Biomedical subjects
Publications and source records attributed to Rodolfo Montironi.
Proper examination of radical prostatectomy (RP) specimens by the pathologists is critical in accurately determining the prediction of patient outcome. The pathology report should include relevant clinical information as well as provide prognostically useful data derived from the evaluation of the RP specimen.
Although prostate cancer has become the most common solid tumor diagnosed in men and the second leading cause of death due to malignancy, the progression of the disease is still somewhat unpredictable, until it becomes locally advanced or metastatic. The clinical problem to distinguish between dormant and progressive cancers is essential to patient care, as surgical and medical therapies have significant risk of morbidity and disability. Multiple gene expression in prostate cancer was surveyed by differential display cloning between the undifferentiated hormone refractory human prostate cancer cell line PC-3 (highly tumorigenic in nude mice) the hormone responsive LNCaP cell line (weakly tumorigenic in nude mice), and the poorly differentiated DU-145 cell line (moderately tumorigenic). ApoE mRNA was found to be highly expressed only in PC-3 cell-line. We further examined its protein expression by immunohistochemistry in 20 prostatectomy specimens and an association between Gleason score for each sample and ApoE expression was determined. ApoE expression correlates directly with the Gleason score in tissue sections, hormone independence as well as local and distant invasiveness. Prostatic intraepithelial neoplasias (PINs) adjacent to clinically manifested cancer were positive whereas more distant PINs were negative for ApoE. ApoE may represent a marker of more aggressive cells in human prostate cancers.
TP53, a gene located on chromosome 17p13, encodes a nuclear protein (p53) involved in cell cycle regulation. This protein degrades in 20 minutes. However, the inactivated gene can produce a protein with a half-life 4-20 times longer than that of the wild type; it can be demonstrated by immunohistochemistry. Unfortunately, all the antibodies recognize both proteins, and the determination of a cutoff in the percentage of positive nuclei is required for the detection of cases with correlation of the TP53 mutation. In urologic tumors, p53 overexpression determination can be diagnostic help in low grade superficial bladder cancer, in cases of cystectomy and pN0, and in penile cancer without clinically involved lymph nodes. It does not seem useful in renal cell carcinoma or testicular germ cell tumors, and its utility is limited in prostate carcinoma.
Chemoprevention is the administration of agents to prevent induction of cancer, or to inhibit or delay its progression. In prostatic neoplasia, the time from tumour initiation and progression to invasive carcinoma often begins in men in the fourth and fifth decades of life and extends across decades. This phenomenon represents a unique opportunity to arrest or reverse the process of carcinogenesis with the use of chemopreventive agents. For prostate cancer, as for other cancer targets, development of successful chemopreventive strategies requires suitable cohorts, reliable biomarkers for evaluating chemopreventive efficacy and well-characterised agents. Histopathologists play an important role in prostate chemoprevention. In fact, they define the high-risk groups, recognise the surrogate end markers and evaluate the morphological effects of the agents on the prostate tissue specimens.
Activating point mutations in the FGFR3 gene occur frequently in low-grade and low-stage bladder carcinomas, whereas they are rare in high-grade carcinomas. This study investigates the incidence of FGFR3 mutations in 12 urothelial papillomas and 79 pTaG1 tumours which were regraded according to the 1998 WHO/ISUP classification system, resulting in 62 papillary urothelial neoplasms of low malignant potential (PUNs-LMP) and 17 low-grade papillary urothelial carcinomas (LG-PUCs). FGFR3 mutation analysis of 21 ovarian Brenner tumours was also performed. Seventy-seven cases were detected with a mutation in the FGFR3 gene. The mutations were exclusively found in bladder neoplasms. In urothelial papilloma, generally considered a benign lesion, 9/12 (75%) mutations were found. This report is the first to describe a genetic defect in urothelial papilloma. A comparable percentage of mutations was found in PUNs-LMP (85%) and LG-PUCs (88%). No mutations were found in matched normal DNA from bladder tumour patients. The mean follow-up was 5.78 years (range 0.21-17.60 years). Five patients developed high-grade papillary urothelial carcinoma from 2.5 to 12 years after first diagnosis. Two patients died of bladder cancer. The mean number of recurrences (recurrence rate) per year was 0.03, 0.21, and 0.46, respectively, for papilloma, PUN-LMP, and LG-PUC. Urothelial papilloma is a rare lesion with a benign natural behaviour compared with PUN-LMP and LG-PUC of the bladder, but from a molecular perspective, papillomas should be classified together with all well-differentiated urothelial neoplasms.
BACKGROUND AND AIMS: This paper summarizes the work done by the members of the Committee no. 2 at the International Consultation on the Diagnosis of Non-Invasive Urothelial Neoplasms held in Ancona, Italy (11-12 May 2001). The committee members discussed and reached consensus regarding the optimal contemporary diagnosis and classification of the preneoplastic non-papillary lesions of the urothelium. An important objective was to promote a precise terminology and to use it consistently in daily practice in pathology and urology. RESULTS AND CONCLUSIONS: The result of the meeting is represented by a refined classification of the non-papillary intraepithelial lesions and conditions of the urothelium. This classification includes epithelial abnormalities (reactive urothelial atypia and flat urothelial hyperplasia), presumed preneoplastic lesions and conditions (keratinizing squamous and glandular metaplasia, and malignancy-associated cellular changes), as well as preneoplastic (dysplasia) and neoplastic non-invasive (carcinoma in situ) lesions. Each of these lesions is defined with strict morphological criteria in order to provide more accurate information to urologists in managing patients.
BACKGROUND AND OBJECTIVE: A Bayesian belief network (BBN), as diagnostic decision support system, enables the processing of our knowledge of histopathology expressed in descriptive terms, words and concepts. The aim of this study was to evaluate the contribution of a BBN in the improvement of inter-observer agreement and certainty level in the diagnosis and grading of papillary urothelial neoplasms. MATERIALS: Inter-observer agreement and certainty level were investigated on 40 cases of non-invasive papillary urothelial neoplasms subdivided according to the WHO 1973 classification. There were 10 urothelial papillomas (UPs), 10 grade 1 papillary carcinomas (G1), 10 grade 2 papillary carcinomas (G2) and 10 grade 3 papillary carcinomas (G3). Five consecutive sessions were held with three observers (RMa, PC and MSt). Sessions A, B and D were based on the morphological evaluation of the specimens with a conventional light microscope only. In sessions C and E, a BBN was used in addition to the microscope. The BBN output was represented by four belief values for four possible diagnostic outcomes. These values ranged from 0.0 to 1.0, with the sum of the belief values being 1.0. Concerning the certainty level, a two-tier system of assessment was adopted in sessions A, B and D: certain versus less certain. In sessions C and E, a belief value equal to or greater than 0.65 was considered as equivalent to "certain". RESULTS: In session A, an all-encompassing or synthetic approach to decision-making was adopted. Agreement with the gold standard was seen in 60% (RMa), 55% (PC) and 65% (MSt) of cases, respectively. The level of subjective confidence was "certain" in 35%, 40% and 35% of cases, respectively. Better agreement-70% (RMa), 68% (PC) and 72% (MSt) of cases-was present in session B where an analytical approach based on the evaluation of a series of morphological features was used. The level of subjective confidence was "certain" in 45%, 50% and 55% of cases, respectively. In session C, where a BBN was utilised, a further increase in degree of agreement with the gold standard was observed, e.g. 85% (RMa), 80% (PC) and 86% (MSt) of cases, respectively. Levels of certainty or belief values were high. Decrease in both the level of agreement-60% (RMa), 62% (PC) and 65% (MSt) of cases-and certainty was seen in session D where the observers were left free to evaluate the cases morphologically without the constrain of either a synthetic or analytical approach. In session E, where the BBN was used again, the percentage of cases in agreement with the gold standard increased to 83% (RMa), 81% (PC) and 84% (MSt), respectively. Increase in certainty or belief was also seen. The difference of the results obtained in the sessions A, B and D with those seen in the BBN-based sessions (C and E) is statistically significant. CONCLUSIONS: Conventional morphological evaluation of papillary urothelial neoplasms is affected by inter-observer variability and, in many instances, by diagnostic uncertainty. The greatest difficulties are found with G1 and G2 cases. Improvement in inter-observer agreement and certainty level can be achieved with a BBN.
The observations of Skakkebaek and the evolution of the concept of intratubular germ cell neoplasia (or testicular intraepithelial neoplasia (TIN)) indicate that most, but not all, germ cell tumors of the testis evolve from a common neoplastic precursor lesion: intratubular germ cell neoplasia, unclassified type (IGCNU). It is defined as the presence of malignant germ cells within the seminiferous tubules. At 5 years about 50% of patients with a testicular biopsy positive for IGCNU have developed invasive germ cell tumors, and only a small fraction remain free of invasive tumors by 7 years. Orchiectomy is the treatment of choice in patients with unilateral IGCNU, and low-dose radiation is efficacious in patients with bilateral IGCNU (although sterility is certain). So far, there is only one published report of occurrence of two cases of germ cell cancer despite previous local radiotherapy to the testis. A recent study demonstrated an estimated risk of recurrent IGCNU following chemotherapy of 21% and 42% at 5 and 10 years, respectively.
Prostatic intraepithelial neoplasia (PIN) is composed of dysplastic cells with a luminal cell phenotype, expressing the androgen receptor as well as prostate-specific antigen. PIN is characterized by progressive abnormalities of phenotype that are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of carcinogenesis. High-grade PIN is considered the most likely precursor of prostatic carcinoma, according to virtually all available evidence. Androgen deprivation decreases the prevalence and extent of PIN and the degree of capillary vascularization (e.g., angiogenesis) in the surrounding stroma via suppression of vascular endothelial growth factor production. Prostatic carcinoma is also likely to arise from precursor lesions other than high-grade PIN such as low-grade PIN, atypical adenomatous hyperplasia, malignancy-associated foci, and atrophy.
Prostate cancer (PCa) is a leading cause of morbidity and mortality in males accounting for approximately 30% of all new cases of cancer and approximately 14% of cancer deaths. Despite considerable advances achieved in the ability to detect and treat PCa, there have not been significant corresponding decreases in PCa-related morbidity and mortality. Proper examination of radical prostatectomy specimens by the pathologists is critical in determining the need for adjuvant treatment and prediction of patient outcome. The goal is to tailor the therapeutic approach to the clinical, morphological and molecular features of each patient.
Tumor expression of the proliferation marker (MIB-1) and the cell cycle-related protein (p27) may predict the biologic behavior of various human tumors. The purpose of this study was to evaluate the role of p27 and MIB-1 expression in predicting lymph node metastasis in male breast carcinomas (MBCs). We studied 67 patients with invasive MBC who had undergone modified radical mastectomy. Pathologic lymph node status was correlated with the p27 protein and the MIB-1 proliferation index. These factors were studied immunohistologically by standard methods. Men in this study ranged from 36 to 92 years of age (mean, 63 years); 43 (64%) were T1 lesions, and 24 (36%) were T2 lesions. Twenty-nine patients (43%) had positive nodes. p27 was expressed in 43 tumors (64%) and MIB-1 in 13 tumors (19.4%). Tumors with positive p27 showed positive lymph nodes in 10 cases (23%). In contrast, p27-negative tumors had positive lymph nodes in 18 cases (75%). Tumors positive for MIB-1 show positive lymph nodes in 11 cases (85%). However, when MIB-1 was negative, only 16 patients (30%) had positive lymph nodes. Multivariate logistic regression analysis confirmed the utility of MIB-1 overexpression in predicting lymph node metastasis ( p < 0.0006). Also, decreased p27 protein expression strongly correlates with lymph node metastasis ( p < or = 0.0001). Furthermore, when p27 was negative and MIB-1 was positive, 100% of the patients had positive lymph nodes. In contrast, when p27 was positive and MIB-1 was negative, only 12% of patients had positive lymph nodes. The reduced expression of the p27 protein and the overexpression of the MIB-1 proliferation index in this study show a significant correlation in predicting lymph nodes metastasis in MBCs.
As we enter the information age we hold strong beliefs in the benefits of digital technology applied to pathology: numerical representation offers objectivity. Digital knowledge may indeed lead to significant information discovery, and, processing systems might be designed to allow a true evolution of capabilities. Questions arise whether the methodology underlying quantitative analysis provides the information that we need and whether it is appropriate for some of the problems encountered in diagnostic and prognostic histopathology. While one certainly would not dispute the value of statistical procedures, the clinical needs call for individual patient targeted prognosis.