Francesca Giunchi

Incidence, Etiology, Histologic Findings, and Course of Thoracic Inflammatory Aortopathies

BACKGROUND The aims of this study were to detect the incidence of thoracic histologically proven aortitis in a large series of 788 patients operated on for thoracic aortic disease, to describe the surgical and histologic features of inflammatory thoracic aortopathies, and to evaluate the frequency of postsurgical complications and mortality. METHODS Thirty-nine patients (4.9%) were affected by aortitis (mean age, 72.6 +/- 9.6). There were 24 women (61.5%). Thirty-four (87.2%) were operated on because of aneurysms and 5 because of dissection. In all cases the diagnosis of aortitis was incidental and was made on the basis of histopathologic findings. RESULTS Histologically, there were 30 cases of giant cell aortitis (76.9%), 3 inflammatory aneurysms (7.7%), 2 cases of aspecific lymphoplasmacellular aortitis (5.1%), 1 of Takayasu aortitis, 1 of systemic erythematosus lupus-associated aortitis, and 1 of Behçets disease-associated aortitis. The only case of infectious aortitis was a syphilitic aortitis. In 79.5% of cases, inflammatory infiltrates were moderate to severe in degree; the most widespread inflammation was seen in Takayasu aortitis, systemic erythematosus lupus-associated aortitis, and in Behçets disease. The overall in-hospital mortality was 10.3% (4 of 39 patients). Neurologic complications occurred in 4 patients (10.3%). CONCLUSIONS During surgery of the thoracic aorta, an inflammatory etiology of aneurysms is found in almost 5% of cases. The inflammatory process is in a histologically advanced phase, often with systemic development. Surgery can be associated with high morbidity and mortality.

Diagnostic Accuracy of 11C-Choline PET/CT in Preoperative Lymph Node Staging of Bladder Cancer: A Systematic Comparison With Contrast-Enhanced CT and Histologic Findings

Aim The aim of this study was to evaluate the role of 11C-choline PET/CT in the preoperative evaluation of the nodal involvement of patients with bladder carcinoma (BC) suitable for radical cystectomy and extended pelvic lymph node dissection in comparison with contrast-enhanced CT (CECT) using the pathologic specimen as reference standard. Patients and Methods Twenty-six consecutive patients (69.5 ± 9.3 years; range, 49–84) with histologically proven transitional cell BC were treated with radical cystectomy and pelvic lymph node dissection and were enrolled from April 2011 to January 2013. In all patients, paravesical, internal, eternal, and common iliac nodes as well as obturatory, presacral, preaortic, and precaval lymph nodes (LNs) were dissected up to the origin of the inferior mesentery artery. The areas of the LN dissection were grouped as follow: region A included preaortic and precaval LNs; region B included paravesical, common, internal and external iliac, obturatory, and presacral LNs in the right pelvis; region C included paravesical, common, internal and external iliac, obturatory, and presacral LNs in the left pelvis. 11C-choline PET/CT and abdominal CECT were used to assess the presence of lymph node metastases on a per patient, region, and lesion analysis using the results of surgical specimens obtained at operation as criterion standard. Results Seven of 26 patients (26.9%) showed nodal metastases at pathologic analysis. Overall, 844 LNs were evaluated, and 38 of them (4.5%) showed metastatic involvement. On a patient-based analysis, 11C-choline PET/CT showed a sensitivity of 42% and specificity of 84%, whereas, CECT showed a sensitivity of 14% and specificity of 89%. On a region-based analysis, 11C-choline PET/CT showed a sensitivity of 11% and specificity of 82%, whereas CECT showed a sensitivity of 5% and specificity of 80%. On a lesion (LN)-based analysis, 11C-choline PET/CT showed a sensitivity of 10% and specificity of 64%, whereas CECT showed a sensitivity of 2% and specificity of 63%. Conclusions 11C-choline PET/CT could provide additional diagnostic information in preoperative nodal staging of patients with invasive BC in comparison with CECT. A study with a larger population should determine if 11C-choline PET/CT could be recommended as a routine technique in high-risk patients with BC.

Prostate cancer heterogeneity: Discovering novel molecular targets for therapy

Prostate cancer (PCa) shows a broad spectrum of biological and clinical behavior, which represents the epiphenomenon of an extreme genetic heterogeneity. Recent genomic profiling studies have deeply improved the knowledge of the genomic landscape of localized and metastatic PCa. The AR and PI3K/Akt/mTOR signaling pathways are the two most frequently altered, representing therefore interestingly targets for therapy. Moreover, somatic or germline aberrations of DNA repair genes (DRGs) have been observed at high frequency, supporting the potential role of platinum derivatives and PARP inhibitors as effective therapeutic strategies. In the future, the identification of driver mutations present at a specific stage of the disease, the classification PCa based on specific molecular alterations, and the selection of the most appropriate therapy based on biomarkers predictors of response represent the foundations for an increasingly more accurate personalized medicine.

The biopsy Gleason score 3+4 in a single core does not necessarily reflect an unfavourable pathological disease after radical prostatectomy in comparison with biopsy Gleason score 3+3: looking for larger selection criteria for active surveillance candidates

Background:To assess whether the addition of clinical Gleason score (Gs) 3+4 to the Prostate Cancer Research International: Active Surveillance (PRIAS) criteria affects pathologic results in patients who are potentially suitable for active surveillance (AS) and to identify possible clinical predictors of unfavourable outcome.Methods:Three hundred and twenty-nine men who underwent radical prostatectomy with complete clinical and follow-up data and who would have fulfilled the inclusion criteria of the PRIAS protocol at the time of biopsy except for the addition of biopsy Gs=3+4 and with at least 10 cores taken have been evaluated. One experienced genitourinary pathologist selected those with real Gs=3+3 and 3+4 in only one core according to the 2005 International Society of Urological Pathology criteria. The primary end point was the proportion of unfavourable outcome (nonorgan confined disease or Gs⩾4+3). Logistic regressions explored the association between preoperative characteristics and the primary end point.Results:Two hundred and four patients were evaluated and 46 (22.5%) patients harboured unfavourable disease at final pathology. After a median follow-up of 73.5 months, there was no cancer-specific death, and 4 (2.0%) patients had biochemical relapse. There were no significant differences in terms of high Gs, locally advanced disease, unfavourable disease and biochemical relapse-free survival among patients with clinical Gs=3+3 vs Gs=3+4. At multivariable analysis, the presence of atypical small acinar proliferation (ASAP) and lower number of core taken were independently associated with a higher risk of unfavourable disease.Conclusion:The inclusion of Gs=3+4 in patients suitable to AS does not enhance the risk of unfavourable disease after radical prostatectomy. Additional factors such as number of cores taken and the presence of ASAP should be considered in patients suitable for AS.

Nodal Occult Metastases in Intermediate- and High-Risk Prostate Cancer Patients Detected Using Serial Section, Immunohistochemistry, and Real-Time Reverse Transcriptase Polymerase Chain Reaction: Prospective Evaluation With Matched-Pair Analysis

BACKGROUND The purpose of the study was to prospectively evaluate the incidence of nodal OCM assessed using SS, IHC, and RT-PCR in prostate cancer patients compared with the standard pathological evaluation (SPE), and to evaluate short-term oncological outcomes of patients with OCM. PATIENTS AND METHODS Fifty-four consecutive patients with intermediate- or high-risk prostate cancer treated with radical prostatectomy and extended pelvic LN dissection comprised the study population (StP). The central sections with the largest diameter of each LN of the StP and a matched-pair population (MpP) with identical characteristics as the StP were used to assess the improved detection rate of OCM. Pathological characteristics and biochemical recurrence-free survival were assessed according to the presence of macroscopic or OCM. RESULTS A total of 1064 LNs were processed in the 54 patients of the StP, with 11 (20.4%) patients with evident metastases at SPE and 7 with OCM (13.0% additional patients); the percentage of positive patients improved from 16.6% (18 of 108) of the MpP to 33.3% (18 of 54) of the StP (16% additional patients). The mean diameter of the 10 additional LNs with OCM found at SS only and of the 6 additional LNs found at IHC only was significantly lower than the mean diameter of the 28 metastases found at routine pathologic examination (RPE) (P < .0001). Patients with OCM showed risk of biochemical recurrence similar to patients with no LN metastases (P = .008). CONCLUSION SS, IHC, and RT-PCR can detect a not negligible percentage of OCM missed at RPE. Patients with OCM showed short-term oncological outcomes more similar to those with macroscopic metastases. Longer follow-up studies considering cancer-specific survival are needed.

Stromal and epithelial transcriptional map of initiation progression and metastatic potential of human prostate cancer

While progression from normal prostatic epithelium to invasive cancer is driven by molecular alterations, tumor cells and cells in the cancer microenvironment are co-dependent and co-evolve. Few human studies to date have focused on stroma. Here, we performed gene expression profiling of laser capture microdissected normal non-neoplastic prostate epithelial tissue and compared it to non-transformed and neoplastic low-grade and high-grade prostate epithelial tissue from radical prostatectomies, each with its immediately surrounding stroma. Whereas benign epithelium in prostates with and without tumor were similar in gene expression space, stroma away from tumor was significantly different from that in prostates without cancer. A stromal gene signature reflecting bone remodeling and immune-related pathways was upregulated in high compared to low-Gleason grade cases. In validation data, the signature discriminated cases that developed metastasis from those that did not. These data suggest that the microenvironment may influence prostate cancer initiation, maintenance, and metastatic progression.Stromal cells contribute to tumor development but the mechanisms regulating this process are still unclear. Here the authors analyze gene expression profiles in the prostate and show that stromal gene signature changes ahead of the epithelial gene signature as prostate cancer initiates and progresses.

Unusual Thyroid Carcinoma Metastases: a Case Series and Literature Review

The most common sites of metastatic differentiated thyroid cancer are the neck lymph nodes, while distant metastases typically involve the lungs, the bones, and less frequently the brain. Uncommon metastatic sites include the liver, adrenal gland, kidney, pancreas, and skin. The epidemiological aspects of thyroid metastases in rare sites are largely unknown and their identification could have a significant impact on patients management. A mini-series of unusual metastatic sites of thyroid carcinoma is proposed as a contribution to current knowledge on anatomopathological characteristics and clinical outcome. Of the six cases that were assessed, the metastases were the following: skin metastases (2), skin and pancreas metastases (1), renal metastasis (1), adrenal metastasis (1), and liver metastasis (1). In our experience, metastases in rare sites do not always represent a negative prognostic factor for disease outcome. In fact they can occur as single distant lesion and if surgically resectable, their treatment can also lead to local disease remission.

Wide spetcrum mutational analysis of metastatic renal cell cancer: a retrospective next generation sequencing approach

Renal cell cancer (RCC) is characterized by histological and molecular heterogeneity that may account for variable response to targeted therapies. We evaluated retrospectively with a next generation sequencing (NGS) approach using a pre-designed cancer panel the mutation burden of 32 lesions from 22 metastatic RCC patients treated with at least one tyrosine kinase or mTOR inhibitor. We identified mutations in the VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1, TP53 genes. Somatic alterations were correlated with response to therapy. Most mutations hit VHL1 (31,8%) followed by PTEN (13,6%), JAK3, FGFR and TP53 (9% each). Eight (36%) patients were wild-type at least for the genes included in the panel. A genotype concordance between primary RCC and its secondary lesion was found in 3/6 cases. Patients were treated with Sorafenib, Sunitinib and Temsirolimus with partial responses in 4 (18,2%) and disease stabilization in 7 (31,8%). Among the 4 partial responders, 1 (25%) was wild-type and 3 (75%) harbored different VHL1 variants. Among the 7 patients with disease stabilization 2 (29%) were wild-type, 2 (29%) PTEN mutated, and single patients (14% each) displayed mutations in VHL1, JAK3 and APC/CDKN2A. Among the 11 non-responders 7 (64%) were wild-type, 2 (18%) were p53 mutated and 2 (18%) VHL1 mutated. No significant associations were found among RCC histotype, mutation variants and response to therapies. In the absence of predictive biomarkers for metastatic RCC treatment, a NGS approach may address single patients to basket clinical trials according to actionable molecular specific alterations.

Perineural Invasion and Risk of Lethal Prostate Cancer

Background: Prostate cancer has a propensity to invade and grow along nerves, a phenomenon called perineural invasion (PNI). Recent studies suggest that the presence of PNI in prostate cancer has been associated with cancer aggressiveness. Methods: We investigated the association between PNI and lethal prostate cancer in untreated and treated prostate cancer cohorts: the Swedish Watchful Waiting Cohort of 615 men who underwent watchful waiting, and the U.S. Health Professionals Follow-Up Study of 849 men treated with radical prostatectomy. One pathologist performed a standardized histopathologic review assessing PNI and Gleason grade. Patients were followed from diagnosis until metastasis or death. Results: The prevalence of PNI was 7% and 44% in the untreated and treated cohorts, respectively. PNI was more common in high Gleason grade tumors in both cohorts. PNI was associated with enhanced tumor angiogenesis, but not tumor proliferation or apoptosis. In the Swedish study, PNI was associated with lethal prostate cancer [OR 7.4; 95% confidence interval (CI), 3.6–16.6; P < 0.001]. A positive, although not statistically significant, association persisted after adjustment for age, Gleason grade, and tumor volume (OR 1.9; 95% CI, 0.8–5.1; P = 0.17). In the U.S. study, PNI predicted lethal prostate cancer independent of clinical factors (HR 1.8; 95% CI, 1.0, 3.3; P =0.04). Conclusions: These data support the hypothesis that perineural invasion creates a microenvironment that promotes cancer aggressiveness. Impact: Our findings suggest that PNI should be a standardized component of histopathologic review, and highlights a mechanism underlying prostate cancer metastasis. Cancer Epidemiol Biomarkers Prev; 26(5); 719–26. ©2017 AACR.

Fading With Time of PD-L1 Immunoreactivity in Non-Small Cells Lung Cancer Tissues: A Methodological Study.

Blockade of inhibitory immune checkpoints is currently arising as a potential immunologic option for tumor therapy. Inhibition of programmed cell death protein 1 and/or its specific ligand programmed death-ligand 1 (PD-L1) was effective in clinical trials in advanced melanoma, non–small cell lung cancer (NSCLC) bladder and kidney cancer. The predictive role of the immunohistochemical (IHC) expression of PD-L1 is highly debated. Different reagents, clones, cutoffs of cell expression and subjective interpretation of PD-L1 immunoreactivity in epithelial cells and lymphocytes are the main issue. In this study we selected 58 consecutive NSCLC surgical specimens that underwent pathologic examination from January 2014 to July 2015. Using a tissue microarray approach we evaluated the IHC expression of PD-L1 in tumor-infiltrating lymphocytes and tumor cells (TCs) and compared the ICH staining with tumor histology, grade and the age of the tissue blocks. The main new finding was the fading of PD-L1 IHC expression in TCs in tissues processed in 2014 compared with 2015. PD-L1 expression in tumor-infiltrating lymphocytes in the 2 years was similar. We also found a significant higher immunoreactivity of TCs in high grade NSCLC and in the squamous carcinoma histotype compared with low grade tumors and the adenocarcinoma histology (P=0.013). We demonstrated that the IHC evaluation of PD-L1 in NSCLC archival tissues is feasible and can be implemented in a routine pathology setting, but it should be carefully assessed in tissue blocks older than 1 year.