Metachronous Carcinogenesis Research Articles

A long-term survivor after radical surgery in early childhood for biliary tract cancer associated with congenital biliary dilatation despite a positive margin for epithelial carcinoma

We previously reported the case of a three-year-old patient with extrahepatic bile-duct cancer with congenital biliary dilatation (CBD), representing the youngest patient reported thus far with this disease. After surgery, a histopathologic examination confirmed well-differentiated adenocarcinoma with fibromuscular invasion and vascular infiltration, and the cut stump was positive for carcinoma -in-situ (CIS) at both the hepatic and distal margin of the bile duct. Since the patient was young, no additional therapy was selected after the surgery, and we have carefully followed the patient for more than 10 years with imaging and hematological examinations. To date, no abnormalities have been observed in his liver function, CA19-9 levels, or MRCP findings, and he has survived without recurrence for over 13 years since the surgery. A molecular biological reexamination of the initial resected specimen revealed that the cancer cells had no mutations in Kras codon 12, 13, 59, 61, 117, or 146 or Braf. The course of this case demonstrated the validity of surgery for pediatric biliary tract cancer associated with CBD. Furthermore, it was revealed that the positive resection margin in CIS of cholangiocarcinoma does not always recur even after a long period of time. However, the possibilities of late term recurrence of the disease and metachronous carcinogenesis at residual biliary tract still remain, so lifelong follow-up will be required for the patient.

Comprehensive risk evaluation for metachronous carcinogenesis after endoscopic submucosal dissection of superficial pharyngeal squamous cell carcinoma.

Pharyngeal squamous cell carcinoma (PSCC) is associated with a high likelihood of metachronous carcinogenesis, which is known to have a poor prognosis. This study aimed to identify comprehensive risk evaluation indicators for metachronous carcinogenesis after endoscopic submucosal dissection (ESD) of superficial PSCC. The risk of metachronous carcinogenesis was evaluated in 144 patients with superficial PSCC (with no history of PSCC or esophageal squamous cell carcinoma) who underwent initial ESD from 2008 to 2020. Multiple lugol-voiding lesions (LVLs) in the background pharyngeal and esophageal epithelium were evaluated as endoscopic indicators. The hemoglobin, albumin, lymphocyte, and platelet (HALP) score was analyzed as a serum marker. The median follow-up period was 4.3years. The coincidence rate for pharyngeal and esophageal LVL grade was 55%. The cumulative 3-year metachronous PSCC rate was 18.9%. The cumulative 3-year second metachronous PSCC rate was 43.9%. Forward stepwise multivariate Cox proportional hazards regression analysis identified pharyngeal LVL grade and a lower HALP score as significant independent predictors. Pharyngeal LVL grade was superior to esophageal LVL grade as a predictor of metachronous PSCC. A lower HALP score was significantly associated with younger age in forward stepwise multivariate logistic regression analysis. Patients with a history of superficial PSCC remain at risk for metachronous carcinogenesis over time, and long-term follow-up is imperative. Comprehensive evaluation of endoscopic features with a novel serum marker, namely, the HALP score, can help predict metachronous carcinogenesis.

Metachronous carcinogenesis of superficial esophagus squamous cell carcinoma after endoscopic submucosal dissection: incidence and risk stratification during long-term observation.

This study aimed to reveal long-term outcomes, such as incidence of metachronous esophageal and head and neck squamous cell carcinomas and overall survival rate, through long-term observation of patients with esophageal carcinoma post-endoscopic submucosal dissection. Risk of metachronous carcinogenesis was evaluated in 88 patients with intramucosal esophageal carcinoma (without history of metachronous esophageal or head and neck squamous cell carcinomas) who underwent endoscopic submucosal dissection from 2007 to 2008 and were endoscopically observed for > 3years. Histologically, the papillary vessel is defined as the clock gear-like structure composed of capillaries directly penetrating the epithelium (starting from the lamina propria) and covering at least two-thirds of it, around which the tumor cells are arranged in a spiral pattern. Median endoscopic follow-up period was 11.0years. Cumulative 2-, 5-, and 10-year metachronous esophageal carcinoma rates were 11.4%, 20.6%, and 39.3%, respectively. Stepwise multivariate Cox proportional hazard regression analysis identified multiple Lugol-voiding lesions (LVLs) as the single significant independent predictor. Cumulative 2-, 5-, and 10-year metachronous head and neck squamous cell carcinoma rates were 6.9%, 10.4%, and 19.6%, respectively. Stepwise multivariate Cox proportional hazard regression analysis identified multiple LVLs, Brinkman index, papillary vessel, and younger age as significant predictive factors. Overall post-endoscopic submucosal dissection survival rates were 98.8% and 87.5% at 5 and 10years, respectively. Patients with a history of esophageal carcinoma remain at risk for metachronous carcinogenesis even > 5years after endoscopic submucosal dissection. Thus, long-term follow-up is important.

Microsatellite Instability did not Confer Protection Towards Anastomotic Recurrence of Colorectal Cancer

The role of microsatellite instability (MSI) in protecting against recurrence after colorectal resection is controversial. This case report adds to the evidence that MSI does not confer protection towards anastomotic recurrence of colorectal cancer, questioning the potential of using MSI status to identify patients that could be treated by surgery alone. A 58-year-old woman with poorly differentiated pT4aN0 adenocarcinoma requiring a right hemicolectomy 3 months prior presented with 1 day of hematochezia. Immunohistochemical stains for mismatch repair showed loss of MLH1 and PMS2, with retention of MSH2/MSH6, suggestive of Lynch syndrome. On presentation, the patient's hemoglobin was 6.3 g/dl from a baseline of 9g/dl 3 weeks prior. She underwent a colonoscopy that revealed a prolapsed ulcerated ileocecal end-to-side anastomosis with spontaneous oozing (Figure 1). Biopsy of the ulcerated mucosa revealed recurrent adenocarcinoma. Repeated resection with pathology revealed a pT2, N1b high-grade medullary carcinoma with involvement of 2 regional lymph nodes. She was started on adjuvant Nivolumab. Colonoscopy 3 months after the second resection revealed no recurrence on pathology. A recent study demonstrated that 21% of malignant recurrences occur at the anastomotic site, and several case reports have shown repeated anastomotic recurrences. Malignant anastomotic recurrences may result from positive distal margins, metachronous carcinogenesis, or implantation of exfoliated tumor cells during surgery. In this case, the latter was most likely given the negative margins on resection and a short interval to recurrence. The association of MSI and enhanced survival and protection against recurrence after resection remains widely debated. While some meta-analyses have showed evidence of a strong association, a recent study published in 2017 demonstrated no association between MSI and recurrence. Our case report supports the latter finding. Few studies are available to analyze the role of MSI in metastatic diseases as fewer than 5% of patients have MSI-associated metastatic colorectal cancer. In conclusion, our case report adds to the accumulating evidence that MSI likely does not offer protection against recurrence after resection.Figure: Interval colonoscopy on presentation with hematochezia: prolapsed end-to-side anastomosis was prolapsed with active oozing and friability.

Two Case Reports of Resectable Cancer in the Remnant Pancreas after Pancreatectomy for Invasive Ductal Carcinoma of the Pancreas

Pancreatic cancer has an extremely poor prognosis. There are several reports on resectable cancer in the remnant pancreas after pancreatectomy; however, few have compared K-ras mutation patterns to clarify recurrent or second primary cancers. Here, we report on 2 cases of cancer in the remnant pancreas after total pancreatectomy for invasive ductal carcinoma. Case 1 is a 56-year-old man who underwent pancreaticoduodenectomy for cancer of the pancreatic head. However, serum carbohydrate antigen (CA19-9) was again elevated 23 months later. A tumor in the pancreatic tail was detected on abdominal computed tomography (CT), and total pancreatectomy was performed. Histologic examination of the tumors from both operations revealed moderately differentiated adenocarcinoma, and the surgical margins of both resected specimens were free of cancerous cells. The K-ras gene mutation was detected at codon 12V of exon 1 in both cancers. Case 2 is a 72-year-old woman who underwent distal pancreatectomy for cancer of the pancreatic body. However, serum CA19-9 was again elevated 4 years postoperatively. A tumor of the pancreatic head was detected on abdominal CT, and total pancreatectomy was performed. Histologic examination of the first and second tumors revealed poorly and moderately differentiated adenocarcinomas, respectively. The surgical margins of both resected specimens were free of cancerous cells. The K-ras gene mutation was detected at codon 12D of exon 1 in both cancers. These patients with rare pancreatic cancers both had metachronous carcinogenesis in the remnant pancreas.

Anastomotic recurrence of colon cancer: Genetic analysis challenges the widely held theories of cancerous cells' intraluminal implantation and metachronous carcinogenesis.

Anastomotic recurrence (AR), whose etiopathogenesis is attributed to intraluminal implantation of cancerous cells or metachronous carcinogenesis, is a major issue for patients undergoing colon cancer (CC) resection. The objective of the study is to throw some light on AR etiopathogenesis and to identify risk factors of AR in selecting patients to undergo early endoscopy. An analysis of clinical and histopathological parameters, including MSI and LOH of seven sites (Myc-L, BAT26, BAT40, D5S346, D18S452, D18S64, D16S402) was performed in primary CC and AR of 18 patients. They were then compared to 36 controls not developing AR. A genetic instability was present in 16/18 patients, with distinct genetic patterns between primaries and ARs. LOH at 5q21 and/or 18p11.23 were found in both primary and AR in >50% of cases, but this rate was no different from control population. CEA resulted as associated with AR (P = 0.03), whereas N status presented a borderline result (P = 0.08). Our findings challenge present theories about AR development. No "genetic marker" has been found. CEA and, to a lesser extent, N status, appear associated with AR. Rectal washout is seemingly meaningless. Iterative resection should be recommended since a long survival may be expected. J. Surg. Oncol. 2016;114:228-236. © 2016 Wiley Periodicals, Inc.

Sa1567 The Possibility of Chemo-Radiotherapy for Prevention of Metachronous Carcinogenesis of Esophageal Carcinoma

With the advancing of endoscopic treatment, many superficial esophageal carcinomas with the potential of lymph node metastasis have been treated by endoscopic procedure. However metachronous carcinogenesis was very serious problem. The aim of this study was to evaluate the utility of chemo-radiotherapy for the prevention of metachronous carcinogenesis after endoscopic treatment.

Repeated anastomotic recurrence of colorectal tumors: Genetic analysis of two cases

To investigate genetics of two cases of colorectal tumor local recurrence and throw some light on the etiopathogenesis of anastomotic recurrence. Two cases are presented: a 65-year-old female receiving two colonic resections for primary anastomotic recurrences within 21 mo, and a 57-year-old female undergoing two local excisions of recurrent anastomotic adenomas within 26 mo. A loss of heterozygosity (LOH) study of 25 microsatellite markers and a mutational analysis of genes BRAF, K-RAS and APC were performed in samples of neoplastic and normal colonic mucosa collected over the years. A diffuse genetic instability was present in all samples, including neoplastic and normal colonic mucosa. Two different patterns of genetic alterations (LOH at 5q21 and 18p11.23 in the first case, and LOH at 1p34 and 3p14 in the second) were found to be associated with carcinogenesis over the years. A role for the genes MYC-L (mapping at 1p34) and FIHT (mapping at 3p14.2) is suggested, whereas a role for APC (mapping at 5q21) is not shown. The study challenges the most credited intraluminal implantation and metachronous carcinogenesis theories, and suggests a persistent, patient-specific alteration as the trigger of colorectal cancer anastomotic recurrence.

Primary jejunal adenocarcinoma as part of multiple primary cancers of the digestive tract

Multiple primary cancers including small intestinal tumors are rare. We describe the first curative resection case of metachronous triple early cancers involving the jejunum as well as the stomach and esophagus. The patient had undergone total gastrectomy for a gastric adenocarcinoma and subsequent esophagectomy for an esophageal squamous cell carcinoma. A jejunal adenocarcinoma, the third primary, occurred at the blind stump of the jejunal limb of a Roux-en-Y esophagojejunostomy reconstructed previously. This tumor was removed by partial resection of the limb with the preservation of the esophagojejunostomy. The patient died from complications of acute pancreatitis 3 years after the last operation, without overt clinical signs of cancer recurrence. Immunohistochemistry of the specimen showed the increased expression of p53 and cyclin D1 proteins in all three cancers, suggesting their involvement in metachronous carcinogenesis in this case. Early diagnosis of each cancer was made possible by regular endoscopic follow-up and favorable anatomical location of each tumor, which were considered to allow less invasive surgery as well as to contribute to the favorable outcome. This case suggests the importance of regular surveillance for metachronous carcinogenesis, especially when the preceding cancers carry genetic abnormalities that may potentially increase the risk for subsequent carcinogenesis.

PANCREATIC CARCINOMA IN THE PANCREATICOGASTROSTOMY SITE AFTER PYLORUS-PRESERVING PANCREATODUODENECTOMY FOR IPMN

: We report a case of pancreatic carcinoma in the pancreaticogastrostomy site after pylorus-preserving pancreatoduodenectomy (PPPD). A 57-year-old man who had undergone PPPD for intraductal papillary mucinous neoplasm (IPMN) of the pancreatic head 11 years before was admitted to our hospital for surgical treatment of gastric carcinoma at the pancreaticogastrostomy site. Reconstruction after the PPPD had been done by pancreaticogastrostomy, end-end duodenojejunostomy, and end-side choledochojejunostomy. The histopathological diagnosis had been papillary adenoma. We performed en bloc resection of the distal stomach, the remnant pancreas 3 cm from the junction of the pancreaticogastrostomy and a small part of the transverse colon, then reconstructed using Whipple's procedure. Histopathological examination showed moderately differentiated tubular adenocarcinoma of the remnant pancreas. Metachronous carcinogenesis in the pancreaticogastrostomy site after PPPD for IPMN is rare, and a very careful follow-up is necessary for a long period after the first operation.

A repeated pancreatectomy in the remnant pancreas 22 months after pylorus-preserving pancreatoduodenectomy for pancreatic adenocarcinoma

We report a case of a repeated curative pancreatic resection in the remnant distal pancreas 22 months after pylorus-preserving pancreatoduodenectomy (PpPD). The patient was a 52-year-old woman with a past history of PpPD for adenocarcinoma of the head of the pancreas 22 months prior to the present operation. The original tumor was histopathologically diagnosed as a papillary adenocarcinoma with clear surgical margin at the surgical cut end of the pancreas (R0, International Union Against Cancer [UICC] classification). Twenty months after the PpPD, a follow-up computed tomography (CT) scan showed multiple low-density lesions in the body and tail of the pancreas without any other distant metastasis. A second operation, curative resection of the remnant pancreas, with splenectomy and distal gastrectomy, was performed. The second tumor was a papillary adenocarcinoma, the same diagnosis as that of the first tumor, and it also showed similar histopathological findings, including immunohistochemical staining of Ki-67 and p53 protein, and the same pattern of K-ras point mutation. The patient is considered to have shown a rare, unique pancreatic cancer with metachronous carcinogenesis in the remnant pancreas.

Evolution of and obstacles in surgical treatment for hepatocellular carcinoma over the last 25 years: differences over four treatment eras.

This study was designed to clarify what differences the last 25 years have made in surgical results for patients with hepatocellular carcinoma (HCC). We examined results for 716 hepatectomized patients in four treatment eras: first era (1973-1980; n = 58), second era (1981-1985; n = 155), third era (1986-1990; n = 243), and fourth era (1991-1997; n = 260). Patient background, tumor characteristics, type of hepatectomy, treatment for intrahepatic recurrences, and surgical results in the four eras were compared by univariate analysis to clarify the factors that have contributed to or impeded progress in the surgical treatment of HCC. Although there were no significant chronological differences in liver pathology and surgical resectability, operative mortality was reduced to 2% in the fourth era, from 29% in the first era. With an increasing proportion of early-stage HCCs (TNM, stages I and II), the cumulative survival rate at 5 years improved in the course of the eras in our overall population of patients (12%, 31%, 38%, and 51%, respectively, for the first, second, third, and fourth eras) and in a subset of the population divided according to tumor stage. Also, we found a chronological improvement in the survival rate at 3 years after intrahepatic recurrence (10%, 28%, 36%, and 44%, respectively in the first second, third, and fourth eras). This improvement was associated with the establishment of an early detection program for intrahepatic recurrences. However, the recurrence rate was similar in any subset of the population through the four eras. Although this univariate study could not determine independent factors that contributed to the chronological progress in results for HCC surgery in the four eras, it is conceivable that the establishment of indication criteria for hepatectomy, an early detection program for primary and recurrent lesions, and the introduction of multimodal treatment for recurrence were contributory factors in this improvement. A strategy for alleviating the frequent recurrences originating from posthepatectomy metachronous carcinogenesis remains to be established.

Viral serostatus and coexisting inflammatory activity affect metachronous carcinogenesis after hepatectomy for hepatocellular carcinoma. A further report.

Little data are available regarding the effects of hepatitis virus serostatus and the severity of coexisting chronic inflammation on intrahepatic recurrence after hepatectomy for hepatocellular carcinoma (HCC). We investigated the extent to which these factors modified the prognosis of hepatectomized patients. A total of 274 patients treated in the period January 1981 to December 1996 were divided into three groups: antihepatitis C-positive (HCV; n = 144), hepatitis B surface antigen-positive and HCV antibody (Ab)-negative (HBsAg; n = 106), and HBsAg-negative and HCV Ab-negative (NBNC; n = 20). Positivity for HBV-related antibody in the HCV group was 76%. Histologic grading of inflammatory activity from coexisting hepatitis was determined according to Knodel's histological activity index (HAI) scoring system. Post-hepatectomy crude survival rates and disease-free survival (DFS) rates were compared, according to tumor characteristics, between the three groups. In the patients overall and also in the patients with a single nodular HCC, the HCV group had significantly higher HAI scores and preoperative serum aspartate aminotransaminase (AST) levels than the other two groups. When the patients were limited to those with a single nodular HCC, the crude survival was similar in the three groups with comparable tumor characteristics; however, the DFS was different (NBNC > HBsAg > HCV). When the patients were further limited to those with a single nodular HCC without microscopic extracapsular spread, in whom removal of the tumor was expected to be microscopically complete, the difference in the DFS became more marked. Irrespective of the viral serostatus, better crude and disease-free survivals were observed in the patients with lower AST levels (< or =50 IU/ 1) than in those with higher AST levels (>50IU/l). In contrast, there were no differences in survivals and HAI scores according to the presence or absence of HBV-related antibody in the HCV group. From our univariate analysis, we can conclude that the severity of virally induced inflammation, which was well correlated with viral serostatus, may be a factor that affects intrahepatic recurrence, which is more likely to originate from metachronous carcinogenesis. Prior co-infection of HBV in HCV patients may not be an adverse risk factor for intrahepatic recurrence.

The Influence of the Interaction of Sutures with the Mucosa on Tumour Formation at Colonic Anastomoses in Rats

In order to explore the respective role of wound healing and suture material on metachronous carcinogenesis at colonic lines in rats, tumour yield was studied after the administration of a chemical carcinogen (azoxymethane) at the moment that in one group of rats most of the suture material was still present and crypt cell proliferation elevated, while in another group, no more suture material was present and crypt cell proliferation rate (CCPR) normalized at the anastomotic site. Azoxymethane (15 mg/kg/week, s.c., during 6 weeks) was administered in male Sprague-Dawley rats (n = 105) 8 weeks after the creation of an anastomosis in the ascending and descending colon with either stainless steel sutures (group A, n = 30) or fast-absorption Vicryl (Vicryl Rapide, group B, n = 30). A control group (group C, n = 30) underwent a sham laparotomy before the administration of azoxymethane, while the animals of a fourth group (group D, n = 15) were not operated upon and received no azoxymethane. Twenty-six weeks after the first injection of azoxymethane there was no significant difference in the total colorectal tumour yield in the three operated groups (A, B, C), but a significantly greater proportion of anastomotic tumours (28/68 vs. 13/88, p < 0.01) and more anastomotic tumours per rat (28/23 vs. 13/28, p = 0.01) as well as more rats with anastomotic tumours (16/23 vs. 11/28, p = 0.04) were found in the steel-sutured group (A), compared with the control group (C).(ABSTRACT TRUNCATED AT 250 WORDS)