L P Fielding

Abstract Background. —Under the auspices of the College of American Pathologists, the current state of knowledge regarding pathologic prognostic factors (factors linked to outcome) and predictive factors (factors predicting response to therapy) in colorectal carcinoma was evaluated. A multidisciplinary group of clinical (including the disciplines of medical oncology, surgical oncology, and radiation oncology), pathologic, and statistical experts in colorectal cancer reviewed all relevant medical literature and stratified the reported prognostic factors into categories that reflected the strength of the published evidence demonstrating their prognostic value. Accordingly, the following categories of prognostic factors were defined. Category I includes factors definitively proven to be of prognostic import based on evidence from multiple statistically robust published trials and generally used in patient management. Category IIA includes factors extensively studied biologically and/or clinically and repeatedly shown to have prognostic value for outcome and/or predictive value for therapy that is of sufficient import to be included in the pathology report but that remains to be validated in statistically robust studies. Category IIB includes factors shown to be promising in multiple studies but lacking sufficient data for inclusion in category I or IIA. Category III includes factors not yet sufficiently studied to determine their prognostic value. Category IV includes factors well studied and shown to have no prognostic significance. Materials and Methods. —The medical literature was critically reviewed, and the analysis revealed specific points of variability in approach that prevented direct comparisons among published studies and compromised the quality of the collective data. Categories of variability recognized included the following: (1) methods of analysis, (2) interpretation of findings, (3) reporting of data, and (4) statistical evaluation. Additional points of variability within these categories were defined from the collective experience of the group. Reasons for the assignment of an individual prognostic factor to category I, II, III, or IV (categories defined by the level of scientific validation) were outlined with reference to the specific types of variability associated with the supportive data. For each factor and category of variability related to that factor, detailed recommendations for improvement were made. The recommendations were based on the following aims: (1) to increase the uniformity and completeness of pathologic evaluation of tumor specimens, (2) to enhance the quality of the data needed for definitive evaluation of the prognostic value of individual prognostic factors, and (3) ultimately, to improve patient care. Results and Conclusions. —Factors that were determined to merit inclusion in category I were as follows: the local extent of tumor assessed pathologically (the pT category of the TNM staging system of the American Joint Committee on Cancer and the Union Internationale Contre le Cancer [AJCC/UICC]); regional lymph node metastasis (the pN category of the TNM staging system); blood or lymphatic vessel invasion; residual tumor following surgery with curative intent (the R classification of the AJCC/UICC staging system), especially as it relates to positive surgical margins; and preoperative elevation of carcinoembryonic antigen elevation (a factor established by laboratory medicine methods rather than anatomic pathology). Factors in category IIA included the following: tumor grade, radial margin status (for resection specimens with nonperitonealized surfaces), and residual tumor in the resection specimen following neoadjuvant therapy (the ypTNM category of the TNM staging system of the AJCC/UICC). Factors in category IIB included the following: histologic type, histologic features associated with microsatellite instability (MSI) (ie, host lymphoid response to tumor and medullary or mucinous histologic type), high degree of MSI (MSI-H), loss of heterozygosity at 18q ( DCC gene allelic loss), and tumor border configuration (infiltrating vs pushing border). Factors grouped in category III included the following: DNA content, all other molecular markers except loss of heterozygosity 18q/DCC and MSI-H, perineural invasion, microvessel density, tumor cell–associated proteins or carbohydrates, peritumoral fibrosis, peritumoral inflammatory response, focal neuroendocrine differentiation, nuclear organizing regions, and proliferation indices. Category IV factors included tumor size and gross tumor configuration. This report records findings and recommendations of the consensus conference group, organized according to structural guidelines defined herein.

BACKGROUND: The American Joint Committee on Cancer (AJCC), which regularly reviews TNM staging systems, established a working party to develop recommendations for colorectal carcinoma. METHODS: A multidisciplinary consensus conference using published literature developed an arbitrary classification system of prognostic marker value (Category I, IIA, IIB, III, and IV), which forms the framework for this report. RESULTS: The working party concluded that several T categories should be subdivided: pTis into intraepithelial carcinoma (pTie) and intramucosal carcinoma (pTim); pT1 into pT1a and pT1b corresponding to the absence or presence of blood or lymphatic vessel invasion, respectively; and pT4 into pT4a and pT4b according to the absence or presence of tumor involving the surface of the specimen, respectively. The working party also recommended that TNM groups be stratified based on the presence or absence of elevated serum levels of carcinoembryonic antigen (CEA) (>/= 5 ng/mL) on preoperative clinical examination. In addition, the working party also concluded that carcinoma of the appendix should be excluded from the colorectal carcinoma staging system because of fundamental differences in natural history. CONCLUSIONS: The TNM categories and stage groupings for colorectal carcinoma published in the current AJCC manual have clinical and academic value. However, a few categories require subdivision to provide increasing discrimination for individual patients. The serum marker CEA should be added to the staging system, whereas multiple other factors should be recorded as part of good clinical practice. Although many molecular and oncogenic markers show promise to supplement or modify the current staging systems eventually, to the authors' knowledge none have yet been evaluated sufficiently to recommend their inclusion in the TNM system.

Clinically evident anastomotic dehiscence was studied in 1466 patients who had undergone resection of a large-bowel adenocarcinoma. The overall incidence of anastomotic leakage was 13%, but the incidence varied between surgeons (range 0.5% to over 30%). Morbidity and mortality were significantly higher in those patients in whom the anastomosis failed to heal primarily. If these results are extrapolated to the national level, it should be possible by achieving results closer to those in patients without leakage to reduce overall post-operative mortality after resection of large-bowel cancer by 2% and to achieve an appreciable reduction in morbidity. Both factors are clinically important and, taken together, could result in appreciable saving of revenue.

The Large Bowel Cancer Project is a collaborative prospective study of 4228 patients with a histologically proven adenocarcinoma, of whom 2336 (55 per cent) survived a 'curative' resection. Follow-up information is available on 2220 patients (95 per cent). Subsequently, 309 (14 per cent) have developed a local recurrence confirmed by: biopsy (127; 41 per cent), clinical examination (77; 25 per cent), X-ray (15; 5 per cent), a raised CEA (2; 1 per cent), or some other method - e.g. CT scan or a confident unbiopsied laparotomy finding (88; 29 per cent). Statistically significant factors (chi2 test, P less than 0.05) associated with local recurrence are: Dukes' classification: A 4 per cent; B 13 per cent; C 18 per cent Tumour differentiation: Well 11 per cent; Moderate 14 per cent; Poor 21 per cent Obstruction: Absent 13 per cent; Present 21 per cent Perforation: Absent 13 per cent; Present 28 per cent Tumour mobility: Freely mobile 11 per cent; Others 21 per cent Operation performed (rectal and rectosigmoid tumours): Abdomino-perineal 12 per cent; Anterior resection 18 per cent; Surgeon (Consultant only): Range less than 5 per cent to greater than 20 per cent. Stratification of the above variables altered only the statistical significance pertaining to tumour differentiation (P less than 0.1, d.f. = 2). In particular, the differences between Consultant surgeons remained.

The purpose of tumour staging for colorectal cancer (CRC) is to help define clinical management, facilitate communication between physicians, provide a basis for stratification and analysis of treatment results in prospective studies, and provide some prognostic information for patients and their families. The World Congresses of Gastroenterology, Digestive Endoscopy, and Coloproctology, Working Party on staging for CRC studied six commonly used systems to review their strengths and weaknesses. Although it was concluded that defining a new staging system was unnecessary, it was recognized that there is a need to define a terminology to describe the full anatomic extent of spread of CRC. Furthermore, we note that there are several additional features, derived from both clinical and pathology information, which have had prognostic significance shown by appropriately constructed multivariate analyses and which can be used to formulate a more accurate prognostic index than that provided by a description of anatomical tumour spread. Thus the Working Party came to two principal conclusions. First, a standard format should be adopted for the collection of the essential data required for prospective studies, and we recommend the 'International Documentation System (IDS) for CRC' for this purpose. Second, a nomenclature which describes the full anatomical extent of tumour spread and residual tumour status in CRC has been defined and should be adopted, from which all currently used staging systems can be derived. We have called this nomenclature the 'International Comprehensive Anatomical Terminology (ICAT) for CRC'. In the event that these recommendations are adopted, we envision that there will be improved clarity in the documentation of treatment outcome for patients with CRC and improved communication of results derived from prospective studies. Furthermore, an acceptance of IDS and ICAT would set the scene to develop a prognostic index for individual patients with CRC by the expansion of anatomical clinicopathology staging information to include additional factors which have independent prognostic significance.