Histopathological growth patterns as biomarker for adjuvant systemic chemotherapy in patients with resected colorectal liver metastases

Abstract

Adjuvant systemic chemotherapy (CTx) is widely administered in patients with colorectal liver metastases (CRLM). Histopathological growth patterns (HGPs) are an independent prognostic factor for survival after complete resection. This study evaluates whether HGPs can predict the effectiveness of adjuvant CTx in patients with resected CRLM. Two main types of HGPs can be distinguished; the desmoplastic type and the non-desmoplastic type. Uni- and multivariable analyses for overall survival (OS) and disease-free survival (DFS) were performed, in both patients treated with and without preoperative chemotherapy. A total of 1236 patients from two tertiary centers (Memorial Sloan Kettering Cancer Center, New York, USA; Erasmus MC Cancer Institute, Rotterdam, The Netherlands) were included (period 2000–2016). A total of 656 patients (53.1%) patients received preoperative chemotherapy. Adjuvant CTx was only associated with a superior OS in non-desmoplastic patients that had not been pretreated (adjusted hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.37–0.73, p < 0.001), and not in desmoplastic patients (adjusted HR 1.78, 95% CI 0.75–4.21, p = 0.19). In pretreated patients no significant effect of adjuvant CTx was observed, neither in the desmoplastic group (adjusted HR 0.83, 95% CI 0.49–1.42, p = 0.50) nor in the non-desmoplastic group (adjusted HR 0.96, 95% CI 0.71–1.29, p = 0.79). Similar results were found for DFS, with a superior DFS in non-desmoplastic patients treated with adjuvant CTx (HR 0.71, 95% CI 0.55–0.93, p < 0.001) that were not pretreated. Adjuvant CTx seems to improve OS and DFS after resection of non-desmoplastic CRLM. However, this effect was only observed in patients that were not treated with chemotherapy.

Clinico‐metabolic characterization improves the prognostic value of histological growth patterns in patients undergoing surgery for colorectal liver metastases

“…Of note, the use of other cut‐offs for HGP categorization, such as desmoplastic features at more than 95%, more than 66% or more than 50% of the TLI, is not associated with an improvement of the prognostic value (data not shown). This result should be interpreted taking into account the fact that a high proportion of patients in the current series received preoperative chemotherapy, a factor that has been shown to increase the ratio of DHGP, while decreasing its intrinsic favorable prognostic value 48,49 . This selection bias in our patient population is due to the fact that we routinely use 18 F‐FDG/PET‐CT to evaluate the response to chemotherapy.…”

“…This result should be interpreted taking into account the fact that a high proportion of patients in the current series received preoperative chemotherapy, a factor that has been shown to increase the ratio of DHGP, while decreasing its intrinsic favorable prognostic value. 48,49 This selection bias in our patient population is due to the fact that we routinely use 18 F-FDG/PET-CT to evaluate the response to chemotherapy. The limited number of patients without chemotherapy before liver resection does not allow comparing the respective prognostic value of HGPs in patients with or F I G U R E 2 Distribution of HGP: Ranking based on percentage desmoplastic HGP.…”

“…An additional caveat of our study is that chemotherapy can change the HGP of a CRLM as has been suggested by several authors. 22,48 Given that the assessment of the mCRS occurs before and the HGP scoring after the administration of chemotherapy, the analyses of the association between these two parameters (Table 2) might have been affected by HGP conversion, for example, from replacement to desmoplastic, in some patients. The elevated preoperative FDG uptake by liver metastases with a postoperative non-DHGP is, however, to be expected, as the replacement HGP is composed of less-differentiated carcinoma with an efficient blood supply by vessel co-option.…”

The Tumor Microenvironment in Liver Metastases from Colorectal Carcinoma in the Context of the Histologic Growth Patterns

“…The relevance of these distinct HGPs falls in their possible utility as a prognostic and predictive tool, due to its numerously described association with tumor recurrence and overall survival [10,[16][17][18] as well as prediction of response to anti-angiogenic therapies [12]. On this matter, patients who present a predominantly desmoplastic growth pattern have superior survival after resection with curative intent when compared with patients presenting the replacement type [9][10][11]16,18,19]. Although a significant percentage of patients present a mixed pattern, with dHGP and non-dHGP areas, the most favorable prognosis is in those patients who present a pure dHGP pattern, complete throughout the entire liver-tumor interface [10].…”

“…On the other hand, liver metastases have displayed a unique histologic feature, a histologic growth pattern (HGP) [9], that will be described in more detail in the next section ( Figure 1). Interestingly, these HGPs displayed prognostic [10,11] and predictive [12] value, suggesting that possibly intratumoral CAFs and peritumoral CAFs are exerting different functions that could be a consequence of either different origins or different cellular precursors, or particular responses of the host against the tumor type.…”