Preservation of penile length after radical prostatectomy: early intervention with a vacuum erection device.

Radical prostatectomy has been shown to have a potential negative impact on penile health. Stretched penile length (SPL), which most closely correlates with erect penile length, was significantly reduced in almost half of men undergoing surgery in several studies. The purpose of this study was to test whether early intervention after surgery with a vacuum erection device could prevent the changes in penile health, as defined by SPL, found in prior studies. Forty-two men with good preoperative sexual function undergoing nerve-sparing radical prostatectomy underwent measurement of SPL preoperative and at 3 months postoperative by a single investigator. Daily use of a vacuum erection device (VED) was begun the day after catheter removal, and continued for 90 days. Men kept a log of their compliance with daily VED use. A decrease in SPL of > or = 1.0 cm was considered significant. Out of 42 men, 39 completed the study. In men who used the VED >50% of possible days, only 1/36 (3%) had a decrease in SPL of > or = 1.0 cm. Of the three men with poor VED compliance, two (67%) had a reduction in SPL of > or = 1.0 cm. When compared to prior studies where 48% of men after surgery had a significant reduction in SPL, early intervention with the daily use of a VED resulted in a significantly lower risk of loss of penile length (P<0.0001). For men wishing to preserve penile health/length after surgery, early intervention with the daily use of a VED should be strongly recommended.

Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial.

OBJECTIVE: To present the results (to January 1996, the end of blinded treatment) of the Nutritional Prevention of Cancer (NPC) Trial, a randomized trial of selenium (200 micro g daily) designed to test the hypothesis that selenium supplementation (SS) could reduce the risk of recurrent nonmelanoma skin cancer among 1312 residents of the Eastern USA. MATERIALS AND METHODS: Original secondary analyses of the NPC to 1993 showed striking inverse associations between SS and prostate cancer incidence. A subsequent report revealed that this effect was accentuated among men with the lowest baseline plasma selenium concentrations. The effects of treatment overall and within subgroups of baseline prostate-specific antigen (PSA) and plasma selenium concentrations were examined using incidence rate ratios and Cox proportional hazards models. RESULTS: SS continued to significantly reduce the overall incidence (relative risk and 95% confidence interval) of prostate cancer (0.51, 0.29-0.87). The protective effect of SS appeared to be confined to those with a baseline PSA level of

Site-specific positive margins at radical prostatectomy: assessing cancer-control benefits of wide excision of the neurovascular bundle on a side with cancer on biopsy.

OBJECTIVE: To determine the potential risk of biopsy-selected nerve-sparing surgery based on the findings of site-specific extracapsular extension (ECE) and positive surgical margins (PSMs) in the area of the neurovascular bundle in radical prostatectomy specimens. PATIENTS AND METHODS: Controlling for surgical technique and pathological interpretation, 221 consecutive patients had their neurovascular bundles removed on the side with a positive biopsy. The surgical specimens were reviewed for ECE and PSM status, specifically in the area of the neurovascular bundle, from apex to base. RESULTS: Of the 221 patients, 38% had ECE and 43 (20%) had a PSM in the area of the neurovascular bundle. This equates to a ratio of 51% for PSM/ECE. An additional 42 men (18%) had ECE with negative margins, but would have been at potential risk for PSMs if the neurovascular bundle had been preserved. CONCLUSION: Preserving the neurovascular bundle on the side with a positive biopsy could result in a significantly greater incidence of PSM than with wide excision. Optimizing cancer control may require excision of the neurovascular bundle on a side known to have cancer on biopsy. In future site-specific analyses, the PSM/ECE ratio could be used as a marker comparing cancer-control outcomes from studies with differing technical approaches and indications for nerve-sparing surgery.

Culturing precision-cut human prostate slices as an in vitro model of prostate pathobiology.

Due to the complex morphology of the prostate, it was hypothesized that precision-cut tissue slices from human prostate would provide a unique in vitro model. Precision-cut slices were generated from zones of human prostate and their viability was assessed under conditions of different media for up to 120 h. Slices were also exposed to several concentrations of CdCI2, which was used as a model toxicant. Maintenance of both stromal and epithelial cells was noted; however, there was a gradual loss of luminal epithelial cells when the medium was not supplemented with dihydrotestosterone (DHT). Minimal leakage of lactate dehydrogenase occurred throughout the incubation. Prostate-specific antigen (PSA) was detected in the medium at all time points, although the rates of secretion fell over time. There was a loss of PSA-positive cells when the medium was not supplemented with DHT, consistent with a loss of luminal cells, whereas PSA-positive cells were maintained in the DHT-supplemented media. A proliferation of basal cells was observed in the presence of media containing 10% fetal bovine serum. Exposure of slices to CdCl2 demonstrated a dose-response effect ranging from proliferation to complete cellular necrosis. Given the retention of stromal-epithelial interactions and the use of acquired human tissue, prostate slices represent a unique in vitro model for investigating human prostate pathobiology.

Pilot study of changes in stretched penile length 3 months after radical retropubic prostatectomy.

OBJECTIVES: To evaluate changes in stretched penile length after radical retropubic prostatectomy (RRP) in a prospective penile measurement study because an occasional complaint from patients after RRP is that their penis is shortened. METHODS: Thirty-one patients undergoing RRP by one surgeon were enrolled. The same physician completed measurements with a paper ruler to the nearest 0.5 cm. The stretched penile length was measured from the tip of the glans to the pubopenile skin junction. The measurements were taken in the preoperative holding area before the patient received anesthetic medication for the RRP and again 3 months postoperatively. The reliability and reproducibility of this measurement were confirmed. RESULTS: All 31 patients were measured at 3 months postoperatively. Of the 31 patients, 22 (71%) had a decrease in stretched penile length (range 0.5 to 4.0 cm). Seven were shortened 0.5 cm, 11 were shortened 1.0 to 2.0 cm, and 4 were shortened more than 2.0 cm. Five patients had no change, and in four the penile length was longer (range 0.5 to 1.0 cm). CONCLUSIONS: The results of this pilot study appear to show that the stretched penile length decreases after RRP at 3 months of follow-up in most men; 48% (15 of 31) had considerable shortening greater than 1.0 cm. If confirmed by other investigators, the cause of this change needs to be elucidated.

PEAZ-1: a new human prostate neoplastic epithelial cell line.

BACKGROUND: The generation of prostatic cell lines provides in vitro models for experimental studies of the pathogenesis of prostate carcinoma. Therefore, we established and characterized a new human prostate epithelial cell line, PEAZ-1 (prostate epithelial Arizona-1). METHODS: The PEAZ-1 cells were grown from a primary human prostate carcinoma specimen obtained from radical prostatectomy. The isolated cells were characterized by immunobiochemistry, immunohistochemistry, and tumorigenicity studies. RESULTS: PEAZ-1 cells are near diploid, tumorigenic, and androgen independent for cell growth. PEAZ-1 cells express N-cadherin, alpha- and beta-catenins, and p120 at cell-cell contacts, cytoplasmic laminin 5, vinculin, paxillin, and phosphotyrosine at focal adhesions, vimentin, and cytokeratins 8 and 18. They do not express plakoglobin, E-cadherin, and PSA, and do not form desmosomes and hemidesomomes. PEAZ-1 respond to ocadaic acid, a pro-apoptotic agent, by expression of p53. CONCLUSIONS: PEAZ-1 cells is a human prostate cancer cell line that has a number of mesenchymal characteristics.

Evaluation of cold knife urethrotomy for the treatment of anastomotic stricture after radical retropubic prostatectomy.

PURPOSE: We evaluated the efficacy of cold knife urethrotomy for anastomotic stricture after radical retropubic prostatectomy. MATERIALS AND METHODS: We contacted all patients who underwent cold knife urethrotomy for a symptomatic anastomotic stricture from May 1, 1992 through January 1, 2000 at our institution. A control group of patients who underwent radical retropubic prostatectomy but did not complain of a decreased urine stream was similarly evaluated. Maximum urinary flow rate, post-void residual urine volume, American Urological Association (AUA) symptom index for benign prostatic hyperplasia, and continence status with a questionnaire adapted from the RAND-University of California-Los Angeles Prostate Cancer Index were determined in each study participant. RESULTS: We identified and contacted 61 patients. Complete data were collected on 36 of the 52 patients (59%) who agreed to participate. Mean time after urethrotomy was 31 months (range 1 to 77). In the control group the mean time after prostatectomy was 18.6 months (range 3 to 95). There was no statistically significant difference in the measured urinary parameters of maximum flow rate, post-void residual urine volume, AUA symptom index or continence status in the study and control groups. CONCLUSIONS: Cold knife urethrotomy provides a safe and effective response for the initial treatment of patients with anastomotic stricture after radical retropubic prostatectomy. Maximum urinary flow, post-void residual volume, AUA symptom score and perceptions of continence are similar to those in patients who underwent radical retropubic prostatectomy and had no complaints of a weak urine stream.

Investigation into the mechanism of the loss of laminin 5 (alpha3beta3gamma2) expression in prostate cancer.

Laminin 5 is a pivotal hemidesmosomal protein involved in cell stability, migration, and anchoring filament formation. Protein and gene expression of the alpha3, beta3, and gamma2 chains of laminin 5 were investigated in normal and invasive prostate carcinoma using immunohistochemistry, Northern analysis, and in situ hybridization. Laser capture microdissection of normal and carcinomatous glands, in conjunction with RNA amplification and reverse Northern analysis, were used to confirm the gene expression data. Protein and mRNA expression of all three laminin 5 chains were detected in the basal cells of normal glands. In contrast, invasive prostate carcinoma showed a loss of beta3 and gamma2 protein expression with variable expression of alpha3 chains. Despite the loss of protein expression, there was retention of beta3 and gamma2 mRNA expression as detected by in situ hybridization, Northern and reverse Northern analysis. Our findings imply that an altered mechanism of translation of beta3 or gamma2 mRNAs into functional proteins contributes to failure of anchoring filaments and hemidesmosomal formation. The resultant hemidesmosome instability or loss would suggest a less stable epithelial-stromal junction, increased invasion and migration of malignant cells, and disruption of normal integrin signaling pathways.

Unique expression pattern of the alpha6beta4 integrin and laminin-5 in human prostate carcinoma.

BACKGROUND: The alpha6beta4 integrin and its ligand, laminin-5, are essential gene products for the maintenance and remodeling of a stratified epithelium. Apparent loss of polarized alpha6beta4 integrin and laminin-5 protein expression in invasive prostate cancer as compared to normal prostate glands is known to occur. It is unknown whether these alterations occur in prostatic intraepithelial neoplasia (PIN) lesions and whether this combined defect occurs in other epithelial cancers. METHODS: Human prostate tissues containing both normal, PIN, and cancerous regions and normal and cancer tissue from breast and colon were obtained at surgery and examined for beta4 integrin and laminin-5 using standard immunofluorescence staining methods. RESULTS: Both normal prostate glands and PIN lesions contain beta4 integrin and laminin-5. Prostate carcinoma was unique in that both beta4 integrin and laminin-5 expression was uniformly absent. In contrast, the beta4 integrin and its ligand, laminin-5 were detected in all of the colon carcinoma cases and in 60% of the breast carcinomas. CONCLUSIONS: The beta4 integrin and its ligand, laminin-5 are altered during the transition of PIN lesions to invasive prostate carcinoma. These data suggest the loss of these proteins during cancer progression. In both prostate and breast carcinoma, the normal expression pattern of the beta4 integrin and laminin-5 is interrupted, in contrast to the persistent beta4 integrin and laminin-5 expression detected in colon carcinoma.

Diagnostic frozen prostate sextant biopsies: an approach for preserving protein and RNA for additional studies.

BACKGROUND: Primary prostate cancer represents 29% of newly diagnosed visceral cancers in men. Despite this common occurrence, relatively little is known about the pathogenesis of this malignancy. High-grade prostatic intraepithelial neoplasia (HGPIN) is generally accepted as a precursor to invasive prostate carcinoma. There is a lack of adequate animal models, and the available cell culture lines are limited. Tissue from prostate needle core biopsies that have been frozen can provide adequate material for both diagnosis and research. METHODS: Transrectal sextant needle biopsies were snap-frozen, serially sectioned and alternately stained with hematoxylin-eosin or reacted with a basal cell-specific antibody. Two pathologists examined all of the sections, which were scored for the presence or absence of carcinoma and HGPIN. Portions of the remaining tissue were used for studies of protein expression and gene expression. RESULTS: The incidence of carcinoma was 39%, comparable to the mean percent positive cases reported using conventional fixation and paraffin embedding. The incidence of HGPIN was 33%, higher than previously reported. CONCLUSIONS: Prostate carcinoma can be accurately diagnosed using frozen material. The observed high frequency of HGPIN is attributed to the instability of nuclear structure in the frozen material of the atypical nuclei, resulting in inflated grading of PIN lesions. Sufficient material remained in the frozen blocks for additional studies of protein and gene expression.

External beam radiotherapy and hyperthermia in the treatment of patients with locally advanced prostate carcinoma.

BACKGROUND: The current study was conducted to evaluate the combination of external beam radiation therapy and hyperthermia in the treatment of patients with locally advanced prostate carcinoma. METHODS: Twenty-six patients were treated on a Phase I/II protocol between June 1990 and April 1993. The median age of the patients was 69 years. Nine patients had well differentiated adenocarcinoma, ten patients had moderately differentiated adenocarcinoma, and six patients had poorly differentiated adenocarcinoma. All patients had American Urologic Society Stage C2-D1 adenocarcinoma. The median pretreatment prostate specific antigen (PSA) level was 29 ng/mL (range, 6-104 ng/mL). All patients received external beam radiation therapy using a four-field technique. The median radiation dose was 6,800 centigrays (cGy) given in 200-cGy fractions. Hyperthermia was administered concurrently with radiation therapy to temperatures of 42.5 degrees C for 30 minutes using a transrectal ultrasound applicator with 3 thermometry probes, given as either a single treatment (9 patients) or as two treatments (17 patients). Overall survival (OS) and biochemical no evidence of disease (bNED) status were calculated using Kaplan-Meier analysis. A consensus conference definition of PSA failure was used. The Cox proportional hazards model was used for multivariate analysis. The median follow-up for all patients was 71 months. RESULTS: The median time to PSA nadir was 15 months with a median PSA nadir value of 1.0 ng/mL. The median and 5-year OS was 88 months and 73%, respectively, and the median and 5-year bNED survival was 36 months and 35%, respectively. Multivariate analysis revealed only the pretreatment PSA level (P = 0.03) and the PSA nadir reached (P < 0.01) to be significant predictors of bNED survival. The duration of hyperthermia therapy showed a trend toward significance for OS (P = 0.06). CONCLUSIONS: The current Phase I/II protocol evaluating the combination of prostate hyperthermia and external beam radiation therapy for the treatment of patients with locally advanced prostate carcinoma suggests prostate hyperthermia to be feasible with no apparent significant increased toxicity, although there was no significant improvement in treatment outcome when compared with other studies reported in the literature evaluating external beam radiation therapy with or without androgen suppression. However, further investigation into the duration as well as the temperature of the hyperthermia with a greater number of patients is warranted.

Differences in sexual function and quality of life after nerve sparing and nonnerve sparing radical retropubic prostatectomy.

PURPOSE: We determine the impact of nerve sparing techniques on quality of life after radical retropubic prostatectomy for prostate cancer. MATERIALS AND METHODS: The RAND/UCLA Prostate Cancer Index and several questions about surgical outcomes, including sexual function, were sent to 170 consecutive patients at least 1 year after radical retropubic prostatectomy. Statistical analysis was performed on data for the entire group as well as subgroups of patients after nerve sparing and nonnerve sparing surgery. RESULTS: Nonnerve sparing surgery was performed in 83 of 129 responders (nonnerve sparing group) and the remaining 46 were treated with unilateral nerve sparing surgery (nerve sparing group). Scores for sexual function, sexual bother, physical function and physical limitation domains were significantly better in the nerve sparing group. Spontaneous erectile activity was reported by 50% of nerve sparing group patients. Nerve sparing status did not affect urinary function, bowel function or disease outcome. CONCLUSIONS: Nerve sparing techniques have positive effects on quality of life and sexual function for patients undergoing radical retropubic prostatectomy.

Accuracy of prostate needle biopsy in predicting extracapsular tumor extension at radical retropubic prostatectomy: application in selecting patients for nerve-sparing surgery.

OBJECTIVES: To evaluate prostate biopsy outcomes along with other clinical parameters in an effort to define the cancer-specific safety of nerve-sparing surgery. METHODS: Sixty-six consecutive men underwent radical retropubic prostatectomy for clinically localized prostate cancer (T1c = 36, T2 = 30). Preoperative prostate needle biopsies were performed on all patients, and radical prostatectomy specimens were processed in their entirety. Our pathologic end point was capsular perforation extending entirely through the prostatic capsule. Each prostatic side was analyzed individually, for a total of 132 specimens. The specimens were further divided into four categories on the basis of biopsy grade (no cancer = 44, low = 20, moderate = 60, high = 8). Additional study variables included preoperative prostate-specific antigen (PSA) and number of positive biopsy cores. RESULTS: Overall, 40 of the 132 specimens had evidence of capsular perforation. Of the 40 capsular perforations, 39 were observed in specimens (sides) that had cancer identified on biopsy. The one specimen with capsular perforation and a negative biopsy result occurred in the setting of high-grade contralateral cancer. PSA, digital rectal examination, and number of positive biopsy cores did not reliably predict capsular perforation. CONCLUSIONS: Our findings suggest that in patients with low- and moderate-grade tumors, the neurovascular bundle can be safely preserved on the side without evidence of cancer having obtained at least three biopsy cores. No safe parameters for considering nerve-sparing surgery were observed in the small number of patients with high-grade tumors, or in any specimen with cancer present on biopsy. Other clinical parameters, such as PSA or number of positive cores, did not aid in identifying candidates for nerve-sparing surgery.

Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial.

OBJECTIVE: To test if supplemental dietary selenium is associated with changes in the incidence of prostate cancer. PATIENTS AND METHOD: A total of 974 men with a history of either a basal cell or squamous cell carcinoma were randomized to either a daily supplement of 200 microg of selenium or a placebo. Patients were treated for a mean of 4.5 years and followed for a mean of 6.5 years. RESULTS: Selenium treatment was associated with a significant (63%) reduction in the secondary endpoint of prostate cancer incidence during 1983-93. There were 13 prostate cancer cases in the selenium-treated group and 35 cases in the placebo group (relative risk, RR=0.37, P=0.002). Restricting the analysis to the 843 patients with initially normal levels of prostate-specific antigen (< or = 4 ng/mL), only four cases were diagnosed in the selenium-treated group and 16 cases were diagnosed in the placebo group after a 2 year treatment lag, (RR=0.26 P=0.009). There were significant health benefits also for the other secondary endpoints of total cancer mortality, and the incidence of total, lung and colorectal cancer. There was no significant change in incidence for the primary endpoints of basal and squamous cell carcinoma of the skin. In light of these results, the 'blinded' phase of this trial was stopped early. CONCLUSIONS: Although selenium shows no protective effects against the primary endpoint of squamous and basal cell carcinomas of the skin, the selenium-treated group had substantial reductions in the incidence of prostate cancer, and total cancer incidence and mortality that demand further evaluation in well-controlled prevention trials.

Prostatic asymmetry as a risk factor for prostatic carcinoma: serial prostate-specific antigen monitoring and cancer detection.

OBJECTIVE: To compare the rates of cancer detection in men with a normal, asymmetric, or suspicious prostate on digital rectal examination (DRE) initially and after 3 years of serial monitoring of prostate specific antigen (PSA) level. PATIENTS AND METHODS: Prostatic 'asymmetry' was defined as asymmetric growth of the lateral lobes of the prostate without induration or nodules, as assessed by a DRE. The study included 963 men with no clinical evidence of prostate cancer and whose serum PSA levels were monitored at 4 month intervals. Prostatic biopsy was recommended if the PSA level became persistently abnormal (> 4ng/mL) or increased by > 20% after having been initially abnormal. Cancer detection rates were compared among groups categorized by the initial DRE findings and serum PSA level. RESULTS: On comparing groups with suspicious and normal DREs, and abnormal with normal PSA levels both, as expected, were associated with a statistically significant increase in cancer detection. However, an asymmetric prostate did not carry an increased risk of detecting prostate cancer when compared with a normal prostate, regardless of PSA level. CONCLUSIONS: An asymmetric prostate does not appear to be an independent risk factor for detecting prostate cancer. Therefore, an asymmetric prostate with no abnormality in PSA level should not mandate prostatic biopsy, or even an increase in monitoring frequency above the presently recommended annual interval.

Prospective longitudinal evaluation of men with initial prostate specific antigen levels of 4.0 ng./ml. or less.

PURPOSE: We evaluated the 3-year longitudinal changes in serial serum prostate specific antigen (PSA) levels in men with an initial PSA of 4.0 ng./ml. or less and no suspicion of prostate cancer. MATERIALS AND METHODS: A total of 760 men with an initial PSA of 4.0 ng./ml. or less plus a normal or suspicious digital rectal examination and a benign prostate biopsy was enrolled into an every 4-month PSA monitoring study. RESULTS: Of the 559 men with an initial PSA of 2.0 ng./ml. or less only 3 (0.5%) had a persistently abnormal PSA for 3 years and 1 cancer (0.2%) was detected, and 48 men had a PSA velocity of 0.8 ng./ml. per year or more at year 1 but only 1 (2%) had a persistent rate of increase (2.4 ng./ml. per year) at 3 years. Of the 201 men with a PSA of 2.1 to 4.0 ng./ml. 85 had an abnormal PSA but only 37 (43%) met the criteria for biopsy. Only 8 of 23 biopsies (35%) revealed cancer. Of the 201 men 24 had a PSA velocity of 0.8 ng./ml. per year or more at year 1 but only 4 had persistence for 3 years. All 4 men had cancer but they were identified as at high risk by PSA criteria. CONCLUSIONS: Men with a PSA of 2.0 ng./ml. or less are at low risk for an abnormal PSA or cancer within 3 years and annual monitoring may not be necessary. However, annual monitoring is clinically useful in men with an initial PSA of 2.1 to 4.0 ng./ml. Also, serial monitoring with interval testing in men whose PSA becomes greater than 4.0 ng./ml. is beneficial in identifying a high risk group requiring biopsy. Finally, PSA velocity did not add further to cancer detection in this population.

Ketoconazole-induced adrenal crisis in a patient with metastatic prostatic adenocarcinoma: case report and review of the literature.

Ketoconazole has been used with success to treat disseminated intravascular coagulation and acute spinal cord compression syndromes associated with metastatic prostatic adenocarcinoma. It effects prompt, reversible medical castration, making it especially useful as empiric therapy when histologic diagnosis is delayed but prostate cancer is suspected. Side effects are usually limited to asthenia, nausea, diarrhea, and gynecomastia, but a theoretical risk of adrenal suppression exists. We report a case of fulminant adrenal crisis precipitated by ketoconazole given on a 6-hour dosing schedule in a patient with nerve root compression secondary to prostatic metastases. Through a review of the literature, we attempt to provide a better understanding of the use and potential dangers associated with ketoconazole therapy.

Differential expression of cytokeratin mRNA and protein in normal prostate, prostatic intraepithelial neoplasia, and invasive carcinoma.

The expression of cytokeratin (CK) mRNA for CK5, -8, -14, -16, and -19 was investigated in normal prostate, prostatic intraepithelial neoplasia (PIN) lesions, and invasive carcinoma using in situ hybridization. Protein localization was carried out in adjacent sections using immunohistochemistry and correlated with mRNA expression. Snap-frozen human prostate samples including 22 examples of normal glands, 20 cases of PIN lesions, and 12 cases of invasive carcinoma were examined. CK5 and -14 mRNA and protein were prominently expressed only in the basal cells of normal glands and PIN lesions. CK14 mRNA was absent in the luminal cells of the most of the PIN lesions but was seen at a low level in some PIN lesions. CK14 protein was not detected in any PIN lesion, suggesting that, if the cell that makes up the PIN lesions is derived from a basal cell, CK14 translation is depressed although a low level of CK14 mRNA may persist. CK8 mRNA and protein were constitutively expressed in all epithelia of normal and abnormal prostate tissues. CK19 mRNA and protein were persistently expressed in both basal and luminal cells of the tubular portion of normal glands as well as PIN lesions, but were expressed heterogeneously in both basal and luminal cells of normal alveoli. CK16 mRNA was expressed in a similar pattern as CK19, but CK16 protein was not detected either in normal or in abnormal prostate tissues. In conclusion, the expression of CK19 in PIN lesions is similar to its tubular expression and would support an origin of PIN lesions from this structure rather than the alveolar portion of the glands. The similar cytokeratin expression between PIN lesions and invasive carcinoma further supports the concept that PIN is a precursor lesion of invasive carcinoma.