UICC World Cancer Congress 2006

[ Importance of comparing mitotic count to any newer systems of evaluating proliferation in prognosis and prediction ]

Recent studies using molecular markers have used a weighted system in an index of indicators, strongly emphasizing elements of proliferation. Unfortunately, the comparison to a combined histologic grade ( CHG, Nottingham) de-emphasizes proliferation recognized by mitotic counts by diminishing it as only a third of the index, even so it reached p=.01. The central importance of proliferation should be measured as a continuous variable, or at least by itself comparing histology to any new indices. This emphasizes that the three elements of the CHG have different implications 1 . The validation of interobserver agreement is multiply available when pathologists are incentivized to use the rules in a consistent fashion.

Use of differentiation only is not informative, and its continued diagnostic use without other attributes , i.e., “moderately differentiated” carcinoma is not acceptable. It is quite clear that abundant lumen formation as measured in the combined grade below indicates an improved prognosis when present, but has little information when absent. Nuclear features are relatively powerful, and are often used alone. However, this practice denies the powerful information of the combined histologic grade that has been multiply validated for interobserver variation and clinical outcome verification. Nuclear grade has the greatest variation between observers, although assignment of grade one and grade three are virtually never overlapping. This leaves the mitotic count as the third and undoubtedly most powerful element of the combined grade, certainly for its ability to identify early failure at 2 to five years. Indeed when compared to S-phase by flow cytometry, mitotic counts are more powerful 2,3, and have been multiply validated 4,5 and there is an element of predictive power also because low proliferative rates are associated with lack of response to chemotherapy 3,6. One provocative study has added the mitotic count a second time to a prognostic index with added predictive power7. It is also relevant to note that tumor grade and proliferation rate do not change often between the primary and recurrences as well as between the closely correlated in situ component and the invasive carcinoma8,9. There are important considerations and correlations of tumor cell proliferation with tumor type and cell density. Cell density has been separately studied only rarely with a link to prognosis10, however, the number of mitoses counted over an area (the manner of reporting in the combined histologc grade) contains a strong consideration of cellularity within the count11.

Finally, as a general consideration of the relation of proliferation rate to patterns and types of infiltrating tumors, it is well known that some tumors are quite homogeneous from the center to the outer area, while others demonstrate a much higher density of mitoses at the outer aspect. This is why the utility of proliferation is emphasized in the formal counting of mitoses at the outer areas and in areas where they are most dense. Microdisssection used in some recent studies probably recognizes this important fact. Connor et al12 have recorded the relation between tumor pattern and location of mitoses within breast carcinomas. Tumors with medullary, lobular or tubular features dominating have no significant different between peripheral and central tumor index. While this study was done with MIB1 antibody, there is solid evidence that this measure of Ki-67 expression and mitotic counts are closely correlated13.

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8. Millis RR, Barnes DM, Lampejo OT, Egan MK, Smith P: Tumour grade does not change between primary and recurrent mammary carcinoma, Eur J Cancer 1998, 34:548-553

9. Millis RR, Pinder SE, Ryder K, Howitt R, Lakhani SR: Grade of recurrent in situ and invasive carcinoma following treatment of pure ductal carcinoma in situ of the breast, Br J Cancer 2004, 90:1538-1542

10. Ambros RA, Trost RC: Cellularity in breast carcinoma, Am J Clin Pathol 1990, 93:98-100

11. Simpson JF, Dutt PL, Page DL: Expression of mitoses per thousand cells and cell density in breast carcinomas: a proposal, Hum Pathol 1992, 23:608-611

12. Connor AJM, Pinder SE, Elston CW, Bell JA, Wencyk P, Robertson JFR, Blamey RW, Nicholson RI, Ellis IO: Intratumors heterogeneity of proliferation in invasive breast carcinoma evaluated with MIB1 antibody, The Breast (U.K.) 1997, 6:171-176

13. Weidner N, Moore DH, 2nd, Vartanian R: Correlation of Ki-67 antigen expression with mitotic figure index and tumor grade in breast carcinomas using the novel "paraffin"-reactive MIB1 antibody, Hum Pathol 1994, 25:337-342