Histopathology of residual rectal carcinoma following preoperative radiochemotherapy

Preoperative radiotherapy with (CRT) or without chemotherapy (RT) in the management of patients with locally advanced rectal carcinoma is increasingly accepted as therapeutic modality to reduce local recurrence and improve survival, decrease tumor size and/or stage, has less toxicity compared to postoperative therapy, improves sphincter preservation and the ability to perform a curative resection. In a brief review of literature we discussed the possible prognostic role of most important pathologic parameters and their clinical implications. At present, predictive value of tumor response to neoadjuvant therapy remains uncertain, whether evaluated as five-point histological tumor regression grade (TRG) or recently proposed three-point rectal cancer regression grade (RCRG). However, most reports emphasize reduced local reccurence rates and disease-free survival advantage in patients with complete tumour regression or tumour down-staging, occuring in up to 20% and 60% of cases, respectively. Patients with advanced post-treatment tumour stage (ypT3/4), positive lymph nodes (ypN1/2), vascular invasion, positive circumferential resection margin, clearance < 2mm, or absence of tumor regression are shown to have poor clinical outcome. Among CRT-induced morphological features, only "fibrotic-type" stromal response with minimal inflammatory infiltrates and absence of surface ulceration are correlated to recurrence-free survival. Preliminary unpublished results of a pilot study from our multidisciplinary prospective trial relate to correlation of histopathologic parameters and morphologic changes to rectal cancer regression grade (RCRG). Therefore, we studied 22 consecutive patients, mean age 56 (range 23-69) years, with transmural cT3/4 stage and were subgrouped as follows: RCRG-1 (7 patients, 31.8%), RCRG-2 (9 patients, 40.,9%) and RCRG-3 (6 patients, 27,2%). In addition, 14 patients (63%) showed tumour downstaging and only 1 patient (4.5%) nodal down-staging after ypTNM restaging. There was the predominance of fibrotic-type stroma (16 patients, 72.8%) versus fibro-inflammatory response (6 patients, 27.2%), frequent tumoral necrosis (13 patients, 59%) but infrequent surface ulceration (5 patients, 22.7%) and peritumoural eosinophylic infiltration as well as endocrine cell differentiation (4 patients, 18%). The second aim of our study was to investigate determinants of radiosensitivity, i.e. the relationship between proliferative activity indices (Ki-67 and PCNA) as well as the induction of apoptosis (p53) and the tumour regression (RCRG) after neoadjuvant CRT. The interaction between Ki-67 and PCNA immunoexpression levels and the benefit of CRT was significant for Ki-67 (p = 0.03), but not for PCNA (p = 0.08) and p53 levels (p = 0.4). In a conclusion, high percentage of Ki-67-positive tumor cells in the preoperative biopsy predicts an decreased treatment response after preoperative CRT of rectal cancer. However, long-term follow-up and large studies are necessary to establish the value of regression grade and the need for its prediction by reliable biological markers.