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Poorly Differentiated Clusters Predict Colon Cancer Recurrence

An In-Depth Comparative Analysis of Invasive-Front Prognostic Markers

Konishi, Tsuyoshi MD*,†; Shimada, Yoshifumi MD*,‡; Lee, Lik Hang MD§; Cavalcanti, Marcela S. MD§; Hsu, Meier MS; Smith, Jesse Joshua MD, PhD*; Nash, Garrett M. MD*; Temple, Larissa K. MD*; Guillem, José G. MD*; Paty, Philip B. MD*; Garcia-Aguilar, Julio MD, PhD*; Vakiani, Efsevia MD, PhD§; Gonen, Mithat PhD; Shia, Jinru MD§; Weiser, Martin R. MD*

The American Journal of Surgical Pathology: June 2018 - Volume 42 - Issue 6 - p 705–714
doi: 10.1097/PAS.0000000000001059
Original Articles

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.

Departments of *Surgery


Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY

Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Supported by National Cancer Institute grant P30 C008748.

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Jinru Shia, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065 and Martin R. Weiser, MD, Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065 (e-mails:;

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