ORIGINAL ARTICLE Colorectal carcinoma grading by quantifying poorly differentiated cell clusters is more reproducible and provides more robust prognostic information than conventional grading Valeria Barresi & Luca Reggiani Bonetti & Giovanni Branca & Carmela Di Gregorio & Maurizio Ponz de Leon & Giovanni Tuccari Received: 26 June 2012 / Revised: 5 September 2012 / Accepted: 27 September 2012 # Springer-Verlag Berlin Heidelberg 2012 Abstract The most widely used system to define the histo- logical grade of colorectal carcinoma (CRC) is based on the degree of gland formation. This system suffers from signifi- cant interobserver variability which may limit its prognostic value and consequently better standardized criteria for the assessment of histological grading of CRC are needed. The present study aims to evaluate and to compare, in a cohort of postsurgical pTNM stage I CRC, conventional histological grading, and a novel grading system based on the number of poorly differentiated clusters of neoplastic cells, in terms of interobserver reproducibility, prognostic significance on progression-free survival, and association with other clinico- pathological characteristics. Grading with both systems was performed by two pathologists independently and blinded to the clinicopathological data. Interobserver agreement was higher when grade was assessed by counting poorly differen- tiated clusters than by assessing the relative proportion of the glandular component. Contrary to conventional grading, the novel system provided significant prognostic information in terms of progression-free survival and was significantly asso- ciated with budding, invasive growth, lymphatic invasion, and occult nodal metastases of CRC. In conclusion, our findings suggest that a tumor grading system based on the number of poorly differentiated clusters is more reproducible and pro- vides better prognostic stratification of pTNM stage I CRC patients than conventional grading. Keywords Colorectal cancer . Grading . Stage I . Poorly differentiated clusters . Nodal occult metastases Introduction Colorectal carcinoma (CRC) is one of the leading causes of cancer death in Western Europe and in the USA [1]. At present, postsurgical tumor node metastasis (pTNM) stage is regarded as the main prognostic factor for its clinical course [2, 3] and therapy protocols for CRC largely depend on the pTNM stage at the time of the initial diagnosis. At pTNM stage I, CRC is confined within the muscular wall of the large bowel in the absence of nodal or distant metastases, and has a 5-year sur- vival rate of approximately 80–90 % [1, 4]. As a consequence, stage I CRC is treated by surgery only, while adjuvant therapy is limited to CRC at a higher TNM stage. However, a propor- tion of patients with stage I CRC show progressive disease and develop locoregional or distant metastases with ultimately ad- verse outcome [4]. Hence, there is a need for prognostic markers which identify patients with stage I CRC who are at increased risk of progression and who may benefit from adju- vant therapy. Identification of histological or immunohisto- chemical prognostic parameters which may be easily determined on cancer tissue taken from the initial surgical specimen would serve this purpose [5–9]. Histological grading is a significant prognostic factor for CRC, independent of TNM V. Barresi : G. Branca : G. Tuccari Department of Human Pathology, University of Messina, Messina, Italy L. Reggiani Bonetti : C. Di Gregorio Department of Laboratory Integrated Activities, Anatomic Pathology and Legal Medicine, University of Modena and Reggio Emilia, Modena, Italy M. Ponz de Leon Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy V. Barresi (*) Dipartimento di Patologia Umana, Policlinico G. Martino, Pad D, Via Consolare Valeria, 98125 Messina, Italy e-mail: vbarresi@unime.it Virchows Arch DOI 10.1007/s00428-012-1326-8