Breast cancer is the leading cause of death among solid tumours in women, and its incidence is increasing in the West. Adjuvant chemotherapy and hormonal treatment improve survival but have ...potentially serious side effects, and are costly. Because adjuvant treatment should be given to high risk patients only, and traditional prognostic factors (lymph node status, tumour size) are insufficiently accurate, better predictors of high risk and treatment response are needed. Invasive breast cancer metastasises haematogenously very early on, so many breast cancer prognosticators are directly or indirectly related to proliferation. Although studies evaluating the role of individual proliferation regulating genes have greatly increased our knowledge of this complex process, the functional end result—cells dividing—has remained the most important prognostic factor. This article reviews the prognostic value of different proliferation assays in invasive breast cancer, and concludes that increased proliferation correlates strongly with poor prognosis, irrespective of the methodology used. Mitosis counting provides the most reproducible and independent prognostic value, and Ki67/MIB1 labelling and cyclin A index are promising alternatives that need methodological fine tuning.
Background: PTEN tumor suppressor gene mutations are the most frequent genetic lesions in endometrial adenocarcinomas of the endometrioid subtype. Testing the hypothesis that altered PTEN function ...precedes the appearance of endometrial adenocarcinoma has been difficult, however, partly because of uncertainties in precancer diagnosis. Methods: Two series of endometrial cancer and precancer (endometrial intraepithelial neoplasia, as diagnosed by computerized morphometric analysis) tissue samples were studied, one for PTEN mutations by the use of denaturing gradient gel electrophoresis and another for PTEN protein expression by immunohistochemistry. Endometria altered by high estrogen levels that are unopposed by progestins—conditions known to increase cancer risk—were also studied by immunohistochemistry. Fisher's exact test was used for statistical analysis. Results: The PTEN mutation rate was 83% (25 of 30) in endometrioid endometrial adenocarcinomas and 55% (16 of 29) in precancers, and the difference in number of mutations was statistically significant (two-sided P = .025). No normal endometria showed PTEN mutations. Although most precancers and cancers had a mutation in only one PTEN allele, endometrioid endometrial adenocarcinomas showed complete loss of PTEN protein expression in 61% (20 of 33) of cases, and 97% (32 of 33) showed at least some diminution in expression. Cancers and most precancers exhibited contiguous groups of PTEN-negative glands, while endometria altered by unopposed estrogens showed isolated PTEN-negative glands. Conclusions: Loss of PTEN function by mutational or other mechanisms is an early event in endometrial tumorigenesis that may occur in response to known endocrine risk factors and offers an informative immunohistochemical biomarker for premalignant disease. Individual PTEN-negative glands in estrogen-exposed endometria are the earliest recognizable stage of endometrial carcinogenesis. Proliferation into dense clusters that form discrete premalignant lesions follows.
Endometrial intraepithelial neoplasia (also known as ‘EIN‘) is a precursor to endometrioid endometrial adenocarcinoma characterized by monoclonal growth of mutated cells, a distinctive ...histopathologic appearance, and 45-fold elevated cancer risk. We have applied diagnostic criteria for EIN to 97 successive endometrial biopsies classified as hyperplastic according to World Health Organization criteria and correlated results with computer-assisted morphometry (D-score) and clinical cancer outcomes. Three pathologists separately reviewed all cases for presence or absence of EIN using published criteria (gland area>stromal area, cytologic change in focus of altered architecture, lesion size >1 mm, and exclusion of cancer and mimics). Discordant cases were resolved by a consensus review at a multiheaded scope. Clinical outcomes were obtained in 84 patients from patient visit and pathology records. Diagnoses of presence or absence of EIN were unanimous among all three pathologists in 75% of cases, and intraobserver-reproducibility was very good (kappa 0.73–0.90). Cases rediagnosed as EIN encompassed hyperplasias previously diagnosed as atypical (n=18) or nonatypical (eight complex, two simple). Eight follow-up cancers were scattered between hyperplasia types (5/21 atypical, 3/63 nonatypical), but all classified as EIN (8/25) and D-score ≤1 (8/38). Subjective application of criteria for diagnosis of EIN correlates well with objective morphometry and successfully segregates patients into high and low cancer risk subgroups with better reproducibility than atypical hyperplasia diagnosis.
To validate the independent strong prognostic value of mitotic activity index (MAI) in lymph node (LN) -negative invasive breast cancer patients younger than 55 years in a nationwide multicenter ...prospective study.
Analysis of routinely assessed MAI and other prognosticators in 516 patients (median follow-up, 118 months; range, 8 to 185 months), without systemic adjuvant therapy or previous malignancies.
Distant metastases occurred in 127 patients (24.6%); 90 (17.4%) died as a result of metastases. MAI (< 10, > or = 10) showed strong association with recurrence (hazard ratio HR, 3.12; 95% CI, 2.17 to 4.50; P < or = .0001) and mortality (HR, 4.42; 95% CI, 2.79 to 7.01; P < .0001). The absolute difference in 10-year Kaplan-Meier estimates of time to distant recurrence as well as survival was 22% between MAI less than 10 versus > or = 10. This effect was independent of age, estrogen receptor (ER) status, and tumor diameter (which were significant prognosticators). In multivariate analysis with regard to patient age, tumor diameter, grade, ER status, and the St Gallen criterion, MAI proved to be an independent and the strongest prognosticator. Tubular formation (TF) and nuclear atypia (NA), as constituents of (expert revised) grade, had no (for TF) or limited (for NA, P = .048) additional prognostic value to the MAI. In the group with MAI less than 10, MAI less than 3 versus more than 3 had additional value but the classical threshold of 0 to 5 v 6 to 10 did not. With this additional subdivision of MAI as less than 3, 3 to 9, and more than 9, NA lost its additive prognostic value.
The MAI is the strongest, most widely available, easily assessable, inexpensive, well-reproducible prognosticator and is well suited to routinely differentiate between high- and low-risk LN-negative breast cancer patients younger than 55 years.
Discovery of somatically mutated cells in human tissues has been less frequent than would be predicted by in vitro mutational rates. We analyzed the PTEN tumor suppressor gene as an early marker for ...endometrial carcinogenesis, and we show that 43% of histologically normal premenopausal endometria contain rare glands that fail to express PTEN protein because of mutation and/or deletion. These persist between menstrual cycles. Histopathology of PTEN-null glands is initially unremarkable, but with progression, they form distinctive high-density clusters. These data are consistent with a progression model in which initial mutation is not rate limiting.
We assessed the reproducibility and prognostic variability of grade and lamina propria invasion in stages Ta, T1 urothelial carcinoma of the bladder.
A total of 130 consecutive stages Ta, T1 ...urothelial carcinomas routinely diagnosed by 15 pathologists (original diagnosis) were reviewed by 3 independent experienced pathologists using 1999 WHO criteria (diagnoses 1 to 3 and reviewer consensus diagnosis). Interreviewer disagreement cases were blindly reviewed again. Each remaining disagreement case was discussed in a multihead microscope session to attempt to solve remaining disagreements. In cases of continuing disagreement the majority diagnosis on stage and grade was considered the consensus diagnosis. Stage progression at followup was the dependent variable. Stage progression-free Kaplan-Meier survival curves and hazard ratios of each stage and grade diagnosis were calculated and prognostic variability was determined.
There was complete interobserver agreement on stage and grade among reviewers in 80% and 59% of cases, while it was 87.7% and 75.4%, respectively, after the second review. More than 1 grade difference occurred in 1.5% of cases (0% after the second review). The consensus and original diagnoses agreed on stage and grade in 68.5% and 62.3% of cases, respectively. Assignment of individual cases to 1 category of the 1999 WHO classification per reviewer varied considerably. The incidence of cases classified as stage T1 grade 3 by the reviewers was between 12.3% and 18.9% (average 14.1%). Consensus diagnosis grade had the strongest prognostic value (HR 68.8, range 8.9 to 528.0). Of the 63 original diagnoses of stage T1 tumors the consensus diagnosis down staged 35 (55.6%) to Ta and up staged 8 (12.7%) to T2–3. Progression was more common in the 20 consensus diagnosis stage T1 cases (5 or 25%) than in the 55 original diagnosis stage T1 cases (11 or 20%). Original diagnosis stage T1 tumors that were down staged by the consensus diagnosis showed less progression than consensus diagnosis confirmed stage T1 tumors (17% versus 25%). The prognostically worst subgroup (T1 grade 3) also showed considerable prognostic variation among reviewers (28% to 76% at 5 years of followup), in that the consensus diagnosis again had the highest prognostic significance (HR 3.5, range 1.2 to 10.2). At the end of the study all pathologists expressed that they were regularly uncertain about stage and grade assessment in an individual case in a considerable percent of all cases.
Observer prognostic variability in staging and grading is considerable with potentially strong implications for patients. Interobserver variation did not decrease using the new 1999 WHO grading classification.
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