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Most prostate cancers (PC) overexpress the ERG oncogene and karyopherin α 2 (KPNA2). These genes play a role in prostatic carcinogenesis, but their prognostic significance is still debated. The aim of this study was to determine the prognostic significance of ERG and KPNA2 expression, and their association to early prostate-specific antigen (PSA) biochemical recurrence in advanced PC with lymph node metastases. A series of 65 consecutive pN1 M0 R0 PC samples obtained by radical prostatectomy with lymphadenectomy has been analyzed for ERG and KPNA2 expression by immunohistochemistry. For each case, the following clinical data were collected: age, preoperative serum PSA levels, Gleason grade group, TNM stage, and follow-up. PC recurrence was investigated by serum PSA assay and defined by a PSA concentration >0.2 ng/mL after a nadir of <0.1 ng/mL following radical prostatectomy. ERG-positive staining was found in 25/65 cases (38%), and KPNA2 in 56/65 cases (86%); neither was detected in normal prostatic tissue. Immunohistochemical concordance was found between primary tumor and lymph node metastases in 24/25 (96%) of ERG and 53/56 (95%) of KPNA2-positive cases. The follow-up was known in all cases, and early PSA recurrence occurred in 25/65 cases (38%). ERG positivity, both alone and in conjunction with KPNA2 positivity, was strongly associated with early PSA recurrence [both ERG+ and KPNA+, odds ratio: 22.2 (95% confidence interval, 6.0-82.3); ERG+ alone odds ratio: 17.9 (95% confidence interval, 5.1-63.5); P<0.0001 for both]. KPNA2 expression was significantly associated with the tumor stage (P<0.00001). The results suggest that the ERG+ phenotype might be selected in metastasis-initiating clones. ERG and KPNA2 may have a prognostic value, and their positivity in PC might warrant more aggressive treatments.

Ovarian clear cell carcinoma (oCCC) is a distinctive subtype of ovarian carcinoma, with peculiar genetic and environmental risk factors, precursor lesions, molecular events during oncogenesis, patterns of spread, and response to treatment. Because of low response to chemotherapy and poor prognosis in advanced stages, there is growing interest in investigating the molecular pathways involved in oCCC development, in order to individualize novel/molecular targeted therapies. Until now, the main molecular genetic changes associated with oCCC remain to be identified, and, although several molecular changes have been reported in clear cell tumors, most studies have analyzed a limited number of cases; therefore, the true prevalence of those changes is not known. The present review will present the clinicopathologic features of oCCC, from morphology to molecular biology, discussing the diagnostic and treatment challenges of this intriguing ovarian carcinoma.

The aim of the present paper is to study a cohort of pure selected endometrial clear cell carcinomas (ECCCs) from an immunohistochemical and molecular perspective to provide new data about the molecular profile of this disease. In detail, 45 consecutive patients with a proven diagnosis of pure ECCC, according to World Health Organization criteria, were included into the study. We determined the incidence of KRAS, BRAF, and PIK3CA mutations as well as the immunohistochemical expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, PMS2), estrogen, progesterone receptors, p16, and p53. Immunohistochemical analyses for α-methylacyl-coenzyme-A racemase and Napsin A were performed to support the diagnosis of ECC. All cases were positive for at least 1 of the 2 markers. In detail, 34 of 45 (75.5%) cases were positive for α-methylacyl-coenzyme-A racemase, and 40 of 45 (88.8%) cases showed positive staining for Napsin A. All selected cases exhibited negative immunostain for estrogen receptor and progesterone receptor, a "patchy" immunostain for p16, and a "wild-type" staining pattern for p53. Fifteen patients (15/45; 33.3%) showed loss of 1 or more MMR proteins by immunohistochemistry. Seven patients showed dual loss of MSH2 and MSH6, 4 patients (8.8%) showed isolated loss of MSH6, and the remaining 4 patients showed isolated loss of PMS2, respectively. Pyrosequencing analysis revealed the presence of 5 of 45 mutations (11%) at codon 12 in exon 2 of KRAS (3/5 p.G12D, 60%; 2/5 p. G12V, 40%) and 5 of 45 (11%) mutations in PIK3CA gene, of which 3 of 5 (60%) were in exon 9 of PIK3CA (2 p.E542K and 1 p.Q546K) and 2 of 5 (40%) were in exon 20 (p.H1047R). Two synchronous mutations affecting exon 9 of PIK3CA (p.Q546K) and exon 2, codon 12 of KRAS (p.G12D) were found. No mutations were detected in the hot spot region of BRAF. In conclusion, we provided detailed immunohistochemical and molecular data in a series of ECC, demonstrating a high incidence (33%) of MMR deficiencies detected by immunohistochemistry as well as a synchronous mutation affecting PIK3CA and KRAS genes. A more extensive interrogation of the genomic features of a much larger series of clear cell carcinomas will be required to define the genomic landscape of this subtype and to determine whether there are molecular alterations that are unique to, or significantly enriched in, clear cell tumors compared to other subtypes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: A whole slide image (WSI) is typically comprised of a macro image (low-power snapshot of the entire glass slide) and stacked tiles in a pyramid structure (with the lowest resolution thumbnail at the top). The macro image shows the label and all pieces of tissue on the slide. Many whole slide scanner vendors do not readily show the macro overview to pathologists. We demonstrate that failure to do so may result in a serious misdiagnosis., Materials and Methods: Various examples of errors were accumulated that occurred during the digitization of glass slides where the virtual slide differed from the macro image of the original glass slide. Such examples were retrieved from pathology laboratories using different types of scanners in the USA, Canada, Europe, and Asia., Results: The reasons for image errors were categorized into technical problems (e.g., automatic tissue finder failure, image mismatches, and poor scan coverage) and human operator mistakes (e.g., improper manual region of interest selection). These errors were all detected because they were highlighted in the macro image., Conclusion: Our experience indicates that WSI can be subject to inadvertent errors related to glitches in scanning slides, corrupt images, or mistakes made by humans when scanning slides. Displaying the macro image that accompanies WSIs is critical from a quality control perspective in digital pathology practice as this can help detect these serious image-related problems and avoid compromised diagnoses., Competing Interests: There are no conflicts of interest.

Purpose: We evaluated the diagnostic accuracy of multiparametric magnetic resonance imaging to diagnose clinically significant prostate cancer and compared it with the diagnostic accuracy of transperineal saturation prostate biopsy., Materials and Methods: From January 2011 to February 2018 repeat saturation prostate biopsy (the reference test) was done due to suspicion of cancer in 1,032 men with a median age of 63 years in whom median prostate specific antigen was 8.6 ng/ml. All patients underwent 3.0 Tesla pelvic multiparametric magnetic resonance imaging before saturation prostate biopsy. Additional targeted fusion prostate biopsy was done of lesions with a PI-RADS™ (Prostate Imaging Reporting and Data System) score of 3 or greater., Results: T1c prostate cancer was found in 372 of the 1,032 patients (36%). Of these cases 272 (73.1%) were classified as clinically significant prostate cancer. Saturation prostate biopsy vs targeted fusion prostate biopsy and a PI-RADS score of 3 or greater vs targeted fusion prostate biopsy and a PI-RADS score of 4 or greater diagnosed 95.6% vs 83.8% vs 60.3% of clinically significant prostate cancers (p <0.0001). Saturation prostate biopsy missed 12 of 272 clinically significant prostate cancers (4.5%) vs 44 (16.2%) and 108 of 272 (39.7%) missed by targeted fusion prostate biopsy and a PI-RADS score of 3 or greater and a score of 4 or greater, respectively (p <0.0001). As a triage test multiparametric magnetic resonance imaging would have spared 49.3% vs 73.6% of patients using a PI-RADS cutoff of 3 or greater vs 4 or greater., Conclusions: Multiparametric magnetic resonance imaging could significantly reduce the number of unnecessary repeat prostate biopsies in about 50% of cases in which a PI-RADS score of 3 or greater is used. At the same time patients should be informed of the 16.2% and 39.7% false-negative rates of clinically significant prostate cancer for targeted fusion prostate biopsy of PI-RADS 3 or greater and 4 or greater lesions, respectively., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Successful implementation of whole slide imaging (WSI) for routine clinical practice has been accomplished in only a few pathology laboratories worldwide. We report the transition to an effective and complete digital surgical pathology workflow in the pathology laboratory at Cannizzaro Hospital in Catania, Italy., Methods: All (100%) permanent histopathology glass slides were digitized at ×20 using Aperio AT2 scanners. Compatible stain and scanning slide racks were employed to streamline operations. eSlide Manager software was bidirectionally interfaced with the anatomic pathology laboratory information system. Virtual slide trays connected to the two-dimensional (2D) barcode tracking system allowed pathologists to confirm that they were correctly assigned slides and that all tissues on these glass slides were scanned., Results: Over 115,000 glass slides were digitized with a scan fail rate of around 1%. Drying glass slides before scanning minimized them sticking to scanner racks. Implementation required introduction of a 2D barcode tracking system and modification of histology workflow processes., Conclusion: Our experience indicates that effective adoption of WSI for primary diagnostic use was more dependent on optimizing preimaging variables and integration with the laboratory information system than on information technology infrastructure and ensuring pathologist buy-in. Implementation of digital pathology for routine practice not only leveraged the benefits of digital imaging but also creates an opportunity for establishing standardization of workflow processes in the pathology laboratory., Competing Interests: There are no conflicts of interest.

Plasmablastic lymphoma is a rare, highly aggressive lymphoma characterized by large lymphoid cells with immunoblastic or plasmablastic features, absent expression of CD45 and CD20, positivity for CD138, and monoclonal rearrangement of the immunoglobulin heavy chain gene. It was originally reported in oral cavity in the setting of underlying human immunodeficiency viral infection but may occur also in lymph nodes or extranodal sites after transplantation and, more rarely, immunocompetent patients. Herein, we report a case of PBL presenting as an ulcerated lesion of the tongue in an HIV-negative patient, 6 years after renal transplantation. To date, only rare cases of plasmablastic lymphoma presenting after solid organ transplantation have been reported. Although a reduction of immunosuppression and an aggressive chemotherapy were performed, the patient died after a few months because of septic and cardiovascular complications.

Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer with characteristic biological features and aggressive clinical behavior. OCCCs show a pattern of gene mutations different from other type I ovarian malignancies, notably a higher frequency of PIK3CA mutations. In low grade serous ovarian cancer, KRAS and BRAF mutations are frequent, but little data are available on the mutational status of these genes in OCCCs. To clarify this issue, we designed a clinicopathological study with the aim to establish the incidence of KRAS, NRAS, and BRAF hot spot mutations in OCCC. Between December 2006 and June 2012, 22 patients with a proven diagnosis of OCCC were admitted to our Institutions. In all cases, final diagnosis was established according to FIGO and WHO criteria. All women received complete surgical staging. The PyroMark Q24 system (Qiagen GmbH, Hilden, Germany) was used for pyrosequencing analysis of KRAS, NRAS, and BRAF hot spot regions on 2.5-μm sections of formalin-fixed paraffin-embedded tissue from primary OCCC. Pyrosequencing analysis of KRAS, NRAS, and BRAF hot spot regions revealed the presence of mutations only at codon 12 in exon 2 of KRAS in 3 of 22 (14 %) cases. We found no mutations in the hot spot regions of NRAF (exons 2, 3, 4) or BRAF (exon 15). The median age of women with a KRAS mutated OCCC was 74 years. These OCCC were unilateral FIGO stage IA lesions in two cases associated with foci of endometriosis. We conclude that in 14 % of OCCCs, a KRAS mutation occurs in codon 2 exon 2. NRAS and BRAF mutations were not found.

Purpose: Preoperative findings, pathological stage PSA recurrence in patients with prostate cancer incidentally detected (iPCa) at radical cystectomy (RCP) were prospectively evaluated., Methods: From July 2000 to July 2013, 242 men 71 years old (median) underwent RCP; preoperatively, all patients underwent digital rectal examination (DRE), total and free/total PSA. The bladder was totally examined; moreover, the prostate gland was step-sectioned at 4-mm intervals. The incidence of iPCa that fulfilled criteria for clinically significant iPCa was recorded: tumor volume ≥0.5 mL, Gleason grade ≥4, extracapsular extension, seminal vesicle invasion, lymph node metastasis or positive surgical margins. In the presence of iPCa, the patients underwent PSA evaluation during the follow-up and recurrence was defined as two subsequent rises >0.2 ng/mL., Results: Among the 50 (20.6%) out of 242 patients submitted to RCP, an iPCa was found and 18 (36%) of them met criteria for insignificant iPCa; moreover, 30% of the patients had apex involvement. Median total PSA and PSA F/T values were not significantly different in the presence versus the absence of iPCa (2.6 vs 2.7 ng/mL and 26 vs 27%; p > 0.05) and between significant versus insignificant iPCa (p > 0.05). None of the patients during the follow-up (median 58 months; range 6-102 months) had PSA recurrence., Conclusions: PSA and PSA F/T values are provided for poor accuracy in distinguishing preoperatively significant from insignificant iPCa; however, the life expectancy of the patients is dramatically influenced by bladder cancer pTN (in our series, none developed PSA failure). In younger men in whom a prostate-sparing cystectomy could be proposed, an accurate preoperative evaluation should be mandatory to rule out significant iPCa at the risk of apex involvement (in our series equal to 30% of the cases).

Aim: The prostate-specific antigen (PSA) nadir and long-term outcome in patients with pT3b prostate cancer were evaluated., Patients and Methods: From July 2000 to December 2012, in 100 patients (median age=62 years) with pT3b prostate cancer following radical retropubic prostatectomy (RRP) preoperative and pathological findings predictive of PSA nadir (≤0.2 vs. >0.2 ng/ml) were retrospectively evaluated; moreover, biochemical recurrence-free survival (bRFS), cancer specific survival (CSS) and overall survival (OS) in patients who underwent watchful waiting (16 cases), adjuvant (84 cases) and salvage (10 cases) therapy were recorded., Results: A PSA nadir >0.2 ng/ml was correlated with node involvement, Gleason score ≥9, cT2, PSA >20 ng/ml, positive surgical margins and total cancer percentage >20%. At a median follow-up of 90 months (range=10-155 months) bRFS, OS and CSS were 92%, 96% and 80%, respectively., Conclusion: Radical retropubic prostatectomy combined with adjuvant and salvage treatments demonstrated a satisfactory outcome for pT3b prostate cancer.

Prostate cancer (PCa) is the cancer most frequently diagnosed in older men and the second most frequent for incidence of all tumors. With the widespread use of serum prostate-specific antigen (PSA), the detection rate as well as the incidence of localized tumors has been increasing, thus leading to a drop in PCa-related mortality. However, a corresponding estimated rate of overdiagnosis as high as 50% has been reported, and the adverse side effects related to unnecessary treatments make the overall benefit of PSA mass screening unclear. The lower PSA threshold and extended prostate biopsy protocols have led to a marked increase of small, low-grade tumors that will never threaten a patient's survival. Sextant biopsy technique, extended biopsy protocols (12-18 cores) and saturation prostate schemes are already familiar terms, together with quantitative histology in the pathology departments. This brief review will try to focus on what usually is done and what should be improved in prostate needle biopsy in order to answer many critical points such as the clinical implication of different modalities of prostate biopsy (transrectal, transperineal or even targeted), the use of quantitative histology and the importance of the new molecular findings in addition to conventional histological parameters in the era of the active surveillance protocols.

The aim of the study is to evaluate the efficacy and safety of a three-drug chemotherapy regimen including gemcitabine, carboplatin, and paclitaxel as induction therapy in clinical stage III non-small cell lung cancer (NSCLC). Patients aged 18-75 years, ECOG PS 0-1, with unresectable clinical stage IIIA or IIIB NSCLC suitable for definitive radiation treatment, were treated in a phase II study with i.v. carboplatin AUC 5 and i.v., paclitaxel 175 mg/m(2) on day 1, and i.v. gemcitabine 800 mg/m(2) on days 1 and 8, every 3 weeks for 3 cycles, as previously assessed in a dose-finding study. Primary end point was overall response rate (ORR). Secondary end points included: toxicity, progression-free survival (PFS), resection rate, and overall survival (OS). Out of the 60 enrolled patients, 49 were males and 11 females, 31 patients had stage IIIA and 29 stage IIIB NSCLC. Forty-four partial responses and one complete response were observed, for an ORR of 75 %. The most frequent G3-G4 toxicity included: neutropenia (in 23 % of cases), hypertransaminasemia (12 %), and diarrhea (5 %). With a median follow-up of 15 months (range 2-72), median PFS was 10.5 months (95 % CI 9.9-11.4) and median OS was 21.1 months (95 % CI 19.7-22.8). Fourteen stage IIIA patients underwent surgery, for a resection rate of 45 %. A median PFS of 17.8 months (95 % CI 16.2-19.7) and a median OS of 25.5 months (95 % CI 23.0-28.4) were observed in stage IIIA patients. The three-drug chemotherapy regimen, at the employed dose, demonstrated a considerable disease response and resection rate, with acceptable toxicity.

In this study, we investigated the expression and localisation of the proteins, osteopontin (OPN) and prominin-1 (CD133), as well as the plasma OPN levels in the endometrium of patients with endometriosis. Samples of ectopic endometriotic lesions and normal endometrium were obtained from 31 women with endometriosis and 28 healthy control subjects. The mRNA and protein expression of OPN and CD133 was analysed by real‑time RT-PCR and immunohistochemistry. The plasma levels of OPN were determined by ELISA. Our results revealed that OPN mRNA and protein expression, as well as its release in the blood, was significantly increased in the endometriotic lesions in comparison to normal tissue. Although the presence of CD133+ cells was detected in the normal endometrium, as well as in the endometriosis specimens, a significant quantitative variation of this protein was not demonstrated in the patients with endometriosis. In conclusion, our data indicate that OPN is involved in the development of endometriosis by enhancing the invasiveness, proliferation and survival of endometrial cells in ectopic lesions. CD133 cannot be used as a disease marker for endometriosis, although an involvement of this protein in the pathogenesis of endometriosis cannot be excluded.

Aim: Magnetic resonance imaging (MRI) accuracy in prostate cancer (PCa) diagnosis in men submitted to saturation prostate biopsy (SPBx) was evaluated., Materials and Methods: From June 2011 to December 2012, 78 patients (median 63 years) underwent repeat SPBx (median 28 cores). Multiparametric MRI using a 3 Tesla pelvic phased-array coil was performed before SPBx and lesions suspicious for PCa were submitted to additional targeted biopsies., Results: A T1c PCa was found in 32 (41%) cases. SPBx vs. MRI-suspicious targeted biopsy diagnosed 28 (87.5%) vs. 26 (81.2%) PCa missing four (12.5%) and six (18.8%) cancers localized in the anterior zone and in the lateral margin of the prostate, respectively; moreover, MRI diameter lesions correlated with PCa diagnosis and Gleason score (p<0.05)., Conclusion: Multiparametric MRI improved SPBx accuracy in diagnosing PCa of the anterior zone; moreover, suspicious areas >10 mm resulted as highly predictive of cancer (about 70% of the cases).

Clinical recurrence in the absence of biochemical PSA failure is uncommon and accounts for less than 1%; we report a rare case of solitary lung metastasis in a patient with undetectable PSA level (<0.1 ng/mL) after radical prostatectomy (RP) for prostate cancer (PCa). An asymptomatic 75-year-old man nine years after RP showed a solitary lung mass (about 2 cm) at chest radiography; the 18-FDG-PET/CT confirmed the presence of an isolated mass suspicious for primitive pulmonary cancer. The initial histological specimen after RP showed a mixed acinar and ductal PCa (Gleason score 7, pT3aNO stage, negative surgical margins). A segmental pulmonary resection was performed and definitive specimen demonstrated a single ductal PCa metastasis; after six months from surgery the patient was free from recurrence. In conclusion, in patients with atypical PCa variants imaging studies may be considered in the follow up even in presence of undetectable PSA because they could benefit from early salvage therapy.

To evaluate accuracy of Ki-67 expression on biopsy specimens in comparison with quantitative histology findings for preoperative prostate cancer (PCa) staging. From January 2008 to January 2010, 126 patients (median age 63 years) underwent radical retropubic prostatectomy; median PSA was 9.1 ng/mL; 98 and 28 patients had a clinical stage T1c and T2, respectively. The following variables of quantitative histology were evaluated as predictive of non organ-confined (OC) PCa: Gleason score > 6, TPC > 20%, GPC > 50%, cancer-positive cores > 2, presence of cancer-positive cores in both lateral margins and bilateral PCa. Value of Ki-67% staining in all cancerous cores was calculated. Sixty (47.7%) patients had a non OC-PCa with positive nodes in 12 (20%) cases. The mean Ki-67 score was 4.4%: 3.7% in OC-PCa and 5.6% in non-OC-PCa, respectively. Predictive positive value (PPV) of quantitative histology, Ki-67 (cut-off > 5%) and both parameters to predict a non-OC-PCa vs an OC-PCa was equal to 90%, 40% and 93.4%, vs 36.6%, 78.8% and 78.8%, respectively. Ki-67 staining on biopsy specimens does not improve quantitative histology in predicting non-OC-PCa; moreover, the low expression of Ki-67, even in presence of advanced disease, decreases its prognostic value in predicting an OC-PCa.

A case of sarcomatoid carcinoma of the bladder (SCB) presenting as a giant intravesical mass in a 75-year-old man complaining of lower urinary tract swmptoms (LUTS), abdominal pain and fever is reported. SCB is a rare (0.1% of all primary bladder tumors), aggressive cancer with a complex histology (a biphasic tumor with malignant epithelial and mesenchymal elements) and poor prognosis.

Objective: To evaluate the concordance between the PSAD (PSA density) values calculated using the actual prostate weight and the PSAD values calculated by using the dimensions of the gland given by the pathologist when freshly excised (volume 1) or using TRUS measures (volume 2). Diagnostic accuracy of PSAD in diagnosing PCa (prostate cancer) was evaluated and compared with accuracy obtained using PSA free/total (FIT)., Material and Methods: 102 consecutive patients with PSA included between 2 and 10 ng/mL underwent radical prostatectomy. Indications to perform prostate biopsy were: abnormal digital rectal examination, PSA < or = 2.5 ng/mL, PSA between 2.6 and 4 ng/mL and between 4.1 and 10 ng/mL with PSA F/T (free/total) < or = 15%, < or = 20% and < or = 25%, respectively We compared the PSAD values obtained using the actual prostate weight (PSAD1) vs those calculated using volume 1 (PSAD2) and volume 2 (PASD3)., Results: The mean weight of prostate specimen was 55.61 grams, while the estimated mean volumes were 50.02 mL (volume 1) and 48.49 mL (volume 2). A statistically significant difference among actual weight vs volume 1 vs. volume 2 (p < 0.0001) was found. In the patients with PSA ranging from 4.1 to 10 ng/mL a cumulative accuracy of 82.6% was found using a cut-off > 0.10 whereas, with a cut-off > 0.15, a diagnostic accuracy of 36.9% (PSAD1), 58.6% (PSAD2) and 60.8% (PSAD3) was reported., Conclusions: No concordance between the actual prostate weight and the estimated volume was found; moreover PSAD accuracy was of poor value in diagnosing PCa in comparison with PSA F/T.

Purpose: : The saphenous vein is the most commonly used bypass conduit for coronary surgery. Endoscopic harvesting techniques are associated with significant reduction of wound complications but are time-consuming and expensive. The authors developed a device to perform minimally invasive harvesting of the saphenous vein-rapidly, inexpensively, and safely., Description: : Patients hospitalized for isolated CABG (n = 134) participated in the study. Each vein had been harvested through the use of our minimally invasive system., Evaluation: : The veins were harvested in 130 cases; 378 vein samples were collected for pathology study, with complete integrity of the vein as the result of the "no touch" technique with the device. This integrity could be very important for the long-term patency of the vein graft. After surgery, there were no wound dehiscences, infections, or major hematomas. There was 1 case (0.76%) of superficial hematoma and 3 cases (2.30%) of lymphoceles., Conclusions: : Although commercial disposable systems are now available to allow minimally invasive harvesting of the saphenous vein, the authors think that harvesting the greater saphenous vein with the cylinder steel device is easy to learn can be used safely and at much-reduced costs.