June 6, 2019

Should We Rethink Cancer Risk Staging in Familial Adenomatous Polyposis?

Research examines risk factors


The presence of Spigelman stage (SS) IV duodenal polyposis is considered the most significant risk factor for duodenal cancer in patients with familial adenomatous polyposis (FAP).


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But recent Cleveland Clinic research highlights the inconsistency of SS as a cancer prediction risk indicator; more than half of FAP patients diagnosed with duodenal cancer in the case-control study lacked SS IV duodenal polyposis.

The results suggest that certain individual characteristics of duodenal polyps in FAP patients have heightened significance in predicting cancer risk, irrespective of stage, and that the formula for staging duodenal polyposis may need to be adjusted to take that into account, rather than focusing solely on the presence or absence of SS IV disease.

“Traditionally, SS IV polyposis has been a trigger for offering prophylactic duodenal surgery to prevent duodenal cancer in FAP,” says study co-author Carol Burke, MD, Vice Chair of Cleveland Clinic’s Department of Gastroenterology and Hepatology and Section Head of Polyposis in the Sanford R. Weiss, MD, Center for Hereditary Colorectal Neoplasia. “Our research shows that earlier SS patients with large or microscopically advanced polyps are also at high risk of cancer, and aggressive endoscopic intervention or duodenectomy should be considered if polyp burden cannot be controlled.”

Dr. Burke and her colleagues believe their research is the first to examine individual SS components and papilla pathology in relation to duodenal cancer risk in FAP.

The pluses and minuses of Spigelman staging

FAP is an inherited colorectal cancer syndrome caused by a germline mutation in the adenomatous polyposis coli gene. Without colectomy, progression of colorectal polyposis to colorectal cancer is inevitable, usually by ages 40 to 50. The second leading cause of cancer in FAP is duodenal cancer, which arises from duodenal adenomatous polyposis and has an overall cumulative lifetime incidence of 4.5 % by age 57.

The five-stage (0 to IV) SS system was developed 30 years ago to predict duodenal cancer risk and dictate the frequency of endoscopic surveillance and the timing of prophylactic duodenectomy. In calculating the SS score and stage, equal weight is assigned to each of the four polyp criteria — number, size, histology and degree of dysplasia.


Previous research showed FAP patients with SS IV polyposis had 10-year cumulative risk levels as high as 36 percent of developing duodenal cancer, versus 2.5 percent risk in patients with SSs 0-III. But those data also showed that many FAP patients who developed cancers did not have SS IV polyposis.

That variability of SS predictive accuracy is what prompted the Cleveland Clinic researchers to assess the relationship of SS and other factors with duodenal cancer in FAP.

Analyzing the data

The researchers queried the Cleveland Clinic hereditary colon cancer database for FAP patients with duodenal polyposis seen between 1988 and 2013. They identified 18 patients with duodenal cancer and, for comparison, randomly selected 85 similarly aged patients with FAP but without duodenal cancer. The researchers reviewed clinical data, including results of esophagogastroduodenoscopy (EGD) performed on the cases and controls.

Statistical analysis found that SS IV polyposis was associated with duodenal cancer, but that 53 percent of patients with duodenal cancer had no prior SS IV polyposis — a considerably higher proportion than in previous research.

Regarding individual SS characteristics, duodenal polyps larger than 10 mm and polyps with high-grade dysplasia (HGD) were positively associated with cancer. Large polyps were present in 76.5 percent of cancer patients versus 47.1 percent of FAP patients without duodenal cancer (p = .027). Polyps with HGD were identified in 29.4 percent of cancer patients versus 5.9 percent of those without cancer (p = .003). The presence of more than 20 duodenal polyps and duodenal polyps with advanced histology (tubulovillous adenoma or villous adenoma, TVA/VA) were not associated with cancer risk.

“The demonstration that not all SS characteristics have comparable predictive value for duodenal cancer begs the question of whether it is prudent to rethink the equal weighting of those components in risk stratification, instead giving greater consideration to large polyp size and dysplasia,” Dr. Burke says.


The frequency of finding advanced pathology of the papilla with any villous features or HGD was greater in the cancer patients than those without cancer (80% vs 22% for villous features and 30% vs 4%, for HGD), regardless of whether the cancer was of the papilla/ampulla or elsewhere in the duodenum.

“There is no consensus on including endoscopic or histologic features of the duodenal papilla characterization in SS calculations,” Dr. Burke says. “Our data support the importance of the histology of the papilla in assessing duodenal cancer risk and bolster the case for routine biopsy of the papilla and inclusion in SS.”

The study also identified a personal and family history of colon cancer and the absence of desmoid tumors as characteristics in FAP patients developing duodenal cancer, which may be a function of the gene mutation causing the disease.

Clinical implications

Although larger studies are needed to validate the overall findings, re-assessing the Spigelman staging system with a larger population should be considered, the authors conclude.

Meanwhile, Dr. Burke and her colleagues advocate regular duodenal polyposis surveillance, biopsy of the duodenal papilla and inclusion of histology findings of the papilla in the current SS. The presence of HGD, whether papillary or in the duodenum, should be a potential indicator of a high-risk patient and warrants close follow-up, the researchers say.

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