J Korean Med Sci.  2015 Jan;30(1):16-23. 10.3346/jkms.2015.30.1.16.

Clinicopathologic Impacts of Poorly Differentiated Cluster-Based Grading System in Colorectal Carcinoma

• Kim JW
• Shin MK
• Kim BC

• KMID: 2155443
• DOI: http://doi.org/10.3346/jkms.2015.30.1.16

Abstract

Differentiation-based histologic grading of colorectal carcinoma (CRC) is widely used, but its clinical impact is limited by insufficient prognostic value, interobserver disagreement, and the difficulty of its application to CRC with specific histologic types such as mucinous and medullary carcinoma. A recently proposed novel grading system based on quantifying poorly differentiated clusters (PDCs) claims to have the advantages of reproducibility and improved prognostic value, and might apply to heterogeneous CRC. We aimed to validate the clinicopathologic significance of the PDCs-based grading system and to determine the relationship between this grading system and microsatellite instability (MSI). Two hundred and one patients who had undergone radical surgery were reviewed. Based on the number of PDCs, 85, 58, and 58 tumors were classified as grade (G) 1 (42.3%), G2 (28.9%), and G3 (28.9%), respectively. PDCs-based grade was significantly associated with T, N, and M stages; lymphovascular invasion; conventional histologic grade; and frequent tumor budding (all P <0.001). In multivariate analysis, PDCs-based grade was found to be an independent prognostic factor for disease-free survival (P = 0.022; hazard ratio, 3.709 [G2], 7.461 [G3]). G3 CRC significantly correlated with high MSI (MSI-H) compared to G1 and G2 (P = 0.002; odds ratio, 5.750). In conclusion, this novel grading would provide valuable prognostic information to a greater number of patients and would require continued verification. PDCs-based grading is feasible for CRCs with heterogeneous morphology, and we propose that the association between G3 and MSI-H be further evaluated in different histological subtypes of CRC.

Keyword

Colorectal Neoplasms; Carcinoma; Prognosis; Neoplasm Grading; Microsatellite Instability

MeSH Terms

Colorectal Neoplasms/*genetics/*pathology/surgery
Disease-Free Survival
Female
Humans
Lymphatic Metastasis/pathology
Male
*Microsatellite Instability
Middle Aged
Neoplasm Grading/*methods
Tumor Burden/*physiology

Figure

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  Fig. 1 Histopathological findings of poorly differentiated clusters (PDCs) of colon cancer. (A) Cancer cell clusters located in the stroma, comprising 5 or more cancer cells and lacking glands are defined as PDCs. (B) Small clusters of tumor cells surrounded by lacunar spaces forming the so-called "invasive micropapillary" pattern are classified as PDCs. (C) In mucinous carcinoma, a cancer cell cluster is considered a PDC when the size of the mucinous area does not exceed that of the cancer cell cluster. (D) PDCs with signet ring cells are noted (Hematoxylin and eosin stain; original magnification, × 200).

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  Fig. 2 Kaplan-Meier curves and P values from the log-rank test analysis of survival time differences according to grade based on numbers of poorly differentiated clusters. (A) Disease-free and (B) disease-specific survival.

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  Fig. 3 Poorly differentiated clusters (PDCs)-based grading on tumors with medullary features. (A) Typical medullary carcinoma component showing large sheets is classified as grade 1. (B) However, there is a tumor with many PDCs in a medullary-like background and it is classified as PDCs-based grade 3 (Hematoxylin and eosin stain; original magnification, × 200).

Reference

1. Hamilton SR, Bosman FT, Boffetta P, Ilyas M, Morreau H, Nakamura S-I, Quirke P, Riboli E, Sobin LH. Carcinoma of the colon and rectum. In : Bosman FT, editor. World Health Organization, International Agency for Research on Cancer. WHO classification of tumours of the digestive system. Lyon: International Agency for Research on Cancer;2010. p. 134–146.

2. Thomas GD, Dixon MF, Smeeton NC, Williams NS. Observer variation in the histological grading of rectal carcinoma. J Clin Pathol. 1983; 36:385–391.

3. Chandler I, Houlston RS. Interobserver agreement in grading of colorectal cancers-findings from a nationwide web-based survey of histopathologists. Histopathology. 2008; 52:494–499.

4. Redston M. Epithelial neoplasms of the large intestine. In : Odze RD, Goldblum JR, editors. Surgical pathology of the GI tract, liver, biliary tract, and pancreas. 2nd ed. Philadelphia, PA: Saunders Elsevier;2009. p. 621.

5. Schmoll HJ, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, Nordlinger B, van de Velde CJ, Balmana J, Regula J, et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making. Ann Oncol. 2012; 23:2479–2516.

6. Prall F, Nizze H, Barten M. Tumour budding as prognostic factor in stage I/II colorectal carcinoma. Histopathology. 2005; 47:17–24.

7. Ueno H, Kajiwara Y, Shimazaki H, Shinto E, Hashiguchi Y, Nakanishi K, Maekawa K, Katsurada Y, Nakamura T, Mochizuki H, et al. New criteria for histologic grading of colorectal cancer. Am J Surg Pathol. 2012; 36:193–201.

8. Barresi V, Reggiani Bonetti L, Branca G, Di Gregorio C, Ponz de Leon M, Tuccari G. Colorectal carcinoma grading by quantifying poorly differentiated cell clusters is more reproducible and provides more robust prognostic information than conventional grading. Virchows Arch. 2012; 461:621–628.

9. Ueno H, Hase K, Hashiguchi Y, Shimazaki H, Tanaka M, Miyake O, Masaki T, Shimada Y, Kinugasa Y, Mori Y, et al. Site-specific tumor grading system in colorectal cancer: multicenter pathologic review of the value of quantifying poorly differentiated clusters. Am J Surg Pathol. 2014; 38:197–204.

10. Barresi V, Bonetti LR, Ieni A, Branca G, Baron L, Tuccari G. Histologic grading based on counting poorly differentiated clusters in preoperative biopsy predicts nodal involvement and pTNM stage in colorectal cancer patients. Hum Pathol. 2014; 45:268–275.

11. Barresi V, Branca G, Ieni A, Reggiani Bonetti L, Baron L, Mondello S, Tuccari G. Poorly differentiated clusters (PDCs) as a novel histological predictor of nodal metastases in pT1 colorectal cancer. Virchows Arch. 2014; 464:655–662.

12. Young J, Simms LA, Biden KG, Wynter C, Whitehall V, Karamatic R, George J, Goldblatt J, Walpole I, Robin SA, et al. Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am J Pathol. 2001; 159:2107–2116.

13. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. American Cancer Society. AJCC cancer staging handbook : from the AJCC cancer staging manual. 7th ed. New York: Springer;2010.

14. Morodomi T, Isomoto H, Shirouzu K, Kakegawa K, Irie K, Morimatsu M. An index for estimating the probability of lymph node metastasis in rectal cancers. Lymph node metastasis and the histopathology of actively invasive regions of cancer. Cancer. 1989; 63:539–543.

15. Lai YH, Wu LC, Li PS, Wu WH, Yang SB, Xia P, He XX, Xiao LB. Tumour budding is a reproducible index for risk stratification of patients with stage II colon cancer. Colorectal Dis. 2014; 16:259–264.

16. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998; 58:5248–5257.

17. Zlobec I, Bihl MP, Foerster A, Rufle A, Lugli A. The impact of CpG island methylator phenotype and microsatellite instability on tumour budding in colorectal cancer. Histopathology. 2012; 61:777–787.

18. Jass JR, O'Brien MJ, Riddell RH, Snover DC. Association of Directors of Anatomic and Surgical Pathology (ADASP). Recommendations for the reporting of surgically resected specimens of colorectal carcinoma. Hum Pathol. 2007; 38:537–545.

19. Jass JR, Barker M, Fraser L, Walsh MD, Whitehall VL, Gabrielli B, Young J, Leggett BA. APC mutation and tumour budding in colorectal cancer. J Clin Pathol. 2003; 56:69–73.

20. Kim ST, Lee J, Park SH, Park JO, Lim HY, Kang WK, Kim JY, Kim YH, Chang DK, Rhee PL, et al. Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy. Cancer Chemother Pharmacol. 2010; 66:659–667.

21. Lin CC, Lin JK, Lin TC, Chen WS, Yang SH, Wang HS, Lan YT, Jiang JK, Yang MH, Chang SC. The prognostic role of microsatellite instability, codon-specific KRAS, and BRAF mutations in colon cancer. J Surg Oncol. 2014; 110:451–457.

22. Chang SC, Lin JK, Yang SH, Wang HS, Li AF, Chi CW. Relationship between genetic alterations and prognosis in sporadic colorectal cancer. Int J Cancer. 2006; 118:1721–1727.