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Context.—: Squamous lesions of the esophagus encompass a spectrum of disorders ranging from reactive changes and benign papilloma to squamous dysplasia and squamous cell carcinoma, which may pose diagnostic challenges especially in superficial biopsies., Objective.—: To provide a review on the typical features of squamous neoplasia in the esophagus, with an emphasis on the key diagnostic features as well as differential diagnosis from mimicking lesions., Data Sources.—: Data sources include published peer-reviewed literature and personal experiences of the authors., Conclusions.—: Accurate diagnosis of squamous neoplasia requires adherence to established diagnostic criteria, attention to subtle histologic features, and correlation with clinical and imaging findings. In difficult cases, multiple biopsies may be necessary to reach a definitive diagnosis., (© 2021 College of American Pathologists.)

Background: Mucosal diseases of the oral cavity are relatively common, and patients often seek initial assessment from their general practitioner., Objective: The aim of this article is to provide an overview of common oral mucosal diseases to help with formulating a differential diagnosis and stratifying the urgency of referral., Discussion: Pathological mucosal conditions of the oral cavity and jaws commonly present as a mucosal ulcer or a white, red or pigmented lesion. In this review, the authors outline the most common conditions organised according to their clinical presentation and describe their typical appearance and management.

Non-melanoma skin cancer is the most prevalent malignancy in fair-skinned people and its incidence is increasing. Recently, studies have suggested that antihypertensive drugs may increase the risk of these tumors, particularly hydrochlorothiazide, due to its photosensitizing properties. The Portuguese National Authority for Medicines and Health Products, INFARMED, has issued an alert to healthcare professionals concerning the increased risk of non-melanoma skin cancer in patients exposed to cumulative doses of this drug. However, study results have been heterogeneous and sometimes conflicting. The high incidence of non-melanoma skin cancer and the large number of patients under chronic hydrochlorothiazide therapy may thus have important public health consequences. In this article, the authors review the published evidence and conclude that there may be an association between hydrochlorothiazide use and the risk of non-melanoma skin cancer, but also point out some limitations of the studies in the literature. It is important to promote preventive strategies against sun exposure, regular skin examinations, and individual assessment of the benefits of hydrochlorothiazide use, particularly in patients with previous skin cancer., (Copyright © 2020 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Lung cancer is the most common cancer worldwide and in Nepal. Non small cell carcinoma is the commoner histological type. The incidence of adenocarcinoma subtype is increasing globally. This study aims to evaluate the clinical-radiological and histological profile and the diagnostic yield of various modalities in the diagnosis of lung cancer at a tertiary hospital in Nepal., Methods: This is a prospective cross-sectional study conducted at National Academy of Medical Sciences, Kathmandu. Patients presenting with clinical and radiological features consistent with lung cancer and undergoing tissue sampling were included. The clinical and radiological characteristics, distribution of various histological subtypes and the diagnostic yield of various modalities were evaluated., Results: Of the 253 patients screened, 77 meeting the inclusion criteria were enrolled into the study. Lung cancer was diagnosed in 53 patients. Forty (75.5%) patients had non small cell carcinoma and 13 (24.5%) had small cell carcinoma. Among the non small cell variants, 20 (37.7%) had adenocarcinoma and 19 (35.9%) had squamous cell carcinoma. Hitopathological diagnosis of lung cancer was established in 39 of the 42 (92.9%) patients by bronchoscopy. Image guided biopsy and/or aspiration yielded the diagnosis in 13 (24.5%) patients. The diagnostic yields of endobronchial biopsy, needle aspiration, bronchial brush and bronchial wash cytology were 86.5%, 70%, 63% and 34.3%respectively., Conclusions: The result of this study concurs with the global trend of rising incidence of adenocarcinoma subtype. Bronchoscopy remains the most commonly used tool for diagnosis of lung cancer and combination of procedures such as biopsy, bronchial brush, needle aspiration and bronchial wash provided the highest yield in our study.

Background: This was a validation study of a regional register of oral cancer in Örebro, Sweden. The purpose was to assess the rate of errors in baseline, and treatment, and the completeness and accuracy of data on recurrences., Materials and Methods: A total of 653 cases with squamous cell cancer in the oral cavity were identified from the register. A randomized sample of 73 (11%) was selected, and a set of relevant data was compared to medical records., Results: Data on patient and tumour characteristics showed high accuracy, with 98% correct data and more than 99% of treatment data were correct. Follow-up data had a higher rate of errors, with 23% of recurrences not recorded, 13.6% misclassified, and 9.1% of cases showing errors in timing of the recurrence., Conclusion: data concerning patients, tumour status, and treatment in the Regional Head and Neck Register in Örebro are highly accurate. However, the follow-up data contain a higher rate of errors, that must be taken into consideration when evaluating outcome after treatment., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Heat shock protein 70 (HSP70) was a highly conserved protein which was significantly induced in response to cellular stresses. HSP70 played an important role in the pathogenesis of cancer which stabilized the production of large amount of oncogenic proteins and finally supported growth and survival of tumor. However, there was no report about the diagnosis of circulating HSP70 in lung cancer patients. In this study, a total of 297 participants (lung cancer: 197, healthy control: 100) were enrolled in the detection of circulating HSP70 level in plasma by ELISA assay. The results indicated that circulating HSP70 significantly decreased in lung cancer patients compared to healthy controls ( P < 0.0001). Receiver operating characteristic (ROC) analysis showed that HSP70 (AUC: 82.2%, SN: 74.1%, SP: 80.0%) had higher diagnosis value than clinical existing biomarkers CEA (AUC: 80.1%, SN: 76.8%, SP: 67.3%) and CA 19-9 (AUC: 63.7%, SN: 64.2%, SP: 54.0%). In the analysis of early lung cancer patients, ROC results also revealed that HSP70 (AUC: 83.8%, SN: 71.2%, SP: 84.0%) have higher sensitivity, specificity, and AUC than CEA (AUC: 73.7%, SN: 73.2%, SP: 69.1%) and CA 19-9 (AUC: 61.5%, SN: 69.4%, SP: 53.4%). In analysis of specific histological classifications, HSP70 showed more valuable in the diagnosis of SCC (AUC: 85.9%, SN: 86.1.9%, SP: 81.0%) than ADC (AUC: 81.0%, SN: 69.1%, SP: 81.0%). Combined analysis of HSP70 and existing biomarker: CEA and CA 19-9 exhibited that HSP70 combined CEA and CA 19-9 showed the highest AUC (0.945, 95% CI, 0.855-1.000). The importance of our results was that we found decreased circulating HSP70, in combination with elevated CEA and CA 19-9, could be utilized in the diagnosis of early (stage I and II) lung cancer.

Objective: To investigate the clinical values of colposcopy and cervical biopsy and/or endocervical curettage (ECC) in the diagnosis of cervical lesion. Methods: Clinical data of 128 cases of cervical lesion diagnosed by Xuzhou Cancer Hospital from January 23, 2014 to October 11, 2016 were collected and retrospectively analyzed, all patients underwent colposcopy and cervical biopsy and/or ECC. Results: Among them, the age between 30 to 50 years old were 70 cases, whose transformation zone types of Ⅰ, Ⅱ and Ⅲ were 28 cases (40.0%), 23 cases (32.9%) and 19 cases (27.1%), respectively. The age older than 50 years were 45 cases, whose transformation zone types of Ⅱ and Ⅲ were 1 case (2.2%) and 44 cases (97.8%), respectively. Among the 128 cases of cervical lesions, diagnostic results of colposcopy showed that the chronic inflammation were 57 cases, cervical intraepithelial neoplasia (CIN)Ⅰwere 35 cases, CINⅡor CINⅡ~Ⅲ were 8 cases, CIN Ⅲ were 5 cases and cervical cancer were 23 cases. Alternatively, the pathological results showed that the chronic inflammation were 81 cases, CINⅠwere 17 cases, CINⅡor CINⅡ~Ⅲ were 7 cases, CIN Ⅲ were 5 cases and cervical cancer were 18 cases, respectively. Among the 81 cases of chronic inflammation diagnosed by pathology, 52 cases (64.2%) were consistent with the diagnostic results of colposcopy. Among the 17 cases of low grade squamous epithelial cell lesion (LSIL) diagnosed by pathology, 10 cases were in agree with the diagnostic results of colposcopy. Among the 12 cases of high-grade squamous epithelial cell lesion (HSIL) diagnosed by pathology, 9 cases were concordant with the diagnostic results of colposcopy. Among the 18 cases of cervical cancer diagnosed by pathology, 17 cases were consistent with the diagnostic results of colposcopy. Conclusions: The type of transformation zone is positively correlated with the age, and it can help to choose biopsy and therapeutic manner. The diagnostic accuracies of HSIL and early stage of cervical cancer by multi-point biopsy of colposcopy and/or ECC are high. The cervical lesions which are difficultly found by direct visualization can be identified by colposcopy, and thus provides objective evidence to determine the therapeutic manner for patients with stage ⅡA of cervical cancer.

Cervical cancer has increased in Sweden in recent years. The increase is 17% in 2014-15 compared to the reference period 2002-13. The increase is largest for adenocarcinoma (+ 31%) and shows remarkable differences between counties, from continued incidence decreases to increases of >80%. The increase is seen in most ages that are offered screening, but is confined to early stage cancers and there is no increase in mortality. Population test coverage of screening has increased since 2002. The Swedish National Cervical Screening Registry has analysed the increase in relation to screening history. The most significant increase (+ 30%) is seen in women who had a normal cervical smear (P < 0.0001) in the preceding screening interval. The cancer risk for women who previously had a high grade abnormality has also increased (P = 0.0009). Data from several laboratories still show very low cancer risk following normal cytology, indicating that the increase is related to factors that can be addressed. All data on re-review of samples taken before cancer and high grade intraepithelial neoplasia will be requested and nationally analyzed to further elucidate the exact cause.

Purpose: Aberrant fibroblast growth factor receptor (FGFR) expression is thought to contribute to the development of many types of cancer. As yet, however, their impact on the course and prognosis of head and neck cancer remains to be determined. Here, we aimed to investigate the effects of expression of the FGFR family members FGFR1 and FGFR3, as well as their downstream PI3K/AKT signal-regulated kinases, on the aggressiveness and prognosis of laryngeal cancer., Methods: In total 137 surgically removed squamous cell laryngeal cancer (SCLC) and 100 matched non-cancerous laryngeal mucosa (NCLM) samples were assessed for mRNA expression using quantitative real-time PCR. The corresponding proteins were analyzed by Western blotting. SLUG expression was assessed by immunohistochemistry. The expression data were subsequently related to tumor front grading (TFG), local/nodal recurrences, prognosis and overall survival., Results: The FGFR1, FGFR3 and PI3K/AKT kinase mRNA and protein levels were found to be significantly higher in the SCLC than the NCLM samples (p < 0.05). A high FGFR1 mRNA/protein expression level was found to be associated with an increased invasion rate, according to TFG scale and SLUG level, a high local/nodal recurrence rate and a poor prognosis (p < 0.05). Similarly, we found that a high FGFR3 mRNA/protein expression level was associated with a shorter survival time (p < 0.05). In addition, we found that high PI3K/AKT kinase mRNA/protein levels were associated with a high TFG (p < 0.05). We also found that FGFR1/3 mRNA and FGFR1 protein levels were inversely associated with overall survival (log-rank test: FGFR1 mRNA p = 0.03, FGFR3 mRNA p = 0.04, FGFR1 protein p = 0.03). Subsequent multivariate analyses revealed that high FGFR3 mRNA expression may serve as an independent poor prognostic factor (HR 2.32, 95% CI 1.03-6.59; p = 0.04). We also found that the p-PI3K regulatory kinase protein level was significantly associated with survival in the cohort studied (HR 1.78, 95% CI 0.64-8.53; p = 0.03)., Conclusions: From our data we conclude that FGFR1 and FGFR3, as well as its downstream regulatory PI3K/AKT kinases, may serve as potential biomarkers for the invasiveness and prognosis of laryngeal cancer. The expression of FGFR1/3-PI3K/AKT regulatory pathway members may be instrumental for the identification of patients at risk for an unfavorable clinical outcome.

Aim: Alongside the proven efficacy, immunotherapy in treatment of malignant diseases can cause immune-related adverse events different from commonly known chemotherapy-related toxicities., Case Presentation: During nivolumab treatment of metastatic squamous cell lung cancer, the patient developed a symptomatic inflammatory myositis confirmed with muscle biopsy and primary hypothyroidism. After initiation of corticosteroids and thyroid hormone replacement, the clinical and laboratory improvement occurred. To the best of our knowledge, this is the first description of a case of nivolumab-induced synchronous manifestation of immune-related myositis and hypothyroidism., Conclusion: Immunotherapy can trigger a wide spectrum of immune-related adverse events that could occur simultaneously. If not detected and treated, these events could become severe or even fatal and require clinicians' awareness and routine check-ups.

Background: Epigenetic alterations are strongly associated with the development of cancer. The aim of this study was to identify epigenetic pattern in squamous cell lung cancer (LUSC) on a genome-wide scale., Results: Here we performed DNA methylation profiling on 24 LUSC and paired non-tumor lung (NTL) tissues by Illumina Human Methylation 450 K BeadArrays, and identified 5214 differentially methylated probes. By integrating DNA methylation and mRNA expression data, 449 aberrantly methylated genes accompanied with altered expression were identified. Ingenuity Pathway analysis highlighted these genes which were closely related to the carcinogenesis of LUSC, such as ERK family, NFKB signaling pathway, Hedgehog signaling pathway, providing new clues for understanding the molecular mechanisms of LUSC pathogenesis. To verify the results of high-throughput screening, we used 56 paired independent tissues for clinical validation by pyrosequencing. Subsequently, another 343 tumor tissues from the Cancer Genome Atlas (TCGA) database were utilized for further validation. Then, we identified a panel of DNA methylation biomarkers (CLDN1, TP63, TBX5, TCF21, ADHFE1 and HNF1B) in LUSC. Furthermore, we performed receiver operating characteristics (ROC) analysis to assess the performance of biomarkers individually, suggesting that they could be suitable as potential diagnostic biomarkers for LUSC. Moreover, hierarchical clustering analysis of the DNA methylation data identified two tumor subgroups, one of which showed increased DNA methylation., Conclusions: Collectively, these results suggest that DNA methylation plays critical roles in lung tumorigenesis and may potentially be proposed as a diagnostic biomarker., Trial Registration: ChiCTR-RCC-12002830 Date of registration: 2012-12-17.

Multiple (selected) reaction monitoring (MRM/SRM) of peptides is a growing technology for target protein quantification because it is more robust, precise, accurate, high-throughput, and multiplex-capable than antibody-based techniques. The technique has been applied clinically to the large-scale quantification of multiple target proteins in different types of fluids. However, previous MRM-based studies have placed less focus on sample-preparation workflow and analytical performance in the precise quantification of proteins in saliva, a noninvasively sampled body fluid. In this study, we evaluated the analytical performance of a simple and robust multiple reaction monitoring (MRM)-based targeted proteomics approach incorporating liquid chromatography with mass spectrometry detection (LC-MRM/MS). This platform was used to quantitatively assess the biomarker potential of a group of 56 salivary proteins that have previously been associated with human cancers. To further enhance the development of this technology for assay of salivary samples, we optimized the workflow for salivary protein digestion and evaluated quantification performance, robustness and technical limitations in analyzing clinical samples. Using a clinically well-characterized cohort of two independent clinical sample sets (total n = 119), we quantitatively characterized these protein biomarker candidates in saliva specimens from controls and oral squamous cell carcinoma (OSCC) patients. The results clearly showed a significant elevation of most targeted proteins in saliva samples from OSCC patients compared with controls. Overall, this platform was capable of assaying the most highly multiplexed panel of salivary protein biomarkers, highlighting the clinical utility of MRM in oral cancer biomarker research., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Purpose: Inflammatory bowel disease may be associated with extraintestinal manifestations. We report a case of severe reactive epithelial atypia resembling ocular surface squamous neoplasia (OSSN) in a patient with ulcerative colitis (UC)., Methods: Case report., Results: A 32-year-old woman presented with sequential, progressive keratoconjunctival lesions in the left and right eyes, and both lesions were excised. Anterior segment optical coherence tomography demonstrated features similar to OSSN, whereas histological examination revealed severe reactive epithelial atypia mimicking severe dysplasia. Shortly after treatment of the second eye, the patient was diagnosed with UC. Residual disease improved dramatically in response to systemic corticosteroids., Conclusions: Severe ocular surface epithelial atypia resembling OSSN may be seen in association with UC.

Background: To analyze the efficacy of fluorescence visualization in early detection of oral early neoplastic processes when used by an inexperienced and an adept oral examiner., Methods: A dental student and an expert professional in oral diagnosis examined 15 randomly selected patients using conventional oral examination and fluorescence visualization searching for early signs of epithelial dysplasia and oral potentially malignant disorders. Patients detected with oral lesions in any of examinations were submitted to incisional biopsy for definitive diagnosis., Results: Taking histopathologic analysis as Gold Standard, sensitivity, specificity, positive and negative predictive values and accuracy of inexperienced examiner for detecting both epithelium dysplasia and oral potentially malignant disorders increased when using fluorescence visualization compared to conventional white light examination, matching the same values found for expert professional in oral diagnosis. Furthermore, it was possible to observe discrete increase in the efficacy of expert professional's examination when using fluorescence visualization., Conclusion: This study indicates fluorescence visualization is capable of improve inexperienced professionals' efficacy for early detecting oral lesions more prone to be dysplastic and oral potentially malignant disorders., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Raman spectroscopy and mapping are capable of probing the molecular changes due to oncogenesis. Here Raman maps of cervical tissues under different pathological conditions were studied. Multivariate analytical methods were utilized to reconstruct these Raman maps and were compared with Hematoxylin and Eosin stained histological images. The maps showed clear differences between the different regions of the tissue and there were spectral changes associated with neoplasia and malignancy. A semi-quantitative biochemical modeling was carried out to quantify these spectral changes and the relative contributions of the biochemicals. This method revealed gradual biochemical changes (nucleus to cytoplasm ratio, glycogen, collagen, lipids, protein and carotene) associated with the progression of cervical cancer. These biomolecules extracted for the disease prognosis would have greater significance for cervical cancer diagnosis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The diagnosis and treatment of rare genitourinary tumors is inherently challenging. The Rare Diseases Act of 2002 initially defined a rare disorder as one that affects fewer than 200,000 Americans. The lack of widely available clinical guidelines, limited research funding, and inaccessible clinical trials often lead to difficulty with treatment decisions to guide practitioners in rendering effective care for patients with rare genitourinary cancers. This article will discuss basic tenets of diagnosis and treatment as well as recent developments and clinical trials in rare non-urothelial bladder cancers and penile squamous cell cancers.

Introduction: Breast cancer is a commonly diagnosed cancer, in which most patients' metastases (about 75%) occurred in 5 years after the initial diagnosis, especially in 3 years. Recrudescence exceeding 20 years is rarely reported in the past several decades.Case information: A 68-year-old female patient presented with breast cancer in which 3 focal increased 18F-fluorodeoxyglucose uptake in the right supraclavicular lymph node, the mediastinum and sternum were found on positron emission tomography and computed tomography. Then we learned that the patient had suffered from breast cancer and been given a right-sided mastectomy 24 years ago. Histopathology from the mediastinum revealed metastatic, moderately differentiated breast adenomatous cell carcinoma., Conclusion: We report this late recurrence of breast cancer 24 years following mastectomy, suggesting that possible recurrence of this disease with a 24-year latency period should be taken into consideration.

Treatment of patients with oropharyngeal squamous cell carcinoma (OPSCC) requires interdisciplinary collaboration. Besides oncologic control, organ and function preservation are important priorities. One treatment option is primary concomitant chemoradiotherapy (CRT), particularly for locally advanced head and neck cancer. Another option is sequential CRT, where induction chemotherapy may be followed either by radiation alone or by CRT. An important aspect of these modalities is the development of functional sequelae with regards to swallowing as a direct consequence of radiogenic fibrosis, as well as tissue ctoxicity associated with cisplatin-based chemotherapy. Conventional open surgical approaches are being increasingly replaced by transoral surgical modalities with less treatment-related morbidity. As a further, equally important goal of appropriately indicated surgery, adjuvant (C)RT may be omitted or the dose significantly reduced. The advantages of primary surgery over primary CRT may be less obvious in cases still requiring adjuvant treatment, although not necessarily completely eliminated. For patients with human papillomavirus (HPV)-driven OPSCC, it is important to note that primary surgery may provide comparable or even increased survival benefit. To date, there is no evidence for a clear advantage of primary CRT over primary surgery in this group. In these cases, a de-escalated treatment package may be the preferred option. Here, the application of radioimmunotherapy as well as a reduced radiation dose may minimize long-term treatment-related morbidities.

Background: The advent of noninvasive urine-based markers as well as other novel modalities has yielded improved diagnostic accuracy. However, the new markers failed to reach higher sensitivity and specificity. We therefore evaluated the potential role of epithelial membrane antigen (EMA) and nuclear matrix protein 52 (NMP-52) singly and combined as noninvasive biomarkers for the detection of bladder cancer (BC)., Methods: A total of 160 individuals including 66 patients with BC, 54 patients with benign urologic disorders and 40 healthy volunteers were investigated. Urinary EMA at 130 kDa and NMP at 52 kDa were identified, purified and quantified by Western blot, electroelution and enzyme-linked immunosorbent assay (ELISA). The diagnostic performance of each biomarker and their combination were compared using area under receiver operating characteristic curves (AUC)., Results: Mean urinary EMA, 2.42 µg/mL, and NMP-52, 17.85 µg/mL, were significantly elevated in patients with BC compared to controls, 1.18 and 3.44 µg/mL, respectively (p&lt;0.0001). The combined use of these markers yielded values which were increased 4.4- and 13.7-fold in the benign and malignant disease groups, respectively, with respect to the normal group. The values of EMA and NMP-52 were significantly higher in patients with higher-grade tumors than those with lower-grade tumors (p&lt;0.0001). Moreover, this combination could predict all BC stages and grades with 0.91 AUC, 94% sensitivity and 80% specificity., Conclusions: EMA and NMP-52 in combination could be promising noninvasive biomarkers for BC detection.

Background: Recent studies have indicated that human papillomavirus is an etiologic agent for a subset of head and neck cancers associated with better prognosis, therefore, prompt confirmation of such etiology seems to be crucial for choosing the optimal therapeutic option. Standard HPV diagnosis is currently based on histopathological material. In the present study, the novel diagnostic method based on pharyngeal brush biopsy is proposed., Objectives: The aim of this study was to evaluate the usefulness of the Real-Time PCR-based (RT-PCR) test in detecting HPV-related cancer of the oropharynx using superficial scraps taken from the oropharyngeal region., Study Design: Ninety patients with head and neck squamous cell cancer were enrolled in the study. The presence of HPV DNA in pharyngeal superficial scrapes assessed by RT-PCR was compared to the HPV status in the tumor tissue samples determined by a combined RT-PCR/P16(INK4A) expression algorithm. Analytical sensitivity and specificity were calculated and the clinical outcome was analyzed in correlation to the HPV status., Results: HR-HPV DNA in pharyngeal swabs was revealed in 25 cases (28.4%) and simultaneously confirmed in all corresponding tissue samples. Sensitivity and specificity of the viral status assessment in the brush biopsies in respect to the RT-PCR/P16(INK4A) 20 were 100% and 96.2%, respectively. HR-HPV positive status was associated with an excellent clinical outcome and reduced hazard ratio of recurrence and disease-related death., Conclusions: The proposed novel method of HPV status assessment using RT-PCR and superficial scraps appeared to be highly sensitive, specific, and useful in predicting the clinical outcome., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Distinguishing anogenital squamous intraepithelial lesions from benign conditions and mimics may be problematic. Immunohistochemistry for surrogate markers of HPV infection, such as Ki-67, p16, and ProEx™ C, may aid the diagnosis in equivocal cases. The main diagnostic pitfall in the diagnosis of LSIL is the occurrence of "pseudokoilocytes" in benign squamous mucosa, which may lead to overdiagnosis. When interpreted correctly, Ki-67 is a sensitive and specific marker for dysplasia in mature squamous epithelium and is therefore useful for confirmation of LSIL and condyloma. A Ki-67 positive result is defined as the presence of a cluster of at least two strongly stained epithelial nuclei in the upper two-thirds of the epithelial thickness. With such a definition, there is almost complete concordance between consensus diagnosis of LSIL/condyloma confirmed by detection of HPV DNA and positive Ki-67. A related proliferation marker, ProEx™ C, has similar staining patterns and utility for the diagnosis of low grade dysplasia. The differential diagnosis of HSIL includes atypical immature squamous metaplasia and atrophy. A marker with high sensitivity and specificity for the detection of HSIL in cervical, vulvar, and anal mucosa is p16. A 2-tier scoring system is used to evaluate p16 staining. No staining or a discontinuous, patchy nuclear and cytoplasmic staining pattern is considered as a negative result. A positive result is defined as diffuse and strong staining of cells of the basal and parabasal layers of the squamous epithelium, with or without staining of superficial cell layers. New markers that are undergoing evaluation for their clinical utility include stathmin-1, phosphorylated S6, and SOX2. Confirmation of the diagnosis of dysplasia by HPV detection in tissue sections using HPV capsid protein immunohistochemistry, HPV DNA or HPV RNA in situ hybridization offers lower sensitivity as compared to immunohistochemistry for surrogate markers and therefore has more limited utility in this context., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background & Aims: Esophageal squamous cell neoplasia has a high mortality rate as a result of late detection. In high-risk regions such as China, screening is performed by Lugol's chromoendoscopy (LCE). LCE has low specificity, resulting in unnecessary tissue biopsy with a subsequent increase in procedure cost and risk. The purpose of this study was to evaluate the accuracy of a novel, low-cost, high-resolution microendoscope (HRME) as an adjunct to LCE., Methods: In this prospective trial, 147 consecutive high-risk patients were enrolled from 2 US and 2 Chinese tertiary centers. Three expert and 4 novice endoscopists performed white-light endoscopy followed by LCE and HRME. All optical images were compared with the gold standard of histopathology., Results: By using a per-biopsy analysis, the sensitivity of LCE vs LCE + HRME was 96% vs 91% (P = .0832), specificity was 48% vs 88% (P < .001), positive predictive value was 22% vs 45% (P < .0001), negative predictive value was 98% vs 98% (P = .3551), and overall accuracy was 57% vs 90% (P < .001), respectively. By using a per-patient analysis, the sensitivity of LCE vs LCE + HRME was 100% vs 95% (P = .16), specificity was 29% vs 79% (P < .001), positive predictive value was 32% vs 60%, 100% vs 98%, and accuracy was 47% vs 83% (P < .001). With the use of HRME, 136 biopsies (60%; 95% confidence interval, 53%-66%) could have been spared, and 55 patients (48%; 95% confidence interval, 38%-57%) could have been spared any biopsy., Conclusions: In this trial, HRME improved the accuracy of LCE for esophageal squamous cell neoplasia screening and surveillance. HRME may be a cost-effective optical biopsy adjunct to LCE, potentially reducing unnecessary biopsies and facilitating real-time decision making in globally underserved regions. ClinicalTrials.gov, NCT 01384708., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Morphologic evaluation of anal dysplasia remains problematic, especially in cases with limited biopsy samples or obscuring inflammation. Studies in cervical neoplasia have shown that human papillomavirus (HPV) L1 capsid production is highest in low-grade squamous intraepithelial lesions (LSILs) and progressively decreases in high-grade squamous intraepithelial lesions (HSILs). The combined utility of HPV L1 and p16 expression in assessing anal squamous intraepithelial lesions (SILs) has never been analyzed and forms the basis of this study., Methods: In total, 145 anal lesions were reviewed and immunohistochemically stained for HPV L1 and p16. p16 expression was recorded as negative, patchy/focal, or diffuse. For analytical purposes, condylomas were evaluated separately from rest of the LSILs., Results: There were 34 (23%) condylomas, 64 (44%) LSILs, and 47 (32%) HSILs. HPV L1 was significantly associated with condylomas (68%) and LSILs (52%) compared with HSILs (9%; P < .0001). Diffuse p16 staining was present only in HSILs (P < .0001), whereas a patchy/focal p16 staining pattern was observed in both LSILs and condylomas., Conclusions: HPV L1 and diffuse p16 expression is mutually exclusive in most anal SILs and helps separate LSIL and HSIL cases. Application of both HPV L1 and p16 can not only facilitate accurate grading but also contribute to risk assessment in anal neoplasia., (Copyright© by the American Society for Clinical Pathology.)

Objectives: Cervical screening guidelines now recommend repeat cotesting of patients aged 30 years and older having a human papillomavirus (HPV)-negative low-grade squamous intraepithelial lesion (LSIL) in 1 year as preferred management. Only limited follow-up data on patients with HPV-negative LSILs are available from routine US clinical practice settings., Methods: In total, 680 patients with Hybrid Capture 2 (Qiagen, Hinden, Germany) high-risk HPV-negative LSIL ThinPrep (Hologic, Marlborough, MA) results were identified. Patients' ages and histopathologic, cytologic, and HPV follow-up results were identified., Results: Among 680 patients with HPV-negative LSILs, 468 had follow-up within 1 year. During the study period, 14 (3.0%) of 468 had follow-up high-grade squamous intraepithelial lesion (HSIL) and 184 (39.3%) LSIL findings. No diagnoses of cervical carcinoma were documented. There were no significant follow-up differences between age groups. Of the 321 patients who had follow-up HPV testing, 271 (84.4%) had negative and 50 (15.6%) had positive HPV results., Conclusions: This is the largest study documenting follow-up results for patients with HPV-negative LSIL results based on prevalent US FDA-approved co-testing methods from one collection vial. These data document that risk for follow-up HSILs in these patients is low and also that no cervical cancers were diagnosed. These findings support recent recommendations for repeat co-testing after 1 year as an appropriate option for patients with HPV-negative LSIL results., (Copyright© by the American Society for Clinical Pathology.)

Tumors of the Ocular Surface clinically manifest with a very wide spectrum and include several forms of epithelial, stromal, caruncular, and secondary tumors. As a group, these tumors are seen commonly in the clinical practice of a comprehensive ophthalmologist, cornea specialist, and an ocular oncologist. This review is aimed to discuss the common tumors of the ocular surface and emphasize on their clinical diagnosis and appropriate management.

Purpose: Systemic voriconazole treatment was reported to cause photosensitivity and related cutaneous malignancies. The aim of this report is to demonstrate a graft-related Candida endophthalmitis case that developed ocular surface dysplastic changes after receiving topical 1% voriconazole treatment., Methods: Full ocular examination, photography, and in vivo confocal microscopy examination (Rostock Cornea Module/HRT II, Heidelberg, Germany) were performed., Results: A 73-year-old male with graft-related Candida endophthalmitis that was on topical 1% voriconazole for 4 months developed a whitish gelatinous lesion on the cornea originating from the nasal limbus. In vivo confocal microscopy examination revealed mild dysplastic changes in the cornea epithelium., Conclusion: Topical voriconazole might trigger neoplastic changes on the ocular surface as reported with systemic use in other sun-exposed parts of the body. Further studies are needed to relate topical use of voriconazole with ocular surface dysplasia.

Purpose: To determine the accuracy of visual inspection with acetic acid (VIA) in detecting high-grade cervical intraepithelial neoplasia (CIN) in pre- and post-menopausal women with atypical squamous cells of undetermined significance (ASC-US) and low grade squamous intraepithelial lesion (LSIL) Papanicolaou (Pap) smears., Materials and Methods: Two hundred women (150 pre-menopausal and 50 post-menopausal) with ASC- US and LSIL cytology who attended the colposcopy clinic, Thammasat University Hospital, between March 2013 and August 2014 were included. All women underwent VIA testing and colposcopy by gynecologic oncologists. Diagnostic values of VIA testing including sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for detecting high-grade CIN were determined using the histopathology obtained from colposcopic-directed biopsy as a gold standard., Results: VIA testing was positive in 54/150 (36%) pre-menopausal women and 5/50 (10%) post-menopausal women. Out of 54 pre-menopausal women with positive VIA testing, 15 (27.8%) had high-grade CIN and 39 (72.2%) had either CIN 1 or insignificant pathology. Ten (10.4%), 43 (44.8%) and 43 (44.8%) out of the remaining 96 pre-menopausal women with negative VIA testing had high- grade CIN, CIN 1 and insignificant pathology, respectively. Out of 5 post-menopausal women with positive VIA testing, there were 4 (80%) women with high-grade CIN, and 1 (20%) women with insignificant pathology. Out of 45 VIA-negative post-menopausal women, 42 (93.3%) women had CIN 1 and insignificant pathology, and 3 (6.7%) had high-grade CIN. Sensitivity, specificity, PPV and NPV of the VIA testing were 59.4%, 76.2%, 32.2% and 90.8%, respectively (60%, 68.8%, 27.8% and 89.6% in pre-menopausal women and 57.1%, 97.7%, 80% and 93.3% in post-menopausal women)., Conclusions: VIA testing may be used as a screening tool for detecting high-grade CIN in women with minor cervical cytological abnormalities in a low-resource setting in order to lower the rate of colposcopy referral.

Objectives: We aimed to analyze the false-negative (FN) liquid-based cytology diagnoses from the 5 years preceding all the 2013 histologically proven cervical intraepithelial neoplasia (CIN)2-3 and squamous cell carcinoma (SCC) and to propose corrective actions., Study Design: This was a retrospective, blinded rescreening ('5-year look-back') of liquid-based cytology samples with negative categorizations, which occurred before histologically proven CIN2-3 and SCC., Results: The FN rate was 7.8% (21/256 samples preceding CIN2-3 and 0/13 samples preceding SCC). Slides confirmed as 'negative', 'interpretation error' and 'screening error', respectively, were 3.3% (9/269), 2.6% (7/269) and 1.9% (5/269). In 9/12 cases, error was associated with small atypical cells. In 7/12 cases, these diagnostic cells were less than 5/10 HPF. Inflammation and prominent reactive changes were present in 5/12 cases. Five patients had a positive clinical history. In 2 cases, there were multiple-cell-layer artifacts. Dense groups of small blue atypical cells were missed in 2 other cases. Dotting was imprecise in 6/7 samples., Conclusion: Considering the above results, we specifically reoriented our continuous education activities, focusing rapid rescreening on scanty, isolated, small, atypical cells and dense cell groups. Prior to final diagnosis, pathologists should systematically review the entire surface of the dotted slides, with special attention being devoted to slides with multiple cell layers and tridimensional groups., (© 2015 S. Karger AG, Basel.)

Imaging head and neck cancer is crucial for treatment decisions and follow-up of patients. The choice of the appropriate imaging modality for staging and re-staging head and neck cancer can be troublesome. This review highlights the important questions of imaging from a clinician's perspective. The recommendations focus on mucosal squamous cell carcinoma of the head and neck since this is the most common one.

Aim: To analyze the cervical screening history in women with cervical cancer and their outcome., Design: All women diagnosed with cervical cancer between January 2009 and December 2010 in the South Sweden region were included in the audit., Materials and Methods: Cervical cancer was registered in 165 women in 2009 and 2010. Their screening history was analyzed, and was classified as normal or imperfect. The method of discovering the cancer was either by symptoms or by screening. The main outcome measured was overall survival in cervical cancer related to cervical screening history., Results: Women above 65 years of age were more frequently diagnosed with advanced-stage disease (The International Federation of Gynecology and Obstetrics II-IV) (n=36 out of 43; 84%) compared to women below 65 years of age (n=35 out of 122; 29%) (p<0.001). All patients diagnosed by the cervical screening program were still alive (30/30) at the median follow-up time (36 months), showing better overall survival compared to women below screening age in whom cancer was discovered due to symptoms (68/98; p<0.001). Cox proportional hazards model showed that women beyond screening age (>65 years old) with normal screening history had a worse prognosis, with a hazard ratio of 4.8 (95% confidence interval=1.9-12.1, p=0.001), and women (>65 years old) who had not followed the screening program had a hazard ratio of 5.9 (95% confidence interval I 2.4-14.6, p<0.001), compared to women under 65 years old who had followed the screening program., Conclusion: Cervical cancer in women above the age of 65 years is discovered at advanced stages of the disease and their prognosis is poor., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: It is known that lung cancer incidence and mortality rate are higher in African Americans (AA) than whites. In Eastern North Carolina, there is a higher percentage of AA population than the national average (30.2% vs. 12.4%) and a higher incidence of lung cancer in this region. We investigated demography and survival of lung cancer patients diagnosed and treated in a single institution., Methods: The study includes 2351 patients diagnosed with lung cancer between 2001 and 2010 at East Carolina University. AA and whites were compared by age, sex, race, stage, histology, smoking history and insurance information using chi-square analyses. Patient survival was modeled using Cox proportional hazards regression (SAS version 9.2)., Results: The distribution of lung cancer was 70% in whites and 30% in AA. The proportion of AA and whites differed significantly for age, sex, histology, stage, and insurance. Patients aged > 70 (p < 0.0001) and 51-70 (p = 0.0064) died sooner than those ≤ 50 years old. Compared with squamous cell, SCLC had inferior survival (HR = 2.0, 95% CI = 1.7-2.3). Privately insured patients survived longer than those with medicare (p < 0.0001), medicaid (p = 0.0009), or no insurance (p < 0.0001). The survival disadvantage for medicaid (p = 0.0076) and no insurance (p = 0.0033) persisted on multivariable analysis. Race was not a significant predictor of survival on multivariable analysis (p = 0.66)., Conclusion: This is one of the largest lung cancer patient populations from a single institution showing demographic differences between the two races with similar survival outcome. Age, histology and type of insurance were strong predictors of survival outcome. Older age, small cell histology and medicaid and no insurance had significantly shorter overall survival., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

This study assessed the utility and limitations of anal cytology as a screening method for women infected with human papilloma virus (HPV) in the lower genital tract. Furthermore, this study aimed to establish risk factors for pathological anal cytology/biopsy findings, the prevalence of anatomopathological lesions associated with positive anal brushings, and the frequency of concomitant lesions of the lower genital tract. A cross-sectional, retrospective, descriptive study in 207 women with HPV-associated lesions of the lower genital tract and 25 women with immunosuppression was carried out. Anal cytology, high resolution anoscopy, and biopsy of suspicious lesions were performed. In total, 232 anal brushings were performed: 184 (79.3%) were negative, 24 (10.34%) showed atypical squamous cells of undeterminated significance, 18 (7.7%) showed low-grade squamous intraepithelial lesions, and 6 (2.6%) showed high-grade squamous intraepithelial lesion. Cytohistological correlation was obtained for 70 cases. The sensitivity of anal cytology in detecting intraepithelial lesions was 70%, whereas the specificity was 93%. The sensitivity of the method for detecting high-grade lesions (84%) was higher, than that for detecting low-grade lesions (66%). The most frequently associated pathology was vulvar lesion. It is important to perform anal brushings in women who have had lower genital tract biopsies for HPV-associated lesions due to the high prevalence of anal lesions in such patients. Anal cytology is useful for detecting high-grade lesions but the sensitivity for detecting low-grade lesions is low. It is of the utmost importance to perform high-resolution anoscopy and biopsy in women with suspicious lesions in order to confirm the pathology., (Copyright © 2013 Wiley Periodicals, Inc.)

Objectives: Endocervical curettage (ECC) has been used with colposcopy-directed biopsy to increase diagnostic sensitivity for detecting cellular abnormality. Our objective was to determine if routine ECC was cost-effective compared with colposcopy alone in women with atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion cervical cytology, who are older and younger than 50 years., Materials and Methods: We generated a cost-effectiveness model using outcomes from cervical screening including repeat Pap smears, colposcopy, and loop electrosurgical excision procedure. Cervical cancer costs, survival, as well as incidence and complications after loop electrosurgical excision procedure (preterm birth, cervical stenosis, dysmenorrhea, amenorrhea, and infertility) were modeled. Cost and probability values were obtained from published literature and Medicare databases. Direct medical costs were analyzed in 2011 US dollars. Effectiveness outcomes were cervical cancer deaths and incident cases of cancer prevented. Model robustness was evaluated using probabilistic sensitivity analysis., Results: For women older than 50 years, routine ECC is the dominant strategy (less expensive and more effective at reducing cervical cancer deaths/incidence). For women younger than 50 years, routine ECC costs $96,737 more per cervical cancer death prevented. Cost per incident cancer case prevented ranged from $21,894 (local spread or greater) to $235,873 (distal spread). Sensitivity analysis confirmed these conclusions. In women older than 50 years, routine ECC was always the most likely cost-effective choice. In women younger than 50, routine ECC was most likely cost-effective for all willingness-to-pay thresholds greater than $80,000 to prevent 1 cancer death., Conclusions: In women older than 50 years, routine ECC is favored over colposcopy alone because this strategy is cost saving and reduces the number of cancer deaths and incident cancer cases. For women younger than 50 years, cost-effectiveness is dependent on willingness to pay to prevent 1 cancer death but still seems to be cost-effective.

Background: The ability to detect and treat pre-malignant anal lesions suggests screening may prevent anal cancer. The incidence of anal cancer in men who have sex with men (MSM) living with HIV exceeds that of cervical cancer before screening was introduced., Methods: High-resolution anoscopy (HRA) with intervention for high-grade squamous intraepithelial lesions (HSILs) was offered to asymptomatic HIV-positive MSM. Patients with HSILs were treated and follow-up HRA performed after 6 months, whilst patients with low-grade squamous intraepithelial lesions had a repeat HRA after 12 months., Results: Three hundred and sixty-eight asymptomatic MSM had a total of 1497 HRAs during a median follow-up of 4.2 years (maximum 13 years). At first HRA, 36% had normal appearances, 16% had no dysplasia, 15% anal intraepithelial neoplasia (AIN)-1, 19% AIN-2 and 13% AIN-3. During follow-up, five patients (1.4%) developed invasive anal cancer (incidence 2.7 per 1000 person-years). The 5-year cancer rate for the 368 patients was 0.3% [95% confidence interval (CI) 0-0.6%]. Progression to cancer was associated with higher age (P=0.049) and AIN-3 (P=0.024). Ninety patients had AIN-3 present at least at one HRA. The cumulative risk of cancer from first AIN-3 diagnosis was 3.2% (95% CI 0-7.8%) at 5 years. One hundred and seventy-one patients had HSILs (AIN-2 or 3) present at least once. The cumulative risk of cancer from first HSIL diagnosis was 0.6% (95% CI 0-1.8%) at 5 years., Conclusion: AIN-3 is a significant risk factor for subsequent anal cancer, although the tumours detected in screened patients were small localized, and generally the outcomes were favourable.

Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) represents an emerging disease that differs from HPV-negative OPSCC in natural history and prognosis. Contrast-enhanced PET/CT is essential to accurately stage the primary site when there are smaller tumors; neck nodal metastases, which tend to have a more cystic component; and distant metastases that manifest in unusual sites (disseminating phenotype) such as bones and other solid organs, including brain. Metastases tend to appear later in the disease course during follow-up for HPV-positive OPSCC than for HPV-negative OPSCC. Because HPV-positive OPSCC patients have a better clinical outcome, there is a need for treatment deintensification to spare the patient from treatment-related toxicities. (18)F-FDG PET/CT would play a role in monitoring patients with deintensified treatments to ensure that no adverse outcome is introduced. The better prognosis and outcome of HPV-positive OPSCC patients would warrant imaging follow-up that is less intense but continues longer because of the manifestation of distant metastases later in the disease course and at unusual sites. All these clinical paradigms facilitate a definite role for PET/CT imaging in the management of HPV-positive OPSCC.

Objective: We aimed to investigate the diagnostic accuracy of contact endoscopy in evaluating oral and oropharyngeal mucosal lesions., Methods: Between January 2010 and December 2011, 34 patients with lesions of the oral and oropharyngeal mucosa were enrolled in the study. Comparison between initial contact endoscopy results and 'gold standard' tissue biopsy was undertaken., Results: Nine patients had histologically confirmed squamous cell carcinoma, 2 had carcinoma in situ, 3 had dysplastic lesions and 20 patients had various benign lesions. Contact endoscopy demonstrated sensitivity and specificity of 89 and 100 per cent respectively in the evaluation of malignant lesions. Benign lesions were correctly categorised in 50 per cent of cases (10/20). The video images from contact endoscopy could not be interpreted in six cases., Conclusions: Contact endoscopy demonstrates high sensitivity and specificity in the imaging of malignant lesions with reduced reliability in the evaluation of benign lesions. Significant shortcomings also exist in the design of current technology that we believe represent a significant barrier to the reliable collection of useful video data.

Squamoid cyst of pancreatic ducts (SCPD) is a benign pancreatic cyst often misdiagnosed preoperatively as a mucinous cyst. The histopathologic features are well described but the cytology and quantitative fluid chemistry profiles from fine-needle aspiration have not been reported. This case series discusses the cytology and cyst fluid chemistry profiles in 2 SCPDs and describes morphologic and immunohistochemical features that have not been previously reported. Fine-needle aspiration of 2 SCPDs yielded acellular debris lacking mucin or exfoliated squamous cells. Two cysts had elevated fluid carcinoembryonic antigen (CEA) and amylase levels. Positive immunohistochemical staining included cytokeratin 5/6, pCEA, synaptophysin, and chromogranin (both focal). MUC2 and MUC5AC showed negativity in all cases, while PAX8 showed negative nuclear staining. An accurate preoperative diagnosis of SCPD is potentially difficult in the setting of elevated fluid CEA levels, and acellular cytology as a mucinous cyst cannot be confidently excluded.

Background: To evaluate the performance of Siriraj liquid-based cytology (LBC) for cervical neoplasia screening after increasing use of this technology., Materials and Methods: Cytological reports of 103,057 Siriraj-LBC specimens obtained in 2007-2009 were compared with those of 23,676 specimens obtained in 2006., Results: Comparing with the year 2006, the 2007-2009 patients were slightly older (43.4 ± 12.yr vs 42.7 ± 12.2 yr, p <0.001), and their specimens had much lower proportion of unsatisfactory slides (OR=0.06, 95%CI 0.04-0.09) with comparable detection rates (3.96% vs 3.70%, p=0.052) but different proportions of various cytological abnormalities (p<0.001). The 2007-2009 Siriraj-LBC had a negative predictive value (NPV) for cervical intraepithelial neoplasia 2+ (CIN2+) of 97.6% and an overall positive predictive value (PPV) of 43.9%. The PPV for CIN2+ varied with types of abnormal cytology, from 13.7% to 93.8% in atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cells cannot exclude HSIL (ASC-H), high-grade squamous intraepithelial lesion (HSIL), atypical glandular cells (AGC), to squamous cell carcinoma (SCC), respectively. The PPVs for CIN2+ in ASCUS and LSIL were comparable, but the PPV for CIN1 was higher for LSIL than for ASCUS (41.63% vs 16.32%)., Conclusions: Siriraj-LBC has demonstrated a stable detection rate and NPV for CIN2+ of >95% since the first year of use. The comparable PPVs for CIN2+ of ASCUS and LSIL suggests that these two conditions may undergo similar management; other cytological abnormalities need immediate evaluation.

Mixed squamous cell and glandular papilloma (mixed papilloma) of the lung is exceedingly rare, with only 18 cases reported in the literature. Herein, we report a case of mixed papilloma and its associated immunohistochemical and positron emission tomographic (PET) findings. A 60-year-old Japanese male with a smoking history of 40 pack-years presented with a smooth-edged pulmonary lesion in the right S5 segment on computed tomography (CT). F18-fluorodeoxyglucose (FDG) PET revealed abnormally increased FDG uptake in the mass (maximum standardized uptake value, 3.4). We performed right middle lobectomy and combined partial resection of the S8 segment. The 1.8-cm tumor that filled the enlarged lumen of the B5b was histologically diagnosed as mixed papilloma. Immunohistochemically, the pseudostratified columnar epithelium was positive for cytokeratin (CK) 5/6 and CK7. p40 positivity was predominant in the basal and squamous cells. Thyroid transcription factor-1 and carcinoembryonic antigen were negative on immunostaining. Malignant features were absent. The postoperative course has been uneventful for 3 months after the surgery. No recurrences were reported after the surgical resection of the mixed papilloma. Therefore, surgical resection may be considered the mainstay of curative treatment.