recurrence-free.

The median survival following CRLM resection was 52 months, the 3 and 5-year overall survival was 68.5% and 47.5%, respectively, while 3 and 5-year disease-free survival was 29.9 and 21.7, respectively. Forty patients (36%) died of disease, 29 of them (73%) due to progression of liver metastases and 9 patients (23%) due to

Discussion

Metastatic spread to the liver of colorectal cancer is still a challenging disease. Significant host and tumor factors are at play and need to be considered for individualized multidisciplinary management. The design of this study aimed to identify pathological prognostic factors for these patients and to discuss its value on treatment decisions.

Recent studies proved the importance of chemotherapy as neoadjuvant approach [19], [20]. In our study NAC was provided to patients with more advanced

Conflicts of interest statement

The authors declare that they do not have any conflict of interests.

Acknowledgment

The authors wish to acknowledge the leadership, mentorship, personal warmth and dedication to the Science and Art of Surgery of Professor Francisco Castro e Sousa, who sadly passed away during the review process of this article.

References (41)

  • G. Folprecht et al.

    Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates

    Ann Oncol

    (2005)
  • B. Döme et al.

    Alternative vascularization mechanisms in cancer : pathology and therapeutic implications

    Am J Pathol

    (2007)
  • R. Siegel et al.

    Cancer statistics, 2012

    CA A Cancer J Clin

    (2012)
  • R. Adam et al.

    The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus

    Oncologist

    (2012)
  • R. Adam et al.

    Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival

    Ann Surg

    (2004)
  • H. Ito et al.

    Effect of postoperative morbidity on long-term survival after hepatic resection for metastatic colorectal cancer

    Ann Surg

    (2008)
  • R.H. Bhogal et al.

    Predictors of early recurrence after resection of colorectal liver metastases

    World J Surg Oncol

    (2015)
  • H. Ekberg et al.

    Determinants of survival in liver resection for colorectal secondaries

    Br J Surg

    (1986)
  • C. Are et al.

    The impact of margins on outcome after hepatic resection for colorectal metastasis

    Ann Surg

    (2007)
  • H. Tranchart et al.

    Prognostic impact of positive surgical margins after resection of colorectal cancer liver metastases: reappraisal in the era of modern chemotherapy

    World J Surg

    (2013)
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