Clonal evaluation of early onset prostate cancer by expression profiling of ERG, SPINK1, ETV1, and ETV4 on whole-mount radical prostatectomy tissue.

BACKGROUND: Expression profiles of erythroblast transformation-specific (ETS)-related gene fusions and serine protease inhibitor Kazal-type 1 (SPINK1) in early onset prostate cancer have not been thoroughly explored. METHODS: We retrieved 151 radical prostatectomy specimens from young men with prostate cancer (<55 years) and characterized the expression of ETS-related gene (ERG), SPINK1, ETS Variant 1 (ETV1), and ETV4 by dual immunohistochemistry and dual RNA in situ hybridization. Age, race, family history, preoperative prostate-specific antigen, biochemical recurrence, and pathological variables using whole-mount radical prostatectomy tissue were collected. RESULTS: A total of 313 tumor nodules from 151 men including 68 (45%) Caucasians and 61 (40%) African Americans were included in the analysis. Positive family history of prostate cancer was seen in 65 (43%) patients. Preoperative prostate-specific antigen ranged from 0.3 to 52.7 ng/mL (mean = 7.04). The follow-up period ranged from 1 to 123.7 months (mean = 30.3). Biochemical recurrence was encountered in 8 of 151 (5%). ERG overexpression was observed in 85 of 151 (56%) cases, followed by SPINK1 in 61 of 151 (40%), ETV1 in 9 of 149 (6%), and ETV4 in 4 of 141 (3%). There were 25 of 151 (17%) cases showing both ERG and SPINK1 overexpression within different regions of either the same tumor focus or different foci. Higher frequency of ERG overexpression was seen in younger patients (≤45 years old; 76% vs 49%, P = .002), Caucasian men (71% vs 41% P = .0007), organ-confined tumors (64% vs 33%, P = .0008), and tumors of Gleason Grade groups 1 and 2 (62% vs 26%, P = .009). SPINK1 overexpression was more in African American men (68% vs 26%, P = .00008), in tumors with high tumor volume (>20%) and with anterior located tumors. ETV1 and ETV4 demonstrated rare overexpression in these tumors, particularly in the higher-grade tumors. CONCLUSION: This study expands the knowledge of the clonal evolution of multifocal cancer in young patients and support differences in relation to racial background and genetics of prostate cancer.

Significance of lymphovascular space invasion in uterine serous carcinoma: what matters more; extent or presence?

To analyze the clinical significance of the extent of lymphovascular space invasion (LVI) in patients with uterine serous carcinoma. After IRB approval, 232 patients with uterine serous carcinoma from the pathology databases of 4 large academic institutions were included. Patients were divided into 3 groups based on extent of LVI. Extensive LVI (E-LVI) was defined as ≥3 vessel involvement; low LVI (L-LVI) was defined <3 vessel involvement; and the third group consisted of tumors with no LVI (A-LVI). The association between LVI and myometrial invasion, cervical involvement, lower uterine segment involvement, positive peritoneal washings, lymph node involvement, stage, and survival were analyzed. Of 232 patients, 47 had E-LVI (20.3%), 83 had L-LVI (35.8%), and 102 had A-LVI (44%). A total of 9.8% of the patients with A-LVI had lymph node involvement as compared with 18.1% in the L-LVI group and 55.4% in the E-LVI group (P<0.0001). Fifty-nine percent of the patients in A-LVI, 85% in L-LVI, and 100% in the E-LVI group demonstrated myometrial invasion (P<0.0001). Cervical involvement was noted in 23%, 43%, 66% (P<0.0001) and lower uterine segment involvement involvement in 31%, 43%, and 42% of A-LVI, L-LVI, and E-LVI (P<0.0001), respectively. Stage III and IV disease were seen in 29%, 38%, and 79% of the patients with A-LVI, L-LVI, and E-LVI, respectively (P<0.0001). The median overall survival was 172, 95, and 39 mo for the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). The racial distribution was significant with African American patients demonstrating significantly more L-LVI (27.8%) and E-LVI (40.4%) when compared with A-LVI (19.6%) (P=0.040). In a subgroup analysis including patients with Stage I and II (n=123) revealed median survivals of 172, 169, and 38 mo in the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). Fifty percent of these patients with E-LVI, 20% in L-LVI group, and 15% in A-LVI group had disease recurrence (P=0.040). The extent of LVI was associated with multiple pathologic factors and was found to be a negative prognostic factor for overall survival and disease recurrence.

Differential expression of aurora-A kinase in T-cell lymphomas.

Aurora-A is a mitotic kinase implicated in oncogenesis and is known to be overexpressed in B-cell lymphomas and plasma cell myeloma. The expression of Aurora-A kinase (henceforth referred to as Aurora-A) in T-cell lymphomas is not well characterized. In this study, we assessed Aurora-A expression by immunohistochemical analysis in 100 lymphomas encompassing a variety of T-cell lymphomas as categorized in the World Health Organization classification. Aurora-A expression was highest in anaplastic large-cell lymphomas and variably expressed in other types of T-cell lymphomas. In addition, the pattern of Aurora-A expression was predominantly cytoplasmic in ALK-positive anaplastic large-cell lymphoma and was nuclear in ALK-negative anaplastic large-cell lymphoma and other T-cell lymphomas, suggesting altered biochemical mechanisms of Aurora-A nuclear transport in ALK-positive anaplastic large-cell lymphoma. Reverse transcriptase-PCR analysis showed that Aurora-A is more highly expressed in ALK-positive anaplastic large-cell lymphoma than in ALK-negative anaplastic large-cell lymphoma, and is relatively lower in peripheral T-cell lymphomas. Using western blot analysis and the DEL cell line (derived from ALK-positive anaplastic large-cell lymphoma), we showed that Aurora-A expression is decreased after treatment with either MYC or MEK inhibitors, consistent with the MYC and MAP kinase signaling pathways being involved in driving Aurora-A expression; the greatest decrease was observed after MYC inhibition. These findings provide insights into the possible importance of Aurora-A overexpression in anaplastic large-cell lymphoma pathogenesis, and also suggest that Aurora-A inhibition could be a potential therapeutic approach for patients with anaplastic large-cell lymphoma.

Clinical and pathologic characteristics of serous carcinoma confined to the endometrium: a multi-institutional study.

The objective of this study was to analyze the clinical and pathologic factors in patients with uterine serous carcinoma confined to the endometrium. A total of 236 uterine serous carcinoma patients from the pathology databases of 4 large academic institutions were included in the study. Clinical and pathologic variables were analyzed, including patient demographics, tumor size (≤2 vs. >2 cm), myometrial invasion, lymphovascular invasion, lymph node status, tumor location (endometrium vs. polyp), cervical involvement, lower uterine segment involvement, FIGO stage, pelvic washings, recurrence, overall survival, and progression-free survival. Of 236 patients, 55 (23%) had tumors limited to the endometrium. Forty-four patients (80%) had Stage IA tumors. The tumor was confined to a polyp in 17 (30.9%) patients. Twenty patients (36.4%) had tumor sizes >2 cm and 12 (21.8%) exhibited lymphovascular invasion. Only 3 patients (5.4 %) had cervical stromal involvement. Thirty-three (66%) patients underwent pelvic and para-aortic lymphadenectomy with 2 positive para-aortic lymph nodes identified. Seven (12.7%) patients had positive washings, whereas 8 patients (14.5 %) had disease recurrence. At a median follow-up of 46 months, there was no difference in overall survival (P = 0.216) or progression-free survival (P=0.063) between patients with tumors confined to a polyp, patients with tumors confined to the endometrium, and patients with tumors present in both polyp and the endometrium. Uterine serous carcinoma with only endometrial involvement, even when confined to a polyp, can be associated with poor prognosis, further stressing the importance of complete surgical staging and adjuvant treatment in this setting.

Cystic tumor of the atrioventricular node: an unexpected finding in an explanted heart.

SUMMARY: We report herein a unique case of cystic tumor of atrioventricular (AV) node (CTAVN), which, to our knowledge, is the first of its kind diagnosed in an explanted heart specimen and only the fourth diagnosed antemortem. Often, this rare tumor can only be diagnosed by careful gross examination and adequate sampling of AV node region. It is an important differential diagnosis in young patients with syncopal attacks and varying degrees of heart blocks. CONTEXT: CTAVN is a rare, benign tumor. Most cases have been reported in young females (mean age, 38 years). Patients typically present with conduction abnormalities including complete heart block leading to sudden cardiac death. Most cases have been identified at autopsy; no cases to our knowledge have been reported in an explanted heart. DESIGN: A 19 year-old female presented to the cardiac transplant clinic for evaluation of severe congestive heart failure felt to be secondary to postpartum cardiomyopathy. The patient's history was significant for congenital heart block requiring placement of a permanent pacemaker at 12 years of age. At the time of this presentation, electrocardiogram revealed second-degree AV block, and two-dimensional echocardiogram showed lipomatous hypertrophy of the interatrial septum. Seven months later, orthotopic cardiac transplantation was performed. RESULTS: On gross examination, the explanted heart weighed 500 g and had biventricular dilatation. Histologic sections of left and right ventricle revealed myocyte hypertrophy and interstitial fibrosis consistent with dilated cardiomyopathy. Sections from the AV node showed a lesion with morphological features of CTAVN. It was composed of cysts of varying sizes lined by transitional, cuboidal and squamous epithelium. Some cysts were filled with proteinaceous debris that were periodic acid Schiff-positive and diastase resistant. CONCLUSIONS: CTAVN occurs exclusively in the area of the AV node, tricuspid valve, and inferior atrial septum. These lesions are now believed to be endodermal in origin, although mesothelial origin was earlier proposed. We report herein a case of CTAVN, the first of its kind diagnosed in an explanted heart specimen and only the fourth diagnosed antemortem.

Amended reports: development and validation of a taxonomy of defects.

Amended pathology reports produce rework, confusion, and distrust. To develop a reproducible amendment taxonomy we derived a classification from 141 amended reports, then validated it with 130 new cases before 4 observers independently reviewed 430 cases measuring agreement (k). Next, agreement in classifying 30 other amended reports in 7 institutions was measured. We further tracked amendment rates, defect categories, defect discoverers, and discovery mechanisms. In the 430-case validation set agreement was excellent (k = 0.8780 [range, 0.8416-0.9144]). Among the 7 institutions, agreement was good (k = 0.6235 [range, 0.3105-0.8975]). Amendment rates ranged from 2.6 to 4.8 per 1,000 reports. Misinterpretation fractions varied least (23%-29%). Misidentification fractions ranged more widely (20%-38%). Specimen defects were least frequent (4%-10%) and report defects most frequent (29%-48%). Misidentifications and report defects inversely correlated. Pathologists discovered most misinterpretations, and clinicians found most misidentifications. Conference review revealed 40% to 80% of misinterpretations. This taxonomy produced excellent reproducibility and good agreement across institutions.