Abstract
We evaluated the degree of tubular differentiation in 172 samples of invasive ductal breast cancer in order to determine numerical thresholds for histological breast cancer grading. The tubular differentiation in each sample was defined as the fraction of fields showing tubular differentiation (FTD). The analysis was based on Kaplan–Meier curves reflecting survival and recurrence of disease, univariate and multivariate analyses of Cox's regression, and maximum efficiencies of ROC analysis. The minimum P -value cut-off for FTD was determined at 59%. The practical interpretation is that tubular differentiation in the neoplasm observed in at least 60% of microscopical fields in the tumour area indicates favourable prognosis of disease. The relative risks for breast cancer death for patients with FTD below 59% as compared with those with FTD above 59% were 6.7- and 6.3-fold (univariate and multivariate analyses respectively). Another threshold could be determined at FTD 23%, although this threshold was associated with clearly lower statistical significancies. The paper introduces two possible solutions for application of the thresholds to the morphometric breast cancer grading system. The study also emphasizes the clinical relevance of the evaluation of tubular differentiation in breast cancer. The consistent morphometric evaluation method was vital in allowing the full weight of the biological significance of tubular differentiation to emerge. © 2000 Cancer Research Campaign
Keywords: breast carcinoma, prognosis, grading, tubular differentiation
Full Text
The Full Text of this article is available as a PDF (131.0 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Altman D. G., Lausen B., Sauerbrei W., Schumacher M. Dangers of using "optimal" cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst. 1994 Jun 1;86(11):829–835. doi: 10.1093/jnci/86.11.829. [DOI] [PubMed] [Google Scholar]
- BLACK M. M., OPLER S. R., SPEER F. D. Survival in breast cancer cases in relation to the structure of the primary tumor and regional lymph nodes. Surg Gynecol Obstet. 1955 May;100(5):543–551. [PubMed] [Google Scholar]
- BLOOM H. J., RICHARDSON W. W. Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer. 1957 Sep;11(3):359–377. doi: 10.1038/bjc.1957.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baak J. P., Van Dop H., Kurver P. H., Hermans J. The value of morphometry to classic prognosticators in breast cancer. Cancer. 1985 Jul 15;56(2):374–382. doi: 10.1002/1097-0142(19850715)56:2<374::aid-cncr2820560229>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
- Beck J. R., Shultz E. K. The use of relative operating characteristic (ROC) curves in test performance evaluation. Arch Pathol Lab Med. 1986 Jan;110(1):13–20. [PubMed] [Google Scholar]
- Berger U., Wilson P., McClelland R. A., Davidson J., Coombes R. C. Correlation of immunocytochemically demonstrated estrogen receptor distribution and histopathologic features in primary breast cancer. Hum Pathol. 1987 Dec;18(12):1263–1267. doi: 10.1016/s0046-8177(87)80411-2. [DOI] [PubMed] [Google Scholar]
- Black M. M., Barclay T. H., Hankey B. F. Prognosis in breast cancer utilizing histologic characteristics of the primary tumor. Cancer. 1975 Dec;36(6):2048–2055. doi: 10.1002/cncr.2820360919. [DOI] [PubMed] [Google Scholar]
- CUTLER S. J., EDERER F. Maximum utilization of the life table method in analyzing survival. J Chronic Dis. 1958 Dec;8(6):699–712. doi: 10.1016/0021-9681(58)90126-7. [DOI] [PubMed] [Google Scholar]
- Clayton F. Pathologic correlates of survival in 378 lymph node-negative infiltrating ductal breast carcinomas. Mitotic count is the best single predictor. Cancer. 1991 Sep 15;68(6):1309–1317. doi: 10.1002/1097-0142(19910915)68:6<1309::aid-cncr2820680621>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
- Collan Y. General principles of grading lesions in diagnostic histopathology. Pathol Res Pract. 1989 Nov;185(5):539–543. doi: 10.1016/S0344-0338(89)80189-X. [DOI] [PubMed] [Google Scholar]
- Dalton L. W., Page D. L., Dupont W. D. Histologic grading of breast carcinoma. A reproducibility study. Cancer. 1994 Jun 1;73(11):2765–2770. doi: 10.1002/1097-0142(19940601)73:11<2765::aid-cncr2820731119>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
- Davis B. W., Gelber R. D., Goldhirsch A., Hartmann W. H., Locher G. W., Reed R., Golouh R., Säve-Söderbergh J., Holloway L., Russell I. Prognostic significance of tumor grade in clinical trials of adjuvant therapy for breast cancer with axillary lymph node metastasis. Cancer. 1986 Dec 15;58(12):2662–2670. doi: 10.1002/1097-0142(19861215)58:12<2662::aid-cncr2820581219>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
- Dufer J., Liautaud-Roger F., Barbarin D., Coninx P. Nucleus image analysis as a possible prognostic tool in grading breast cancer. Biomed Pharmacother. 1993;47(4):131–135. doi: 10.1016/0753-3322(93)90003-4. [DOI] [PubMed] [Google Scholar]
- Elston C. W., Ellis I. O. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991 Nov;19(5):403–410. doi: 10.1111/j.1365-2559.1991.tb00229.x. [DOI] [PubMed] [Google Scholar]
- Fisher E. R., Anderson S., Redmond C., Fisher B. Pathologic findings from the National Surgical Adjuvant Breast Project protocol B-06. 10-year pathologic and clinical prognostic discriminants. Cancer. 1993 Apr 15;71(8):2507–2514. doi: 10.1002/1097-0142(19930415)71:8<2507::aid-cncr2820710813>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
- Fisher E. R., Gregorio R. M., Fisher B., Redmond C., Vellios F., Sommers S. C. The pathology of invasive breast cancer. A syllabus derived from findings of the National Surgical Adjuvant Breast Project (protocol no. 4). Cancer. 1975 Jul;36(1):1–85. doi: 10.1002/1097-0142(197507)36:1<1::aid-cncr2820360102>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
- Fisher E. R. Prognostic and therapeutic significance of pathological features of breast cancer. NCI Monogr. 1986;(1):29–34. [PubMed] [Google Scholar]
- Fisher E. R., Redmond C., Fisher B. Histologic grading of breast cancer. Pathol Annu. 1980;15(Pt 1):239–251. [PubMed] [Google Scholar]
- Fisher E. R., Sass R., Fisher B. Pathologic findings from the National Surgical Adjuvant Project for Breast Cancers (protocol no. 4). X. Discriminants for tenth year treatment failure. Cancer. 1984 Feb 1;53(3 Suppl):712–723. doi: 10.1002/1097-0142(19840201)53:3+<712::aid-cncr2820531320>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
- Garne J. P., Aspegren K., Linell F., Rank F., Ranstam J. Primary prognostic factors in invasive breast cancer with special reference to ductal carcinoma and histologic malignancy grade. Cancer. 1994 Mar 1;73(5):1438–1448. doi: 10.1002/1097-0142(19940301)73:5<1438::aid-cncr2820730519>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
- Hanley J. A., McNeil B. J. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982 Apr;143(1):29–36. doi: 10.1148/radiology.143.1.7063747. [DOI] [PubMed] [Google Scholar]
- Haybittle J. L., Blamey R. W., Elston C. W., Johnson J., Doyle P. J., Campbell F. C., Nicholson R. I., Griffiths K. A prognostic index in primary breast cancer. Br J Cancer. 1982 Mar;45(3):361–366. doi: 10.1038/bjc.1982.62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kairisto V., Poola A. Software for illustrative presentation of basic clinical characteristics of laboratory tests--GraphROC for Windows. Scand J Clin Lab Invest Suppl. 1995;222:43–60. doi: 10.3109/00365519509088450. [DOI] [PubMed] [Google Scholar]
- Kronqvist P., Kuopio T., Collan Y. Morphometric grading in breast cancer: thresholds for mitotic counts. Hum Pathol. 1998 Dec;29(12):1462–1468. doi: 10.1016/s0046-8177(98)90017-x. [DOI] [PubMed] [Google Scholar]
- Kronqvist P., Kuopio T., Collan Y. Morphometric grading of invasive ductal breast cancer. I. Thresholds for nuclear grade. Br J Cancer. 1998 Sep;78(6):800–805. doi: 10.1038/bjc.1998.582. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kronqvist P., Kuopio T., Pirvu C., Collan Y. The fraction of fields showing neoplastic tubules: a practical estimate of tubular differentiation in breast cancer. Histopathology. 1999 Nov;35(5):401–410. doi: 10.1046/j.1365-2559.1999.035005401.x. [DOI] [PubMed] [Google Scholar]
- Le Doussal V., Tubiana-Hulin M., Friedman S., Hacene K., Spyratos F., Brunet M. Prognostic value of histologic grade nuclear components of Scarff-Bloom-Richardson (SBR). An improved score modification based on a multivariate analysis of 1262 invasive ductal breast carcinomas. Cancer. 1989 Nov 1;64(9):1914–1921. doi: 10.1002/1097-0142(19891101)64:9<1914::aid-cncr2820640926>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
- Lipponen P. K., Collan Y., Eskelinen M. J. Volume corrected mitotic index (M/V index), mitotic activity index (MAI), and histological grading in breast cancer. Int Surg. 1991 Oct-Dec;76(4):245–249. [PubMed] [Google Scholar]
- Parham D. M., Hagen N., Brown R. A. Simplified method of grading primary carcinomas of the breast. J Clin Pathol. 1992 Jun;45(6):517–520. doi: 10.1136/jcp.45.6.517. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Parl F. F., Dupont W. D. A retrospective cohort study of Histologic risk factors in breast cancer patients. Cancer. 1982 Dec 1;50(11):2410–2416. doi: 10.1002/1097-0142(19821201)50:11<2410::aid-cncr2820501128>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
- Rank F., Dombernowsky P., Jespersen N. C., Pedersen B. V., Keiding N. Histologic malignancy grading of invasive ductal breast carcinoma. A regression analysis of prognostic factors in low-risk carcinomas from a multicenter trial. Cancer. 1987 Sep 15;60(6):1299–1305. doi: 10.1002/1097-0142(19870915)60:6<1299::aid-cncr2820600623>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
- Robbins P., Pinder S., de Klerk N., Dawkins H., Harvey J., Sterrett G., Ellis I., Elston C. Histological grading of breast carcinomas: a study of interobserver agreement. Hum Pathol. 1995 Aug;26(8):873–879. doi: 10.1016/0046-8177(95)90010-1. [DOI] [PubMed] [Google Scholar]
- Roberts A. N., Hähnel R. Oestrogen receptor assay and morphology of breast cancer. Pathology. 1981 Apr;13(2):317–325. doi: 10.3109/00313028109081671. [DOI] [PubMed] [Google Scholar]
- Schumacher M., Schmoor C., Sauerbrei W., Schauer A., Ummenhofer L., Gatzemeier W., Rauschecker H. The prognostic effect of histological tumor grade in node-negative breast cancer patients. Breast Cancer Res Treat. 1993;25(3):235–245. doi: 10.1007/BF00689838. [DOI] [PubMed] [Google Scholar]
- Simpson J. F., Page D. L. Status of breast cancer prognostication based on histopathologic data. Am J Clin Pathol. 1994 Oct;102(4 Suppl 1):S3–S8. [PubMed] [Google Scholar]
- Theissig F., Kunze K. D., Haroske G., Meyer W. Histological grading of breast cancer. Interobserver, reproducibility and prognostic significance. Pathol Res Pract. 1990 Dec;186(6):732–736. doi: 10.1016/S0344-0338(11)80263-3. [DOI] [PubMed] [Google Scholar]
- Todd J. H., Dowle C., Williams M. R., Elston C. W., Ellis I. O., Hinton C. P., Blamey R. W., Haybittle J. L. Confirmation of a prognostic index in primary breast cancer. Br J Cancer. 1987 Oct;56(4):489–492. doi: 10.1038/bjc.1987.230. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tosi P., Luzi P., Sforza V., Santopietro R., Bindi M., Tucci E., Barbini P., Baak J. P. Correlation between morphometrical parameters and disease-free survival in ductal breast cancer treated only by surgery. Appl Pathol. 1986;4(1-2):33–42. [PubMed] [Google Scholar]
- Zweig M. H., Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem. 1993 Apr;39(4):561–577. [PubMed] [Google Scholar]
- van der Linden J. C., Lindeman J., Baak J. P., Meijer C. J., Herman C. J. The Multivariate Prognostic Index and nuclear DNA content are independent prognostic factors in primary breast cancer patients. Cytometry. 1989 Jan;10(1):56–61. doi: 10.1002/cyto.990100110. [DOI] [PubMed] [Google Scholar]
