Aspectos prácticos sobre la determinación de PD-L1 en el tratamiento de carcinoma urotelial. Consenso del grupo de uropatología de la SEAP / Practical aspects of PD-L1 assessment in the treatment of urothelial carcinoma: Consensus of the uropathology group of the SEAP

La reciente llegada de nuevos fármacos de inmunoterapia para el tratamiento del carcinoma urotelial hace necesario establecer criterios para armonizar la determinación de PD-L1 mediante inmunohistoquímica como factor pronóstico y para la selección de pacientes a tratar. En este escenario, un grupo de uropatólogos de la Sociedad Española de Anatomía Patológica, junto con un oncólogo médico como colaborador externo subespecializado en urooncología, ha elaborado este documento de recomendaciones basadas en la evidencia disponible. En la determinación de PD-L1 son especialmente relevantes la selección de la muestra analizada, su procesamiento, la plataforma de inmunohistoquímica y anticuerpo empleados, así como el algoritmo que se aplique para la lectura. Todos estos aspectos deben indicarse en el informe de resultados, que debería poder ser fácilmente interpretable en un contexto de rápida evolución de terapias inmunológicas.(AU)

The recent addition of novel immunotherapy drugs for the treatment of urothelial carcinoma makes it necessary the establishment of criteria to harmonize the immunohistochemical assessment of PD-L1, both as a prognostic factor and for the selection of patients to be treated. In this scenario, a group of uropathologists from the Spanish Society of Pathological Anatomy, together with a medical oncologist as an external collaborator subspecialized in uro-oncology, have prepared this document of recommendations based on the available evidence. During PD-L1 assessment it is especially relevant the selection of the sample, its processing, the immunohistochemical platform and antibody used, and the algorithm applied in the interpretation of results. All these aspects must be indicated in the results report, which should be easily interpretable in a context of rapid evolution of immunological therapies.(AU)

[Practical aspects of PD-L1 assessment in the treatment of urothelial carcinoma: Consensus of the uropathology group of the SEAP]. / Aspectos prácticos sobre la determinación de PD-L1 en el tratamiento de carcinoma urotelial. Consenso del grupo de uropatología de la SEAP.

The recent addition of novel immunotherapy drugs for the treatment of urothelial carcinoma makes it necessary the establishment of criteria to harmonize the immunohistochemical assessment of PD-L1, both as a prognostic factor and for the selection of patients to be treated. In this scenario, a group of uropathologists from the Spanish Society of Pathological Anatomy, together with a medical oncologist as an external collaborator subspecialized in uro-oncology, have prepared this document of recommendations based on the available evidence. During PD-L1 assessment it is especially relevant the selection of the sample, its processing, the immunohistochemical platform and antibody used, and the algorithm applied in the interpretation of results. All these aspects must be indicated in the results report, which should be easily interpretable in a context of rapid evolution of immunological therapies.

PTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small Cell Lung Cancer by Increasing Tumor Infiltration of Regulatory T Cells.

Immunotherapy resistance in non-small cell lung cancer (NSCLC) may be mediated by an immunosuppressive microenvironment, which can be shaped by the mutational landscape of the tumor. Here, we observed genetic alterations in the PTEN/PI3K/AKT/mTOR pathway and/or loss of PTEN expression in >25% of patients with NSCLC, with higher frequency in lung squamous carcinomas (LUSC). Patients with PTEN-low tumors had higher levels of PD-L1 and PD-L2 and showed worse progression-free survival when treated with immunotherapy. Development of a Pten-null LUSC mouse model revealed that tumors with PTEN loss were refractory to antiprogrammed cell death protein 1 (anti-PD-1), highly metastatic and fibrotic, and secreted TGFß/CXCL10 to promote conversion of CD4+ lymphocytes into regulatory T cells (Treg). Human and mouse PTEN-low tumors were enriched in Tregs and expressed higher levels of immunosuppressive genes. Importantly, treatment of mice bearing Pten-null tumors with TLR agonists and anti-TGFß antibody aimed to alter this immunosuppressive microenvironment and led to tumor rejection and immunologic memory in 100% of mice. These results demonstrate that lack of PTEN causes immunotherapy resistance in LUSCs by establishing an immunosuppressive tumor microenvironment that can be reversed therapeutically. SIGNIFICANCE: PTEN loss leads to the development of an immunosuppressive microenvironment in lung cancer that confers resistance to anti-PD-1 therapy, which can be overcome by targeting PTEN loss-mediated immunosuppression.

A slightly different polyp: melanoma metastasis diagnosed by colonoscopy.

Melanoma metastases are rare in the colon. Its diagnosis is difficult because they do not usually produce symptoms. They can present through the endoscopic image of a non-pigmented polyp. This is the case of a 56-year-old woman diagnosed with melanoma metastasis through polypectomy of an unusual-looking polyp.

Focal Therapy of Prostate Cancer Index Lesion With Irreversible Electroporation. A Prospective Study With a Median Follow-up of 3 Years.

PURPOSE: Our aim was to assess oncologic, safety, and quality of life-related outcomes of focal therapy with irreversible electroporation in men with localized prostate cancer. MATERIALS AND METHODS: This was a single-center, phase II study. INCLUSION CRITERIA: prostate cancer International Society of Urological Pathology grade 1-2, prostate specific antigen ≤15 ng/ml, ≤cT2b. Patients were selected based on multiparametric magnetic resonance imaging and transperineal systematic and targeted magnetic resonance imaging-ultrasound fusion-guided biopsy. Ablation of index lesions with safety margin was performed. Primary end point was cancer control, defined as the absence of any biopsy-proven tumor. A control transperineal biopsy was planned at 12 months and when suspected based on prostate specific antigen and/or multiparametric magnetic resonance imaging information. Quality of life was assessed using Expanded Prostate Cancer Index Composite Urinary Continence domain, International Index of Erectile Function, and International Prostate Symptom Score. RESULTS: From November 2014 to July 2021, 41 consecutive patients were included with a median follow-up of 36 months. Thirty patients (73%) had International Society of Urological Pathology grade 1 tumors, 10 (24%) grade 2, and 1 (2.4%) grade 3. Recurrence was observed in 16 of 41 (39%) of the whole cohort, and 16 of 33 (48.4%) who underwent biopsy. In-field recurrence was detected in 5 (15%) and out-of-field in 11 (33.3%). Ten of 41 (24.6%) including 3 of 5 (60%) with in-field recurrences had significant tumors (Gleason pattern 4-5; more than 1 core or any >5 mm involved). Median recurrence-free survival was 32 months (95% CI 6.7-57.2). Twenty-six patients (63.4%) were free from salvage treatment. All patients preserved urinary continence. Potency was maintained in 91.8%. CONCLUSIONS: Irreversible electroporation can achieve satisfactory 3-year in-field tumor control with excellent quality of life results in selected patients.

miRNome profiling of lung cancer metastases revealed a key role for miRNA-PD-L1 axis in the modulation of chemotherapy response.

Locally advanced non-small cell lung cancer (NSCLC) is frequent at diagnosis and requires multimodal treatment approaches. Neoadjuvant chemotherapy (NACT) followed by surgery is the treatment of choice for operable locally advanced NSCLC (Stage IIIA). However, the majority of patients are NACT-resistant and show persistent lymph nodal metastases (LNmets) and an adverse outcome. Therefore, the identification of mechanisms and biomarkers of NACT resistance is paramount for ameliorating the prognosis of patients with Stage IIIA NSCLC. Here, we investigated the miRNome and transcriptome of chemo-naïve LNmets collected from patients with Stage IIIA NSCLC (N = 64). We found that a microRNA signature accurately predicts NACT response. Mechanistically, we discovered a miR-455-5p/PD-L1 regulatory axis which drives chemotherapy resistance, hallmarks metastases with active IFN-γ response pathway (an inducer of PD-L1 expression), and impacts T cells viability and relative abundances in tumor microenvironment (TME). Our data provide new biomarkers to predict NACT response and add molecular insights relevant for improving the management of patients with locally advanced NSCLC.

Recomendaciones del grupo de trabajo de Uropatología de la Sociedad Española de Anatomía Patológica / Prostate pathology recommendations from the Uropathology working group of the Spanish Society of Pathology

Estas recomendaciones del grupo de trabajo de Uropatología de la Sociedad Española de Anatomía Patológica (SEAP) suponen un resumen del Libro blanco 2017. Se basan en recomendaciones del Colegio Americano de Patólogos, ISUP 2015, Clasificación OMS 2016 y TNM (AJCC) 2017. Incluyen recomendaciones de tallado, examen macroscópico y microscópico, así como de uso de inmunohistoquímica. Se detalla que el patrón Gleason 3 incluye glándulas hiperplásicas, atróficas y microquísticas, y el patrón 4 todas las glándulas cribiformes y glomeruloides. El Gleason en pieza de prostatectomía se modifica, y si existe un patrón terciario mayor que el primario y el secundario que comprende más del 5% del tumor, se incorpora como secundario. Tanto para biopsias como para prostatectomías, si el Gleason es 7, se recomienda informar el porcentaje de patrón 4. Se especifica el Gleason en variantes tumorales y situaciones especiales. Estas recomendaciones deben ser adaptadas según la práctica individual e institucional de acuerdo con los medios disponibles

These guidelines from the uropathology working group of the Spanish Society of Pathology (SEAP) are based on the European and ISUP 2015 recommendations and those of the College of American Pathologists, as well as the latest WHO 2016, TNM (AJCC) 2017 classifications. They include recommendations for specimen sampling, macro- and microscopic examination and immunohistochemistry. Gleason patterns are specified: Gleason pattern 3 includes hyperplastic, atrophic and microcystic glands, while pattern 4 includes all cribriform or glomeruloid glands. The Gleason score in prostatectomy specimens may change; if a tertiary pattern occurs in more than 5% of the tumour, it becomes a secondary pattern. In both biopsies and prostatectomy specimens, if the Gleason score is 7, the percentage of pattern 4 should be stated. Gleason scoring in tumor variants and special situations should also be specified. These recommendations should be adapted according to the resources available

[Prostate pathology recommendations from the Uropathology working group of the Spanish Society of Pathology]. / Recomendaciones del grupo de trabajo de Uropatología de la Sociedad Española de Anatomía Patológica.

These guidelines from the uropathology working group of the Spanish Society of Pathology (SEAP) are based on the European and ISUP 2015 recommendations and those of the College of American Pathologists, as well as the latest WHO 2016, TNM (AJCC) 2017 classifications. They include recommendations for specimen sampling, macro- and microscopic examination and immunohistochemistry. Gleason patterns are specified: Gleason pattern 3 includes hyperplastic, atrophic and microcystic glands, while pattern 4 includes all cribriform or glomeruloid glands. The Gleason score in prostatectomy specimens may change; if a tertiary pattern occurs in more than 5% of the tumour, it becomes a secondary pattern. In both biopsies and prostatectomy specimens, if the Gleason score is 7, the percentage of pattern 4 should be stated. Gleason scoring in tumor variants and special situations should also be specified. These recommendations should be adapted according to the resources available.

Insulin degrading enzyme is up-regulated in pancreatic ß cells by insulin treatment.

Insulin Degrading Enzyme (IDE) is an endopeptidase that degrades insulin and glucagon. Ide gene has been associated with type-2 diabetes mellitus (DM2). However, the physiological role(s) of IDE in glucose homeostasis and its potential therapeutic benefit remain not completely known. To contribute in the understanding of IDE's role in glucose metabolism, we analyzed IDE protein level in pancreatic islets from two hyperinsulinemic mouse models, db/db and high-fat diet (HFD) mice, as well as in human islets from DM2 patients treated with oral hypoglycemic agents (OHAs) or insulin. IDE protein level was detected by staining and by western-blot. INS1E cells, rat and human islets were treated with insulin and IDE protein level was studied. We have shown for the first time IDE staining in rodent and human tissue, using the proper negative control, IDE null mouse tissue. Our staining indicates that IDE is expressed in both beta- and alpha-cells, with higher expression in alpha-cells. Db/db and HFD mice islets showed increased IDE protein level. Interestingly, human islets from DM2 patients treated with OHAs showed decreased IDE protein level in beta-cells. Meanwhile, islets from insulin-treated DM2 patients showed augmented IDE protein level compared to OHAs patients, pointing to an upregulation of IDE protein level stimulated by insulin. These data correlate nicely with insulin-stimulated upregulation of IDE in cultured INS1E cells, as well as in rat and human islets. In conclusion, our study shows that IDE is expressed in pancreatic beta- and alpha-cells of both rodents and humans, having higher expression in alpha-cells. Furthermore, insulin stimulates IDE protein level in pancreatic beta-cells. These results may have implications in how DM2 patient's treatment affects their beta-cell function.

Aligning digital CD8+ scoring and targeted next-generation sequencing with programmed death ligand 1 expression: a pragmatic approach in early-stage squamous cell lung carcinoma.

AIMS: To study programmed death ligand 1 (PD-L1) expression, tumour-infiltrating T lymphocytes (TILs) and the molecular context in patients with early-stage squamous cell lung carcinomas (SCCs). METHODS AND RESULTS: The study included samples from 40 patients (discovery cohort) and 29 patients (validation cohort) diagnosed with early-stage SCC. PD-L1 immunohistochemistry (IHC) was performed with three commercially available clones (E1L3N, SP263 and SP142). CD8+ TILs were scored with a digital algorithm. All tumours were analysed with targeted next-generation sequencing (NGS). Additionally, TP53 mutations were investigated with direct sequencing. In both cohorts, we observed a significant association between CD8+ TILs density and high PD-L1 IHC expression in tumour cells (TCs). Furthermore, high SP142 PD-L1 expression in immune cells (ICs) was also associated significantly with CD8+ TILs density. Therefore, CD8+ TILs density discriminated between patients with high versus low PD-L1 IHC expression with excellent sensitivity and specificity. Interestingly, the highest percentages of PD-L1-positive TCs with the three antibodies were found in samples with cyclin-dependent kinase 6 (CDK6) amplification, with high amplification of proto-oncogene C-Myc (CMYC) or with cyclin D1-PI3 kinase subunit alpha (CCND1-PIK3CA) co-amplification. High SP142 PD-L1 IHC expression in ICs showed a non-significant correlation with TP53 mutations. Conversely, most cases with fibroblast growth factor receptor 1 (FGFR1) amplification were negative for all PD-L1 clones. CONCLUSIONS: Our preliminary results support the use of digital CD8+ TILs scoring and targeted NGS alongside PD-L1 expression. The approach presented herein could help define patients with SCCs candidates to immune checkpoints inhibitors.

S100P as a Marker for Urothelial Histogenesis: A Critical Review and Comparison With Novel and Traditional Urothelial Immunohistochemical Markers.

S100P, or placental S100, is a member of a large family of S100 proteins and considered to be a promising immunohistochemical marker to support urothelial differentiation. This review synthesizes published data regarding the expression of S100P in urothelial carcinoma across histological grade and variant patterns, and in other malignancies, in an effort to summarize the state of understanding of this marker and evaluate its potential. We provide also a broad comparison of S100P with other contemporary and traditional urothelial markers and outline the potential utility of S100P in various diagnostically challenging scenarios. Taken in context, we recommend that to provide immunohistochemical support for consideration of urothelial differentiation, S100P may be included in a panel of markers (due to its high sensitivity), with better established (GATA3) and more specific (uroplakin 2) markers, for comparison with corresponding markers of other primary sites under consideration, depending on the clinical context. We emphasize that the overall most appropriate panel for any given case depends on the differential diagnosis engendered by the morphology encountered, and the constellation of clinical findings. As always with immunohistochemical panels, expected positive and negative markers for each diagnostic consideration should be included. Finally, since as of date there are no optimally sensitive or specific markers of urothelial differentiation, all final diagnoses relying on immunohistochemical support should be made in the appropriate clinical and histological context.

Ewing-like sarcoma with CIC-DUX4 gene fusion in a patient with neurofibromatosis type 1. A hitherto unreported association.

Sarcoma with CIC-DUX4 gene fusion is emerging as the most prevalent subset of Ewing-like undifferentiated small round cell sarcomas with around 50 cases published. We report hereby the case of a 40-year-old male who presented a CIC-DUX4 sarcoma in deep soft tissues in his thigh. He had been diagnosed with neurofibromatosis type 1 at age 19 and over the years underwent resection of multiple neural neoplasms, including two malignant peripheral nerve sheath tumors with classical spindle-cell histopathology. The CIC-DUX4 sarcoma was treated with surgical resection, radiation and chemotherapy, but lung and brain metastases developed and the patient died from the disease 14 months after diagnosis. This is the first case of sarcoma with CIC-DUX4 gene fusion reported in a patient with NF1. Whether this association is coincidental or CIC-DUX4 sarcomas could be related to NF1 remains to be clarified. Study of alternative molecular alterations in EWSR1-negative undifferentiated small round cell sarcomas is clinically relevant, since CIC-DUX4 sarcomas seem to be a very aggressive subset with poor response to the presently used therapeutic regimens.

Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome in which affected individuals are predisposed to the development of multiple leiomyomas of the skin and uterus and aggressive forms of kidney cancer. Affected individuals harbor a germline heterozygous loss-of-function mutation of the fumarate hydratase (FH) gene. Uterine leiomyomas are present in up to 77% of women with this syndrome. Previous studies have shown that inactivation of the FH gene is unusual for nonsyndromic leiomyomas. Therefore, it might be possible to distinguish 2 genetic groups of smooth muscle tumors: the most common group of sporadic uterine leiomyomas without FH gene inactivation and the more unusual group of HLRCC leiomyomas in patients who harbor a germline mutation of FH, although the exact prevalence of hereditary HLRCC is unknown. We reviewed the clinical, morphologic, and genotypic features of uterine leiomyomas in 19 HLRCC patients with FH germline mutations. Patients with HLRCC syndrome were younger in age compared with those with regular leiomyomata. DNA was extracted by microdissection, and analysis of loss of heterozygosity (LOH) at 1q43 was performed. Uterine leiomyomas in HLRCC have young age of onset and are multiple, with size ranging from 1 to 8 cm. Histopathologically, HLRCC leiomyomas frequently had increased cellularity, multinucleated cells, and atypia. All cases showed tumor nuclei with large orangeophilic nucleoli surrounded by a perinucleolar halo similar to the changes found in HLRCC. Occasional mitoses were found in 3 cases; however, the tumors did not fulfill the criteria for malignancy. Our study also showed that LOH at 1q43 was frequent in HLRCC leiomyomas (8/10 cases), similarly to what has been previously found in renal cell carcinomas from HLRCC patients. LOH is considered to be the second hit that inactivates the FH gene. We conclude that uterine leiomyomas associated with HLRCC syndrome have characteristic morphologic features. Both, uterine leiomyomas and renal cell carcinoma share some morphologic nuclear changes and genotypic features in HLRCC patients. The specific morphologic features of the uterine leiomyomas that we describe may help in the identification of patients who may be part of the hereditary syndrome.

Serrated polyps of the colon: how reproducible is their classification?

For several years, the lack of consensus on definition, nomenclature, natural history, and biology of serrated polyps (SPs) of the colon has created considerable confusion among pathologists. According to the latest WHO classification, the family of SPs comprises hyperplastic polyps (HPs), sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs). The term SSA/P with dysplasia has replaced the category of mixed hyperplastic/adenomatous polyps (MPs). The present study aimed to evaluate the reproducibility of the diagnosis of SPs based on currently available diagnostic criteria and interactive consensus development. In an initial round, H&E slides of 70 cases of SPs were circulated among participating pathologists across Europe. This round was followed by a consensus discussion on diagnostic criteria. A second round was performed on the same 70 cases using the revised criteria and definitions according to the recent WHO classification. Data were evaluated for inter-observer agreement using Kappa statistics. In the initial round, for the total of 70 cases, a fair overall kappa value of 0.318 was reached, while in the second round overall kappa value improved to moderate (kappa = 0.557; p < 0.001). Overall kappa values for each diagnostic category also significantly improved in the final round, reaching 0.977 for HP, 0.912 for SSA/P, and 0.845 for TSA (p < 0.001). The diagnostic reproducibility of SPs improves when strictly defined, standardized diagnostic criteria adopted by consensus are applied.

Study of KRAS new predictive marker in a clinical laboratory.

BACKGROUND: The presence of somatic mutations in the KRAS gene has been identified as a reliable strong negative predictor for the response to targeting the epidermal growth factor receptor (EGFR), in patients with metastatic colorectal cancer and the use of anti-EGFR monoclonal antibodies such as Cetuximab and Panitumumab is now restricted to patients with no detectable KRAS mutations. Between 30 and 40 % of colorectal cancers contain a mutated KRAS oncogene. The aim of this study was to evaluate concordance between three methods to analyze KRAS mutational status in regard to clinical testing. METHODS: We analyzed KRAS mutations in codons 12 and 13 of exon 2 in one hundred formalin-fixed paraffin-embedded (FFPE) colorectal cancer samples by three different methods: Direct Sequencing and two commercial kits on allele-specific oligonucleotide hybridization (KRAS StripAssay, Vienna Lab.) and Amplification Refractory Mutation System/Scorpions (ARMS/S; TheraScreen KRAS Mutation kit DxS) based on q-PCR. RESULTS: We have found similar frequencies of KRAS mutations by TheraScreen and Strip-Assay (44 and 48 %), with a κ value of 0.90, indicating almost perfect agreement between methods. The frequency by direct sequencing was much lower (26 %) and the κ values were 0.67 (compared to TheraScreen) and 0.57 (compared to Strip-Assay) indicating low sensitivity. CONCLUSIONS: On analyzing KRAS mutation in FFPE tumor samples, direct sequencing sensitivity is too low to be used in a clinical setting. Choosing between ARMS/S; TheraScreen KRAS Mutation kit DxS and KRAS StripAssay, Vienna Lab, will depend on laboratory facilities and expertise.

Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior.

BACKGROUND: Colon cancer patients with the same stage show diverse clinical behavior due to tumor heterogeneity. We aimed to discover distinct classes of tumors based on microarray expression patterns, to analyze whether the molecular classification correlated with the histopathological stages or other clinical parameters and to study differences in the survival. METHODS: Hierarchical clustering was performed for class discovery in 88 colon tumors (stages I to IV). Pathways analysis and correlations between clinical parameters and our classification were analyzed. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the main subtype was generated using the 3-Nearest-Neighbor method. Coincidences with other prognostic predictors were assesed. RESULTS: Hierarchical clustering identified four robust tumor subtypes with biologically and clinically distinct behavior. Stromal components (p < 0.001), nuclear ß-catenin (p = 0.021), mucinous histology (p = 0.001), microsatellite-instability (p = 0.039) and BRAF mutations (p < 0.001) were associated to this classification but it was independent of Dukes stages (p = 0.646). Molecular subtypes were established from stage I. High-stroma-subtype showed increased levels of genes and altered pathways distinctive of tumour-associated-stroma and components of the extracellular matrix in contrast to Low-stroma-subtype. Mucinous-subtype was reflected by the increased expression of trefoil factors and mucins as well as by a higher proportion of MSI and BRAF mutations. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the Low-stroma-subtype distinguished low risk patients from high risk patients in the external cohort (Dukes B and C:HR = 8.56(2.53-29.01); Dukes B,C and D:HR = 1.87(1.07-3.25)). Eight different reported survival gene signatures segregated our tumors into two groups the Low-stroma-subtype and the other tumor subtypes. CONCLUSIONS: We have identified novel molecular subtypes in colon cancer with distinct biological and clinical behavior that are established from the initiation of the tumor. Tumor microenvironment is important for the classification and for the malignant power of the tumor. Differential gene sets and biological pathways characterize each tumor subtype reflecting underlying mechanisms of carcinogenesis that may be used for the selection of targeted therapeutic procedures. This classification may contribute to an improvement in the management of the patients with CRC and to a more comprehensive prognosis.

Clinicopathological variables, immunophenotype, chromosome 1p36 loss and tumour recurrence of 247 meningiomas grade I and II.

The WHO grading scheme distinguishes benign (grade I), atypical (grade II) and anaplastic (grade III) meningiomas. Both atypical and anaplastic meningiomas exhibited an overall increased rate of recurrence, but between 15-20% benign meningiomas will also exhibit an unfavourable clinical course with recurrence before 10 years despite aggressive surgery. We investigated 247 cases of meningiomas grade I and II. The immunohistochemical expression of 30 different molecular biomarkers of cell adhesion molecules, cell-cycle and apoptosis regulators and checkpoints was analyzed. We also determined apoptosis by in-situ hybridization (APOPDETEKTM) and loss of chromosome 1p36 by FISH. The study revealed a statistically significant co-variation (p<0.05) between meningiomas grade II associated with several clinicopathological features (Simpson grade of clinical resection, necrosis, nuclear atypia, macronucleoli, transition to small cell, sheet-like growth, high cellularity), increased expression of several biomarkers of tumour proliferation (Cyclin A, Cyclin E, MIB-1 or MDM2), proteases (Cathepsin D) or cell-adhesion (CD44) and lower expression of progesterone receptors than meningiomas grade I. The presence of Psammoma bodies or the location at convexity were protective prognostic factors for tumour recurrence while high cellularity and early age of onset (<57 year-old) were indicators of increased recurrence risk. The expression of COX-2, gamma-catenin, Topoisomerase IIa, VEGF and MIB-1 was significantly higher in the cohort of recurrent meningiomas. Meningiomas with chromosome 1p36 loss showed a higher recurrence rate (33.3%) than meningiomas with normal chromosome 1p36 (18%). Increased COX-2 expression in recurrent meningioma may also suggest a putative role of COX-2 inhibitors as a chemopreventive treatment for recurrence.