F. K. Mostofi

The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder

In October 1997, Dr. F.K. Mostofi assembled a group of individuals interested in bladder neoplasia at a meeting in Washington DC. The participants included urologic pathologists, urologists, urologic oncologists, and basic scientists with an interest in bladder neoplasia. The purpose of this meeting was to discuss bladder terminology and make recommendations to the World Health Organization (WHO) Committee on urothelial tumors. Following this meeting, a group of the urologic pathologists who attended the Washington meeting decided to broaden the representation of the group and arranged a meeting primarily of the members of the International Society of Urologic Pathologists (ISUP) at the 1998 United States and Canadian Academy of Pathology Meeting held in Boston. Massachusetts. At this meeting. issues regarding terminology of bladder lesions, primarily neoplastic and putative preneoplastic lesions, were discussed, resulting in a consensus statement. The WHO/ ISUP consensus classification arises from this consensus conference committees recommendations to the WHO planning committee and their agreement with virtually all of the proposals presented herein. 29 The effort involved in reaching such a consensus was often considerable. Many of those involved in this process have compromised to arrive at a consensus. The aim was to develop a universally acceptable classification system for bladder neoplasia that could be used effectively by pathologists, urologists, and oncologists.

Renal medullary carcinoma: the seventh sickle cell nephropathy

Over the last 22 years, we have encountered 34 examples of a highly aggressive neoplasm with a microscopic morphology that is highly predictive of finding sickled erythrocytes in the tissue. With the exception of one patient, all are believed to have had sickle cell trait or, in one case, hemoglobin SC disease. These 33 patients are the subject of this report and, where their race was known, they were all blacks between the ages of 11 and 39 years. Between the ages of 11 and 24 years, males predominated by 3 to 1. Beyond age 24, however, the tumors occurred equally in men and women. The dominant tumor mass was in the medulla and ranged from 4 to 12 cm in diameter. Mean size was 7 cm; median, 6 cm. Peripheral satellites in the renal cortex and pelvic soft tissues, as well as venous and lymphatic invasion, were usually present. The lesions exhibited a reticular, yolk sac-like, or adenoid cystic appearance, often with poorly differentiated areas in a highly desmoplastic stroma admixed with neutrophils and usually marginated by lymphocytes. The tumors had usually metastasized when first discovered, and none was confined to the kidney at the time of nephrectomy. The mean duration of life after surgery was 15 weeks. These tumors probably arise in the calyceal epithelium in or near the renal papillae, the same site that produces the more familiar picture of unilateral hematuria in patients with sickle cell trait. We have concluded that renal medullary carcinoma represents another example of renal disease associated with sickle cell disorders. The other six are unilateral hematuria, papillary necrosis, nephrotic syndrome, renal infarction, inability to concentrate urine, and pyelonephritis.

Carcinoma of the prostate: Prognostic evaluation of certain pathologic features in 208 radical prostatectomies

In a study of 208 total prostates removed surgically for early carcinoma of the prostate and studied by the step‐section technique, we found that 97% were located either peripherally or both peripherally and centrally; 80% were bilateral, and 85% were multifocal. In most of the cases, the tumor was actually more extensive than detected by rectal examination, but there was reasonable agreement (74.5%) between the urologist and pathologist in assessing the presence of local extension of carcinoma. Evaluation of various factors affecting survival and mortality disclosed that an extension of the tumor to seminal vesicles or invasion of the capsule, whether detected clinically or pathologically, had an unfavorable prognosis while the side involved, the location of the tumor, and perineural invasion had no significant effect on the prognosis.

Testicular tumors. Epidemiologic, etiologic, and pathologic features

Observations on 6,000 testicular tumors revealed the following: Testicular tumors constitute the fourth most common cause of deaths from neoplasia in the age group of 15–34 years of age. There is a definite geographic, racial, and age distribution. The cause of testicular tumors is unknown, but cryptorchidism, trauma, infections, and genetic and endocrine factors appear to play a role in their development. Germ cell tumors comprise the large majority of testicular tumors and present one or more of 4 bask histologic patterns: seminoma, embryonal carcinoma, choriocarcinoma, and teratoma. In 40% the tumors show admixtures of 2 or more of these basic cell types. Tumors of specialized gonadal stroma constitute about 6% of testicular tumors and consist of Leydig cell, Sertoli cell, and granulosa‐theca cell tumors, or admixtures of these. The most important metastatic tumor of the testes is malignant lymphoma, initially manifested as testicular tumor.

Elevated levels of apoptosis regulator proteins p53 and BCL-2 are independent prognostic biomarkers in surgically treated clinically localized prostate cancer

PURPOSE The tumor suppressor gene (TSG) p53 and the proto-oncogene bcl-2 have been shown to be involved in the regulation of cell growth and apoptosis and have been implicated in hormone refractory prostate cancer (PC) and poor prognosis. The goal of this study was to determine the clinical utility of the presence of p53 and bcl-2 immunohistochemical (IHC) protein in the primary tumor as predictors of disease progression following radical prostatectomy (RP). MATERIALS AND METHODS The expression of p53 and bcl-2 was evaluated in archival paraffin-embedded RP specimens from 175 patients followed from 1 to 9 years (mean = 4.6 years) and correlated with stage, grade, race and serologic (PSA) recurrence following surgery. RESULTS Overexpression of bcl-2 was noted in 47 of 175 (26.9%) patients; these patients had a significantly higher 5-year failure rate than those who did not overexpress bcl-2 (67.0% versus 30.7%). Expression of p53 was noted in 114 of 175 (65.1%) patients with a 5-year failure rate of 51.1% compared with a 5-year failure rate of only 22% in p53 negative patients. When expression rates for p53 and bcl-2 were combined, the 5-year failure rate was 75.3%. Conversely, when both p53 and bcl-2 IHC staining were negative, the 5-year failure rate was 20.4%. Univariate Kaplan-Meier analysis showed a statistically significant difference between p53 and bcl-2 positive and negative patients (p < 0.001). Multivariate Cox Regression Analysis with backward elimination controlling for age, race, stage and grade showed both p53 (p = .0185) and bcl-2 (p = .004) to be independent predictors of disease-free survival. CONCLUSION p53 and bcl-2 appear to be important biomarkers that predict recurrence in clinically localized PC after RP.

Ki-67 EXPRESSION IS A PROGNOSTIC MARKER OF PROSTATE CANCER RECURRENCE AFTER RADICAL PROSTATECTOMY

PURPOSE We assessed the cellular proliferation of clinically localized prostate cancer by immunohistochemistry using the monoclonal antibody MIB to Ki-67 antigen in an attempt to identify associations between proliferative indexes and disease progression following radical prostatectomy. MATERIALS AND METHODS Ki-67 proliferative antigen was evaluated using MIB 1 monoclonal antibody in archival paraffin embedded radical prostatectomy specimens from 180 patients followed for 1 to 9 years (mean 4.4). The percentage of tumor nuclei expressing Ki-67 antigen was measured and assigned and MIB 1 score (none or rare--negative, 1+--low score and 2 to 4+--high score) and analyzed for prostate specific antigen, stage, age, race, grade and serological recurrence postoperatively. RESULTS There was a significant association between MIB 1 score and nuclear grade (p < 0.001), Gleason score (p < 0.001) and pathological stage (p = 0.01). Patients with a high MIB 1 score had earlier progression and a lower 5-year recurrence-free survival rate (44%) than those with negative MIB 1 scores (71%, p < 0.001). In multivariate Cox regression analysis with backward elimination, pathological stage (p < 0.01), pretreatment prostate specific antigen (p = 0.04) and MIB 1 score (p = 0.05) were statistically significant predictors of disease-free survival, and patients with a high MIB 1 score were 3.1 times as likely to have recurrence as those with a negative score. Controlling for stage, patients with organ confined disease and a high MIB 1 score had a lower 5-year disease-free survival rate (68%) than those with a low MIB 1 score (95%, p < 0.01). CONCLUSIONS Proliferative activity as measured by the Ki-67 proliferative antigen, MIB 1, appears to be a prognostic marker of recurrent prostate cancer after radical prostatectomy.

Staging of early prostate cancer: A proposed tumor volume-based prognostic index

Current staging of early prostate cancer separates patients into two groups: those with palpable and non-palpable tumors. Such staging relies on digital rectal examination in making this separation, despite the low sensitivity, low specificity, and low positive predictive value of this method. As an alternative, tumor volume may be useful for staging because of its powerful prognostic ability and its potential to be assessed clinically due to recent advances in imaging techniques such as transrectal ultrasound. In this study, we evaluate the utility of tumor volume in predicting progression of early prostate cancer based on the composite published evidence from nine pathologic studies of serially-sectioned prostates. Logistic regression revealed that tumor volume was a good positive predictor of all measures of tumor progression. There was a 10 percent probability of capsular invasion in tumors measuring about 0.5 cm3; 10 percent probability of seminal vesicle invasion in tumors measuring about 4.0 cm3; and 10 percent probability of metastases in tumors measuring about 5.0 cm3. These composite results suggest that tumor volume is a significant predictor of cancer progression. A volume-based prognostic index is proposed as an adjunct to staging for early prostate cancer.

Characteristics of prostate cancers detected in a multimodality early detection program

Background. Few data are available to describe the clinical and pathologic characteristics of prostate cancers detected through early detection programs. The American Cancer Society National Prostate Cancer Detection Project (ACS‐NPCDP) is a multimodality, multicenter study of the feasibility of early prostate cancer detection using digital rectal examination (DRE), transrectal ultrasound (TRUS), and prostate specific antigen (PSA). One hundred fifty‐six prostate cancers are available from this project for analysis.

Large acinar atypical hyperplasia and carcinoma of the prostate

Step‐sections of 429 whole prostate glands were studied. Large acinar atypical hyperplasia was graded as mild, moderate, and severe based on the degree of cellular anaplasia. The relationship between atypical hyperplasia and prostatic carcinoma was investigated. There was a strong association between prevalence and grade of atypical hyperplasia and prostatic carcinoma in patients up to 60 years old. Beyond the age of 60 no association was detected. In the younger age groups (36 to 60 years) atypical hyperplasia was found in 86.8% of prostates with carcinoma, but only in 37.9% of benign glands. Corresponding figures for the over‐60 age group were 68.8% and 65.1%, respectively. A biologic explanation of the association between atypical hyperplasia and carcinoma in the younger age groups has been proposed. It was suggested that these men with atypical hyperplasia, particularly with severe atypical hyperplasia, have a greater risk for developing prostatic carcinoma.

RACIAL DIFFERENCES IN TUMOR VOLUME AND PROSTATE SPECIFIC ANTIGEN AMONG RADICAL PROSTATECTOMY PATIENTS

PURPOSE Black men with and without prostate cancer in general have higher prostate specific antigen (PSA) before screening and treatment than other racial groups. A preliminary study suggested that higher PSA levels may be primarily due to greater tumor burden. We compared PSA and 3-dimensional (D) tumor volume in a consecutive cohort of black and white radical prostatectomy patients in an equal access military health care setting to determine racial differences in these parameters. MATERIALS AND METHODS Prospective data collection, 2.25 mm. step section whole mount specimen processing and 3-D tumor volume assessment were performed in 226 patients with clinical stage T1-T3 prostate cancer undergoing radical prostatectomy at our center between April 1993 and March 1997. Of the patients 25 were excluded from further analysis because of neoadjuvant hormone treatment, T3 disease or Asian race. A total of 155 white and 46 black patients were compared. RESULTS There was no significant racial difference in the distribution of patients by age, clinical stage, pathological stage, Gleason sum or benign prostate gland volume. A significant racial difference was noted for pretreatment PSA and 3-D tumor volume. PSA values were higher in black men than in white men, and the racial difference remained statistically significant in multivariate analysis adjusting for 3-D tumor volume, benign gland volume, age, stage and Gleason sum. CONCLUSIONS Racial difference in PSA persists, despite rigorous covariate adjustment, and further study is needed to explain this PSA difference.