Fadi Brimo

Renal epithelioid angiomyolipoma with atypia: a series of 40 cases with emphasis on clinicopathologic prognostic indicators of malignancy.

As epithelioid cellular morphology can be seen in clinically benign usual angiomyolipomas (AMLs), we divide epithelioid AMLs into those without and with atypia, the latter category associated in the literature with malignant potential. We herein report the histologic spectrum and biologic behavior of 40 consecutive cases of epithelioid AML with atypia and assess whether cases can be stratified prognostically based on clinical and pathologic features. Atypical epithelioid cells were defined as atypical polygonal cells with abundant cytoplasm, vesicular nuclei, prominent nucleoli, and nuclear size that exceeds ×2 the size of adjacent nuclei. The degree of atypia was divided to moderate and severe. Cases with bland epithelioid cells with minimal variation in nuclear size were not included. Mean age was 50.5 years (range 17 to 81), and the female to male ratio was 1.6:1. Average tumor size was 7.2 cm (range 1.0 to 17.7). The percentage of epithelioid component ranged from 5%-100% (mean 68%). Of the epithelioid component, the percentage of cells exhibiting nuclear atypia ranged in individual cases from 5% to 100% (mean of 58.4% atypical cells); 26/40 (65%) cases showed severe nuclear atypia. Cells displaying severe nuclear atypia were typically of large size with abundant cytoplasm, compared with those with moderate atypia being of small to intermediate in size with scant to moderate amount of cytoplasm. Neoplastic multinucleated giant cells and necrosis was present in 22 cases (55%) and 15 cases (37.5%), respectively. Mitoses were identified in 72.5% (29/40) of cases and ranged from 1 to 6 per 10 hpf with 7 cases showing atypical mitotic figures. Lymphovascular invasion or renal vein invasion was present in 3 cases each. Hilar and perinephric fat involvement was present in 5 and 6 cases, respectively. Clinical follow-up was available in 34 out of the 40 cases. Of the 34 cases, 9 (26%) were malignant and showed local recurrence or distant metastases. Of the 9 patients with malignant tumors, 4 died of the disease at 6, 12, 15, and 34 months after the original diagnosis was rendered, and 4 were alive with disease (mean follow-up period of 52 mo, range 24 to 72 mo). Twenty-four patients showed no evidence of recurrence and/or metastases with a mean follow-up period of 34 months (range 1 to 156 mo). We compared the 21 cases of atypical epithelioid AMLs that exhibited a benign clinical course with a minimum follow-up period of 6 months postsurgery to the 9 cases with malignant behavior. All of these were more frequently observed in clinically malignant cases: older age, larger tumor size, higher percentage of epithelioid component, severe atypia, higher percentage of atypical cells, higher mitotic count, atypical mitotic figures, necrosis, lymphovascular invasion, and renal vein invasion. Using these features, we developed a predictive model of 4 atypical features that included: (1) ≥70% atypical epithelioid cells, (2) ≥2 mitotic figures per 10 hpf, (3) atypical mitotic figures, and (4) necrosis; the presence of 3 or all of the features was highly predictive of malignant behavior. This model accurately categorized 78% of clinically malignant and 100% of the clinically benign epithelioid AMLs with atypia.

Contemporary Grading for Prostate Cancer: Implications for Patient Care

CONTEXT The Gleason grading system is one of the most powerful predictors of outcome in prostate cancer and a cornerstone in counseling and treating patients. Since its inception, it has undergone several modifications triggered by a change in clinical practice and a better understanding of the cancers histologic spectrum and variants and their prognostic significance. OBJECTIVE To provide an overview of the implementation and the impact of the Gleason system as a predictive and prognostic tool in all available treatment modalities, and to compare the original and modified Gleason systems in major pathologic and clinical outcome data sets. EVIDENCE ACQUISITION A comprehensive nonsystematic Medline search was performed using multiple Medical Subject Headings such as Gleason, modified, system, outcome, biopsy, prostatectomy, recurrence, prognosis, radiotherapy, and focal therapy, with restriction to the English language and a preference for publications within the last 10 yr. All Gleason grade-related studies in the last 3 yr were reviewed. For studies before this date, we relied on prior culling of the literature for various recent books, chapters, and original articles on this topic. EVIDENCE SYNTHESIS Using the modified grading system resulted in disease upgrading with more cancers assigned a Gleason score ≥ 7 than in the past. It also resulted in a more homogeneous Gleason score 6, which has an excellent prognosis when the disease is organ confined. The vast majority of studies using both systems showed that Gleason grading of adenocarcinomas on needle biopsies and radical prostatectomies was strongly associated with pathologic stage, status of surgical margins, metastatic disease, biochemical recurrence, and cancer-specific survival, with the modified system outperforming the original one in some large series. A description of the continuous incorporation of this parameter in the clinical decision making for treating prostate cancer using all currently used treatment modalities is presented, and the findings of studies before and after the inception of the modified grading system, if available, are compared. The proposed contemporary grading prognostic categories are 3+3, 3+4, 4+3, 8, and 9-10. CONCLUSIONS The Gleason score is one of the most critical predictive factors of prostate cancer regardless of the therapy used. Modernization of the Gleason grading system has resulted in a more accurate grading system for radical prostatectomy (RP) but has complicated the comparison of data before and after the updating. A better prognostication with the updated Gleason grading system for patients treated with modalities other than surgery can only be postulated at this time because there are limited conflicting data on radiation and no studies on other treatment modalities. Its greatest impact is the uniformly excellent prognosis associated with Gleason score 6 in RPs.

Tumor Grade at Margins of Resection in Radical Prostatectomy Specimens Is an Independent Predictor of Prognosis

OBJECTIVES To assess whether reporting the grade of cancer at the site of positive margins in a radical prostatectomy (RP) specimen was independently prognostic of the outcome. METHODS We restricted our study to 108 patients with Gleason score (GS) 7, nonfocal extraprostatic extension (EPE) (Stage pT3a), and positive surgical margins. Patients with a tertiary pattern 5, those who had received neoadjuvant therapy, and those with positive margins because of an intraprostatic incision were excluded. RESULTS The overall GS was 3 + 4 in 73 patients (67%) and 4 + 3 in 35 (33%). The median length of the positive margin was 3.0 mm (range 0.5-10). The GS at the margin was 3 + 3, 3 + 4, 4 + 3, and 4 + 4 in 40 (37%), 41 (38%), 16 (14.8%), and 11 (10.2%) cases, respectively. Of the 108 patients, 45 (42%) remained free of disease after RP (median follow-up 6 years, range 3-13). Univariate and multivariate analyses showed no correlation between biochemical recurrence and either the preoperative serum prostate-specific antigen level (P = .7) or overall GS (P = .5). A strong association was noted between biochemical recurrence and the GS at the positive surgical margin (P = .007), with length of cancer at the margin also predictive (P = .015) on multivariate analysis. Using the median length of the positive margin (3 mm) as the cutoff, the association with biochemical recurrence was significantly different between the 2 groups (P = .004) using Kaplan-Meier analysis. CONCLUSIONS This is the first study to show that the grade of cancer at the site of a positive margin influences the outcome. We were able to stratify the grade into 3 categories: 3 + 3, 3 + 4, and 4 + 3 or greater (4 + 3 and 4 + 4 at the positive margin provided equal prognostic information).

PTEN genomic deletion predicts prostate cancer recurrence and is associated with low AR expression and transcriptional activity

BackgroundProstate cancer (PCa), a leading cause of cancer death in North American men, displays a broad range of clinical outcome from relatively indolent to lethal metastatic disease. Several genomic alterations have been identified in PCa which may serve as predictors of progression. PTEN, (10q23.3), is a negative regulator of the phosphatidylinositol 3-kinase (PIK3)/AKT survival pathway and a tumor suppressor frequently deleted in PCa. The androgen receptor (AR) signalling pathway is known to play an important role in PCa and its blockade constitutes a commonly used treatment modality. In this study, we assessed the deletion status of PTEN along with AR expression levels in 43 primary PCa specimens with clinical follow-up.MethodsFluorescence In Situ Hybridization (FISH) was done on formalin fixed paraffin embedded (FFPE) PCa samples to examine the deletion status of PTEN. AR expression levels were determined using immunohistochemistry (IHC).ResultsUsing FISH, we found 18 cases of PTEN deletion. Kaplan-Meier analysis showed an association with disease recurrence (P=0.03). Concurrently, IHC staining for AR found significantly lower levels of AR expression within those tumors deleted for PTEN (P<0.05). To validate these observations we interrogated a copy number alteration and gene expression profiling dataset of 64 PCa samples, 17 of which were PTEN deleted. We confirmed the predictive value of PTEN deletion in disease recurrence (P=0.03). PTEN deletion was also linked to diminished expression of PTEN (P<0.01) and AR (P=0.02). Furthermore, gene set enrichment analysis revealed a diminished expression of genes downstream of AR signalling in PTEN deleted tumors.ConclusionsAltogether, our data suggest that PTEN deleted tumors expressing low levels of AR may represent a worse prognostic subset of PCa establishing a challenge for therapeutic management.

Low-grade papillary urothelial carcinoma of the urinary bladder: a clinicopathologic analysis of a post-World Health Organization/International Society of Urological Pathology classification cohort from a single academic center.

CONTEXT Few large cohort studies have addressed outcome in patients with noninvasive low-grade papillary urothelial carcinoma (LG-UrCa) following implementation of the 2004 World Health Organization/International Society of Urological Pathology (WHO/ISUP) consensus classification. OBJECTIVE To evaluate our cohort of LG-UrCa cases classified according to 2004 WHO/ISUP to reassess outcome and interobserver agreement. DESIGN Files were searched for all patients diagnosed with LG-UrCa between 1998 and 2008. All sections were reevaluated for accuracy of classification. RESULTS A total of 112 cases initially diagnosed as LG-UrCa were identified. Of those, 8 of 55 cases (15%) initially diagnosed by nonurologic pathologists were reclassified as high-grade papillary urothelial carcinoma and were excluded. The mean length of follow-up was 40.1 months (range, 2-113 months). Tumor recurrence was encountered in 56 of 104 patients (53.8%), including 37 (35.6%) with LG-UrCa or lower-grade tumors and 19 (18.3%) with high-grade papillary urothelial carcinoma. Of the 19 patients demonstrating grade progression, 7 (37%) also developed stage progression (invasive carcinoma, n = 5; metastatic carcinoma, n = 2). Seven patients eventually underwent radical cystectomy. None of the 104 patients died of bladder cancer. The mean number of recurrence episodes was 3.11. The mean durations of time to first recurrence and time to grade progression were 13.9 months and 25.1 months, respectively. The mean size of initial tumors was 1.73 cm. There was no significant correlation between tumor size, patient age, sex, or smoking history and the likelihood for recurrence or grade progression. A significantly higher rate of recurrence was seen in patients with multiple tumors at initial diagnosis (P = .04). CONCLUSIONS A tendency to underdiagnose high-grade papillary urothelial carcinoma continues to exist. More than half (53.8%) of patients with LG-UrCa developed recurrence, with an 18.3% incidence of grade progression and a 6.7% incidence of stage progression. Patients with multiple initial tumors had significantly higher risk of developing recurrence.

Is the performance of urinary cytology as high as reported historically? A contemporary analysis in the detection and surveillance of bladder cancer

OBJECTIVES The goal of this study was to evaluate sensitivity and specificity of urine cytology during a contemporary period at our institution in comparison with historical analysis and other reported urinary biomarkers. MATERIALS AND METHODS Data from 1,114 consecutive patients corresponding to 3,251 specimens (2,979 cytologic and 272 histologic specimens) between January 2006 and July 2006 were retrieved. Subsequent cytologic and surgical specimen reports were examined with a minimum 2-year follow-up period. Collected parameters included the date of collection, reason for urinary evaluation, type of specimen, and tumor grade. Atypical diagnosis was considered negative. RESULTS On cytologic examination, 71% of specimens were benign, 23% atypical, and 6% suspicious or positive for urothelial carcinoma. Reason for collection was surveillance in 61% and new symptoms in 28%. Depending on the tumor grade, sensitivity results ranged from 10% for low-grade to 51% for high-grade tumors. Importantly, specificity of urine cytology ranged from 83% to 88% (depending on the type of urine collection and type of clinical presentation). Anticipatory positive rate was 44% after a median time of 15 months. Specificity of other reported urinary markers ranges from 40% to 90%. CONCLUSION Our institutions experience with regard to specificity of urine cytology is lower than reported historically. Whether this is a consequence of heterogeneous study designs and parameters is open to debate. As the anticipatory positive rate was high, close surveillance remains recommended in patients with positive urine cytology and negative workup. Other institutions are encouraged to evaluate whether there remains a significant advantage for urine cytology over other urinary marker assays within their own clinical setting.

Correlating metabolic activity on 18F-FDG PET/CT with histopathologic characteristics of osseous and soft-tissue sarcomas: a retrospective review of 136 patients.

OBJECTIVE The objective of our study was to determine whether there is a statistically significant correlation between metabolic activity of osseous and soft-tissue sarcomas as measured by the maximum standardized uptake value (SUV(max)) on (18)F-FDG PET/CT and histopathologic characteristics such as mitotic counts, the presence of necrosis, and the presence of a myxoid component. MATERIALS AND METHODS We retrospectively evaluated 238 consecutive patients with known soft-tissue or osseous sarcoma who underwent (18)F-FDG PET/CT for initial staging or assessment for recurrence of disease. The SUV(max) of each primary or of the most intense metastatic lesion was measured and was compared with the histologic data provided in the final pathology reports. RESULTS Histopathologic data were available for 136 sarcomas. The median SUV(max) values of sarcomas with mitotic counts of less than 2.00 (per 10 high-power fields [HPF]), 2.00-6.99, 7.00-16.24, and 16.25 or greater were 5.0, 6.6, 10.3, and 13.0, respectively (p = 0.0003). The median SUV(max) for the sarcomas with necrosis (90 patients) was 8.6 and for those without necrosis (43 patients), 6.0 (p = 0.026). The median SUV(max) for the sarcomas without a myxoid component (118 patients) was 7.7 and with a myxoid component (16 patients) was 6.2 (p = 0.28). CONCLUSION There was a statistically significant correlation between the mitotic count and the SUV(max) as well as between the presence of tumor necrosis and the SUV(max). Although a correlation between the presence of a myxoid component and SUV(max) was shown, it was not found to be statistically significant. These findings improve on the current information in the literature regarding the use of PET/CT for guidance in sarcoma biopsy. Correlating the SUV(max) with histologic markers that also feature prominently in major sarcoma grading systems may help improve the accuracy of grading and of prognostication by allowing the SUV(max) to potentially serve as a surrogate marker in these grading systems, particularly in cases in which there is interobserver disagreement in the pathologic diagnosis or in cases in which the sarcoma cannot be properly classified on the basis of histopathologic evaluation alone.

Prognostic value of various morphometric measurements of tumour extent in prostate needle core tissue

Aims:  Predicting prostatic cancer patients’ outcome is a major objective for clinicians and patients. Several nomograms are currently implemented prior to treatment to help predict clinical and pathological outcome. The aim of this study was to investigate the prognostic significance of morphometric measurements of cancer on the needle biopsy specimen in relation to the final pathological stage or the biochemical failure status following radical prostatectomy, and to determine which measurement of tumour length in cases with discontinuous foci of cancer (DFC) is most reliably reflective of the pathological stage.

Prognostic factors and outcome in patients with T1 high-grade bladder cancer: can we identify patients for early cystectomy?

Study Type – Therapy (case series)

Primary leiomyosarcoma of the kidney: A clinicopathologic study of 27 cases

Primary leiomyosarcoma of the kidney is a rare entity that has not been well characterized. We retrieved 27 cases of primary renal leiomyosarcomas diagnosed at 3 institutions between 1986 and 2009. Mean patient age at diagnosis was 58.5 years (range 22 to 85), and 59% were female. Mean tumor size was 13.4 cm (range 4 to 26), and 59% of the tumors were identified in the right kidney. Detailed histologic examination was possible for 24 of the cases. Average mitotic count per 10 high-power fields was 11.1 (range 0 to 50), and the average extent of necrosis was 21% (range 0 to 60). Cellular pleomorphism was classified as either focal (n=13) or extensive (n=11) and graded as mild (n=3), moderate (n=7) or severe (n=14). Tumors were either grade 2 (n=12) or grade 3 (n=12) using the French Federation of Cancer Centers System. Direct extension beyond the kidney capsule was identified in 55% of the cases, and lymphovascular invasion was identified in 26%. Clinical follow-up information was available for 20 of the cases, and patients were followed for an average of 2.8 years (range 0.25 to 9). Distant metastases were identified in 90% of the patients, and 75% eventually died from their tumors burden. In conclusion, primary renal leiomyosarcomas have a grim prognosis regardless of the underlying histology.