Poorly Differentiated Clusters Predict Colon Cancer Recurrence

Abstract

This study aimed to compare common histologic markers at the invasive front of colon adenocarcinoma in terms of prognostic accuracy and interobserver agreement. Consecutive patients who underwent curative resection for stages I to III colon adenocarcinoma at a single institution in 2007 to 2014 were identified. Poorly differentiated clusters (PDCs), tumor budding, perineural invasion, desmoplastic reaction, and Crohn-like lymphoid reaction at the invasive front, as well as the World Health Organization (WHO) grade of the entire tumor, were analyzed. Prognostic accuracies for recurrence-free survival (RFS) were compared, and interobserver agreement among 3 pathologists was assessed. The study cohort consisted of 851 patients. Although all the histologic markers except WHO grade were significantly associated with RFS (PDCs, tumor budding, perineural invasion, and desmoplastic reaction: P<0.001; Crohn-like lymphoid reaction: P=0.021), PDCs (grade 1 [G1]: n=581; G2: n=145; G3: n=125) showed the largest separation of 3-year RFS in the full cohort (G1: 94.1%; G3: 63.7%; hazard ratio [HR], 6.39; 95% confidence interval [CI], 4.11-9.95; P<0.001), stage II patients (G1: 94.0%; G3: 67.3%; HR, 4.15; 95% CI, 1.96-8.82; P<0.001), and stage III patients (G1: 89.0%; G3: 59.4%; HR, 4.50; 95% CI, 2.41-8.41; P<0.001). PDCs had the highest prognostic accuracy for RFS with the concordance probability estimate of 0.642, whereas WHO grade had the lowest. Interobserver agreement was the highest for PDCs, with a weighted kappa of 0.824. The risk of recurrence over time peaked earlier for worse PDCs grade. Our findings indicate that PDCs are the best invasive-front histologic marker in terms of prognostic accuracy and interobserver agreement. PDCs may replace WHO grade as a prognostic indicator.

Update of the recommendations for the determination of biomarkers in colorectal carcinoma: National Consensus of the Spanish Society of Medical Oncology and the Spanish Society of Pathology

“…TB should be evaluated with caution in medullary carcinomas and can be very difficult to count in tumours with glandular fragmentation with marked acute inflammation. TB must be distinguished from PDCs, defined as groups of five or more tumour cells in the invasive tumour front that do not form glandular structures [4]. TB should not be reported in rectal tumours treated with neoadjuvancy, or in mucinous carcinomas with signet ring cells within mucus lakes.…”

“…One example is the incorporation into pathology diagnostic protocols the analysis of the tumour budding (TB), defined as the presence of isolated tumour cells or small groups of less than five tumour cells at the invasive tumour front, or the poorly differentiated clusters (PDC), defined as groups of five or more tumour cells at the invasive front of the stroma of the CRC which does not form glandular structures. Both, TB and PDC are prognostic factors in CRC [3,4].…”

Quantitative assessment of tumor-infiltrating lymphocytes in mismatch repair proficient colon cancer

“…Pathologists determined T and N classifications of the American Joint Committee on Cancer (AJCC) as well as high risk of recurrence features including venous invasion, lymphovascular invasion, or perineural invasion (VELPI). TIL in the advancing margin were measured as previously described, 21 which has an acceptable interobserver agreement. 10,24,25 In brief, TIL were first identified at scanning magnification to select areas with the highest counts.…”

“…14 Once MMR evaluation became standard, TIL measurement was removed from the CAP guidelines; 20 however, recent investigations have renewed interest in TIL, as they have been shown to be prognostic independent of MMR status. 21,22 Development of TIL measurement protocols has been hindered by tumor heterogeneity, including areas of necrosis, and a lack of a universally accepted cutoff to define a robust TIL response. 2,3,[15][16][17]23 The goal of this investigation was to quantitate TIL in the tumor invasive front 21 using hematoxylineosin-stained slides; determine whether the highest TIL count in a single high-power field (HPF) or sum TIL count in five HPFs is more closely associated with recurrence-free survival (RFS); define the TIL cutoff for designating tumors as high or low TIL in relation to RFS; and examine the association between TIL and RFS in dMMR and MMR-proficient (pMMR) colon cancer.…”

“…14 Once MMR evaluation became standard, TIL measurement was removed from the CAP guidelines; 20 however, recent investigations have renewed interest in TIL, as they have been shown to be prognostic independent of MMR status. 21 , 22 …”