Search

Pancreatic carcinoma is a relatively common malignant tumor with increasing incidence and mortality. The tumor is usually diagnosed at an advanced stage and generally has a poor prognosis, with only 5% of patients surviving 5 years from the time of diagnosis. The stage of the disease at the time of diagnosis is a crucial factor for the prognosis; 25% of patients with localized tumors survive 3 years from diagnosis, compared to only 1% of those with generalized tumors. Radical surgical removal of the tumor (partial or total pancreatectomy) is a key factor in improving survival. Therefore, the topic is highly relevant to surgeons. Statistics on pancreatic carcinoma mainly focus on ductal adenocarcinoma, which is the most common and least favorable malignant tumor of the pancreas. This review focuses on ductal adenocarcinoma, its variants, and precancerous lesions. The article summarizes information from the latest WHO classification of 2019, which was released 11 years after the previous edition. Compared to the previous version, this new WHO classification introduced rather minor changes in the field of ductal adenocarcinoma. The delineation of rare variants of ductal adenocarcinoma is justified based on genetic and morphological similarities and clinical relevance, as individual subtypes significantly differ in prognosis. The article also includes a description of macroscopic and microscopic precursors of ductal adenocarcinoma and their definitions. Genetic and immunohistochemical differential diagnostic aspects are briefly discussed, as these are more relevant to pathologists than to surgeons.

Aims: This study investigated the relationship between the differentiation of tumour cells into crypts, which is determined by cell differentiation into Paneth and neuroendocrine cells, and tumour infiltration in gastric dysplasia., Methods and Results: The lesions were endoscopically biopsied low-grade dysplasia (LGD), endoscopically resected high-grade dysplasia (HGD) or cancer with submucosal invasion. LGD (n = 32) displayed crypt differentiation across the entire width of the tumour in all cases. Crypt differentiation was identified as a characteristic of tumours with low biological malignancy. HGD (n = 40) included tumours with a mixture of areas with and without crypt differentiation (n = 25) and tumours with crypt differentiation throughout the entire width (n = 15). Of the cancers with submucosal invasion (n = 30), the morphological progression of the HGD area with crypt differentiation, the HGD area without crypt differentiation and invasive cancer without crypt differentiation was confirmed for 23 samples. In two lesions, invasive cancer without crypt differentiation developed from HGD without crypt differentiation throughout the tumour width. In five samples, well-differentiated tubular adenocarcinoma with crypt differentiation developed from HGD with crypt differentiation and invaded with lamina propria-like stroma., Conclusions: Loss of crypt differentiation could be an objective indicator of infiltration in the progression of HGD to invasive cancer. The invasive potential of dysplasia depends upon the presence or absence of crypt differentiation., (© 2021 John Wiley & Sons Ltd.)

Background and Aim: Recently, the BLI Adenoma Serrated International Classification (BASIC) system was developed by European experts to differentiate colorectal polyps. Our aim was to validate the BASIC classification system among the US-based endoscopy experts., Methods: Participants utilized a web-based interactive learning system where the group was asked to characterize polyps using the BASIC criteria: polyp surface (presence of mucus, regular/irregular and [pseudo]depressed), pit appearance (featureless, round/non-round with/without dark spots; homogeneous/heterogeneous distribution with/without focal loss), and vessels (present/absent, lacy, peri-cryptal, irregular). The final testing consisted of reviewing BLI images/videos to determine whether the criteria accurately predicted the histology results. Confidence in adenoma identification (rated "1" to "5") and agreement in polyp (adenoma vs non-adenoma) identification and characterization per BASIC criteria were derived. Strength of interobserver agreement with kappa (k) value was reported for adenoma identification., Results: Ten endoscopy experts from the United States identified conventional adenoma (vs non-adenoma) with 94.4% accuracy, 95.0% sensitivity, 93.8% specificity, 93.8% positive predictive value, and 94.9% negative predictive value using BASIC criteria. Overall strength of interobserver agreement was high: kappa 0.89 (0.82-0.96). Agreement for the individual criteria was as follows: surface mucus (93.8%), regularity (65.6%), type of pit (40.6%), pit visibility (66.9%), pit distribution (57%), vessel visibility (73%), and being lacy (46%) and peri-cryptal (61%). The confidence in diagnosis was rated at high ≥4 in 67% of the cases., Conclusions: A group of US-based endoscopy experts have validated a simple and easily reproducible BLI classification system to characterize colorectal polyps with >90% accuracy and a high level of interobserver agreement., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Contemporary catalogues of cancer driver genes rely primarily on high mutation rates as evidence for gene selection in tumors. Here, we present The Functional Alteration Bias Recovery In Coding-regions Cancer Portal, a comprehensive catalogue of gene selection in cancer based purely on the biochemical functional effects of mutations at the protein level. Gene selection in the portal is quantified by combining genomics data with rich proteomic annotations. Genes are ranked according to the strength of evidence for selection in tumor, based on rigorous and robust statistics. The portal covers the entire human coding genome (∼18,000 protein-coding genes) across 33 cancer types and pan-cancer. It includes a selected set of cross-references to the most relevant resources providing genomics, proteomics, and cancer-related information. We showcase the portal with known and overlooked cancer genes, demonstrating the utility of the portal via its simple visual interface, which allows users to pivot between gene-centric and cancer type views. The portal is available at fabric-cancer.huji.ac.il. SIGNIFICANCE: A new cancer portal quantifies and presents gene selection in tumor over the entire human coding genome across 33 cancer types and pan-cancer., (©2020 American Association for Cancer Research.)

Background: Approximately 60% of colorectal cancer (CRC) precursor lesions are the genuinely-dysplastic conventional adenomas (cADNs). The others include hyperplastic polyps (HPs), sessile serrated lesions (SSL), and traditional serrated adenomas (TSAs), subtypes of a class of lesions collectively referred to as "serrated." Endoscopic and histologic differentiation between cADNs and serrated lesions, and between serrated lesion subtypes can be difficult., Methods: We used in situ hybridization to verify the expression patterns in CRC precursors of 21 RNA molecules that appear to be promising differentiation markers on the basis of previous RNA sequencing studies., Results: SSLs could be clearly differentiated from cADNs by the expression patterns of 9 of the 12 RNAs tested for this purpose (VSIG1, ANXA10, ACHE, SEMG1, AQP5, LINC00520, ZIC5/2, FOXD1, NKD1). Expression patterns of all 9 in HPs were similar to those in SSLs. Nine putatively HP-specific RNAs were also investigated, but none could be confirmed as such: most (e.g., HOXD13 and HOXB13), proved instead to be markers of the normal mucosa in the distal colon and rectum, where most HPs arise. TSAs displayed mixed staining patterns reflecting the presence of serrated and dysplastic glands in the same lesion., Conclusions: Using a robust in situ hybridization protocol, we identified promising tissue-staining markers that, if validated in larger series of lesions, could facilitate more precise histologic classification of CRC precursors and, consequently, more tailored clinical follow-up of their carriers. Our findings should also fuel functional studies on the pathogenic significance of specific gene expression alterations in the initiation and evolution of CRC precursor subtypes.

Benign normal (NL), premalignant (endometrial intraepithelial neoplasia, EIN) and malignant (cancer, EMCA) endometria must be precisely distinguished for optimal management. EIN was objectively defined previously as a regression model incorporating manually traced histologic variables to predict clonal growth and cancer outcomes. Results from this early computational study were used to revise subjective endometrial precancer diagnostic criteria currently in use. We here use automated feature segmentation and updated machine learning algorithms to develop a new classification algorithm. Endometrial tissue from 148 patients was randomly separated into 72-patient training and 76-patient validation cohorts encompassing all 3 diagnostic classes. We applied image analysis software to keratin stained endometrial tissues to automatically segment whole-slide digital images into epithelium, cells, and nuclei and extract corresponding variables. A total of 1413 variables were culled to 75 based on random forest classification performance in a 3-group (NL, EIN, EMCA) model. This algorithm correctly classifies cases with 3-class error rates of 0.04 (training set) and 0.058 (validation set); and 2-class (NL vs. EIN+EMCA) error rate of 0.016 (training set) and 0 (validation set). The 4 most heavily weighted variables are surrogates of those previously identified in manual-segmentation machine learning studies (stromal and epithelial area percentages, and normalized epithelial surface lengths). Lesser weighted predictors include gland and lumen axis lengths and ratios, and individual cell measures. Automated image analysis and random forest classification algorithms can classify normal, premalignant, and malignant endometrial tissues. Highest predictive variables overlap with those discovered independently in early models based on manual segmentation.

Background: In the current version of The Bethesda System (TBS) for thyroid cytopathology, the atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) category has an estimated risk of malignancy of 10% to 30%. Diagnostic criteria include presence of nuclear atypia, suggestive of papillary thyroid carcinoma (PTC), as well as other types of atypia, which can be seen with non-malignant entities. Aim of this study was to investigate differential outcomes of AUS/FLUS, based on specific morphologic criteria, and assess their respective malignancy risks., Methods: From a total of 1233 patients undergoing thyroid FNAs between 2010 and 2014 at the University of Washington, 119 had AUS/FLUS without nuclear atypia, and 64 with nuclear atypia. Outcomes for patients with and without nuclear atypia (with the exception of 24 patients lost to follow-up) were evaluated and results were compared., Results: 16/57 (28.1%) patients with AUS/FLUS and nuclear atypia subsequently had carcinomas on thyroidectomy, statistically higher than the 8/102 patients (7.8%, P = .001) without nuclear atypia. When comparing only patients who underwent surgery (n = 63), again those with AUS/FLUS and nuclear atypia had statistically higher rates of carcinoma (16/31, 51.6%), compared to those without (8/32, 25%; P = .0394). Overall, 24/159 (15.1%) of patients with AUS/FLUS had carcinoma on subsequent histology., Conclusion: Malignancy rates for AUS/FLUS were in line with TBS estimated risks. However, our data demonstrate that the presence or absence of nuclear atypia is associated with different malignancy rates, suggesting the possibility that the AUS/FLUS category may best be split into two subcategories with different implied risks of malignancy., (© 2020 Wiley Periodicals, Inc.)

During the last 60 years numerous significant attempts have been made to achieve a widely acceptable terminology and histological grading for laryngeal squamous intraepithelial lesions. While dysplasia was included in the pathology of the uterine cervix already in 1953, the term dysplasia was accepted in laryngeal pathology first after the Toronto Centennial Conference on Laryngeal Cancer in 1974. In 1963 Kleinsasser proposed a three-tier classification, and in 1971 Kambic and Lenart proposed a four-tier classification. Since then, four editions of the World Health Organisation (WHO) classification have been proposed (1978, 1991, 2005 and 2017). Several terms such as squamous intraepithelial neoplasia (SIN) and laryngeal intraepithelial neoplasia (LIN) are now being abandoned and replaced by squamous intraepithelial lesions (SIL). The essential change between the 2005 and 2017 WHO classifications is the attempt to induce a simplification from a four- to a two-tier system. The current WHO classification (2017) thus recommends the use of a two-tier system with reasonably clear histopathological criteria for the two groups: low-grade and high-grade dysplasia. Problems with interobserver variability apart, subjectivities and uncertainties remain, but to a lesser degree. Ongoing and additional molecular studies may help to clarify underlying events that will increase our understanding and possibly can facilitate our attempts to obtain an even better classification. The classification needs to be easier for the general pathologist to perform and easier for the clinician to interpret. These two objectives are equally important to provide each patient the best personalised treatment available for squamous intraepithelial lesions.

Clinically meaningful molecular subtypes for classification of breast cancers have been established, however, initiation and progression of these subtypes remain poorly understood. The recent development of desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) facilitates the convergence of analytical chemistry and traditional pathology, allowing chemical profiling with minimal tissue pretreatment in frozen samples. Here, we characterized the chemical composition of molecular subtypes of breast cancer with DESI-MSI. Regions of interest were identified, including invasive breast cancer (IBC), ductal carcinoma in situ (DCIS), and adjacent benign tissue (ABT), and metabolomic profiles at 200 μm elaborated using Biomap software and the Lasso method. Top ions identified in IBC regions included polyunsaturated fatty acids, deprotonated glycerophospholipids, and sphingolipids. Highly saturated lipids, as well as antioxidant molecules [taurine (m/z 124.0068), uric acid (m/z 167.0210), ascorbic acid (m/z 175.0241), and glutathione (m/z 306.0765)], were able to distinguish IBC from ABT. Moreover, luminal B and triple-negative subtypes showed more complex lipid profiles compared with luminal A and HER2 subtypes. DCIS and IBC were distinguished on the basis of cell signaling and apoptosis-related ions [fatty acids (341.2100 and 382.3736 m/z) and glycerophospholipids (PE (P-16:0/22:6, m/z 746.5099, and PS (38:3), m/z 812.5440)]. In summary, DESI-MSI identified distinct lipid composition between DCIS and IBC and across molecular subtypes of breast cancer, with potential implications for breast cancer pathogenesis. SIGNIFICANCE: These findings present the first in situ metabolomic findings of the four molecular subtypes of breast cancer, DCIS, and normal tissue, and add to the understanding of their pathogenesis., (©2020 American Association for Cancer Research.)

Background and Aims: Pancreatic cysts are increasingly diagnosed, mainly during abdominal imaging performed for other reasons. Between pancreatic cystic neoplasm, intraductal papillary mucinous neoplasms are the most common pre-malignant entities. Intraductal papillary mucinous neoplasms involving side branches overall harbor a low risk of malignancy, and in the recent past, a progressively more conservative approach has been consolidated. Purpose of this report is to summarize the evidence supporting the current practice for the management of branch duct intraductal papillary mucinous neoplasm and to offer a useful practical guide from first observation to post-operative follow-up., Materials and Methods: Review of the most important scientific literature on intraductal papillary mucinous neoplasms was made. In this review article, we also report the experience of a high volume center in managing Pancreatic cystic neoplasms., Results: The correct management during surveillance still is a matter of debate, since many guidelines have been published suggesting different clinical approaches. Recently, follow-up discontinuation has also been proposed in selected cases., Conclusion: Despite significant improvements made by the increase of evidence, selecting surgical candidates because of an increased risk of malignant progression remains an unsolved issue and a hot topic for pancreatologists.

Background: Basaloid salivary gland neoplasms (BSNs), which include benign primary tumors and primary or metastatic malignancies, show overlapping morphology in fine-needle aspiration (FNA). The Milan system recommends assigning a grade (low or high) to malignant salivary neoplasms because of the impact on surgical planning. This study investigated cytomorphologic features of BSNs on FNA that would help to favor a high-grade malignancy over a low-grade malignancy or a benign tumor., Methods: Two pathologists performed a double-blinded cytologic evaluation of FNA cases diagnosed as BSNs that had corresponding surgical resections. The diagnosis made with the Milan system was correlated with the final surgical diagnosis and grade. Cytologic sensitivity, specificity, and predictive values were calculated., Results: There were 132 BSN FNA cases; cytology slides were available for 77 of 87 patients who had undergone resection. The risk of malignancy for the benign neoplasm (BN), salivary gland neoplasm of uncertain malignant potential (SUMP), suspicious for malignancy (SFM), and malignant categories were 13.6%, 22%, 100%, and 100%, respectively. The sensitivity of the malignant/SFM category was 51.7%; another 37.9% of confirmed malignancies were diagnosed as SUMP. The specificity of the BN category was 86%. Favoring a high-grade malignancy on FNA had 100% accuracy (5 of 5). Favoring a low-grade malignancy on FNA had 75% accuracy (6 of 8). The most specific cytomorphologic clues for a high-grade malignancy were necrotic/apoptotic debris, mitoses, discohesion, and anisonucleosis., Conclusions: BSNs encompass a broad spectrum of primary and metastatic tumors. Necrotic/apoptotic debris, mitotic activity, discohesion, and significant anisonucleosis, alone or especially in combination, should make a cytopathologist suspect a high-grade malignancy., (© 2019 American Cancer Society.)

Background: The prevalence of undefined pancreatic cystic neoplasms (PCNs) is high in the general population, increasing with patient age. PCNs account for different biological entities with different potential for malignant transformation. The clinician must balance his or her practice between the risk of surgical overtreatment and the error of keeping a malignant lesion under surveillance., Methods: We review and discuss the clinical management of PCNs. Specifically, we analyze the main features of PCNs from the surgeon's point of view, as they present in the outpatient clinic. We also review the different consensus guidelines, address recent controversies in the literature, and present the current clinical practice at 4 different European Centers for pancreatic surgery., Results: The main features of PCNs were analyzed from the surgeon's point of view as they present in the outpatient clinic. All aspects of surgical management were discussed, from indications for surgery to intraoperative management and surveillance strategies., Conclusions: Management of PCNs requires a selective approach with the aim of minimizing clinically relevant diagnostic mistakes. Through the evaluation of clinical and radiological features of a PCN, the surgeon can elaborate on a diagnostic hypothesis and assess malignancy risk, but the final decision should be tailored to the individual patient's need., (© 2019 S. Karger AG, Basel.)

Aims: To evaluate OPN, MCM7, Ki-67, p53, Bcl-2 and 53BP1 presence, together with the abnormal adaptive CD4 and CD8 T-cell response markers expression in a series of oral lichen planus (OLP) affected patients and assess their combined contribution for a more objective disease classification., Methods and Results: In this ex-vivo retrospective analysis, biopsy specimens from 28 adults with a clinical diagnosis of OLP at different progression degree (16 reticular, 2 plaque-like, 1 erosive and 9 mixed type) were collected. Sections were immunohistochemically investigated for the proinflammatory cytokine osteopontin (OPN), alpha-beta CD4 and CD8 positive T cells, DNA replication licensing factor (MCM7), proliferating cell marker (Ki-67), apoptotic and tumor antigen (p53), apoptosis modulator (Bcl-2) and cellular response regulator to double-strand breaks tumor suppressor p53-binding protein 1 expression. Statistical analysis revealed that 53BP1 is highly represented among the OLP study patients (p<0.05). Moreover, on the basis of the quantification results of the highly expressed parameters, two illness categories with different severity were evidenced. The classification hypothesis was confirmed by i) OLP lesion persistence, ii) the development of oral severe lesions in the patients belonging to high grade activity OLP group (HGA-OLPs) and iii) the ascertainment of the same evidence both in the oral squamous cell tumor controls (OSCC) and in HGA-OLP cases., Conclusion: This study completes the scenario with respect to early detection, thanks to a more precise histological analysis, for rationalizing the clinical and histological findings toward a sharable international disease scoring system.

Serrated polyps evaluation represents a challenge for pathologists for lacking of univocal criteria that leads to different inter -individual interpretation. The aim of our review is to offer an alternative simpler histologic and endoscopic approach to these lesions for a more correct relationship between endoscopists and pathologists., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The 2014 World Health Organization (WHO) classification of endometrial hyperplasia (EH) defines premalignant EH based on only cytologic atypia, disregarding architecture complexity. We aimed to assess the impact of architecture complexity on the risk of cancer in non-atypical EH. A systematic review and meta-analysis was performed by searching electronic databases form their inception to October 2018. All studies assessing the rates of progression to cancer in non-atypical EH (simple vs complex) were included. Pooled relative risk (RR) for cancer progression was calculated; a p-value < 0.05 was considered significant. Eight studies with 1066 women were included. The risk for progression of non-atypical EH to cancer was significantly higher in complex EH than in simple EH (p < 0.0001), with an RR of 4.90. In conclusion, the complexity of glandular architecture significantly increases the risk of cancer in non-atypical EH. Complex non-atypical EH may be regarded as a low-risk premalignant lesion rather than a benign condition., (© 2019 APMIS. Published by John Wiley & Sons Ltd.)

Vulvar intraepithelial neoplasia (VIN) is a precursor to vulvar squamous cell carcinoma and is defined histopathologically by the presence of atypia. VIN has been classified into two types: usual vulvar intraepithelial neoplasia (uVIN), which is also referred to as a vulvar high-grade squamous intra-epithelial lesion (HSIL), and differentiated VIN (dVIN). The former is associated with chronic infection by sub-types of the human papilloma virus (HPV), whereas dVIN is HPV-independent and frequently associated with lichen sclerosus. The distinction is important because dVIN has a greater risk of, and more rapid transit to, vulvar squamous cell carcinoma. Furthermore, dVIN-associated vulvar cancers have an increased risk of recurrence and higher mortality than those arising from HSIL. Molecular characterization of vulvar squamous cell carcinoma precursors using next-generation sequencing is a relatively novel, but rapidly advancing field. This review appraises recent studies that have investigated the risks of progression to vulvar malignancy associated with HSIL and dVIN, the prognosis of HPV-dependent and HPV-independent vulvar squamous cell carcinomas, and conducted next generation sequencing mutation analyses to elucidate the genomic profiles underlying VIN. These studies suggest that HSIL and dVIN are characterized by different underlying molecular alterations that may have important implications for treatment and follow-up of women diagnosed with vulvar squamous cell cancer., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Endometrial hyperplasia (EH) is classified into benign and precancerous according to two different histomorphological systems: the World Health Organisation (WHO) system (based on the subjective evaluation of cytological atypia) and the endometrial intraepithelial neoplasia (EIN) system (based on a combination of several parameters that are assessable subjectively, or objectively through computerised analysis). The American College of Obstetricians and Gynecologists recommends use of the EIN system. Nonetheless, a higher prognostic value for EIN criteria was demonstrated only with the objective assessment, which is not routinely applicable. The aim of this study was to evaluate which of the subjective classifications of EH (WHO or EIN) has better prognostic value, by assessing the risk of coexistent cancer. Electronic databases were searched for relevant articles from the inception of the databases to July 2018. All studies assessing the presence of cancer on hysterectomy specimens after a preoperative histological diagnosis of EH were included. Odds ratios (ORs), sensitivity and specificity were calculated with 95% confidence intervals (CIs). Sixteen cohort studies and three case-control studies, assessing 2582 EHs, were included. The WHO criteria showed an OR of 11.15 (95% CI 7.65-16.24), a sensitivity of 0.86 (95% CI 0.82-0.90) and a specificity of 0.67 (95% CI 0.64-0.70) for coexistent cancer. The subjective EIN system showed a similar OR (11.85, 95% CI 4.91-28.62; P = 0.90), higher sensitivity (0.98, 95% CI 0.94-0.99), and lower specificity (0.29, 95% CI 0.24-0.34). The WHO system and the subjective EIN system have similar prognostic values. However, the EIN criteria appear to be more sensitive and thus more suitable for selecting women who need to be treated, whereas the WHO criteria, based on cytological atypia, seem to be more specific for lesions at higher risk of cancer. Therefore, integration of the EIN system with cytological atypia should be considered., (© 2018 John Wiley & Sons Ltd.)

We propose an approach for characterizing structural heterogeneity of lung cancer nodules using Computed Tomography Texture Analysis (CTTA). Measures of heterogeneity were used to test the hypothesis that heterogeneity can be used as predictor of nodule malignancy and patient survival. To do this, we use the National Lung Screening Trial (NLST) dataset to determine if heterogeneity can represent differences between nodules in lung cancer and nodules in non-lung cancer patients. 253 participants are in the training set and 207 participants in the test set. To discriminate cancerous from non-cancerous nodules at the time of diagnosis, a combination of heterogeneity and radiomic features were evaluated to produce the best area under receiver operating characteristic curve (AUROC) of 0.85 and accuracy 81.64%. Second, we tested the hypothesis that heterogeneity can predict patient survival. We analyzed 40 patients diagnosed with lung adenocarcinoma (20 short-term and 20 long-term survival patients) using a leave-one-out cross validation approach for performance evaluation. A combination of heterogeneity features and radiomic features produce an AUROC of 0.9 and an accuracy of 85% to discriminate long- and short-term survivors.

Objective: To determine the incidence of penile intraepithelial neoplasia in the Netherlands using a nationwide histopathology registry and to discuss the nomenclature of premalignant penile lesions., Methods: Data from patients in the Netherlands diagnosed with a premalignant penile lesion between January 1998 and December 2007 were collected from the nationwide histopathology registry (PALGA); this database covers all pathology reports of inhabitants in the Netherlands. The premalignant lesions included were erythroplasia of Queyrat; Bowen's disease; bowenoid papulosis; mild, moderate and severe dysplasia; and carcinoma in situ of the penis. The terminology used in the pathological reports was translated to penile intraepithelial neoplasia. The grading was made analogous to that of vulvar premalignant lesions., Results: The PALGA database enrolled 380 patients with premalignant penile lesions. Severe premalignant lesions, penile intraepithelial neoplasia III, were found in 254 patients (67%), penile intraepithelial neoplasia II in 84 (22%) and penile intraepithelial neoplasia I in 42 patients (11%). Most lesions were located on the prepuce (45%), followed by glans (38%) and shaft (3%). The median age of patients with penile intraepithelial neoplasia was 58 years. Progression to malignant disease occurred (2% for penile intraepithelial neoplasia I vs 7% for penile intraepithelial neoplasia III) in 26 patients., Conclusions: Penile intraepithelial neoplasia is a rarely diagnosed condition. Because of the wide variation of terms used for premalignant intraepithelial neoplasia of the penis, we recommend restricting this nomenclature to penile intraepithelial neoplasia., (© 2018 The Japanese Urological Association.)

Pancreatic ductal adenocarcinoma is one of the most aggressive malignant neoplasms with poor outcomes. At the time of diagnosis, the disease is usually at an advanced stage and only a minority is eligible for surgical resection. To improve the prognosis, it is essential to diagnose and treat the disease in an early stage before its progression into an invasive disease. This article reviews clinical features, histopathology, cytopathology, and molecular alterations of pancreatic ductal adenocarcinoma and its precursors. Moreover, we review a recently updated two-tier classification system for precursor lesions, new findings in premalignant cystic neoplasms, and recently updated staging criteria for invasive carcinoma based on the Cancer Staging Manual, eighth edition, from the American Joint Committee on Cancer. Finally, we discuss the potential clinical applications of the rapidly growing molecular and genetic information of pancreatic cancer and its precursors., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The newly unveiled Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has proposed salivary gland neoplasm of uncertain malignant potential (SUMP) as an indeterminate category. The category is reserved for fine-needle aspiration (FNA) cases that are diagnostic of a salivary gland neoplasm but cannot be further designated as a specific tumor type. The objective of the current study was to evaluate the clinical utility of subtyping SUMP cases based on different cell types., Methods: A retrospective search of cytology databases at 2 institutions for salivary gland FNAs from 2006 through 2017 was conducted. The cytologic diagnosis of each case was reclassified according to the MSRSGC. Histologic follow-up was retrieved for correlation. Cases reclassified as SUMP that had a follow-up pathologic diagnosis were subject to cytology review and subtyping into oncocytic/squamoid, basaloid, or myoepithelial subtypes based on cytomorphology. The risk of malignancy (ROM) for each subtype was analyzed., Results: There were 92 SUMP cases, which comprised 5.9% of 1560 consecutive salivary gland FNAs within the 12-year study period. Histologic follow-up was available for 59 patients. After cytology review, there were 18 cases (30.5%) of oncocytic/squamoid subtype, 25 (42.4%) of basaloid subtype, and 16 (27.1%) of myoepithelial subtype. Pathologic correlation revealed an ROM of 61.1% (11 of 18 cases) for the oncocytic/squamoid subtype, 40.0% (10 of 25 cases) for the basaloid subtype, and 18.8% (3 of 16 cases) for the myoepithelial subtype. The differences in ROM among the 3 subtypes were statistically significant (P = .0476)., Conclusions: Subtyping SUMP cases into categories based on cell type demonstrated differential ROMs for better clinical stratification. Future prospective studies are mandatory to confirm this finding., (© 2018 American Cancer Society.)

Background: Colorectal serrated lesions (SLs) are important premalignant lesions whose clinical and biological features are not fully understood., Aims: We aimed to establish accurate colonoscopic diagnosis and treatment of SLs through evaluation of associations among the morphological, pathological, and molecular characteristics of SLs., Methods: A total of 388 premalignant and 18 malignant colorectal lesions were studied. Using magnifying colonoscopy, microsurface structures were assessed based on Kudo's pit pattern classification system, and the Type II pit pattern was subcategorized into classical Type II, Type II-Open (Type II-O) and Type II-Long (Type II-L). BRAF/KRAS mutations and DNA methylation of CpG island methylator phenotype (CIMP) markers (MINT1, - 2, - 12, - 31, p16, and MLH1) were analyzed through pyrosequencing., Results: Type II-O was tightly associated with sessile serrated adenoma/polyps (SSA/Ps) with BRAF mutation and CIMP-high. Most lesions with simple Type II or Type II-L were hyperplastic polyps, while mixtures of Type II or Type II-L plus more advanced pit patterns (III/IV) were characteristic of traditional serrated adenomas (TSAs). Type II-positive TSAs frequently exhibited BRAF mutation and CIMP-low, while Type II-L-positive TSAs were tightly associated with KRAS mutation and CIMP-low. Analysis of lesions containing both premalignant and cancerous components suggested Type II-L-positive TSAs may develop into KRAS-mutated/CIMP-low/microsatellite stable cancers, while Type II-O-positive SSA/Ps develop into BRAF-mutated/CIMP-high/microsatellite unstable cancers., Conclusions: These results suggest that Type II subtypes reflect distinct molecular subclasses in the serrated neoplasia pathway and that they could be useful hallmarks for identifying SLs at high risk of developing into CRC.

In Pakistan, extensive use of several precarious chewable tobacco formulations has made oral cancer the second leading malignancy. Selection of literature was done by a survey of studies published from 1990 to 2017 mainly, from PUBMED and few from other search engines, on naswar, gutka, areca nut and betel quid, which included published reviews, original articles and other data sources on chewable tobacco, its epidemiology, pathological implications, and psychological effects. These studies have revealed that the chemicals in these formulations bind and mutate DNA of oral mucosa through down regulating cellular repair pathways and upregulating genetic networks associated with pathogenesis. Areca nut, having aercoline (the major alkaloid) causes carcinogenicity, mutagenicity, and genotoxicity of oral mucosa through increased production of growth factors and corticotrophin-releasing hormone, and genetic alteration in expression of CASP8, APAF-1, BAX, BAD, and upregulation of caspas-3. Gutka addiction leads to precancerous lesions resulting in characteristic facial abnormalities, following trismus. Naswar, in addition to oral cancer, causes adverse cardiovascular events by reducing glutathione per oxidase (GPx) and super-oxide dismutase (SOD), serum levels of HDL, whereas, increasing the ratio of cholesterol, LDL, triglycerides and LDL-C/HDL-C. Betel quid (Paan), causes psychoactivity affecting central and autonomic nervous systems leading to dependence with decreased cognition, euphoria, sweating, salivation, palpitation, heightened alertness and zest to work. Metabolically, cardio-acceleration, cortical desynchronisation of EEG, elevated plasma noradrenaline and adrenaline were found. This review highlights the corrosive effects of various most popular chewable tobacco formulations; and damage done by their cocktail of carcinogenic substances and added ingredients, leading to oropharangeal cancer.

Background: Penile cancer is rare in Germany and in western European countries. Our understanding of the pathogenesis and pathology of this malignancy has increased considerably in recent years., Objectives: Clinical management has become more complex, with organ-preserving strategies being increasingly favored. Associated with these developments, the demands on the pathology reports of biopsies and surgical specimens from the penis have also increased., Materials and Methods: According to guidelines and the relevant literature, this review outlines the most important aspects that must be considered in the classification and pathological reporting of penile cancer., Results: Correct histological subtyping of penile cancer is important for prognostic and therapeutic considerations. There are also some peculiarities with the current TNM classification system of this tumor compared to other entities., Conclusion: Handling of specimens and histopathological typing must be performed by experienced pathologists according to recent developments in the pathogenesis, classification, and therapeutic strategies of penile cancer.

Objectives: To obtain data on the prevalence of oral mucosal lesions (OMLs) among Cambodians, and to assess the relationship between known risk habits of oral diseases with prevalence of oral potentially malignant disorders (OPMDs)., Design: This was a population-based, cross-sectional study whereby subjects were adults aged 18 years old and above. A workshop on the identification of OML was held to train and calibrate dental officers prior to data collection in the field. Sociodemographic and risk habits data were collected via face-to-face interview, whilst presence of OML and clinical details of lesions such as type and site were collected following clinical oral examination by the examiners. Data analysis was carried out using the Statistical Package for Social Science (SPSS) version 12.0. The association between risk habits and risk of OPMD was explored using logistic regression analysis., Results: A total of 1634 subjects were recruited. Prevalence of OML for this population was 54.1%. Linea alba was the most common lesion seen (28.7%). This study showed an overall OPMD prevalence of 5.6%. The most common type of OPMD was leukoplakia (64.8%), followed by lichen planus (30.8%). Subjects who only smoked were found to have an increased risk for OPMD of almost four-fold (RR 3.74, 95%CI 1.89-7.41). The highest risk was found for betel quid chewers, where the increased risk observed was more than six times (RR 6.75, 95%CI 3.32-13.72). Alcohol consumption on its own did not seem to confer an increased risk for OPMD, however when practiced concurrently with smoking, a significant risk of more than five times was noted (RR 5.69 95%CI 3.14-10.29)., Conclusion: The prevalence of OML was 54.1%, with linea alba being the most commonly occurring lesion. Smoking, alcohol consumption and betel quid chewing were found to be associated with the prevalence of OPMD, which was 5.6%.

Cancer evolution is a step-wise non-linear process that may start early in life or later in adulthood, and includes pre-malignant (indolent) and malignant phases. Early somatic changes may not be detectable or are found by chance in apparently healthy individuals. The same lesions may be detected in pre-malignant clonal conditions. In some patients, these lesions may never become relevant clinically whereas in others, they act together with additional pro-oncogenic hits and thereby contribute to the formation of an overt malignancy. Although some pre-malignant stages of a malignancy have been characterized, no global system to define and to classify these conditions is available. To discuss open issues related to pre-malignant phases of neoplastic disorders, a working conference was organized in Vienna in August 2015. The outcomes of this conference are summarized herein and include a basic proposal for a nomenclature and classification of pre-malignant conditions. This proposal should assist in the communication among patients, physicians and scientists, which is critical as genome-sequencing will soon be offered widely for early cancer-detection., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Context: - Invasive pancreatic ductal adenocarcinoma has a greater than 90% mortality rate at 5 years. Understanding noninvasive, curable precursor lesions gives us the best hope for reducing mortality from pancreatic ductal adenocarcinoma. The 3 pancreatic precursor lesions that have been well studied include intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, and pancreatic intraepithelial neoplasia., Objective: - To give an update on the latest clinical, molecular, and pathologic advances in intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, and pancreatic intraepithelial neoplasia for the general surgical pathologist., Data Sources: - The current literature was analyzed and the authors' experiences with institutional and consult material were incorporated., Conclusions: - Our understanding of the molecular alterations that lead from pancreatic precursor lesion to invasive carcinoma continues to evolve. These advances aid clinicians in their treatment decisions and researchers in their search for actionable, druggable targets.

Gastric precancerous diseases (GPD) may deteriorate into early gastric cancer if misdiagnosed, so it is important to help doctors recognize GPD accurately and quickly. In this paper, we realize the classification of 3-class GPD, namely, polyp, erosion, and ulcer using convolutional neural networks (CNN) with a concise model called the Gastric Precancerous Disease Network (GPDNet). GPDNet introduces fire modules from SqueezeNet to reduce the model size and parameters about 10 times while improving speed for quick classification. To maintain classification accuracy with fewer parameters, we propose an innovative method called iterative reinforced learning (IRL). After training GPDNet from scratch, we apply IRL to fine-tune the parameters whose values are close to 0, and then we take the modified model as a pretrained model for the next training. The result shows that IRL can improve the accuracy about 9% after 6 iterations. The final classification accuracy of our GPDNet was 88.90%, which is promising for clinical GPD recognition.

Ulcerative colitis and Crohn's diseases are relapsing longstanding inflammatory bowel diseases, associated with an increased risk of developing colorectal cancer. Continuous surveillance is necessary to detect the preneoplastic lesions in an early stage. New endoscopic techniques have improved the diagnostic accuracy and have resulted in a new and more simplified classification system of the dysplastic lesions in the bowel. Histopathologically these lesions are very heterogenous, consisting of adenomatous, villous and the more recently discovered serrated dysplasia. Its diagnosis may be hampered by the inflamed mucosa, resulting in a high interobserver variability in the categories of indefinite for dysplasia and low-grade dysplasia. Therefore the ECCO guidelines recommend to confirm the diagnosis of dysplasia by a pathologist with expertise in gastrointestinal pathology. In this article we give an overview of colitis-associated dysplasia from the point of view of the endoscopist and the pathologist., (© Acta Gastro-Enterologica Belgica.)

Objective: Introduction: Actinic keratosis (AK) is precancerous skin lesion that occurs in the sun-exposedskin areas characterized by local intraepidermal dysplasia of different severity (KIN I, KIN II and KIN III). The aim of this research was to study distribution patterns and morphological features of AK histological types., Patients and Methods: Materials and Methods: The study included skin biopsy material from 68 patients with different clinical forms of AK. The diagnosis of AK was histologically confirmed in 100% of cases., Results: Results: There were 63.21% of men and 36.8% of women among all patients with AK. The average age of patients was 73.3 ± 8.3.The most common clinico-histological forms of actinic keratosis were typical (41.2%), hypertrophic (16.2%), atrophic (14.7%) and pigmentary (11.7%), bowenoid (8.8%), acantholytic (7.4%). Among the rate of epidermal dysplasia there diagnosed cases of KIN І (50%), KIN ІІ (36.8%) and KIN III (13.2%)., Conclusion: Conclusions: It was found a direct correlation between KIN I and typical and pigment forms of AK, KIN II and hypertrophic and bowenoid forms of AK.

The majority of precancerous lesions of the lower female genital tract (intraepithelial neoplasia, IN) are caused by human papillomavirus (HPV) infections resulting in cellular atypia and in turn an altered tissue architecture. Depending on the pathogenesis, a distinction is made between vulvar intraepithelial neoplasia (VIN) classified as classical VIN associated with high-risk HPV infections (u-VIN) and differentiated VIN (d-VIN), which is associated with lichen sclerosus et atrophicus and p53 alterations. In the current World Health Organization (WHO) classification a novel grading system for squamous cell precancerous lesions of the lower female genital tract has been proposed, differentiating low grade squamous intraepithelial lesions (L-SIL) including condyloma and HPV-associated alterations plus VIN 1, vaginal intraepithelial neoplasia (VaIN 1) and cervical intraepithelial neoplasia (CIN 1) from high grade squamous intraepithelial lesions (H-SIL) with VIN 2 and 3, VaIN 2 and 3 as well as CIN 2 and 3. The use of p16 immunohistochemistry can assist the differentiation. The new binary classification, however, contradicts the German cytological nomenclature (Munich nomenclature III), which differentiated three grades of dysplasia in order to avoid overtreatment of patients with moderate IN. The individual nomenclatures are compared to each other. It is recommended to report the grade of precancerous lesions in addition to the SIL classification of the WHO.

The 2014 World Health Organization (WHO) classification of uterine tumors revealed simplification of the classification by fusion of several entities and the introduction of novel entities. Among the multitude of alterations, the following are named: a simplified classification for precursor lesions of endometrial carcinoma now distinguishes between hyperplasia without atypia and atypical hyperplasia, the latter also known as endometrioid intraepithelial neoplasia (EIN). For endometrial carcinoma a differentiation is made between type 1 (endometrioid carcinoma with variants and mucinous carcinoma) and type 2 (serous and clear cell carcinoma). Besides a papillary architecture serous carcinomas may show solid and glandular features and TP53 immunohistochemistry with an "all or null pattern" assists in the diagnosis of serous carcinoma with ambiguous features. Neuroendocrine neoplasms are categorized in a similar way to the gastrointestinal tract into well differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas (small cell and large cell types). Leiomyosarcomas of the uterus are typically high grade and characterized by marked nuclear atypia and lively mitotic activity. Low grade stromal neoplasms frequently show gene fusions, such as JAZF1/SUZ12. High grade endometrial stromal sarcoma is newly defined by cyclin D1 overexpression and the presence of the fusion gene YWHAE/FAM22 and must be distinguished from undifferentiated uterine sarcoma. Carcinosarcomas (malignant mixed Mullerian tumors MMMT) show biological and molecular similarities to high-grade carcinomas.

Making an incorrect histopathological diagnosis of an endometrial lesion may lead to unwanted loss of fertility and therapy-associated morbidity; therefore, endometrial carcinomas need to be correctly typed and differentiated from hyperplastic precursors, benign lesions and artifacts. Typical diagnostic pitfalls are described in this article. Misdiagnosing endometrial lesions can be avoided by paying thorough attention to gross as well as microscopic features and by taking crucial differential diagnoses into consideration. These are, in particular, well-differentiated endometrioid adenocarcinoma of the endometrium versus atypical endometrial hyperplasia, myoinvasive endometrioid adenocarcinoma versus atypical polypoid adenomyoma and endometrioid carcinoma versus serous carcinoma of the endometrium with a predominantly glandular pattern. It is also important to consider the possibility of a false positive diagnosis of atypical endometrial hyperplasia or carcinoma in cases of biopsy-induced artifacts.

The correlation between the cytological findings from the PAP smear and the histological outcome in cases where the cytological findings must be histologically verified, is an integral component of the German screening program for cervical cancer. These data are collected nationwide as part of a benchmarking process by the individual Associations of Statutory Health Insurance Physicians (KV) in the federal states and reported to the National Association of Statutory Health Insurance Physicians (KBV) in Berlin. In most cases there is a good correlation between cytology and histology but in some cases either a different grade of severity of cervical intraepithelial neoplasia (CIN) is found or the histological findings are negative. The reasons for a lack of correlation can be insufficient sampling in the cytology or the biopsy or a misinterpretation of the individual findings. Although the findings from H&E sections are considered to be the gold standard in the histological evaluation, it has long been known that the interobserver agreement in these preparations is only moderate. A significant improvement becomes apparent, firstly by the classification of cervical cancer precursors into low-grade and high-grade groups and secondly by the targeted application of biomarkers, in particular p16 and Ki-67, according to the recommendations of the lower anogenital squamous terminology standardization (LAST) project. The biomarkers p16 and Ki-67 should be used in the differential diagnostics between reactive and reparative alterations and for further differentiation of a CIN grade 2 but not to confirm a CIN grade 3. It is still unclear whether p16 is suitable as a prognostic marker for low-grade lesions.

Gastric dysplasia is a neoplastic lesion and a precursor of gastric cancer. The Padova, Vienna, and World Health Organization classifications were developed to overcome the discrepancies between Western and Japanese pathologic diagnoses and to provide a universally accepted classification of gastric epithelial neoplasia. At present, the natural history of gastric dysplasia is unclear. Much evidence suggests that patients with high-grade dysplasia are at high risk of progression to carcinoma or synchronous carcinoma. Therefore, endoscopic resection is required. Although patients with low-grade dysplasia have been reported to be at low risk of progression to carcinoma, due to the marked histologic discrepancies between forceps biopsy and endoscopic specimens, endoscopic resection for this lesion is recommended, particularly in the presence of other risk factors (large size; depressed gross type; surface erythema, unevenness, ulcer, or erosion; and tubulovillous or villous histology). Helicobacter pylori eradication in patients with dysplasia after endoscopic resection appear to reduce the incidence of metachronous lesions.

Laryngeal carcinogenesis is a multistep process, characterized by an accumulation of genetic changes associated with architectural and cytologic alterations, ranging from squamous hyperplasia to carcinoma in situ and encompassed by the terminology of squamous intraepithelial lesions (SILs). The etiology, classification, genetic changes, and malignant progression of these lesions are reviewed. Tobacco remains the principal etiological factor with gastroesophageal reflux disease recently considered as a possible factor. In contrast, there is little evidence that microbiological agents, especially human papillomavirus infection, are frequently involved in laryngeal carcinogenesis and probably <10% of SILs are driven by biologically active human papillomavirus infection. Light microscopy, despite a degree of subjectivity, remains the mainstay of accurate diagnosis, prognosis, and guidance for a patient's treatment. The currently used classifications, the dysplasia system, squamous intraepithelial neoplasia, and the Ljubljana classification, reflect different standpoints on this important topic. The modified Ljubljana classification, with good interobserver agreement, could be considered as a proposal for a unified classification of laryngeal SILs. This review also briefly discusses recently discovered genetic changes, such as CDKN2A and CTNNB1 genes, and chromosome instability of chromosomes 1 and 7; however, none of these can at present improve histologic diagnosis. Malignant progression of precursor lesions varies from 2% to 74%, according to different studies. Cold-steel microinstruments, CO2 laser, and radiotherapy are used to treat the different grades of precursor lesions. There is as yet no worldwide agreement on the treatment of high-grade lesions and carcinoma in situ.

As even a mere thickening of the urothelium can harbor genetic changes identical to that of low grade papillary urothelial tumors, it is not always possible to clearly recognize a precursor lesion of urothelial carcinoma by routine histological diagnostics. Complementary immunohistochemical and molecular diagnostic methods assist the recognition of these entities. These methods especially help to identify clinically important genetically unstable cells as the hallmark of carcinoma in situ (CIS). Little is known about the clinical significance of the morphological subtypes of CIS, which range from large cell to micropapillary variants. For a better understanding of special types of bladder cancer (e.g. adenocarcinoma and squamous cell carcinoma), it seems to be important to define the phenotype and the molecular pattern of non-urothelial lesions, such as intestinal metaplasia and squamous metaplasia, better and more precisely.

International experts met to discuss recent advances and to revise the 2004 recommendations for assessing and reporting precursor lesions to invasive carcinomas of the pancreas, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm, and other lesions. Consensus recommendations include the following: (1) To improve concordance and to align with practical consequences, a 2-tiered system (low vs. high grade) is proposed for all precursor lesions, with the provision that the current PanIN-2 and neoplasms with intermediate-grade dysplasia now be categorized as low grade. Thus, "high-grade dysplasia" is to be reserved for only the uppermost end of the spectrum ("carcinoma in situ"-type lesions). (2) Current data indicate that PanIN of any grade at a margin of a resected pancreas with invasive carcinoma does not have prognostic implications; the clinical significance of dysplasia at a margin in a resected pancreas with IPMN lacking invasive carcinoma remains to be determined. (3) Intraductal lesions 0.5 to 1 cm can be either large PanINs or small IPMNs. The term "incipient IPMN" should be reserved for lesions in this size with intestinal or oncocytic papillae or GNAS mutations. (4) Measurement of the distance between an IPMN and invasive carcinoma and sampling of intervening tissue are recommended to assess concomitant versus associated status. Conceptually, concomitant invasive carcinoma (in contrast with the "associated" group) ought to be genetically distinct from an IPMN elsewhere in the gland. (5) "Intraductal spread of invasive carcinoma" (aka, "colonization") is recommended to describe lesions of invasive carcinoma invading back into and extending along the ductal system, which may morphologically mimic high-grade PanIN or even IPMN. (6) "Simple mucinous cyst" is recommended to describe cysts >1 cm having gastric-type flat mucinous lining at most minimal atypia without ovarian-type stroma to distinguish them from IPMN. (7) Human lesions resembling the acinar to ductal metaplasia and atypical flat lesions of genetically engineered mouse models exist and may reflect an alternate pathway of carcinogenesis; however, their biological significance requires further study. These revised recommendations are expected to improve our management and understanding of precursor lesions in the pancreas.

Colorectal cancer (CRC) is considered a heterogeneous disease, both regarding pathogenesis and clinical behaviour. Four decades ago, the adenoma-carcinoma pathway was presented as the main pathway towards CRC, a conclusion that was largely based on evidence from observational morphological studies. This concept was later substantiated at the genomic level. Over the past decade, evidence has been generated for alternative routes in which CRC might develop, in particular the serrated neoplasia pathway. Providing indisputable evidence for the neoplastic potential of serrated polyps has been difficult. Reasons include the absence of reliable longitudinal observations on individual serrated lesions that progress to cancer, a shortage of available animal models for serrated lesions and challenging culture conditions when generating organoids of serrated lesions for in vitro studies. However, a growing body of circumstantial evidence has been accumulated, which indicates that ≥15% of CRCs might arise through the serrated neoplasia pathway. An even larger amount of post-colonoscopy colorectal carcinomas (carcinomas occurring within the surveillance interval after a complete colonoscopy) have been suggested to originate from serrated polyps. The aim of this Review is to assess the current status of the serrated neoplasia pathway in CRC and highlight clinical implications.

Due to increasing utilization of cross-sectional imaging, asymptomatic pancreatic cysts are frequently being diagnosed. Many of these cysts have premalignant potential and offer a unique opportunity for cancer prevention. Mucinous cystic neoplasm and intraductal papillary mucinous neoplasm are the major premalignant cystic neoplasms of pancreas. The prediction of the risk of malignancy (incidental and future risk of malignant transformation) and balancing the risks of watchful waiting with that of operative management with associated mortality and morbidity is the key to the management of these lesions. We review the literature that has contributed to the development of our approach to the management of these cystic neoplasms. We provide an overview of the key features used in diagnosis and in predicting malignancy. Particular attention is given to the natural history and management decision making., (Copyright © 2015. Published by Elsevier Inc.)

Porokeratosis is a family of several disorders characterized histologically by the presence of cornoid lamellae. The presence of cornoid lamellae represents an abnormal form of keratinization, which unifies all types of porokeratosis. A significant variation in lesional morphology can result from peculiarities involving the cornoid lamellae and changes related to epidermal hyperplasia and dermal inflammation. This diversity has led to the recognition of several unusual clinicopathological variants of porokeratosis in recent years. Cornoid lamellation, however, is not pathognomonic of porokeratosis and can be seen in some inflammatory and inherited cutaneous disorders and also as an incidental finding. Some of these conditions can be confused with an atypical presentation of porokeratosis and vice versa. An awareness of the broad morphological spectrum of porokeratosis is crucial to avoid missing the diagnosis when appearances are far from typical. This issue is critical in patient management given the potential premalignant nature of porokeratosis.

Hepatocellular carcinoma (HCC) is currently the sixth most common type of cancer with a high mortality rate and an increasing incidence worldwide. Its etiology is usually linked to environmental, dietary or life-style factors. HCC most commonly arises in a cirrhotic liver but interestingly an increasing proportion of HCCs develop in the non-fibrotic or minimal fibrotic liver and a shift in the underlying etiology can be observed. Although this process is yet to be completely understood, this changing scenario also has impact on the material seen by pathologists, presenting them with new diagnostic dilemmas. Histopathologic criteria for diagnosing classical, progressed HCC are well established and known, but with an increase in detection of small and early HCCs due to routine screening programs, the diagnosis of these small lesions in core needle biopsies poses a difficult challenge. These lesions can be far more difficult to distinguish from one another than progressed HCC, which is usually a clear cut hematoxylin and eosin diagnosis. Furthermore lesions thought to derive from progenitor cells have recently been reclassified in the WHO. This review summarizes recent developments and tries to put new HCC biomarkers in context with the WHOs reclassification. Furthermore it also addresses the group of tumors known as combined hepatocellular-cholangiocellular carcinomas.

Despite major improvements concerning its diagnosis and treatment, pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease with an extremely poor prognosis. Pathology, as interface discipline between basic and clinical medicine, has substantially contributed to the recent developments and has laid the basis for further progress. The definition and classification of precursor lesions of PDAC and their molecular characterization is a fundamental step for the potential identification of biomarkers and the development of imaging methods for early detection. In addition, by integrating findings in humans with the knowledge acquired through the investigation of transgenic mouse models for PDAC, a new model for pancreatic carcinogenesis has been proposed and partially validated in individuals with genetic predisposition for PDAC. The introduction and validation of a standardized system for pathology reporting based on the axial slicing technique has shown that most pancreatic cancer resections are R1 resections and that this is due to inherent anatomical and biological properties of PDAC. This standardized assessment of prognostic relevant parameters represents the basis for the successful conduction of multicentric studies and for the interpretation of their results. Finally, recent studies have shown that distinct molecular subtypes of PDAC exist and are associated with different prognosis and therapy response. The prospective validation of these results and the integration of molecular analyses in a comprehensive pathology report in the context of individualised cancer therapy represent a major challenge for the future.

Aims: To verify the applicability, reproducibility and predictive value of a proposed unified classification (amended Ljubljana classification) for laryngeal squamous intraepithelial lesions (SILs)., Methods and Results: Six internationally recognized experts and three pathologists from Ljubljana contributed to this study by evaluating a set of laryngeal SILs using the new system: low-grade SIL, high-grade SIL, and carcinoma in situ (CIS). The overall agreement among reviewers was good. Overall unweighted and weighted κ-values and 95% confidence intervals were 0.75 (0.65-0.84) and 0.80 (0.71-0.87), respectively. The results were stratified between the international reviewers and the Ljubljana pathologists. The former had good overall agreement, and the latter had very good agreement. Kaplan-Meier survival curves showed a significant difference (P < 0.0001) between patients with low-grade and high-grade SILs; 19 of 1204 patients with low-grade SILs and 30 of 240 patients with high-grade SILs progressed to malignancy in 2-15 years and in 2-26 years, respectively., Conclusions: The proposed modification to the Ljubljana classification provides clear morphological criteria for defining the prognostic groups. The criteria facilitate better interobserver agreement than previous systems, and the retrospective follow-up study demonstrates a highly significant difference in the risk of malignant progression between low-grade and high-grade SILs., (© 2014 John Wiley & Sons Ltd.)