Colorectal cancer (CRC) is the second most common malignancy in women and third most common malignancy in men worldwide.1 2 Since tubular adenoma is recognized as precursor lesion of CRC by adenoma-carcinoma sequence,3 regular colonoscopy with excision of adenomatous polyps is associated with a significantly reduced incidence of CRC.4 5 Endoscopic resection (ER) is an effective treatment option for colon neoplasm including adenoma, carcinoma in situ, and cancer with minimal submucosal invasion. However, ER of the polyp is not always possible at the initial colonoscopy. In actual practice, ER is not widely performed at primary medical centers owing to the risk of complications such as bleeding and perforation. In addition, the patients taking antiplatelet or anticoagulant drugs at the time of procedure are not suitable for ER. In such cases, endoscopic forceps biopsy (EFB) is usually performed in a portion of the polyp, and the patient is referred to a more specialized center. However, EFB prior to ER may sometimes result in submucosal fibrosis, making lifting of the lesion with submucosal injection difficult.6

Although recent advances in endoscopic techniques such as contrast-enhancement techniques, whether dye-based or computed, optical microscopy, autofluorescence imaging, and narrow-band imaging would help distinguish clinically significant lesions,7 these techniques are not widely available in real clinical practice yet. Determination of histologic subtype of colorectal neoplasm by EFB is still an important step before deciding the treatment strategy of ER, surgical resection, or close observation. However, since only a small portion of the polyp is obtained with EFB, there is a risk of missing the advanced lesions or neoplastic foci within the lesion.8 There have been many studies about the histologic discrepancy (HD) between EFB and ER specimens in patients with gastric neoplasm.8 9 10 11 12 13 However, only few studies have evaluated HD in patients with colorectal neoplasm.8 14 15 16 17 18

The aim of this study was to evaluate the validity of a cold biopsy sample as representative for the whole resected specimen, investigate the rate of HD in colorectal neoplasm, evaluate the clinicopathological characteristics of discordant cases, and analyze the risk factors of under-diagnosis (UD) before complete removal of colorectal polyp by ER.

Polyps are generally classified as neoplastic or nonneoplastic polyps.20 Neoplastic polyps are adenomas which are benign epithelial tumors with variable malignant potential.21 The adenoma-carcinoma sequence is widely accepted, and it is known that more than 95% of CRC originate from adenomas.22 Inherited CRC syndromes such as familial polyposis and hereditary nonpolyposis CRC support such evidence and recent findings on ras gene mutation and chromosomal deletions additionally provide biological evidence of the adenoma-carcinoma sequence.3

In recent years, changes in the dietary lifestyle in the Korean population along with nationwide conducted cancer screening programs led to an increase in the prevalence of colorectal polyp and malignancy.23 24 Complete removal of adenomatous polyps is by far the most effective method to reduce the risk of CRC occurrence and subsequent cancer-related death.25 However, complete polypectomy is not always attainable in actual clinical practice for several reasons. Possible complications of ER, such as bleeding,2 perforation, and postpolypectomy electrocoagulation syndrome, makes prompt total excision of colorectal polyp difficult, especially in primary medical institutions. Moreover, patients with coagulation disorders such as non-compensating cirrhosis or patients taking antiplatelet drugs or anticoagulants at the time of initial colonoscopy are not suitable candidates for one-step total excision of colorectal polyp. In such cases, EFB of the lesion followed by planned ER is usually performed. However, indiscriminate EFB prior to polypectomy may lead to submucosal fibrosis and non-lifting of lesions,6 which makes the complete excision of the lesion more difficult. Therefore, careful biopsy for accurate histology with minimal effect on the procedure is critical. We performed this study to evaluate the value of EFB in accurately reflecting the actual nature of the totally resected colorectal polyp specimen, and to analyze the risk factors of HD, especially UD which is the most important pressing issue in clinical practice.

There have been several studies8 9 10 11 12 13 on HD between EFB and ER specimens in gastric neoplasm, with the HD rate ranging from 10% to approximately 50%. In previously published reports of the stomach, significant predictors of HD include larger lesion size, depressed morphology, surface nodularity, presence of ulcer or ulcer scars within the lesion, or presence of erythema. However, the results are widely conflicting, thus complete histologic investigation of the ER specimen is essential for developing an optimal management plan.

Few studies have been conducted regarding HD between EFB and ER specimens in colon neoplasm, reporting a variable rate ranging between 10% and 40%.14 15 16 17 18 Pugliese et al.17 published a study of 59 colorectal polyps which underwent repetitive EFB before ER, and reported that small polyps (n=41) had 88% agreement between the histologic result of the EFB and ER specimen, but in large polyps (n=18), only 28% agreement was noted. Gondal et al.14 presented a histologic comparison of 532 colorectal polyps detected by flexible sigmoidoscopy screening that subsequently underwent colonoscopy for complete polypectomy. The HD and UD rate was about 10% and 7% respectively, and the diameter of the polyp was positively associated with an increased risk of UD at the time of EFB. In a similar study in Korea by Song et al.,26 a histological investigation of 206 colorectal polyps in 137 patients was performed, and the HD rate was found to be 18.4%. Polyps >16 mm irrespective of morphology and polyps ≤10 mm with pedunculated morphology were more likely to be histologically discordant. On the other hand, most of the other studies failed to demonstrate significant predictors of HD.8 15 16

In our study, the HD and UD rates were 47.2% and 29.7%, respectively. These rates are relatively higher than those reported in previous studies. The difference may be attributed to the nature of tertiary university medical center, as most of the cases in the present study were referred cases of relatively large sized polyps that could not be easily polypectomized in other hospitals.

Polyp size >10 mm was a significant predictor of both HD and UD in the present study. In terms of polyp morphology, protruding or flat subtype was not significantly relevant. However, among LST subtypes, mixed nodular type showed an increasing tendency for HD when compared with other subtypes. It is a reasonable assumption that as the size of the polyp increases, the possibility of histopathological heterogeneity also increases, which explains why the findings of EFB of larger polyps and those of totally resected specimens tend to be discordant and malignant lesions could be underdiagnosed. Similarly, assuming the size is the same, protruding lesions have a larger volume of tissue when compared to flat subtypes, which may lead to HD by EFB. Considering that the main aim is to obtain a smaller biopsy specimen with highly accurate histologic diagnosis, biopsy should be performed carefully at the nodular portion so as not to miss the possibility of malignancy. Our study provides clear evidence of a relationship between polyp size and HD, and draw a conclusion that the polyp size is the single most important predictive factor of both HD and UD.

Interestingly, our study showed that polyp size was also associated with OD by EFB. It is well known that the distribution of histopathological features is not uniform in single adenoma.27 This may explain the case of OD as well as UD, as small foci of well differentiated adenocarcinoma may be removed by cold biopsy, leaving the bulk of the lesion with less severe histological features in totally resected specimens, as in the single case of OD observed in our study. In this case, we retrospectively reviewed the EFB specimen in our hospital again and the same pathologic assessment was made. In some respects, we can assume that OD cases are those that were relatively well-biopsied at critical portion within a polyp, especially in large polyp that has higher possibility of histopathological heterogeneity.

The present study has some limitations due to the retrospective nature of the study. We could only review the pathology reports from each local medical institutions, not the pathology specimens themselves. Since the pathologic assessment of EFB and ER specimens was made by different pathologists, it inevitably resulted in inter-observer variability. Assessing the degree of dysplasia of an adenoma as low or high is substantially subjective. There is no absolute definition of “high-grade” dysplasia. The same applies to assessing tubulovillous or villous adenoma as well as differentiation of adenocarcinoma. A study by Gondal et al.14 found that inter-pathologist variation is an independent predictor of HD between EFB and ER specimens, along with the polyp size. In our study, in only 5 cases, both EFB and ER were performed in our hospital, while in the rest of the cases, the patients were transferred from local medical centers after EFB and then underwent polypectomy in our hospital. This was associated with the nature of referral hospitals. Because of the enormous difference in the number of cases that underwent both procedures in our hospital and one procedure (5 vs. 285, respectively), we could not include inter-observer variation as a statistical variable, although this might be a potential confounding factor that may affect the frequency of HD. However on the other side, in actual clinical practice, most patients come to tertiary hospital with just the pathology report, not with pathology specimen. We believe that our result may reflect the actual clinical situation in referral hospitals.

Besides, due to such nature of referral hospital, there might be a referral bias. Not all colorectal polyps found in the clinical settings are needed to be referred to tertiary hospital. Thus, the results of our study cannot be generalized to all colorectal polyps. Also, since each EFB were performed at different medical centers in retrospective setting, we could not standardize biopsy protocol. Among cases that were stated with specific number of EFB performed (198 cases out of 290 polyps), most of the EFB (96.5%) were performed only once per polyp. However, the number of biopsy and the optimal location of biopsy within a polyp was not perfectly controlled. Thus, the absence of standardized biopsy protocol may have affect the rate of HD.

Despite these limitations, however, our study is the first to evaluate the rate of HD based on fully examined colonoscopic findings, and further analyze the risk factors of HD, UD and OD in a relatively larger number of subjects compared with those included in previous reports. HD was noted in 47.2% of colorectal neoplasm, and about 29.7% of polyps were underestimated and 14.5% of polyps were overestimated by EFB prior to complete polypectomy. Polyp size >10 mm was the single most important predictive factor for HD, UD or OD. Careful biopsy for an accurate histological diagnosis before the procedure and choosing the optimal treatment strategy for complete resection of colorectal neoplasm is warranted, especially when the size of the polyp is >10 mm.