Synchronous Colorectal Cancer: Improving Accuracy of Detection and Analyzing Molecular Heterogeneity-The Main Keys for Optimal Approach

Abstract

Background: In patients with synchronous colorectal cancer (SCRC), understanding the underlying molecular behavior of such cases is mandatory for designing individualized therapy. The aim of this paper is to highlight the importance of transdisciplinary evaluation of the pre- and post-operative assessment of patients with SCRCs, from imaging to molecular investigations.

Methods: Six patients with SCRCs presented with two carcinomas each. In addition to the microsatellite status (MSS), the epithelial mesenchymal transition was checked in each tumor using the biomarkers β-catenin and E-cadherin, same as KRAS and BRAF mutations.

Results: In two of the patients, the second tumor was missed at endoscopy, but diagnosed by a subsequent computed-tomography-scan (CT-scan). From the six patients, a total of 11 adenocarcinomas (ADKs) and one squamous cell carcinoma (SCC) were analyzed. All the examined carcinomas were BRAF-wildtype microsatellite stable tumors with an epithelial histological subtype. In two of the six cases, KRAS gene status showed discordance between the two synchronous tumors, with mutations in the index tumors and wildtype status in the companion ones.

Conclusions: Preoperative CT-scans can be useful for detection of synchronous tumors which may be missed by colonoscopy. Where synchronous tumors are identified, therapy should be based on the molecular profile of the indexed tumors.

Keywords: BRAF; E-cadherin; KRAS; colorectal cancer; microsatellite status; synchronous tumors.

Figure 1

Case No. 1: synchronous cecal and rectal tumor. Circumferential thickening with inhomogenous enhancement and showing infiltration of the mesenteric fat at the level of the caecum (white arrow). Suspected lymph nodes (LNs) are visible on pelvic MRI scan, T2 weigthed FRFSE axial (A) and sagital (B) view. They are also marked on contrast-enhanced abdominal CT scan, venous phase, axial view (C). (D)—Based on imagistic aspects, the map of nodal stations is edited—adapted with permission from Yamamoto S et al. [14]—black circle—visible LN stations, without suspicious criteria; red circle- suspect LN stations. Table: imagistic-histopathological correlation of node stations. The two suspicious LN in 201 nodal station were negative by pathologic report. The perirectal tumor deposit was imagistically detected as suspected for LN metastasis.

Figure 2

Case No. 2: synchronous cecal and rectal tumor. LNs can be seen on an abdominopelvic contrast-enhanced CT scan, venous phase, axial (A,B) and coronal view (C). No suspected LNs are detected. (D)—The map of LN stations—black circles emphasize LN stations, without suspicious features. Table: correlation of LN stations, based on imaging studies and pathological reports. Imaging did not detect any suspicious LNs that was confirmed by pathology report.

Figure 3

Case No. 4: synchronous sigmoid ADK and SCC of the anal canal. Circumferential thickening with inhomogeneous enhancement at the level of sigmoid, proves infiltration of the mesenteric fat (white arrow). Perisigmoid and inferior mesentery LN stations were seen on contrast-enhanced CT, venous phase, axial views (A,C). The tumor mass in the anal region shows heterogenous enhancement in the arterial phase (B), with no visible LNs. (D) A map of nodal stations involved was made: black circle—visible LN, without suspicious features; red circle—suspicious LN for malignancy. Table: map correlation showed that positive LN was successfully detected on CT scan.

Figure 4

Case No. 5. Two synchronous sigmoid tumors. Parietal thickening of the colic wall with contrast-enhancement (white arrows), infiltration of pericolic fat. Association of regional LNs (yellow circle), some with suspicious criteria, seen on contrast-enhancement CT scan, venous-phase, axial-views (A,B) and sagittal view (C). A map of nodal stations was made: black circle: visible, non-suspicious LNs, red circle: suspicious LNs (D). Table: correlation of LNs stations - two of the four suspect LNs were positive, both of them found in the index tumor.

Figure 5

Case No. 6. Synchronous sigmoid and cecal tumors (white arrow), seen on contrast-enhanced CT scan, venous phase, axial views (A,B) and coronal view (C), with infiltration of pericolic fat, regional LNs (yellow circle) and left fallopian tube metastasis (white arrow-head). Map of nodal stations shows nodal stations with suspect LNs (rec circle) and nodal stations with visible LNs, without suspicious criteria (D). Table: correlation of suspect nodal stations with LN metastasis.

Figure 6

The microsatellite stable status is immunohistochemically proved by nuclear expression of MLH1 (A), MSH2 (B), PMS2 (C) and MSH6 (D).

Figure 7

Histological aspect, correlated with the molecular subtype determined with E-cadherin and β-catenin. All tumors expressed membranar E-cadherin and β-catenin in the tumor core (A–F). In the epithelial subtype, the membrane expression of E-cadherin (B) and beta-catenin (C) can be seen in both tumor core and invasion area (buds). The hybrid molecular subtype is characterized by membranar expression of E-cadherin and beta-catenin in the tumor core (E,F) with nuclear positivity of β-catenin in the buds (F).