Histopathological Image Analysis: A Review <s> A. Need for Quantitative Image Analysis for Disease Grading <s> BACKGROUND ::: Using the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute and American total mortality rates, the authors calculated the probability at birth of having a diagnosis of prostate cancer within a man's life to be 8.8% and then subtracted the incidence of microscopic Stage A cancers too small to ever be clinically significant. This gave a final probability of 8%. ::: ::: ::: METHODS ::: Prostates were examined after 139 consecutive unselected cystoprostatectomies from patients with bladder cancers in whom it was unknown whether they had prostate cancer. Prostate cancer was found in 55 patients (40%); the volume of the largest cancer in each specimen was determined using histologic morphometry. The authors identified the 8% of these 139 cytoprostatectomy specimens with the largest volume of prostate cancer. ::: ::: ::: RESULTS ::: The largest 11 of the 55 cancers represented 7.9% of the total 139 samples. These cancers ranged in volume from 0.5-6.1 ml, representing only 20% of all patients with prostate cancer. ::: ::: ::: CONCLUSIONS ::: If the strong evidence is accepted that cancer progression is proportional to cancer volume, it was concluded that prostate cancers larger than 0.5 ml appear to correspond to the 8% of men who will be diagnosed with a clinically significant carcinoma, as derived previously. Conversely, those 80% of prostate cancers smaller than 0.5 ml probably are not likely to reach a clinically significant size in view of the long doubling time of this cancer. <s> BIB001 </s> Histopathological Image Analysis: A Review <s> A. Need for Quantitative Image Analysis for Disease Grading <s> Low reproducibility reduces the clinical value of morphologic grading of malignant tumors, and the replacement of subjective classification by objective quantification has been suggested. Simple mitosis counting has been employed for objective malignancy grading most frequently and has proved its prognostic significance in, e.g., sarcomas and carcinomas of the breast and ovary. These and other measurements of morphometry are, however, obtained in two dimensions only, introducing bias due to ignorance of the fact that biologic structures are three-dimensional. Stereologic estimators are, to that end, well-suited, because they enable the assessment of spatial structure from sections. Studies addressing the impact of stereology in tumor pathology are the subject of the current review. Details of estimation are provided of stereologic variables of tumor size, numbers and densities of cancer cell nuclei and mitoses, mean size and size variability of cancer cell nuclei and variables of tissue architecture. Besides a description of their practical estimation the influence on variables of sampling method, tissue processing and observer variability is assessed, and estimator efficiency and measuring equipment is evaluated. Exemplifying the clinical importance of objective grading, results are summarized of prognostic studies of quantitative histopathology in women with breast cancer. It has been shown that many stereologic estimators are applicable to ordinary histologic sections processed under routine conditions. If a systematic random scheme of sampling is employed then the efficiency of estimation is usually high, and reproducible, accurate and representative results are ensured. For objective malignancy grading of breast cancer especially the volume-weighted mean nuclear size, vv (nuc), seems valuable, and the variable usually provides independent information to that of staging parameters. The prognostic value of vv (nuc) seems greatest in lymph node positive subsets, whereas the importance in lymph node negative patients should be further investigated. The clinical significance of some stereologic variables may be restricted due to relatively time consuming measurement procedures. However, the unbiased technique may provide precise measures of basic parameters like "tumor burden" and tumor growth pattern, and thereby be highly useful in experimental oncology. In conclusion, stereology is of great value for quantifying tumor elements. For objective malignancy grading especially assessment of the three-dimensional mean nuclear size seems useful. Prognostic significance of this variable has been demonstrated in, e.g., malignant melanoma and carcinomas of the breast, lung, bladder, prostate and uterine cervix. To determine the real clinical value of the measurements, further evaluation in a routine setting is necessary. In case such prospective studies confirm previous findings, the future replacement of subjective grading techniques by reproducible, objective variables seems feasible. <s> BIB002 </s> Histopathological Image Analysis: A Review <s> A. Need for Quantitative Image Analysis for Disease Grading <s> Potential reasons for discordance between the Gleason score in biopsies and surgical specimens are: 1) pathological interpretation bias, and 2) sampling effects. The importance of sampling effects in grading errors was examined in a series where the number of biopsy cores obtained was high. Biopsies were obtained using a technique whereby 18 directed cores were systematically obtained and mapped out within the gland. Gleason scores from biopsies and matched prostatectomy specimens were compared among 28 consecutive patients with localized prostate cancer. A pooled database from 10 series (n = 2,687) served as a baseline for comparison in the accuracy of Gleason score grading. With the present biopsy technique, an exact Gleason score match was achieved in 57% of cases, compared with the pooled database (PD) mean of 42% (P = 0.055), and was within 1 point in 93% of cases compared with 78% (PD) (P = 0.029). Upgrading of biopsies was seen in 35% of cases, compared with 43% (PD) (P = 0.19). With respect to Gleason score 7, an exact match was present in 78% of cases, compared with 63% (PD) (P = 0.17), and upgrading was 0%, compared with 20% (PD) (P = 0.07). The data suggest a significant reduction in grade errors by minimizing sampling effects, one that it is of the same order of magnitude as the reduction achieved from consensus pathologic evaluation. In our study, seven patients (25%) would have had their cancers missed altogether with sextant biopsies. Sampling effects may contribute significantly to grading errors in prostate needle biopsies, although a larger study is needed to confirm this. A methodology which adopts a higher number of cores combined with a consensus pathologic evaluation could potentially reduce grading errors substantially. The optimal number of cores remains to be determined in a larger study. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 326–330 (2000). © 2000 Wiley-Liss, Inc. <s> BIB003 </s> Histopathological Image Analysis: A Review <s> A. Need for Quantitative Image Analysis for Disease Grading <s> Abstract Only a few large studies of interobserver reproducibility of Gleason grading of prostatic carcinoma exist. Thirty-eight biopsies containing prostate cancer were distributed for Gleason grading to 41 general pathologists in Georgia. These cases had "consensus" Gleason grade groups (2-4, 5-6, 7, and 8-10) that were agreed on by at least 7 of 10 urologic pathologists. The overall kappa (κ) coefficient for interobserver agreement for these 38 cases was 0.435, barely moderate agreement, with a κ range from 0.00 to 0.88. There was consistent undergrading of Gleason scores 5-6 (47%), 7 (47%) and, to a lesser extent, 8-10 (25%). In cases with consensus primary patterns, there was consistent undergrading of patterns 2 (32%), 3 (39%), and 5 (30%). Pattern 2 was often (17%) mistaken for pattern 3. Pattern 4 was often undergraded (21%) and also mistaken for pattern 5 (17%). The most significant ( P <s> BIB004 </s> Histopathological Image Analysis: A Review <s> A. Need for Quantitative Image Analysis for Disease Grading <s> There is consensus that the Gleason system should be used for grading of prostate cancer. However, a number of controversial issues remain as regards how this grading is applied. A questionnaire was sent to 91 genitourinary pathologists in countries around the world with the purpose to survey current practice of Gleason grading. The response rate was 74%, including 43 North American pathologists and 24 from other continents. Of all participants, only 13% and 36%, respectively, ever diagnosed a Gleason score (GS) of 2 to 3 or 4 on needle biopsies (NBX), and 88% of those who did so assigned a GS 4 to <1% of cancers. Cribriform Gleason pattern (GP) 3 was acknowledged by 88% but a majority of them would classify < or =20% of cribriform patterns as GP 3. One third only accepted cribriform or fusion patterns as GP 4, but two thirds also included incomplete or poorly defined glands. For GP 5 to be identified on NBX, 83% required clusters of individual cells, strands, or nests seen at less than x40 lens magnification. Only 26% defined GS on NBX as primary + tertiary GP, and a majority would mention a tertiary pattern separately. For NBX, global or highest GS was reported by 40% and 10%, respectively, whereas 46% only gave a separate GS for each individual NBX core. In conclusion, there is a need to standardize practical application of Gleason grading both in terms of interpretation of patterns as well as how grading is reported. Our survey data provide information to general pathologists about the most common grading practices among genitourinary pathologists. <s> BIB005
Currently, histopathological tissue analysis by a pathologist represents the only definitive method (a) for confirmation of presence or absence of disease and (b) disease grading, or the measurement of disease progression. The need for quantitative image analysis in the context of one specific disease (prostate cancer) is described below. Similar conclusions hold for quantitative analysis of other disease imagery. Higher Gleason scores are given to prostate cancers, which are more aggressive, and the grading scheme is used to predict cancer prognosis and help guide therapy. The Gleason grading system is based solely on architectural patterns; cytological features are not evaluated. The standard schematic diagram created by Gleason and his group (see Fig. 1 ) separated architectural features into 1 of 5 histological patterns of decreasing differentiation, pattern 1 being most differentiated and pattern 5 being least differentiated. The second unique feature of Gleason grading is that grade is not based on the highest (least differentiated) pattern within the tumor. Recently several researchers have reported discrepancies with the Gleason grading system for grading prostate cancer histopathology. Many researchers have found grading errors (both under-and over-grading) in prostate cancer studies BIB004 - BIB005 . Similar issues with cancer grading have been reported for other diseases such as breast cancer BIB002 . In light of the above, Luthringer et al.  have discussed the need for changes to be made to Gleason grading system. In late 2005, the International Society of Urologic Pathologists in conjunction with the World Health Organization (WHO) made a series of recommendations for modifications to the Gleason grading system, including reporting any higher grade cancer, no matter how small quantitatively. Luthringer et al.  have also suggested the need for re-evaluation of original biopsy material by a highly experienced pathologist which could help guide patient management. Stamey et al. BIB001 discussed need for developing methods to accurately measure cancer volume and better estimate prostate cancer to better predict progression of cancer. King et al. BIB003 has similarly called for developing a methodology to help reduce pathologic interpretation bias which would likely result in significantly improved accuracy of prostate cancer Gleason grading.