Commentary on "Prognostic effect of carcinoma in situ in muscle-invasive urothelial carcinoma patients receiving neoadjuvant chemotherapy."

BACKGROUND: Carcinoma in situ (CIS) is a poor prognostic finding in urothelial carcinoma. However, its significance in muscle-invasive urothelial carcinoma (MIUC) treated with neoadjuvant chemotherapy (NAC) is uncertain. We assessed the effect of CIS found in pretreatment transurethral resection of bladder tumor (TURBT) biopsies on the pathologic and clinical outcomes. MATERIALS AND METHODS: Subjects with MIUC treated with NAC before cystectomy were identified. The pathologic complete response (pCR) rates stratified by TURBT CIS status were compared. The secondary analyses included tumor response, progression-free survival (PFS), overall survival (OS), and an exploratory post hoc analysis of patients with pathologic CIS only (pTisN0) at cystectomy. RESULTS: A total of 137 patients with MIUC were identified. TURBT CIS was noted in 30.7% of the patients. The absence of TURBT CIS was associated with a significantly increased pCR rate (23.2% vs. 9.5%; odds ratio = 4.08; 95% CI: 1.19-13.98; P = 0.025). Stage pTisN0 disease was observed in 19.0% of the TURBT CIS patients. TURBT CIS status did not significantly affect the PFS or OS outcomes. Post hoc analysis of the pTisN0 patients revealed prolonged median PFS (104.5 vs. 139.9 months; P = 0.055) and OS (104.5 vs. 152.3 months; P = 0.091) outcomes similar to those for the pCR patients. CONCLUSION: The absence of CIS on pretreatment TURBT in patients with MIUC undergoing NAC was associated with increased pCR rates, with no observed differences in PFS or OS. Isolated CIS at cystectomy was frequently observed, with lengthy PFS and OS durations similar to those for pCR patients. Further studies aimed at understanding the biology and clinical effect of CIS in MIUC are warranted.

Prostate cancer DNA ploidy and response to salvage hormone therapy after radiotherapy with or without short-term total androgen blockade: an analysis of RTOG 8610.

PURPOSE: DNA ploidy has consistently been found to be a correlate of prostate cancer patient outcome. However, a minority of studies have used pretreatment diagnostic material and have involved radiotherapy (RT)-treated patients. In this retrospective study, the predictive value of DNA ploidy was evaluated in patients entered into Radiation Therapy Oncology Group protocol 8610. The protocol treatment randomization was RT alone versus RT plus short-course (approximately 4 months) neoadjuvant and concurrent total androgen blockade (RT+TAB). PATIENTS AND METHODS: The study population consisted of 149 patients, of whom 74 received RT alone and 75 received RT+TAB. DNA content was determined by image analysis of Feulgen stained tissue sections; 94 patients were diploid and 55 patients were nondiploid. Kaplan-Meier univariate survival, the cumulative incidence method, and Cox proportional hazards multivariate analyses were used to evaluate the relationship of DNA ploidy to distant metastasis and overall survival. RESULTS: DNA nondiploidy was not associated with any of the other prognostic factors in univariate analyses. In Kaplan-Meier analyses, 5-year overall survival was 70% for those with diploid tumors and 42% for nondiploid tumors. Cox proportional hazards regression revealed that nondiploidy was independently associated with reduced overall survival. No correlation was observed between DNA ploidy and distant metastasis. The diminished survival in the absence of an increase in distant metastasis was related to a reduction in the effect of salvage androgen ablation; patients treated initially with RT+TAB and who had nondiploid tumors had reduced survival after salvage androgen ablation. CONCLUSIONS: Nondiploidy was associated with shorter survival, which seemed to be related to reduced response to salvage hormone therapy for those previously exposed to short-term TAB.

P504S immunohistochemical detection in 405 prostatic specimens including 376 18-gauge needle biopsies.

P504S is a recently described, prostate cancer-specific gene that encodes a protein involved in the beta-oxidation of branched chain fatty acids. A recent study has shown that immunohistochemical detection of P504S gene product is a sensitive and specific marker of prostatic carcinoma in formalin-fixed, paraffin-embedded tissues. We performed a detailed analysis of P504S protein expression in a large series of prostate and bladder specimens with special emphasis on staining in specific morphologic patterns of prostatic adenocarcinoma, posthormonal and radiation therapy cases, and invasive urothelial carcinoma. A total of 366 prostate needle core biopsies from 124 patients with prostate cancer, 10 biopsies from 2 patients without prostate cancer, 28 prostatectomy specimens (16 with specific morphologic patterns, 7 posthormonal therapy and 5 postradiation therapy specimens), 5 bladder specimens with invasive urothelial carcinoma, and a single transurethral resection specimen from a patient with hormonally treated prostate cancer and invasive urothelial carcinoma were stained with P504S monoclonal antibody at a 1:250 dilution using standard heat-induced epitope retrieval and avidin-biotin technique. Extent (0, no staining; 1+, 1-10% staining; 2+, 11-50% staining; 3+, > or =51% staining) and location (luminal, subluminal, and diffuse cytoplasmic) of immunoreactivity in carcinoma and benign tissues were recorded. A total of 153 of 186 biopsies (82%) with prostatic adenocarcinoma stained for P504S. Pseudohyperplastic, atrophic, ductal, and mucinous prostatic carcinomas stained similarly, as did cases treated with hormone or radiotherapy. In 81 of 377 (21%) foci of benign prostatic tissue there was staining that was almost always focal, faint, and noncircumferential. Seminal vesicles did not stain for P504S. Five of six (83%) specimens with invasive urothelial carcinoma had 2+ staining and one case had focal staining. We conclude that immunohistochemistry for P504S has potential utility in the diagnosis of prostate cancer, including those treated by hormones and radiation. Circumferential luminal to subluminal and diffuse cytoplasmic staining is the most specific staining pattern for prostatic carcinoma and is almost never associated with benign prostatic tissue. However, a negative P504S immunostain does not automatically rule out prostate cancer, as 18% of cases were negative. Additionally, occasional benign glands, high-grade prostatic intraepithelial neoplasia, atypical adenomatous hyperplasia, and urothelial carcinoma may express P504S. Therefore, we think that P504S is best used only in conjunction with strict light microscopic correlation and preferably with high molecular weight cytokeratin immunostaining.

How accurately does prostate biopsy Gleason score predict pathologic findings and disease free survival?

OBJECTIVE: Due to the significant impact on prognosis by subgrouping of prostatectomy Gleason scores < 7, 7, and > 7, we undertook this study to answer whether the biopsy Gleason score was as predictive of disease free survival and assess the correlation with the prostatectomy Gleason score in a modern prostatectomy series. METHODS: An analysis of 1,031 patients who underwent radical prostatectomy for clinically localized prostate cancer was performed. All data was prospectively collected. The Gleason score was categorized into 3 different groups (< 7, 7, and > 7) for biopsy and prostatectomy specimens. Disease free survival was then analyzed for each group. Discrepancies between scores and outcomes were evaluated. RESULTS: Accurate correlation was noted in 54.8, 66.8, and 47.4% of Gleason scores < 7, 7, and > 7, respectively. Overall accuracy was 58.3%. Both, biopsy and prostatectomy Gleason score correlated significantly with disease free survival (P = 0.001), furthermore the classification (Gleason scores < 7, 7 and > 7) was highly significant (P = 0.001). Patients with prostatectomy Gleason < 7 tumors had significant survival advantage over those with biopsy Gleason < 7, (P = 0.001). However, disease free survival was superior for patients with biopsy Gleason > 7 than those with prostatectomy Gleason > 7, (P = 0.02). The overall disease free survival was similar among the patients with Gleason score of 7 (P = 0.12). CONCLUSIONS: It appears that biopsy Gleason score, although oftentimes not correlating strongly with the prostatectomy Gleason score, is an important prognostic factor in prostate cancer. There are significant differences in disease free survival between biopsy and prostatectomy Gleason score categories.

Structural alteration of p53 protein in patients with muscle invasive bladder transitional cell carcinoma.

PURPOSE: Recent data imply that 3-dimensional (D) p53 protein modeling provides more specific information on its function in patients with pancreatic adenocarcinoma. In addition to immunohistochemical and single strand conformational polymorphism analysis, we performed 3-D p53 protein modeling and correlated our results with the disease-free survival of patients with muscle invasive transitional cell carcinoma of the bladder who underwent surgery. MATERIALS AND METHODS: We identified 43 patients and analyzed p53 status in each by immunohistochemical testing, single strand conformational polymorphism and DNA sequencing with 3-D protein modeling. Median followup was 38 months (range 4 to 92). The results of each analysis were compared and correlated with cancer specific survival. Statistical analysis was performed using the log rank test on Kaplan-Meier survival curves. RESULTS: The population included 30 men and 13 women 35 to 84 years old (median age 65). Nuclear over expression of p53 protein was observed in 26 of the 43 cases (60%). Lymph node involvement did not correlate with p53 over expression. Significantly more patients with lymph node metastasis died of cancer. Median survival in the 26 patients with p53 over expression was 28 months versus 57 in those with negative staining (p = 0.25). Mutation analysis by single strand conformational polymorphism revealed no abnormality in 24 patients (56%) with a median survival of 28 months, whereas we noted abnormal mutational analysis in 19 (44%) with a median survival of 38 months (p = 0.33). Of 19 single strand conformational polymorphism positive cases DNA sequencing showed mutation near the DNA binding site in 10 (53%), mutation away from the site in 6 (32%) and no mutation in 3 (17%). No survival difference was detected in cases with mutation away and near the DNA binding site, respectively (p = 0.69). CONCLUSIONS: In this group of patients treated with radical cystectomy for muscle invasive bladder transitional cell carcinoma, analysis of p53 protein and the p53 gene by immunohistochemical testing, single strand conformational polymorphism and mutational analysis did not correlate with cancer specific survival.

Expression of inflammatory modulator COX-2 in pancreatic ductal adenocarcinoma and its relationship to pathologic and clinical parameters.

Despite the exceedingly poor prognosis of pancreatic cancer, it is often histologically well to moderately differentiated. The apparent resistance to conventional therapeutic modalities is poorly understood and may be related to the molecules involved in its progression or its propensity for perineurial invasion. Cyclooxygenase-2 (COX-2) is an inducible enzyme homologous to COX-1 that is responsible for production of prostaglandins at sites of inflammation. It is activated by a variety of growth factors and tumor promoters, and it has been implicated in cancer progression. It may also have a role in the resistance to therapy. Anti-COX-2 agents have been documented to have antitumor activity, and some are now being tested in the therapy for various cancers, including those of the pancreas. Experience regarding the rate of COX-2 expression in pancreatic cancer and its relationship to the clinical and biologic parameters is very limited. In this study, immunohistochemical stains for COX-2 have been performed on 120 cases of pancreatic ductal adenocarcinoma. The stains were scored according to the percentage (0: no staining, 1: < 10%, 2: 10-50%, and 3: >50% of the cells staining) and intensity (0 for no staining, 1 for mild staining, and 2 for dark staining) of staining. Based on the combined score for each case, they were divided into low expressors (percentage and intensity < or =1) and high expressors (percentage or intensity >1). In addition to global scoring for each case, the glandular and solid (poorly differentiated) components, when present, were scored separately. The global scores were correlated with clinical and biologic parameters. Seventy-four percent of the cases exhibited expression of COX-2 and 53% were high expressors. No significant association was observed when comparing the global COX-2 expression to survival, tumor size, stage, and vascular invasion. Increased perineural invasion was found to be significantly associated with COX-2 expression (p < 0.05). Increased expression was also more common in the glandular component as compared with the solid component of the tumors (68% versus 35%, p < 0.05). Of the 34 patients who received radiotherapy, 9 were low expressor (median survival 19.5 months) and 25 were high expressors (median survival 14 months). The difference in survival was not statistically significant.

Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors.

PURPOSE: The prognostic significance of Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder is largely unknown. Accurate determination of Her-2/neu overexpression may have therapeutic importance. EXPERIMENTAL DESIGN: Eighty consecutive cases of muscle-invasive urothelial carcinoma of the bladder treated by radical cystectomy with available follow-up were analyzed. In each case, one representative section was stained with anti-Her-2/neu. Staining was graded as 1 = faint/equivocal, 2 = moderate, and 3 = strong and was considered positive if > or =2. In those cases with a metastasis, the stain was also performed in the metastatic tumor. Results were correlated with survival. RESULTS: Twenty-two (28%) cases were considered Her-2/neu-positive in the primary tumor, and 17 of 32 (53%) were considered Her-2/neu-positive in the lymph node metastasis. Median survival for Her-2/neu-positive primary tumors was 33 months, compared with 50 months for Her-2/neu-negative cases (P = 0.46). Similarly, Her-2/neu overexpression in the lymph node metastasis did not predict survival. Sixty metastatic urothelial carcinomas were further studied by comparing Her-2/neu expression in the primary tumor with that of the lymph node and/or distant metastasis. Forty-five percent of Her-2/neu-negative primary tumors had a Her-2/neu-positive lymph node metastasis, whereas only one case (8%) of Her-2/neu-positive primary tumors was Her-2/neu-negative in the lymph node metastasis (P = 0.009). Similarly, 67% of Her-2/neu-negative primary tumors had a Her-2/neu-positive distant metastasis, whereas no Her-2/neu-positive primary tumor was negative in the metastasis (P = 0.429). CONCLUSIONS: Her-2/neu overexpression in primary or metastatic tumor did not predict survival in this cohort of muscle-invasive tumors. Overexpression in the primary tumors consistently predicts overexpression in a distant or regional metastasis. However, some Her-2/neu-negative primary tumors may show overexpression in their corresponding metastasis. Her-2/neu analysis in a metastasis may be necessary to accurately determine Her-2/neu status in metastatic bladder urothelial carcinoma.

Impact of preoperative serum PSA level from 0 to 10 ng/ml on pathological findings and disease-free survival after radical prostatectomy.

BACKGROUND: To determine the impact of various preoperative serum prostate specific antigen (PSA) levels in the range from 0.1 to 10 ng/ml on pathological stage and disease-free survival after radical prostatectomy. METHODS: We selected a cohort of 585 patients who underwent radical prostatectomy between 1991-1996 for clinically localized prostate cancer and presented with preoperative serum PSA levels from 0.1 to 10 ng/ml. RESULTS: Pathological organ-confined disease was present in 57.6% of patients. The rate of organ-confined disease decreased from an average of 85% for patients with a PSA value < 2 ng/ml, to 46.8% for patients with a PSA value > 7 ng/ml. We found statistically significant correlations between preoperative serum PSA level and overall pathological stage (P = 0.001), pathologically organ-confined disease (P = 0.001), margin positive rates (P = 0.001), extra prostatic extension (P = 0.001), and seminal vesicle invasion (P = 0.001). The overall disease-free survival rate was 87%, with a median follow up of 42.4 months. Disease free survival was significantly better for patients with PSA up to 4 ng/ml (P = 0.005). CONCLUSIONS: Our data suggests that PSA detection programs should strive to detect prostate cancer in men before the PSA level rises above 7 ng/ml. In addition, since patients with a PSA level < 4 ng/ml had better disease-free survival rates than those with a PSA level between 4.1-10 ng/ml, eliminating an arbitrary cutoff of 4 ng/ml, may lead to improved disease-free survival.

Mixed epithelial and stromal tumor of the kidney lacks the genetic alterations of cellular congenital mesoblastic nephroma.

Mixed epithelial and stromal tumor of the kidney is a recently recognized neoplasm that occurs almost exclusively in perimenopausal women. Because it frequently contains areas of smooth muscle in which epithelial structures are embedded, some have concluded that it is the adult form of congenital mesoblastic nephroma. Others have concluded that the morphology and epidemiology of mixed epithelial and stromal tumor indicate that it is unrelated to congenital mesoblastic nephroma. Although the genetic alterations of mixed epithelial and stromal tumor have not been previously elucidated, much is known about the genetic alterations of cellular congenital mesoblastic nephroma. The present study was undertaken to determine if mixed epithelial and stromal tumors have any of the genetic alterations recognized as typical of cellular congenital mesoblastic nephroma. RNA extraction was performed on formalin-fixed, paraffin-embedded tissue from 7 mixed epithelial and stromal tumors followed by reverse-transcription polymerase chain reaction to detect the ETV6-NTRK3 gene fusion. Fluorescent in situ hybridization with centromere-specific probes for chromosomes 8, 11, and 17 was performed to evaluate polyploidy of these chromosomes in 11 cases of mixed epithelial and stromal tumor. None of the mixed epithelial and stromal tumors showed any of these genetic alterations. We conclude that mixed epithelial and stromal tumor of the kidney lacks the genetic alterations typical of cellular congenital mesoblastic nephroma, is unrelated to it, and the appellation "adult mesoblastic nephroma" should not be used for these tumors.

Concurrent angiomyolipoma and renal cell neoplasia: a study of 36 cases.

Little is known about the association of angiomyolipoma and adult renal-cell neoplasia. We studied the clinicopathologic features of 36 patients with concurrent angiomyolipoma and renal-cell neoplasia from the consultation and surgical pathology files of nine institutions. HMB-45 immunoreactivity was analyzed in both neoplasms. Twenty-five sporadic cases of patients with angiomyolipoma and renal-cell neoplasia and 11 cases of patients with tuberous sclerosis, as defined by Gomez' criteria, had mean ages of 59 and 53 years, respectively, and female-male ratios of 2:1 and 5:1, respectively. The mean size of the angiomyolipomas was 1 cm in the sporadic cases and 3 cm in those patients with tuberous sclerosis (medians: 0.5 and 3 cm, respectively, P =.002). The mean sizes of the renal-cell neoplasms were 5 cm in sporadic cases and 6 cm in patients with tuberous sclerosis (medians: 4 and 5 cm, respectively; P =.88). In both clinical settings, angiomyolipoma was more commonly the incidental tumor. Clear-cell (conventional) renal-cell carcinoma was the most common renal-cell neoplasm in both groups of patients, accounting for approximately two thirds of the tumors. In patients with tuberous sclerosis, 27% of renal-cell neoplasms were oncocytomas, compared with 8% in sporadic cases (P =.15). Papillary neoplasia, chromophobe, and collecting-duct renal-cell carcinoma were found only in sporadic cases. All of the 22 renal-cell neoplasms studied were negative for HMB-45, whereas all 25 angiomyolipomas studied were positive.

Neutron or photon irradiation for prostate tumors: enhancement of cytokine therapy in a metastatic tumor model.

We have shown that implantation of human prostate carcinoma PC-3 cells in the prostates of nude mice led to the formation of prostate tumors with metastases to para-aortic lymph nodes. We found that day 6 prostate tumors were responsive to systemic injections of interleukin 2 (IL-2) therapy. We have now investigated the combination of primary tumor irradiation and IL-2 for metastatic prostate cancer in this preclinical tumor model. The effect of neutron radiation was compared with that of photon radiation. Advanced prostate tumors (approximately 0.4 cm) were irradiated, and a day later, mice were treated with systemic IL-2 for three weekly cycles. In separate experiments, mice were either sacrificed on day 30 to assess prostate tumor size and tumor histology or followed for survival. A dose-dependent inhibition of prostate tumor growth was caused either by photons or neutrons, but neutrons were more effective than photons with a relative biological effectiveness of 2. The tumor inhibition obtained with 250 cGy neutrons and 500 cGy photons was significant (>75%) and was further increased (> or = 90%) by addition of IL-2 therapy. In survival studies, the combination of radiation and IL-2 showed a significant survival advantage compared with untreated mice (P < or = 0.005) or radiation alone (P < or = 0.003) and an increase in median survival compared with IL-2 alone. Histologically, the combined regimen resulted in a greater degree of tumor destruction, inflammatory response, and vascular damage than that observed with each modality alone. After this combined treatment, no tumor was histologically detected in the para-aortic lymph nodes of these mice, and the lymph nodes were significantly smaller. These findings showed that primary tumor irradiation, either with neutrons or photons, enhanced IL-2 therapeutic effect for the treatment of advanced prostate cancer. This combined modality induced an antitumor response that controlled the growth of prostate tumors and their metastases.

Pathology of kidney tumors.

The classification of epithelial tumors of the kidney has undergone considerable change in the last two decades. Systems based on cytoplasmic characteristics and cytogenetic analysis have expanded our understanding of this group of tumors. These new, nontraditional systems have led to the development of a more clinically significant pathological classification (1,2). Although many questions remain unanswered and debate continues concerning the validity of these proposals, research studies on epithelial neoplasms of the kidney must take these advances into consideration. Scientific studies of any type should incorporate information regarding the type of tumor(s) included in the study group. This chapter briefly reviews the accepted subtypes of renal epithelial neoplasms, with a focus on the morphological features that distinguish them.

Gleason score 7 prostate cancer: a heterogeneous entity? Correlation with pathologic parameters and disease-free survival.

OBJECTIVES: Gleason score 7, in different proportions of grades 3 and 4, is the score most frequently assigned to prostate cancer in our radical prostatectomy specimens (RPSs). We correlated the major grade component of score 7 tumors with clinicopathologic parameters and disease-free survival. METHODS: All Gleason score 7 RPSs were classified as having a major grade of 3 or 4 carcinoma. The two groups were compared according to patient age, race, serum prostate-specific antigen (PSA) level, clinical and pathologic stage, tumor volume, and biochemical recurrence. RESULTS: Of the 534 patients analyzed, 356 and 178 had major grade 3 or 4 tumors, respectively. Compared with patients with 3+4 tumors, those with 4+3 had significantly more advanced clinical and pathologic stages, larger tumor volume, higher preoperative PSA levels, and older age and a higher proportion were African American (P <0.05 for all above parameters). With a mean follow-up of 34.6 months, patients with 3+4 tumors experienced lower rates of PSA recurrence than did those with 4+3 tumors (P = 0.0021). Furthermore, for the subset of patients with organ-confined disease, multivariable analysis that included race, age, clinical stage, preoperative PSA level, tumor volume, and major grade component found only the latter to be a significant predictor of recurrence, with patients who had major grade 4 component tumors experiencing a higher incidence of PSA recurrence than those with major grade 3 tumors (P = 0.012). CONCLUSIONS: The major grade 4 component in Gleason score 7 carcinoma indicates a higher likelihood of biochemical recurrence, particularly for the increasing proportion of patients with organ-confined disease after radical prostatectomy.

Epidemiology and molecular biology of early prostatic neoplasia.

This paper provides our institutional data with respect to the prevalence of early neoplastic changes within the prostate gland and the age and race distribution of the patients. The changes examined were prostatic intraepithelial neoplasia (PIN) and preclinical (latent) cancers. The literature on the prevalence of these early lesions among different geographic and ethnic groups is summarized, and an abbreviated review of the more common molecular alterations reported at this early phase of prostatic neoplasia is offered.

Significance of the Gleason scoring system after neoadjuvant hormonal therapy.

Neoadjuvant hormonal therapy (NHT) induces morphologic changes in prostate adenocarcinoma that result in the assignment of higher Gleason scores on average than in pretreatment biopsy specimens. This outcome has led to the recommendation that the Gleason scoring system not be applied to prostate adenocarcinoma specimens after NHT. We reviewed the radical prostatectomy specimens of 116 patients who had received NHT. Gleason scores were assigned on the post-treatment specimens by applying the usual criteria; in addition, an estimated pretreatment Gleason score was assigned on the basis of knowledge of the morphologic alterations associated with NHT. Finally, an estimate of the degree of therapy effect was assigned: little or no evidence of hormonal effect (grade 1) to marked therapy-related changes (grade 3). Both the post-treatment and the estimated pretreatment Gleason score correlated significantly with biochemical progression (P = 0.03 and P = 0.03, respectively; log-rank test). The degree of therapy effect did not correlate with progression (P = 0.46; log-rank test). This limited analysis suggests that despite the morphologic alterations induced by NHT, post-treatment Gleason score remains a significant prognostic measure. Further studies in more uniformly treated populations are required to confirm this observation.

Unilateral hydronephrosis resulting from intraluminal obstruction of the ureter by adenosquamous endometrioid carcinoma arising from disseminated endometriosis.

A case of adenosquamous carcinoma arising in the background of disseminated pelvic endometriosis presented as unilateral hydronephrosis and a polypoid intraluminal ureteral mass. This is the first case of a malignancy arising in endometriosis presenting as an obstructive ureteral mass. The patient had a history of total hysterectomy and bilateral salpingo-oophorectomy 5 years earlier because of an endometriotic cyst, and had since been under unopposed estrogen replacement therapy. An analysis of the case and related literature is presented. Possible pathogenic mechanisms are discussed.

Mixed epithelial and stromal tumor of the kidney.

We describe the clinicopathologic features of 12 patients with a distinctive tumor of the kidney characterized by a mixture of epithelial and stromal elements that form solid and cystic growth patterns. Similar tumors were reported previously in the literature under various names, including adult mesoblastic nephroma. All but one of the patients were women. The only man had a long history of treatment with lupron and diethylstilbesterol. Seven of the women had histories of long-term oral estrogen use of whom six had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy several years prior, and the seventh patient had been using oral contraceptives for many years. Another woman had this operation but did not receive any hormone therapy. Ages ranged from 31 to 71 years (mean, 56 yrs). Six patients presented with symptoms, including pain and infections attributable to mass effect, and in six the tumor was detected incidentally. Grossly, the tumors were well-circumscribed (mean size, 6 cm; range, 3-12 cm) and consisted of solid and cystic components, most often in equal proportions but in variable distribution. Microscopically, the spindle cell component ranged in appearance from scar-like fibrous tissue to leiomyoma-like interlacing fascicles; usually there was a mixture of both. More cellular foci reminiscent of ovarian stroma or solitary fibrous tumor were also present. No blastema was present. Epithelial elements (composed of clusters of tubules with variable lining) were scattered amidst the spindle cells, and focally transformed into large cysts lined by cells with abundant pink cytoplasm and a hobnail appearance. Immature epithelial elements typical of Wilms' tumor were not present. Muscle markers (desmin and smooth muscle actin) were positive diffusely and strongly in the spindle cells of all tumors, whereas HMB-45 and CD34 were absent. Estrogen receptors were detected in the nuclei of spindle cells in seven tumors and progesterone receptors in three. The distinctive clinicopathologic characteristics of these lesions warrant their classification as a separate category of kidney tumor. We suggest the descriptive term "mixed epithelial and stromal tumor" for this group until its nature and relationship to other kidney lesions are further clarified. Its preponderance in females with a history of long-term estrogen replacement and the history of long-term sex-steroid use in the only male patient, combined with the frequent content of estrogen and progesterone receptors in the spindle cells, suggest that the hormonal milieu plays a role in the evolution of these tumors. The clinical and pathologic parallels with mucinous cystic tumors of pancreas and liver raise the possibility of a common pathogenetic mechanism that may be linked to the periductal fetal mesenchyme. We think this entity is a benign composite neoplasm in which stroma and epithelium are both integral neoplastic components.

Grading the invasive component of urothelial carcinoma of the bladder and its relationship with progression-free survival.

Although grading is valuable prognostically in pTa and pT1 papillary urothelial carcinoma, it is unclear whether it provides any prognostic information when applied to the invasive component in muscle-invasive carcinoma. The authors analyzed 93 cases of muscle-invasive urothelial carcinoma of the bladder treated with radical cystectomy for which follow-up information was available. Each case was graded using the Malmström grading system for urothelial carcinoma, applied to the invasive component. Pathologic stage, lymph node status, and histologic invasion pattern were also recorded and correlated with progression-free survival. Thirty-four cases (37%) were pT2, 40 (43%) were pT3, and 19 (20%) were pT4. Of the 77 patients who had a lymph node dissection at the time of cystectomy, 34 (44%) had metastatic carcinoma to one or more lymph nodes. The median survival for pT2, pT3, and pT4 stages was 85, 24, and 29 months, respectively (p = 0.0001). Lymph node-negative and lymph node-positive patients had a median survival of 63 and 23 months, respectively (p = 0.0001). Fifteen patients (16%) were graded as 2b and 78 patients (84%) were graded as 3. Median survival of patients graded as 2b was 34 months compared with 31 months for patients graded as 3 (p value not significant). Three invasive patterns were recognized: nodular (n = 13, 14%), trabecular (n = 39, 42%), and infiltrative (n = 41, 44%). The presence of any infiltrative pattern in the tumor was associated with a median survival of 29 months, compared with 85 months in tumors without an infiltrative pattern (p = 0.06). Pathologic T stage and lymph node status remain the most powerful predictors of progression in muscle-invasive urothelial carcinoma. In this group of patients histologic grade, as defined by the Malmström system and as applied to the invasive component, provided no additional prognostic information. An infiltrative growth pattern may be associated with a more dismal prognosis.

College of American Pathologists Conference XXXV: solid tumor prognostic factors-which, how and so what? Summary document and recommendations for implementation. Cancer Committee and Conference Participants.

The College of American Pathologists convened a prognostic factor conference in June 1999 to consider prognostic and predictive factors in breast, colon, and prostate cancer, and to stratify these factors into categories reflecting the strength of published evidence. Because so little progress in prognostic factor clinical utility has been made in the last 5 years, the conference participants focused their attention on decreasing variation in methods, interpretation, and reporting of these factors so that greater clarity of value could be achieved. The conference was organized to promote discussion, broad input, and future planning. An initial plenary session provided an overview of the status of tumor marker research, the impact of variation in medicine and pathology, and statistical issues related to prognostic factor research. In working group sessions for each cancer type, participants interactively evaluated and refined the documents created by the expert panels. A second plenary session dealt with issues common to all 3 groups, including the problem of micrometastases in lymph nodes in these sites; statistical issues that arose during the breakout discussions; and issues of variation in methods, interpretation, and reporting of immunohistochemical assays. A faculty session brainstormed strategies that could be used to implement the changes recommended. This session included invited representatives of the Food and Drug Administration, Health Care Financing Administration, Centers for Disease Control and Prevention, National Cancer Institute, American Joint Committee on Cancer, and International Union Against Cancer. Cancer site and general recommendations were presented and discussed during a final session to achieve consensus of the conference participants and to address feasibility of implementation of these recommendations. A final discussion focused on future initiatives that might lead to implementation of the changes proposed in the conference by the various organizations represented. This report summarizes the general conference recommendations, cancer working group recommendations, and plans for implementation of the recommendations.

Prognostic factors in prostate cancer. College of American Pathologists Consensus Statement 1999.

BACKGROUND: Under the auspices of the College of American Pathologists, a multidisciplinary group of clinicians, pathologists, and statisticians considered prognostic and predictive factors in prostate cancer and stratified them into categories reflecting the strength of published evidence and taking into account the expert opinions of the Prostate Working Group members. MATERIALS AND METHODS: Factors were ranked according to the previous College of American Pathologists categorical rankings: category I, factors proven to be of prognostic importance and useful in clinical patient management; category II, factors that have been extensively studied biologically and clinically but whose importance remains to be validated in statistically robust studies; and category III, all other factors not sufficiently studied to demonstrate their prognostic value. Factors in categories I and II were considered with respect to variations in methods of analysis, interpretation of findings, reporting of data, and statistical evaluation. For each factor, detailed recommendations for improvement were made. Recommendations were based on the following aims: (1) increasing uniformity and completeness of pathologic evaluation of tumor specimens, (2) enhancing the quality of data collected pertaining to existing prognostic factors, and (3) improving patient care. RESULTS AND CONCLUSIONS: Factors ranked in category I included preoperative serum prostate-specific antigen level, TNM stage grouping, histologic grade as Gleason score, and surgical margin status. Category II factors included tumor volume, histologic type, and DNA ploidy. Factors in category III included perineural invasion, neuroendocrine differentiation, microvessel density, nuclear roundness, chromatin texture, other karyometric factors, proliferation markers, prostate-specific antigen derivatives, and other factors (oncogenes, tumor suppressor genes, apoptosis genes, etc).