TERT Promoter Mutational Status in the Management of Cutaneous Melanoma: Comparison with Sentinel Lymph Node Biopsy.

BACKGROUND: While BRAF mutations seem important for early melanomagenesis, mutations in the TERT promoter (TERTp) are related to metastasis. Yet, in conventional melanoma management, risk stratification does not depend on molecular biomarkers that can indicate the stage of progression, but rather on clinical, pathological, sentinel lymph node (SLN), and radiologic evaluation. The aim of this work was to evaluate the frequency and prognostic impact of TERTp mutations, comparing their predictive value to those of conventional procedures in melanoma management. METHODS: Mutational analysis of a series of 91 cases was performed. The correlations between TERTp and BRAF mutational status and clinicopathological features were assessed. RESULTS: The mutation rate was 33% for TERTp and 30% for BRAF. There was 68% concordance between primary and metastatic samples for TERTp mutations and 92% for BRAF mutations. TERTp mutations are significantly associated with the presence of BRAF mutations, features of worse prognosis, and a reduced disease-free survival. Also, TERTp mutational status was similar to SLN biopsy as a predictive factor of cutaneous melanoma recurrence and metastasis. CONCLUSIONS: The predictive value of TERTp mutations may be similar to that of SLN biopsy and its integration in the management algorithm of melanoma patients should be considered.

MOHS micrographic surgery for head and neck nonmelanoma skin cancer: An approach for ENT surgeons.

Surgery is the main approach for skin cancer, with Mohs micrographic surgery (MMS) allowing the highest cure rates, best esthetics and superior functional outcomes. Ear, nose, and throat (ENT) surgeons are often challenged with patients presenting skin cancer, needing appropriate expertise to its adequate management. This paper highlights the most important aspects of MMS, enabling ENT surgeons to become familiar with its fundamental aspects. A review of the literature was performed, concomitantly presenting the author's outcomes as an ENT surgeon. A total of 51 MMSs were performed in 41 patients, and 78.4% of the tumors were cutaneous basal cell carcinomas (cBCCs), 19.6% were cutaneous squamous cell carcinomas (cSCCs), and one case was a microcystic adnexal carcinoma. Most tumors were located in high-risk areas (88.2%), and 84.3% of them were ≥10 mm in diameter. Most tumors (90.2%) required no more than two MMS excision steps to be completely removed. All cases were managed by reconstruction either using flaps or grafts. Recurrence occurred in only 2% of the cases. This study addressed the main issues of MMS, which may be important in ENT surgeons' daily practice.

Embryonal Tumors of the Central Nervous System: The WHO 2016 Classification and New Insights.

Central nervous system tumors comprise 26% of cancer in children, representing the most frequent solid neoplasms. Embryonal tumors comprise 15% of them, and they are defined as "small round blue cells" in which morphology is reminiscent of the developing embryonic nervous system. They are the most common high-grade central nervous system neoplasms. Over the years, molecular research has been improving our knowledge concerning these neoplasms, stressing the need for tumor reclassification. Indeed, the revised 2016 fourth edition of the World Health Organization classification introduced genetic parameters in the classification. Specific molecular signatures allow a more accurate risk assessment, leading to proper therapeutic approach and potentially improved prognosis. Holding this new approach, medulloblastoma is noteworthy. The present classification combines the previous histologic classification with a new genetic definition in WNT-activated, sonic hedgehog-activated and non-WNT/non-sonic hedgehog. Molecular data are also a defining feature in the diagnosis of atypical teratoid/rhabdoid tumors and embryonal tumors with multilayered rosettes. However, there are still embryonal tumors that challenge the present World Health Organization classification, and new molecular data have been underlining the need for novel tumor entities. Likewise, recent research has been highlighting heterogeneity in recognized entities. How to translate these molecular developments into routine clinical practice is still a major challenge.

TERT promoter mutations are associated with poor prognosis in cutaneous squamous cell carcinoma.

BACKGROUND: Telomerase reverse transcriptase gene (TERT) promoter (TERTp) mutations have been reported as potential predictors of poor prognosis in several cancers, but the prognostic value of TERTp mutations for cutaneous squamous cell carcinoma (cSCC) has not been determined. OBJECTIVE: To evaluate the frequency of TERTp mutations and correlate it with clinicopathologic features and patient outcome. METHODS: We performed genetic profiling of TERTp mutations in a retrospective series of cSCCs. The predictive value of TERTp mutations and clinicopathologic parameters were assessed by using logistic regression models. RESULTS: A total of 152 cSCCs from 122 patients were analyzed for TERTp mutations; the mutation rate was 31.6% (48 of 152), and it was higher in invasive cSCC (42 of 121 [34.7%]) than in in situ cSCC (6 of 31 [19.4%]). Age older than 75 years (odds ratio [OR], 14.84; P = .013] and TERTp mutation (OR, 8.11; P = .002) were independent predictors of local recurrence. TERTp mutation (OR, 15.89; P = .022) was independently associated with higher risk of lymph node metastasis. LIMITATIONS: The restricted number of metastatic cases. CONCLUSION: TERTp mutations may prove to be a molecular biomarker with prognostic significance in invasive cSCC, but larger studies are needed.

Lung cancer: a brief review of epidemiology and screening.

The global burden of lung cancer has been increasing over the past years, and is still a major threat to public health worldwide, leading to disabilities and premature mortality. Despite multifactorial cause, smoking remains as the major etiological factor, followed by occupational exposure to carcinogens, genetic predisposition and other concomitant diseases. In order to reduce the individual and social burden due to the direct and indirect costs related to the lung cancer treatment, accurate methods of screening are needed. Among those, x-ray with cytological analysis of sputum was first proposed. Nowadays, more sensitive methods such as low-dose computed tomography are being used to improve the early detection. In the future, molecular biomarkers may complement low-dose computed tomography and improve the robustness of early lung cancer detection.

Malignant Solitary Fibrous Tumor of the Liver: AIRP Best Cases in Radiologic-Pathologic Correlation.

Editor's Note.-RadioGraphics continues to publish radiologic-pathologic case material selected from the American Institute for Radiologic Pathology (AIRP) "best case" presentations. The AIRP conducts a 4-week Radiologic Pathology Correlation Course, which is offered five times per year. On the penultimate day of the course, the best case presentation is held at the American Film Institute Silver Theater and Cultural Center in Silver Spring, Md. The AIRP faculty identifies the best cases, from each organ system, brought by the resident attendees. One or more of the best cases from each of the five courses are then solicited for publication in RadioGraphics. These cases emphasize the importance of radiologic-pathologic correlation in the imaging evaluation and diagnosis of diseases encountered at the institute and its predecessor, the Armed Forces Institute of Pathology (AFIP).

The role of pathology in the management of patients with endometrial carcinoma.

Pathology plays a critical role in every step in the management of endometrial carcinoma patients. In this review, we describe the state of the art of pathological examination, including examination of endometrium biopsy; intra-operative evaluation with gross examination and frozen section; and grossing of hysterectomy specimen and its histological and immunohistochemistry study. The main pathologic findings in each step are described, as well as limitations and difficulties that may ensue. We highlight the important pathologic parameters that determine treatment options and prognosis of endometrial cancer patients.

Genetic polymorphisms in key hypoxia-regulated downstream molecules and phenotypic correlation in prostate cancer.

BACKGROUND: In this study we sought if, in their quest to handle hypoxia, prostate tumors express target hypoxia-associated molecules and their correlation with putative functional genetic polymorphisms. METHODS: Representative areas of prostate carcinoma (n = 51) and of nodular prostate hyperplasia (n = 20) were analysed for hypoxia-inducible factor 1 alpha (HIF-1α), carbonic anhydrase IX (CAIX), lysyl oxidase (LOX) and vascular endothelial growth factor (VEGFR2) immunohistochemistry expression using a tissue microarray. DNA was isolated from peripheral blood and used to genotype functional polymorphisms at the corresponding genes (HIF1A +1772 C > T, rs11549465; CA9 + 201 A > G; rs2071676; LOX +473 G > A, rs1800449; KDR - 604 T > C, rs2071559). RESULTS: Immunohistochemistry analyses disclosed predominance of positive CAIX and VEGFR2 expression in epithelial cells of prostate carcinomas compared to nodular prostate hyperplasia (P = 0.043 and P = 0.035, respectively). In addition, the VEGFR2 expression score in prostate epithelial cells was higher in organ-confined and extra prostatic carcinoma compared to nodular prostate hyperplasia (P = 0.031 and P = 0.004, respectively). Notably, for LOX protein the immunoreactivity score was significantly higher in organ-confined carcinomas compared to nodular prostate hyperplasia (P = 0.015). The genotype-phenotype analyses showed higher LOX staining intensity for carriers of the homozygous LOX +473 G-allele (P = 0.011). Still, carriers of the KDR-604 T-allele were more prone to have higher VEGFR2 expression in prostate epithelial cells (P < 0.006). CONCLUSIONS: Protein expression of hypoxia markers (VEGFR2, CAIX and LOX) on prostate epithelial cells was different between malignant and benign prostate disease. Two genetic polymorphisms (LOX +473 G > A and KDR-604 T > C) were correlated with protein level, accounting for a potential gene-environment effect in the activation of hypoxia-driven pathways in prostate carcinoma. Further research in larger series is warranted to validate present findings.

Portuguese Version of the Pain Beliefs and Perceptions Inventory: A Multicenter Validation Study.

BACKGROUND: We aimed to perform the translation, cultural adaptation, and validation of the Pain Beliefs and Perceptions Inventory (PBPI) for the European Portuguese language and chronic pain population. METHODS: This is a longitudinal multicenter validation study. A Portuguese version of the PBPI (PBPI-P) was created through a process of translation, back translation, and expert panel evaluation. The PBPI-P was administered to a total of 122 patients from 13 chronic pain clinics in Portugal, at baseline and after 7 days. Internal consistency and test-retest reliability were assessed by Cronbach's alpha (α) and intraclass correlation coefficient (ICC). Construct (convergent and discriminant) validity was assessed based on a set of previously developed theoretical hypotheses about interrelations between the PBPI-P and other measures. Exploratory and confirmatory factor analyses were performed to test the theoretical structure of the PBPI-P. RESULTS: The internal consistency and test-retest reliability coefficients for each respective subscale were α = 0.620 and ICC = 0.801 for mystery; α = 0.744 and ICC = 0.841 for permanence; α = 0.778 and ICC = 0.791 for constancy; and α = 0.764 and ICC = 0.881 for self-blame. Exploratory and confirmatory factor analysis revealed a four-factor structure (performance, constancy, self-blame, and mystery) that explained 63% of the variance. The construct validity of the PBPI-P was shown to be adequate, with more than 90% of the previously defined hypotheses regarding interrelations with other measures confirmed. CONCLUSION: The PBPI-P has been shown to be adequate and to have excellent reliability, internal consistency, and validity. It may contribute to a better pain assessment and is suitable for research and clinical use.

The prognostic impact of TERT promoter mutations in glioblastomas is modified by the rs2853669 single nucleotide polymorphism.

Human hotspot TERT promoter (TERTp) mutations have been reported in a wide range of tumours. Several studies have shown that TERTp mutations are associated with clinicopathological features; in some instances, TERTp mutations were considered as biomarkers of poor prognosis. The rs2853669 SNP, located in the TERT promoter region, was reported to modulate the increased TERT expression levels induced by the recurrent somatic mutations. In this study we aimed to determine the frequency and prognostic value of TERTp mutations and TERT rs2853669 SNP in 504 gliomas from Portuguese and Brazilian patients. TERTp mutations were detected in 47.8% of gliomas (216/452). Glioblastomas (GBM) exhibited the highest frequency of TERTp mutations (66.9%); in this glioma subtype, we found a significant association between TERTp mutations and poor prognosis, regardless of the population. Moreover, in a multivariate analysis, TERTp mutations were the only independent prognostic factor. Our data also showed that the poor prognosis conferred by TERTp mutations was restricted to GBM patients carrying the rs2853669 A allele and not in those carrying the G allele. In conclusion, the presence of TERTp mutations was associated with worse prognosis in GBM patients, although such association depended on the status of the rs2853669 SNP. The status of the rs2853669 SNP should be taken in consideration when assessing the prognostic value of TERTp mutations in GBM patients. TERTp mutations and the rs2853669 SNP can be used in the future as biomarkers of glioma prognosis.

Spared nerve injury model to study orofacial pain.

BACKGROUND & OBJECTIVES: There are many difficulties in generating and testing orofacial pain in animal models. Thus, only a few and limited models that mimic the human condition are available. The aim of the present research was to develop a new model of trigeminal pain by using a spared nerve injury (SNI) surgical approach in the rat face (SNI-face). METHODS: Under anaesthesia, a small incision was made in the infraorbital region of adult male Wistar rats. Three of the main infraorbital nerve branches were tightly ligated and a 2 mm segment distal to the ligation was resected. Control rats were sham-operated by exposing the nerves. Chemical hyperalgesia was evaluated 15 days after the surgery by analyzing the time spent in face grooming activity and the number of head withdrawals in response to the orofacial formalin test. RESULTS: SNI-face rats presented a significant increase of the formalin-induced pain-related behaviours evaluated both in the acute and tonic phases (expected biphasic pattern), in comparison to sham controls. INTERPRETATION & CONCLUSIONS: The SNI-face model in the rat appears to be a valid approach to evaluate experimental trigeminal pain. Ongoing studies will test the usefulness of this model to evaluate therapeutic strategies for the treatment of orofacial pain.

Results of Lumbar Endoscopic Adhesiolysis Using a Radiofrequency Catheter in Patients with Postoperative Fibrosis and Persistent or Recurrent Symptoms After Discectomy.

OBJECTIVE: To evaluate the results of lumbar epiduroscopic adhesiolysis using mechanical methods and a radiofrequency catheter followed by epidural steroid and local anesthetic administration in patients with postoperative fibrosis and persistent or recurrent symptoms. STUDY DESIGN: Prospective study. METHODS: Patients with persistent or recurrent low back and/or lower limb pain after lumbar spine surgery, in whom no relevant findings were present on MR images besides epidural scar tissue, were submitted to epiduroscopic adhesiolysis. Patient-reported outcomes including pain and disability were assessed in predefined time intervals and compared to baseline. RESULTS: Twenty-four patients were enrolled. It was possible to elicit the patient's usual pain by probing the epidural scar tissue in all patients. Statistically significant improvement in low back and lower limb pain was observed in all assessment periods up to 12 months. A pain relief over 50% was achieved in 71% of the patients at 1 month, 63% at 3 and 6 months, and 38% at 12 months. Disability scores significantly improved for around 6 months. Mean patient satisfaction rates were 80% at 1 month, 75% at 3 months, 70% at 6 months, and 67% 1 year after intervention. Only 1 transient postprocedural complication was detected. CONCLUSION: Endoscopic adhesiolysis is a potentially useful treatment for the relief of chronic intractable low back and lower limb pain in patients with previous lumbar spine surgery and epidural fibrosis. The use of larger volumes of saline during endoscopy and the employment of radiofrequency for the lysis of epidural adhesions are safe procedures, which may provide an additional benefit to the intervention.

Loss of WNK2 expression by promoter gene methylation occurs in adult gliomas and triggers Rac1-mediated tumour cell invasiveness.

The gene encoding protein kinase WNK2 was recently identified to be silenced by promoter hypermethylation in gliomas and meningiomas, suggesting a tumour-suppressor role in these brain tumours. Following experimental depletion in cell lines, WNK2 was further found to control GTP-loading of Rac1, a signalling guanosine triphosphatase involved in cell migration and motility. Here we show that WNK2 promoter methylation also occurs in 17.5% (29 out of 166) of adult gliomas, whereas it is infrequent in its paediatric forms (1.6%; 1 out of 66). Re-expression of WNK2 in glioblastoma cells presenting WNK2 gene silencing reduced cell proliferation in vitro, tumour growth in vivo and also cell migration and invasion, an effect correlated with reduced activation of Rac1. In contrast, when endogenous WNK2 was depleted from glioblastoma cells with unmethylated WNK2 promoter, changes in cell morphology, an increase in invasion and activation of Rac1 were observed. Together, these results validate the WNK2 gene as a recurrent target for epigenetic silencing in glia-derived brain tumours and provide first mechanistic evidence for a tumour-suppressing role of WNK2 that is related to Rac1 signalling and tumour cell invasion and proliferation.

Endometrial carcinoma in Portugal: demographic, diagnostic and treatment changes in the last 5 decades.

Endometrial carcinoma (EC) is nowadays the most frequent gynecologic malignancy. Incidence is increasing, but studies characterizing the changes in demographics, diagnosis, and treatment over the years are scarce. We performed a retrospective observational study of a consecutive series of EC patients (n=188) diagnosed at a Portuguese tertiary hospital between 2000 and 2010. Clinical data were reviewed, and pathologic material was reevaluated according to the current diagnostic and staging guidelines. In addition, we performed a comprehensive PubMed and IndexRMP search that identified 2 previous Portuguese endometrial cancer studies: Study 1 referred to cases from 1963 to 1968 (n=260) and Study 2 to cases from 1991 to 1993 (n=57). Results from the present and the previous studies were compared. An increased proportion (present study vs. Study 1/Study 2) of elderly women (70.2% vs. 55.0%/57.0%) as well as comorbidities like obesity (54.3% vs. 44.2%/36.4%), hypertension (66.4% vs. 33.8%/42.1%), and diabetes (29.8% vs. 18%/8.7%) was observed over the years. There was a trend (present study vs. Study 1) to increased use of surgical staging (surgery 90.4% vs. 78.2%; lymphadenectomy 27.7% vs. 16.9%) and decreased use of radiotherapy (52.7% vs. 89.6%). The overall 5-yr survival in our series (78.4%) was better than that in Study 1 (57.3%; absent in Study 2). This study provides a perspective of the endometrial cancer epidemiology, diagnosis, and treatment changes that occurred in Portugal during the last 5 decades, these most probably reflecting what happened in other European countries. Substantial improvement in diagnosis and treatment of EC ensued, having a positive impact on survival, even though nowadays patients are older and with additional comorbidities.

Pathology, therapy and prognosis of papillary renal carcinoma.

Papillary renal cell carcinoma (pRCC) accounts for approximately 10% of renal parenchymal tumors. There are two pRCC subtypes reported in several studies, but at present, there is limited molecular evidence to validate this pRCC subtyping in the daily routine. The utility of subtyping pRCC is based on reports describing that pRCC subtype is an independent predictor of outcome, with type 1 tumors showing significantly better survival than type 2 tumors. In this article, we summarize the relevant knowledge on pRCC regarding tumor features: clinical presentation, histopathology, electron microscopy, immunohistochemistry, cytogenetics, genetic/molecular and prognosis. We present an overview of the currently available pRCC treatment options and some of the new promising agents.

Basal cell carcinoma of the skin (part 1): epidemiology, pathology and genetic syndromes.

Basal cell carcinoma (BCC) is the most common skin cancer worldwide with increasing incidence, but difficult to assess due to the current under registration practice. Despite the low mortality rate, BCC is a cause of great morbidity and an economic burden to health services. There are several risk factors that increase the risk of BCC and partly explain its incidence. Low-penetrance susceptibility alleles, as well as genetic alterations in signaling pathways, namely SHH pathway, also contribute to the carcinogenesis. BCC associate with several genetic syndromes, of which basal cell nevus syndrome is the most common.

Basal cell carcinoma of the skin (part 2): diagnosis, prognosis and management.

Basal cell carcinoma (BCC) is a heterogeneous malignant neoplasm with different biological and clinical behaviors, often slow growing and rarely metastatic and conveying an excellent prognosis. However, BCC is the most frequent skin cancer worldwide and can cause great morbidity, as most occur in high visible areas of the body, often relapse and may invade and destroy local tissues. This review aims to present a concise and updated overview of BCC histopathology and clinical presentation and progression. We also present a summary of currently available treatment options and some of the new promising agents.

Biomarker Profiling of Upper Tract Urothelial Carcinoma Only and with Synchronous or Metachronous Bladder Cancer.

BACKGROUND: Molecular profiling in upper tract urothelial carcinoma (UTUC) with synchronous or metachronous urothelial bladder cancer (UBC) is scarce. We intended to assess immunohistochemical (IHC) and genetic differences between UTUC-only and UTUC with synchronous or metachronous UBC (UTUC + UBC) and evaluate the effect of subsequent UBC on the outcome of UTUC patients stratified by luminal-basal subtypes. METHODS: A retrospective cohort of UTUC was divided into UTUC-only (n = 71) and UTUC + UBC (n = 43). IHC expression of cytokeratin 5/6 (CK5/6), CK20, GATA3, and p53 was evaluated to assess relevant subtypes. Genetic characterization comprised TERTp, FGFR3, RAS, and TP53 status. Kaplan-Meier and Cox regression analyses estimated the effect of clinicopathological variables and molecular profiles on progression-free survival (PFS) and overall survival (OS) of UTUC patients. RESULTS: No meaningful differences were detected among both subgroups according to luminal-basal stratification and genetic analysis. UTUC + UBC was independently associated with a worse PFS when stratified by luminal-basal phenotype (HR 3.570, CI 95% 1.508-8.453, p = 0.004) but with no impact in OS (HR 1.279, CI 95% 0.513-3.190, p = 0.597). CONCLUSIONS: This study reveals that both subgroups exhibited equivalent genomic features and luminal-basal subtypes. The involvement of the bladder relates to shorter PFS but does not seem to influence the survival outcome of UTUC, independently of the IHC phenotype.

Feasibility of fine-needle aspiration in the diagnosis of two unusual childhood jaw tumor types: prognoma and cementifying fibroma.

Cytology features of childhood jaw tumors are infrequently reported in the literature. Fine-needle aspiration cytology (FNAC) has been used with good results in the differential diagnosis of bone lesions, being an excellent tool for the diagnosis of metastases and in the frontline approach to primary lesions. We report 3 cases of young children aged 3 years (case 1), 5 months (case 2), and 15 years (case 3) with jaw tumors diagnosed by FNAC. In the first two cases the diagnosis was prognoma, and in the third case cementifying fibroma. Despite the clinical and imaging similarity of the 3 cases - large maxillary/mandibular tumors - their characteristic cytological features allowed a confident diagnosis, excluding other differential alternatives. In both case 1 and case 2 a dual cell population of neuroepithelial and melanocytic cells was identified, consistent with a melanotic neuroectodermal tumor. In case 3 the presence of a bland spindle cell population as well as of several nodular dense eosinophilic, osteoid-like (cement) matrices, indicated a cementifying fibroma. All cases were resected and confirmed by histological examination. A review of the literature, including differential diagnosis, addresses the utility of FNAC in childhood jaw tumors.