Proteoglycan-based diversification of disease outcome in head and neck cancer patients identifies NG2/CSPG4 and syndecan-2 as unique relapse and overall survival predicting factors.

BACKGROUND: Tumour relapse is recognized to be the prime fatal burden in patients affected by head and neck squamous cell carcinoma (HNSCC), but no discrete molecular trait has yet been identified to make reliable early predictions of tumour recurrence. Expression of cell surface proteoglycans (PGs) is frequently altered in carcinomas and several of them are gradually emerging as key prognostic factors. METHODS: A PG expression analysis at both mRNA and protein level, was pursued on primary lesions derived from 173 HNSCC patients from whom full clinical history and 2 years post-surgical follow-up was accessible. Gene and protein expression data were correlated with clinical traits and previously proposed tumour relapse markers to stratify high-risk patient subgroups. RESULTS: HNSCC lesions were indeed found to exhibit a widely aberrant PG expression pattern characterized by a variable expression of all PGs and a characteristic de novo transcription/translation of GPC2, GPC5 and NG2/CSPG4 respectively in 36%, 72% and 71% on 119 cases. Importantly, expression of NG2/CSPG4, on neoplastic cells and in the intralesional stroma (Hazard Ratio [HR], 6.76, p = 0.017) was strongly associated with loco-regional relapse, whereas stromal enrichment of SDC2 (HR, 7.652, p = 0.007) was independently tied to lymphnodal infiltration and disease-related death. Conversely, down-regulated SDC1 transcript (HR, 0.232, p = 0.013) uniquely correlated with formation of distant metastases. Altered expression of PGs significantly correlated with the above disease outcomes when either considered alone or in association with well-established predictors of poor prognosis (i.e. T classification, previous occurrence of precancerous lesions and lymphnodal metastasis). Combined alteration of all three PGs was found to be a reliable predictor of shorter survival. CONCLUSIONS: An unprecedented PG-based prognostic portrait is unveiled that incisively diversifies disease course in HNSCC patients beyond the currently known clinical and molecular biomarkers.

Perforation during TUR of bladder tumours influences the natural history of superficial bladder cancer.

OBJECTIVES: Bladder perforation is the second most common complication during transurethral resection of bladder tumours. It is unknown whether perforation affects the natural history of the tumour through cell seeding. The aim of this study was to study the impact of perforation on the oncologic outcomes of bladder carcinoma. MATERIALS AND METHODS: Between 2003 and 2007, 926 consecutive patients underwent transurethral resection of bladder tumours at our institution; 327 cases were staged ≥ pT2 and were treated immediately with cystectomy and/or multimodal therapy and therefore excluded from the study. An additional 34 cases without urothelial carcinoma were excluded. Of the remaining 565 patients with non-muscle invasive bladder cancer, 457 (80.8 %) were male and 108 (19.2 %) were female with a mean age of 69.5 years in men and 67.3 years in women. Thirty-seven patients (6.5 %) experienced bladder perforation at the time of tumour resection. This group of patients (Group 1) was compared to the remaining 528 patients (Group 2) who did not experience a bladder perforation. RESULTS: Patients with bladder wall perforation experienced a shorter disease-free survival in both univariate (p = 0.003) and multivariate analyses (p = 0.006). In addition, subsequent recurrences revealed stage progression of recurrent disease (p = 0.05) and trended to a higher number of cystectomies in the perforated group of patients (p = 0.06). Nevertheless, perforation did not appear to influence overall survival (p = 0.127) or cancer-specific survival (p = 0.141). CONCLUSION: The results indicate that bladder perforation during resection of superficial bladder tumours is burdened by a shortened disease-free survival and T-stage progression.

Immunohistochemistry for Claudin-4 and BAP1 in the Differential Diagnosis between Sarcomatoid Carcinoma and Sarcomatoid Mesothelioma.

(1) Background. In the differential diagnosis between sarcomatoid carcinoma (SC) and sarcomatoid mesothelioma (SM), we aimed to investigate the role of Claudin-4 and BAP1, a panel recently used to distinguish conventional carcinoma from epithelioid mesothelioma. (2) Methods. We collected 41 surgical pleural biopsies of SM, 46 surgical resections of SC from different sites and 49 pleural biopsies of normal/hyperplastic mesothelium. All the cases were tested for Claudin-4 and BAP1 using immunohistochemistry. The statistical calculations of the sensitivity, specificity and positive and negative predictive values were performed. (3) Results: Claudin-4 was negative in 41/41 SMs, while it was positive in 18/36 (50.1%) SCs (eight diffusely, 10 focally) within their sarcomatous component. BAP1 was lost in 23/41 SMs, while it was regularly expressed in 46/46 SCs. All the cases of the normal/hyperplastic mesothelium were negative for Claudin-4 and retained the regular expression of BAP1. The Claudin-4 expression was useful for detecting SC (sensitivity, 39.1%; specificity, 100%) and the BAP1 loss was useful for diagnosing SM (sensitivity, 56.1%; specificity, 100%). (4) Conclusions. The staining for Claudin-4 and BAP1 exhibited a low/moderate sensitivity in diagnosing SC and SM (39.1% and 56.1%, respectively), but a very high specificity (100%). Claudin-4 was expressed only in SC and BAP1 loss was noted only in SM.

Prognostic Markers of Microinvasive Breast Carcinoma: A Systematic Review and Meta-Analysis.

(1) Background: The prognostic factors of microinvasive (≤1 mm) breast carcinoma are not completely clear. The aim of this study was to perform a systematic review and meta-analysis to clarify these factors. (2) Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was followed. Two databases were interrogated, PubMed and Embase, and papers in English were included to address this question. The selected studies were those that reported on female patients affected by microinvasive carcinoma, and on prognostic factors with a hazard ratio (HR) for disease-free survival (DFS) and overall survival (OS). (3) Results: In total, 618 records were identified. After removing duplicates (166), identification, and screening (336 by title and abstract alone, 116 by full text and eventual supplementary material), 5 papers were selected. Seven different meta-analyses were conducted in this study, all referring to DFS, analyzing the following prognostic factors: estrogen receptor, progesterone receptor, HER2 status, multifocality and grade of microinvasion, patient's age, and lymph node status. Only lymph node status was associated with prognosis and DFS (total number of cases: 1528; Z = 1.94; p = 0.05). The other factors examined did not significantly affect prognosis (p > 0.05). (4) Conclusions: Positive lymph node status significantly worsens prognosis in patients with microinvasive breast carcinoma.

Hemophagocytic lymphohistiocytosis in gastric cancer: A rare syndrome for the oncologist. Case report and brief review.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening condition characterized by uncontrolled activation of the immune system. HLH is a reactive mononuclear phagocytic response that occurs in association with a constellation of conditions such as malignancies and infections. The clinical diagnosis of HLH remains challenging because HLH can present with symptoms that significantly overlap with other causes of cytopenia, such as sepsis, autoimmune diseases, hematological cancers, and multiorgan failure. A 50-year-old man went to the emergency room (ER) for hyperchromic urine, melena, gingivorrhagia, and spontaneous abdominal wall hematomas. The first blood tests showed severe thrombocytopenia, alteration of the INR, and consumption of fibrinogen, and therefore, a diagnosis of disseminated intravascular coagulation (DIC) was made. A bone marrow aspirate showed numerous images of hemophagocytosis. With the suspicion of immune-mediated cytopenia, oral etoposide, intravenous immunoglobulin, and intravenous methylprednisolone were administered. Then, a diagnosis of gastric carcinoma was performed with a lymph node biopsy and gastroscopy. On the 30th day, the patient was transferred to the oncology ward of another hospital. On admission, he had serious piastrinopenia, anemia, hypertriglyceridemia, and hyperferritinemia. He was supported with a platelet transfusion and underwent a bone biopsy that showed a picture compatible with myelophthisis from diffuse medullary localization of a carcinoma of gastric origin. A diagnosis of HLH secondary to solid neoplasm was formulated. The patient started chemotherapy with oxaliplatin, calcium levofolinate, 5-fluorouracil bolus, 5-fluorouracil for 48 h (mFOLFOX6), and methylprednisolone. Six days after the third cycle of mFOLFOX6, the patient was discharged with the stabilization of his piastrinopenia condition. The patient continued chemotherapy with an improvement in his clinical conditions and normalization of hematological values. After 12 cycles of mFOLFOX, it was decided to start maintenance chemotherapy with capecitabine but, unfortunately, after only one cycle, HLH reappeared. The oncologist has to keep in mind the existence of HLH when there is an unusual clinical presentation of cancer, such as cytopenia affecting ≥2 lineages and alterations of ferritin and triglycerides other than fibrinogen and coagulation. Increased attention and additional research as well as a close collaboration with hematologists are needed to benefit patients with solid tumors complicated by HLH.

Clinicopathological Features of Non-Small Cell Lung Carcinoma with BRAF Mutation.

(1) Background: BRAF mutations affect 4-5% of lung adenocarcinomas. This study aimed to analyze the clinicopathological features of lung carcinomas with BRAF mutations, focusing on V600E vs. non-V600E and the presence of co-mutations. (2) Methods: All BRAF-mutated lung carcinomas were retrieved from a molecular diagnostic unit (the reference unit for four different hospitals). The samples were analyzed using next-generation sequencing. Statistical analyses included log-rank tests for overall survival (OS) and progression-free survival (PFS). (3) Results: In total, 60 BRAF-mutated lung carcinomas were retrieved: 24 (40.0%) with V600E and 36 (60.0%) with non-V600E mutations, and 21 (35.0%) with other co-mutations and 39 (65.0%) with only BRAF mutations. Survival data were available for 54/60 (90.0%) cases. Targeted therapy was documented in 11 cases. Patients with V600E mutations exhibited a better prognosis than patients with non-V600E mutations (p = 0.008 for OS, p = 0.018 for PFS); this was confirmed in PFS (p = 0.036) when considering only patients who received no targeted therapy. Patients with co-mutations displayed no prognostic difference compared to patients carrying only BRAF mutations (p = 0.590 for OS, p = 0.938 for PFS). (4) Conclusions: BRAF-mutated lung carcinomas with V600E (40.0%) had a better prognosis than those without V600E. Concomitant co-mutations (35.0%) did not affect the prognosis.

PD-L1 expression in head and neck carcinoma by combined positive score: a comparison among preoperative biopsy, tumor resection, and lymph node metastasis.

Immune checkpoint inhibitors have recently been approved for the treatment of advanced head and neck squamous cell carcinoma (HNSCC). The determination of PD-L1 using the combined positive score (CPS) is of utmost importance in the selection of patients. However, it is unclear which material should be examined. This study aimed to compare PD-L1 CPS in the resections of primary tumors and metastatic lymph nodes, and in the biopsies of the primary tumors.We collected 30 resected HNSCCs with lymph node metastases; in 17 of these, preoperative biopsies were retrieved. PD-L1 immunostaining of 75 samples was performed using the Dako 22C3 antibody on the Ventana ULTRA platform. An appropriate internal control was performed on each slide. CPS was calculated for each reaction. Concordance values and k were calculated for each patient. CPS cut-off values were fixed at 0 and 20.Tumors were resected from the oral cavity (4), oropharynx (17), hypopharynx (1), and larynx (8). The overall concordance of CPS between tumor resection and lymph node metastasis was 76.7% (k = 0.593). The overall concordance of CPS between tumor resection and tumor biopsy was 86.7% (k = 0.688). The agreement was moderate to substantial for each comparison.PD-L1 CPS may be correctly determined not only in resected primary tumors, but also in removed lymph node metastases, as well as in preoperative biopsies.

The role of next-generation sequencing in detecting gene fusions with known and unknown partners: a single-center experience with methodologies' integration.

AIMS: Next-generation sequencing (NGS) is becoming a new gold standard for determining molecular predictive biomarkers. This study aimed to evaluate the reliability of NGS in detecting gene fusions, focusing on comparing gene fusions with known and unknown partners. METHODS: We collected all gene fusions from a consecutive case series using an amplicon-based DNA/RNA NGS platform and subdivided them into two groups: gene fusions with known partners and gene fusions with unknown partners. Gene fusions involving ALK, ROS1 and RET were also examined by immunohistochemistry (IHC) and/or fluorescent in situ hybridization (FISH). RESULTS: Overall, 1174 malignancies underwent NGS analysis. NGS detected gene fusions in 67 cases (5.7%), further subdivided into 43 (64.2%) with known partners and 24 (35.8%) with unknown partners. Gene fusions were predominantly found in non-small cell lung carcinomas (52/67, 77.6%). Gene fusions with known partners frequently involved ALK (20/43, 46.5%) and MET (9/43, 20.9%), while gene fusions with unknown partners mostly involved RET (18/24, 75.0%). FISH/IHC confirmed rearrangement status in most (89.3%) of the gene fusions with known partners, but in only one (4.8%) of the gene fusions with unknown partners, with a significant difference (p < 0.001). In 17 patients undergoing targeted therapy, the log-rank test revealed that the overall survival was higher in the known partner group than in the unknown partner group (p = 0.002). CONCLUSIONS: NGS is a reliable method for detecting gene fusions with known partners, but it is less accurate in identifying gene fusions with unknown partners, for which further analyses (such as FISH) are required.

PD-L1 expression in NSCLC: Role of cell blocks and concordance between samples.

BACKGROUND: PD-L1 immunohistochemistry is currently performed in patients with advanced non-small cell lung carcinoma (NSCLC) to identify responders to immune checkpoint inhibitors. Cell blocks from fine needle aspiration of NSCLC are frequently used for diagnostic purposes. The aims of the study are to analyze: (a) the distribution of PD-L1 in cell blocks, in comparison to biopsies and surgical specimens; (b) the concordance of PD-L1 in specimens of the same patients. METHODS: PD-L1 analyses conducted in NSCLCs were retrieved. Cell blocks were prepared with the self-clotting method. PD-L1 was performed with Dako 22C3 on the Ventana BenchMark ULTRA platform. Results were divided by tumor proportion score (TPS) in 3 categories: <1%; 1% to 49%; ≥50%. RESULTS: A total of 483 samples from 456 patients was collected: 120 cell blocks (24.8%), 307 endoscopic or transthoracic biopsies (63.6%), 56 surgical specimens (11.6%). TPS was: <1% in 230 samples (47.8%), 1% to -49% in 136 (28.3%) and ≥ 50% in 115 (23.9%); in two samples material was insufficient. Statistics did not reveal significant differences in PD-L1 expression among the various materials (χ2 = 2.905; P = .574). In 50 samples from 25 patients, PD-L1 was carried out in two samples of the same patients, with moderate agreement (concordance rate: 68.0%, k = 0.469). CONCLUSION: (a) PD-L1 is similarly distributed in the different materials; (b) PD-L1 shows moderate concordance in different samples of the same patients. PD-L1 may be routinely tested in cell blocks, but interpreted with caution and repeated whenever possible.

Cancer Diagnostic Delay in Northern and Central Italy During the 2020 Lockdown Due to the Coronavirus Disease 2019 Pandemic.

OBJECTIVES: We performed data collection concerning the coronavirus disease 2019 (COVID-19) pandemic-related delay in the diagnosis of cancers to individuate proper corrective procedures. METHODS: A comparison was made among the number of first pathologic diagnoses of malignancy made from weeks 11 to 20 of 2018, 2019, and 2020 at seven anatomic pathology units serving secondary care hospitals in northern-central Italy. RESULTS: Cancer diagnoses fell in 2020 by 44.9% compared with the average number recorded in 2018 and 2019. Melanoma and nonmelanoma skin cancer represented 56.7% of all missing diagnoses. The diagnostic decrease in colorectal (-46.6%), prostate (-45%), and bladder (-43.6%) cancer was the most relevant among internal malignancies; for prostate, however, high-grade tumors were only moderately affected (-21.7%). CONCLUSIONS: Diagnosis of cutaneous malignancies was mostly affected by the lockdown; among internal malignancies, corrective actions were mostly needed for colorectal cancer and invasive bladder cancer.

Surrogate Molecular Classification of Invasive Breast Carcinoma: A Comparison Between Core Needle Biopsy and Surgical Excision, With and Without Neoadjuvant Therapy.

Surrogate molecular classification identifies different subtypes of invasive breast carcinoma on the basis of their immunohistochemical markers. The purpose of the study is to verify whether the immunohistochemical markers and surrogate molecular subtypes can be correctly assessed on the core needle biopsy (CNB) when compared with the corresponding surgical excision (SE), with or without neoadjuvant treatment (NAT). Cases with invasive carcinomas identified on both CNB and SE were retrospectively selected. With immunohistochemistry for estrogen receptors (ER), progesterone receptors (PgR), Ki67, human epidermal growth factor receptor 2 (Her2), and molecular analysis for Her2, surrogate molecular classification was determined in 4 and 5 groups, according to the 2013 St Gallen consensus. A total of 1067 cases was considered and complete data for surrogate molecular classification were available for 988 cases (655 without NAT, 333 with NAT). Without NAT, concordance was strong for ER and Her2, moderate for PgR, and weak for Ki67; concordance for surrogate molecular classification was moderate. After NAT, lower concordance rates were recorded, with significant reduction of PgR (P<0.001) and Ki67 (P<0.001). Without NAT, the surrogate molecular subtypes of breast carcinoma can be reliably assessed on CNB; Ki67 and/or PgR may be repeated on SE when values are close to cutoffs to avoid tumor subtype misclassification. After NAT, it seems advisable to repeat at least Ki67 and PgR.

Role of evaluating tumor­infiltrating lymphocytes, programmed death­1 ligand 1 and mismatch repair proteins expression in malignant mesothelioma.

The tumor immune microenvironment (TME) and immune checkpoints have been reported to serve a role in the pathogenesis of malignant mesothelioma (MM) and treatment outcome. Additionally, mismatch Repair (MMR) deficiency appears to enhance the response to checkpoints blockade in several tumors. The aim of the present study was to analyze programmed death­1 ligand 1 (PD­L1) expression in MM and to characterize the TME. This could help to understand the immune response, and evaluate its prognostic and predictive values. We also investigated MMR protein expression. We retrospectively analyzed 55 mesotheliomas to determine PD­L1, CD4+, CD8+, mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and PMS1 homolog 2, mismatch repair system component (PMS2) expression. We used an immunoscore (1+, 2+ and 3+) to evaluate tumor­infiltrating lymphocytes (TILs). TILs were observed in all but two samples (53/55); the majority had an immunoscore 1+ (30/53), while 2+/3+ was reported for 23/53 samples. A predominance of CD8+ was highlighted in 8 cases (15%). PD­L1 expression of ≥1% on tumor cells was displayed in 40 cases; in 9 of these, ≥50% expression was reported. Of note, alterations in MMR staining was not observed. In addition, survival analysis revealed that epithelioid subtype was associated with better prognosis. We observed a trend towards poorer prognosis for ≥50% PD­L1 expression on tumor cells, lower immunoscore (1+) and CD8+ TIL predominance. The present study highlighted the importance of exploring the TME and the standardization of PD­L1 assessment guidelines to apply in the field of immunotherapy.

Carcinosarcoma of the colon: report of a case with morphological, ultrastructural and molecular analysis.

BACKGROUND: Carcinosarcoma of the colon is a rare histopathological entity with uncertain histogenesis, that shows both epithelial and mesenchymal malignant differentiation. Carcinosarcoma rarely affects the gastrointestinal tract and only few cases are reported in the colon. Herein we describe a carcinosarcoma of the ascending colon, with morphological, ultrastructural and molecular analysis. CASE PRESENTATION: An 81-year-old man was hospitalised for asthenia, weight loss and iron-deficiency anaemia. The patient underwent colonoscopy and adenocarcinoma was diagnosed by endoscopic biopsy. A right hemicolectomy was performed and, during surgical operation, liver metastases were detected. Histological examination of the surgical specimen revealed areas of both carcinomatous and sarcomatous differentiation, completely separated by fibrous septae. The sarcomatous component exhibited areas of smooth muscle and osteoblastic differentiation, with focal osteoid material deposition. Molecular analysis conducted separately on the epithelial and mesenchymal components revealed the same p53 gene mutation (R282W in exon 8) and identical polymorphisms in p53 exon 4, in EGFR exons 20 and 21, and in c-kit exon 17. Microsatellite markers analysis revealed a common loss of heterozygosis on 18q. Overall, the data are consistent with a common origin of the two tumor components. The patient was treated with 8 cycles of oral capecitabine (1250 mg/m2 twice a day for 14 days repeated every 28 days) and two years after surgery is alive with liver metastases. CONCLUSION: Carcinosarcoma of the colon is a rare tumour with both epithelial and sarcomatous components. Molecular analysis of the current case suggests the histogenesis from a common cell progenitor.

Oncocytic modifications in rectal adenocarcinomas after radio and chemotherapy.

The purpose of the study is to highlight oncocytic modifications in rectal adenocarcinomas and evaluate a possible correlation with preoperative radiochemotherapy (RCT). Twenty-eight cases of advanced rectal carcinoma, treated preoperatively by 5-fluorouracil (200-225 mg/m(2)) and 44-46 Gy in 22-23 fractions, were studied. All patients underwent biopsy before RCT. Surgery was performed within 6 weeks after RCT. In all cases oncocytic modifications were searched for on hematoxylin and eosin (H&E) and at immunohistochemistry using an antimitochondrial antibody. In addition, in two cases, both pre- and post-RCT tissues were examined at electron microscopy. All tumors were adenocarcinomas. In pre-RCT biopsies, oncocytic changes were difficult to find on H&E, while the antimitochondrial antibody strongly stained numerous neoplastic cells (mean 48.4%). In post-RCT surgical specimens, oncocytic changes were detected in 24 out of 28 cases on H&E and the antimitochondrial antibody stained most of the residual neoplastic cells (mean 76.7%). Ultrastructural examination revealed large and bizarre mitochondria inside tumor cells both in pre- and post-RCT tissues. In conclusion, the present data suggest that rectal adenocarcinomas are "mitochondrion-rich" tumors. After preoperative RCT, residual neoplastic cells acquire a definite oncocytic phenotype.

Pap-tests with non-hyperchromatic dyskariosis are often associated with squamous intraepithelial lesions of the cervix uteri with eosinophilic features.

BACKGROUND: Squamous intraepithelial lesions of the cervix uteri with eosinophilic features (eosinophilic dysplasia, ED) are a peculiar type of dysplasia with metaplastic phenotype which was described in histological specimens. The cytological features of these lesions have not been studied yet. METHODS: Histological samples from 66 women with features of ED and positive p16(INK4a) staining were included in the study. Within the previous year, all women had at least one pap-test, whose features were recorded and compared with 31 control samples with high-grade dysplasia of usual type. RESULTS: The previous pap-test showed high-grade dysplastic cells with non-hyperchromatic nuclei in 56/66 (84.8%) cases and metaplastic features in 60/66 (90.9%) cases. Conversely, the dysplastic cells of the usual lesions showed non-hyperchromatic nuclei in 6/31 (19.4%) and metaplastic features in 4/31 (12.9%) cases. Statistical analysis showed significant differences in distribution of the non-hyperchromatic nuclei (P < 0.001), metaplastic features (P < 0.001), presence of both non-hyperchromatic nuclei and metaplastic features (P < 0.001) and usual dysplastic features (P < 0.001) among the study and control groups. CONCLUSIONS: A high-grade squamous intraepithelial lesion with non-hyperchromatic nuclei or metaplastic features is often found in the pap-test previous to the histological diagnosis of ED and may represent the cytologic correlate of this particular type of dysplasia. Diagn. Cytopathol. 2016;44:783-786. © 2016 Wiley Periodicals, Inc.

Impact of the IASLC/ATS/ERS classification in pN0 pulmonary adenocarcinomas: a study with radiological-pathological comparisons and survival analyses.

The aim of this study was: (1) to compare the new pathological findings as detected by the IASLC/ATS/ERS classification with the traditional radiological features in pulmonary pN0 adenocarcinomas, (2) to evaluate their prognostic significance on overall survival (OS). A total of 42 surgically resected pN0 pulmonary adenocarcinomas were analyzed. On CT scans, the following radiological data were recorded: sphericity, predominant margins, cavitation and bronchogram, attenuation and percentage of ground glass opacity (GGO). On pathological examination, tumors were categorized according to the IASLC/ATS/ERS classification; Sica score and grade, pathological stage, tumor major axis, pleural invasion, vascular and lymphatic invasion, peritumoral lymphoid infiltration, and cytological features were also determined. Clinical follow up was available in 37 cases (range 1-117 months). Radiologically, 31 solid and 11 semisolid tumors were found. Morphologically, 2 minimally invasive and 40 invasive adenocarcinomas were diagnosed. In radiological-pathological comparisons, (1) the acinar pattern was higher in tumors with solid attenuation and low GGO (p=0.018); (2) the lepidic pattern was more elevated in tumors with high GGO (p=0.012). In multivariate survival analyses with stage, predominant margins on CT scans (p=0.036) and Sica score (p=0.028) significantly affected OS. This study confirms the validity of the new classification of pulmonary adenocarcinomas in radiological-pathological comparisons and underlines the importance of both radiological and pathological findings in correctly identifying their prognostic features.

Long-term follow-up of intermediate-risk non-muscle invasive bladder cancer sub-classified by multi-coloured FISH.

AIM: To examine the long-term follow-up of patients with that previously underwent risk stratification based on multicolour FISH testing. PATIENTS AND METHODS: On 81 patients with intermediate-risk urothelial carcinoma, a multicolour-FISH was performed. Patients were sub-divided into low- and high-risk groups based on chromosomal patterns. Univariate analysis, using Mantel-Cox log-rank test for disease-free, progression-free survival and overall survival, was employed to determine the prognostic significance of FISH analysis. Survival times were calculated according to the Kaplan-Meier product-limit method and multivariate analysis using Cox proportional hazards regression model. RESULTS: The univariate Mantel-Cox log-rank test showed significant differences between the low-risk and the high-risk group for disease-free survival (p=0.005) and overall survival (p=0.038), but not for progression-free survival (p=0.129). CONCLUSION: Our long-term follow-up data appear to be able to divide tumors into low and high risk groups for recurrence based on molecular/genetic changes observed with FISH.

Gene mutations in small-cell lung cancer (SCLC): results of a panel of 6 genes in a cohort of Italian patients.

BACKGROUND: No target therapies are presently available in the treatment of small-cell lung cancer (SCLC). We investigated the presence of potentially drugable mutations in the EGFR, c-MET, BRAF, KRAS, PDGFRa and c-KIT genes in a retrospective series of SCLC from 2 Italian Institutions. Correlations with immunohistochemical, clinical and outcome features were evaluated. MATERIALS AND METHODS: Genes were studied by direct sequencing of DNA extracted from formalin-fixed paraffin-embedded tissues. Immunohistochemical expression of TTF-1, p63, chromogranin, synaptophysin, CD56 and bcl-2 was assessed. RESULTS: Samples from 113 SCLC patients were analyzed. All cases were wild-type for BRAF, KRAS, PDGFRa and c-KIT (data available for 82 patients). Two (1.8%) patients were EGFR-mutated (exon 19 delE746-A750 and exon 21 L858R); both were females, non-smoker and had limited disease. Overall survival of EGFR-mutated patients was 21 months as compared to 11 months in wild-type. Five (4.4%) patients were c-MET-mutated (4 on exon 14: 2 R988C, 1 D990N, 1 D102Y; 1 on exon 17 R1166Q); all were smokers, 3 were males and 4 had extensive disease. Their OS was comparable to wild-type cases (12 vs. 11 months). EGFR and c-MET mutations were mutually exclusive. Gene mutations did not correlate with immunophenotype. CONCLUSIONS: Targetable mutations are uncommon in SCLC. EGFR-mutated patients tended to be female and non-smoker and experienced a prolonged OS suggesting a possible positive prognostic effect. c-MET mutations did not affect survival. Target therapy might be considered in EGFR and c-MET-mutated patients.

uCyt+/ImmunoCyt and cytology in the detection of urothelial carcinoma: an update on 7422 analyses.

BACKGROUND: The aim of the current study was to report the results of 7422 uCyt+/ImmunoCyt and cytology analyses that were performed over the course of 9 years at the study institution for the evaluation and follow-up of patients with urothelial carcinoma. METHODS: Between January 2002 and March 2011, 2217 patients with a mean age of 69.5 years (range, 15 years-99 years) were enrolled in the current study. All patients seen for the follow-up of bladder and/or upper tract urothelial cancer as well as those with a history that was suspicious for bladder cancer were recruited. In all patients, a voided urinary cytology and uCyt+/ImmunoCyt test was performed. Patients underwent routine cystoscopy as well as cystoscopy when cytology and/or the uCyt+/ImmunoCyt test yielded positive results. Lesions that were detected cystoscopically were biopsied and removed transurethrally. A total of 7422 uCyt+/ImmunoCyt and cytology analyses were performed. RESULTS: Of the 7422 uCyt+/ImmunoCyt tests and cytologies that were performed, 7075 (95.3%) were considered adequate. A total of 578 patients (with 1156 analyses) underwent biopsy and 728 (63%) samples had a histologically proven urothelial carcinoma. Overall sensitivity was 34.5% for cytology, 68.1% for uCyt+/ImmunoCyt, and 72.8% for the 2 tests combined. Overall specificity was 97.9% for cytology, 72.3% for uCyt+/ImmunoCyt, and 71.9% for the 2 tests combined. Cytology and the uCyt+/ImmunoCyt test together had an overall sensitivity of 72.8%, with 59% for grade 1, 77% for grade 2, and 90% for grade 3 tumors (according to the 1973 World Health Organization grading classification system). CONCLUSIONS: On the basis of their 9-year experience, the authors confirm the value of uCyt+/ImmunoCyt and cytology analyses in the follow-up of patients with non-muscle-invasive urothelial cancer. This could potentially reduce the number and cost of routine cystoscopic examinations in patients who are followed for bladder carcinoma. Cancer (Cancer Cytopathol) 2013;121:392-397. © 2013 American Cancer Society.