Aberrant Partial Chromosomal Instability With Chemotherapeutically Resistant Metachronous Colorectal Cancer Following a Synchronous Primary Colorectal Cancer: A Case Report

Abstract

The diagnosis of synchronous colorectal cancer (CRC) is crucial as the management, including the extent of surgical resection, depends on it. There have been numerous studies on the clinicopathological features of synchronous CRC; however, only a few studies have discussed synchronous cancer treatment. The guidelines to best manage the synchronous and metachronous CRC are limited, especially the most appropriate surgical treatment and chemotherapy based on mutational analysis of mismatch repair genes and the carcinoma sequence model. We present a rare case of a metachronous CRC with intact nuclear expression of microsatellite instability markers following a synchronous CRC, and it failed to show any significant response to surgical resection and chemoradiotherapy. A 53-year-old female presented in June 2016 with bleeding per rectum for one month, weight loss, and a recent history of altered bowel habits. The per rectal examination revealed a circumferential growth. Colonoscopy and biopsy yielded multiple polyps throughout the colon and invasive adenocarcinoma in the upper and lower one-third of the rectum. The above features were highly suggestive of synchronous CRC. Serologic studies revealed elevated carcinoembryonic antigen (CEA). Excisional biopsy of mesenteric and retroperitoneal lymph nodes during proctocolectomy and end ileostomy was negative for metastasis, including the other metastatic workup preoperatively-eight months post-resection and adjuvant chemotherapy patient developed metachronous CRC. Mutational analysis showed positivity only for adenomatous polyposis coli (APC) while negative for KRAS, NRAS, and BRAF. Immunohistochemistry (IHC) markers for mismatch repair (MMR) proteins showed intact protein expression. The patient was given multiple chemotherapy cycles throughout her course, including oral capecitabine, XELOX (capecitabine + oxaliplatin), cetuximab-capecitabine, cetuximab-irinotecan, and FOLFIRI (5-fluorouracil [5-FU] + irinotecan + folinic acid)-bevacizumab, as is the standard chemotherapy regimen for these tumors. The diagnosis of metachronous CRC with intensive follow up is crucial. IHC markers for MMR proteins showed intact protein expression ruling out the possibility of microsatellite instability and Lynch Syndrome. The only presence of APC mutation indicates a partial chromosomal instability. During the course, the patient had either stable size of the masses or developed new metastatic growth despite intensive chemotherapeutic regimes. Unfortunately, there are no precise guidelines based on aberrant mutational analysis regarding synchronous and metachronous CRCs management.

Keywords: capecitabine; cetuximab; chemotherapeutic resistance; chromosomal instability; irinotecan; metachronous colorectal cancer; metastatic colorectal cancer; microsatellite instability; primary colorectal cancer; synchronous colorectal cancer.

Figure 1. (a) Contrast-enhanced CT abdomen image shows solitary hepatic metastasis. (b) Corresponding fused PET-CT image shows a metabolically active hypodense lesion of size 16 x 14 mm in segment II/III of the left lobe of the liver (standardized uptake value [SUV] Max = 5.5).

PET-CT, positron emission tomography-computed tomography.

Figure 2. (a) Contrast-enhanced CT abdomen image shows gastric serosal deposits. (b) Corresponding fused PET-CT image shows gastric serosal deposits. A peritoneal nodule of size 25 x 20 mm is noted abutting the greater curvature of the stomach with mild metabolic activity.

PET-CT, positron emission tomography-computed tomography.

Figure 3. (a) Contrast-enhanced CT abdomen image shows mesenteric lesions with peritoneal fat stranding. (b) Corresponding fused PET-CT image shows patchy areas of soft tissue thickening in the mesentery adjacent to the ileostomy site with mild increased metabolic activity, measuring ~ 28 x 18 mm (standardized uptake value [SUV] Max = 1.5).

PET-CT, positron emission tomography-computed tomography.

Figure 4. (a) Contrast-enhanced CT abdomen image shows a new solitary hepatic metastasis in the left lobe of the liver. (b) Corresponding fused PET-CT image shows a new metabolically active hypodense lesion of size 20 x 16 mm in the left lobe of the liver.

PET-CT, positron emission tomography-computed tomography.

Figure 5. (a) PET-CT shows hepatic metastasis in the left lobe of the liver. (b) PET-CT shows hepatic metastasis in the right lobe of the liver. (c) PET-CT shows stable hepatic metastasis in the right lobe of the liver.

PET-CT, positron emission tomography-computed tomography.

Figure 6. Adenoma–carcinoma sequence model for microsatellite and chromosomal instability in colorectal cancer. This model is likely to be an oversimplification. Still, it represents the clinicopathological changes with genetic abnormalities in the progression of chromosomally unstable colorectal cancer (CRC) (the gatekeeper pathway involving genes that regulate cell growth).

From [7].