Current WHO Classification Research Articles

PATH-04. AN ENHANCED AI-DRIVEN PLATFORM FOR PRECISION MOLECULAR BRAIN TUMOR DIANOSTICS

Tumors of the CNS represent one of the most complex groups of human cancer, with a vast number of different entities occurring across a spectrum of ages and anatomic locations. This heterogeneity makes accurate diagnosis challenging, with the current gold standard relying on multiple subjective elements. We recently proposed a classification algorithm based on tumor DNA methylation profiling as an objective way to assign samples to over 80 distinct molecular classes. Here we present a substantial update to our machine learning-based algorithm, with more than 170 molecular classes now being represented amongst the 5,915 samples in our reference cohort. These new classes include further subclassification of known groups such as medulloblastoma and ependymoma, as well as multiple new molecular entities described here for the first time. A further improvement is the introduction of a more rationally layered output, making use of ‘families’ of closely-related molecular classes to improve the compatibility with the current WHO classification of CNS tumors. This approach is designed to increase the clinical relevance of the primary output, while also retaining the full information content from the random forest-driven classification. Benchmarking our new algorithm by cross-validation and on an independent validation cohort indicates a retention of the excellent accuracy of diagnosis (error-rate < 4%), with a significant improvement in the proportion of confidently classifiable tumors compared with our previous tool. We believe that this approach, freely accessible through an online web portal, has the potential to enhance diagnostic precision and thereby support clinical care for brain tumor patients.

Double-hit lymphoma of the male breast: a case report

BackgroundWhereas lymphoma of the female breast is already rare, lymphoma of the male breast has only anecdotally been reported. Within a study of 32 lymphoma of the breast reported between 1973 and 2014 as Burkitt lymphoma, we observed a single male case, which we report here.Case presentationA 72-years-old Caucasian man presented with a mass in his left breast. Clinical history included prior basal cell carcinoma, leiomyosarcoma, and administration of spironolactone. The reference pathology diagnosis at presentation was Burkitt lymphoma according to the Kiel Classification. The present re-investigation using fluorescence in situ hybridization revealed an IGH-MYC translocation and a break in the BCL2 locus in the tumor cells. Thus, in light of the current WHO classification, the diagnosis was revised to high-grade B-cell lymphoma with MYC and BCL2 rearrangement, Burkitt morphology (so-called “double-hit” lymphoma). Genome-wide chromosomal imbalance mapping revealed a complex pattern of aberrations in line with this diagnosis. The aberrations, including copy-number gains in chromosomes 3q and 18 and focal homozygous loss in 9p21.3, resembled typical changes of lymphomas affecting “immune-privileged” sites.ConclusionThe present case adds to the understanding of the pathogenesis of male breast lymphomas, about which hardly any molecular characterization has been published yet.

Cracking a Nut with a Sledgehammer? - Broadening the Spectrum of Gene Mutation Analysis in MDS Does Not Add Clinically Relevant Information

Background: Myelodysplastic syndromes (MDS) are a group of clonal stem cell neoplasms, presenting with cytopenias. Diagnosis relies on peripheral blood counts and bone marrow morphology, classifying MDS patients by percentage of blasts and number of cell lineages affected. Although half of the patients show normal karyotypes, cytogenetic profiles allow risk stratification (IPSS-R). A number of recurrently mutated genes were identified (Haferlach et al, Leukemia 2014; Papaemmanuil et al, Blood 2013), but in the current WHO classification gene mutations are still only mentioned as a footnote. However, with increasing sequencing capacities the spectrum of investigated genes is also becoming broader. 85% of MDS patients carry at least one mutation at diagnosis but the median number of mutations per patient is low, illustrating that - genetically speaking - MDS is a quite simple disease. Aim: To determine the actual gain of genetic information with increasing NGS panel sizes, starting with small panels of diagnostic guidelines to the complete coding region (=exome) covered by whole genome sequencing (WGS). Patients and Methods: The cohort comprised 588 patients (234 female and 354 male) with a median age of 72, diagnosed as MDS by cytomorphology and cytogenetics following WHO classification. All patients were previously investigated by next generation deep sequencing with a mean read depth of 1,066x (Haferlach et al, Leukemia 2014) and WGS. WGS libraries were generated with the TruSeq DNA PCR-Free Kit and sequenced with 150 bp paired-end reads on NovaSeq or HiSeqX instruments with a mean coverage of 106x (Illumina, San Diego, CA). Variant interpretation was performed by considering ClinVar, Cosmic, functional impact predictors and a population frequency in gnomAD ≤0.00005. No or discordant information led to classification of variant of uncertain significance (VUS), considering only protein altering mutations. Results: The targeted sequencing and WGS data was analyzed for 2 and 4 virtual gene panels respectively: the 12 genes as given in the MDS NCCN guidelines with a incidence &amp;gt;5% (Version 2.2020; "genes frequently somatically mutated in MDS"), the 34 gene panel summarized in McClure et al. (J Mol Diag 2018; "minimum recommended list for management of the most chronic myeloid neoplasms"), the 723 cosmic cancer gene census (CCGC, v91) panel and finally the exome (figure 1). All of the genes from the NCCN panel were mutated in at least one patient, summing up to an overall count of 1,058 mutations. 81% of patients carried at least one mutation, with a median of 2 mutations per patient. Only a few VUS occurred (n=50) based on our classification strategy. Extending the analysis to the McClure panel revealed 196 additional mutations in 18 additional genes, increasing the number of patients with a least one mutation by 18 to 492 (84%). The number of VUS rose to 73. Reviewing the WGS data for the two panels showed a congruence of 86.8% for the identified mutations. Mainly small clones (VAF &amp;lt;15%, n=151) were missed due to the lower sensitivity of WGS. Addressing the cosmic cancer gene set only 290 mutations were detected on top. The number of patients with at least one mutation increased marginally to 512 (87%), while a large number of additional VUS was detected (n=1,240), illustrating the difficulty in classifying this data. The phenomenon was even more pronounced in the exome data set with a remarkable increase of detected VUS by 20,540. All patients harbored at least one mutation and the number of recurrently mutated genes was elevated to 770. However, most of the gene mutations were unique. The median number of mutations per patient was 10, found in 3,603 different genes, including LUC7L2 and CUX1, located on chromosome 7q, CSNK1A1, located on 5q, and various transcription factors and RAS pathway related genes. Conclusions: MDS cases can be investigated by a small diagnostic gene panel. The higher sensitivity of targeted deep sequencing allows detection of small clones, relevant for cases with CHIP or CCUS. A large gene panel shows only small gain of clinically relevant information but many additional VUS. The restriction to a panel containing less than 30 genes leads to cheaper sequencing costs and especially less time for bioinformatics and clinical interpretation of findings. Therefore, the choice of a small but well selected gene panel is more favorable than large sequencing efforts. Disclosures No relevant conflicts of interest to declare.

Do Canine Pancreatic Neuroendocrine Neoplasms Resemble Human Pancreatic Neuroendocrine Tumours? A Comparative Morphological and Immunohistochemical Investigation

Although canine pancreatic neuroendocrine neoplasms (PanNENs) have been proposed as a model for the counterpart human neoplasms, the type or grade of human PanNEN that they resemble is unclear. PanNENs in animals are classified as adenoma or carcinoma, whereas in humans they are classified as pancreatic neuroendocrine tumour (PanNET) if well-differentiated, or as pancreatic neuroendocrine carcinoma (PanNEC) if poorly differentiated. We evaluated 16 canine primary PanNENs and two metastases histologically and immunohistochemically, and graded them using the animal and human grading systems. All neoplasms had local or vascular invasion and were classified as pancreatic islet cell carcinomas according to the current WHO classification. The Ki-67 index was low in all cases (0.01-1.50%). All had cytoplasmic expression of synaptophysin and insulin but were immunonegative for glucagon, confirming a functional diagnosis of canine insulinoma. Membranous expression of SSTR2A and nuclear expression of ATRX, but no p53 expression, was found in all neoplasms. One primary tumour was diagnosed as a mixed neuroendocrine-non-neuroendocrine neoplasm, which is the first report of this neoplasm in dogs. The other 15 primary tumours and both metastatic tumours were graded as PanNET G1, according to the human WHO classification. We conclude that canine PanNENs share well-differentiated histomorphology, SSTR2A expression and absence of nuclear p53 immunolabelling with human PanNETs G1. However, they differ in ATRX gene expression and functionality, and seem to have a worse prognosis than human PanNETs G1, although their generally low Ki-67 index precludes more precise assessment of prognosis. Membranous SSTR2A expression renders canine PanNENs potentially amenable to treatment with somatostatin analogues or SSTR targeted in-vivoimaging methods.

Solid Pseudopapillary Neoplasm of the Pancreas: Case Report

Solid pseudopapillary neoplasm of the pancreas is a rare pancreatic tumor with low malignant potential, typically affecting young women. In literature this tumor may be referred to as Frantz tumor, solid tumor, cystic tumor, papillary-cystic tumor or solid pseudopapillary tumor. According to the current WHO classification from 2010 these tumors are considered low-grade malignant epithelial tumors of pancreas. In this case report we present a case of 19-years old women with cystic lesion located in left hypogastrium. After thorough evaluation and subsequent multidisciplinary consultation, the patient was indicated to radical resection of the lesion. Final histological evaluation of the surgical specimen revealed the diagnosis of solid-pseudopapillary neoplasm.

Infiltrative gliomas of the thalamus in children: the role of surgery in the era of H3 K27M mutant midline gliomas

BackgroundThe role of surgery in the management of pediatric non-pilocytic infiltrative thalamic gliomas needs to be revisited specifically with regard to molecularly defined subtypes.MethodsA retrospective review of a consecutive series of children operated on a thalamic tumor between 1992 and May 2018 was performed. Neuroimaging data were reviewed for localization and extent of resection; pathology was re-reviewed according to the current WHO classification, including assessment of histone H3 K27 mutational status.ResultsForty-nine patients with a thalamic tumor aged < 18 years at diagnosis were identified. Twenty-five patients (51%) had a non-pilocytic infiltrative glioma, of which the H3 K27M status was available in 22. Fourteen patients were diagnosed as diffuse midline glioma (DMG) H3 K27M mutant. There was no statistically significant difference in survival between patients harboring the H3 K27M mutation and wildtype. Resection (“any resection > 50%” vs “biopsy”) and histological tumor grade (“°II” vs “°III+°IV”) were statistically significant predictors of survival (univariate: p = 0.044 and p = 0.013, respectively). These results remained significant on multivariate analysis (HR 0.371/p = 0.048, HR 9.433/p = 0.035).ConclusionWe advocate to still consider an attempt at maximal safe resection in the multidisciplinary treatment of unilateral thalamic non-pilocytic gliomas irrespective of their H3 K27-mutational status.

Increased M1 Macrophages Infiltration Correlated With Poor Survival Outcomes and Radiation Response in Gliomas.

Background:Gliomas are the malignance of a poor prognosis. The current WHO classification remains unable to predict survival outcomes accurately. Novel surrogates are highly required for improved stratification of patients and hence, allowing to delivery of the most appropriate treatment.Methods:Transcriptional profiles of 301 glioma cases on the platform of Chinese Glioma Genome Atlas (CGGA) were retrospectively studied.Results:Extracellular matrix (ECM) scores were established by integrating a panel of most featured gene-signatures, correlating well with pathological tumor stages. Linear regression analysis revealed that the ECM score corroborated with the infiltration status of monocytes, M0 and M1 macrophages. Furthermore, the WHO stage II-IV dependent abundance of those 3 immune cells was determined. Univariate and multivariate analysis of clinicopathological characteristics in the GBM cohort identified M1 enrichment score as an independent risk factor. A high abundance of M1 macrophages was associated with poor survival outcomes and radiotherapy response in IDH-wildtype GBM.Conclusions:Our study demonstrated that M1 macrophages correlated with WHO grades and predicted robustly for the survival performance for GBM patients. Increased infiltration of M1 macrophages was associated with a poor radiation response for IDH-wildtype GBM. Together, it will facilitate more precise stratifications of glioma patients based on molecular and immunological surrogates.

Infiltrating pattern and prognostic value of tertiary lymphoid structures in resected non-functional pancreatic neuroendocrine tumors

BackgroundTertiary lymphoid structures (TLS) are associated with favorable survival and play a critical role in most solid tumors. However, investigations of TLS are lacking in patients with grade 1 or...

Extraosseous multiple myeloma: imaging spectrum in the abdomen and pelvis.

Multiple myeloma represents a subset of plasma cell dyscrasias characterized by the proliferation of plasma cells typically in the bone marrow, representing approximately 1% of all cancers and 15% of hematologic malignancies. Often multiple myeloma is limited to the skeletal system; however, a small percentage (<5%) of patients will develop extraosseous manifestations. We review the current WHO classification of plasma cell dyscrasias and use multimodality imaging including US, CT, MRI, and PET-CT to illustrate the spectrum of extraosseous multiple myeloma in the abdomen and pelvis. Because extraosseous multiple myeloma is associated with a poorer prognosis and decreased survival, it is important for the radiologist to become familiar with a variety of extraosseous manifestations in the abdomen and pelvis, especially in a patient with a known diagnosis of multiple myeloma and the development of an abdominal or pelvic mass.

The Emperor's New Clothes: A Critique of the Current WHO Classification of Malignant Melanoma.

The World Health Organization's classification of skin tumors of 2018 presents melanoma as a loose assembly of independent biologic entities, each of which is characterized by a distinctive constellation of clinical, histopathologic, and molecular findings that evolve through different pathways of lesional progression from a benign to an intermediate and, ultimately, malignant tumor. The alleged pathways, however, are based on vague correlations and fail to take into account the common occurrence of lesions that cannot be assigned to either of them. Moreover, there is no such thing as a lesional progression. The evolvement of neoplasms is always a clonal and, therefore, initially focal event. In the majority of melanomas, there is no evidence of a juxtaposition of a benign, intermediate, and malignant portion. Occasionally, a melanoma may develop within the confines of a melanocytic nevus, but a nevus cannot transform into melanoma. The concept of lesional progression merely serves to handle problems of differential diagnosis because it obscures and, in fact, denies the difference between benign and malignant neoplasms. In the current classification of the World Health Organization, every lesion is said to bear some risk of malignant progression, intermediate categories are recognized for all alleged pathways, and no distinction is made between "high-grade dysplasia" and melanoma in situ. Differentiation between benign and malignant neoplasms of melanocytes may be difficult, but the concept of lesional progression does not address those problems; it merely offers evasions under the disguise of diagnoses.

Spontaneous Regression and Resolution of Breast Implant-Associated Anaplastic Large Cell Lymphoma: Implications for Research, Diagnosis and Clinical Management

First described in 1997, breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) was recognised by the World Health Organisation in 2016 as a specific disease. It typically presents as a late seromacontaining atypical, monoclonal T cells which are CD30+ and anaplastic lymphoma kinase negative. Until recently, it was thought that the disease was very rare. However, it is being diagnosed increasingly frequently with 56 cases confirmed in Australia by September 2017 and the estimated incidence revised from 1 in 300,000 to between 1 in 1000 and 1 in 10,000 patients with bilateral implants. There is debate about the spectrum of BIA-ALCL. According to the current WHO classification, BIA-ALCL is a cancer in all cases. Treatment guidelines require that it is treated urgently with a minimum of bilateral removal of implants and capsulectomies. Whilst acknowledging the disease has been under diagnosed in the past, with some notable exceptions the BIA-ALCL literature has given scant attention to the epidemiological evidence. Now that it is known that the disease may occur in up to 1 in 1000 patients with a median of 7.5 years from implantation to diagnosis, understanding it in its epidemiological context is imperative. The epidemiology of cancer and lymphoma in women with breast implants strongly suggests that most patients do not have a cancer that will inevitably progress without treatment but instead a self-limiting lympho-proliferative disorder. Although the possibility of spontaneous regression has been raised and the observation made that treatment delay did not seem to increase the risk of spread, the main objection to the lympho-proliferative hypothesis has been the lack of documented cases of spontaneous regression or resolution. Because all cases currently are considered malignant and treated urgently, only case report evidence, interpreted in the proper epidemiological context, is likely to be available to challenge this thinking. New observations and interpretation of the epidemiology of BIA-ALCL are made. These are supported by the presentation of two cases, which to the best of our knowledge comprise the first documented evidence of spontaneous regression and spontaneous resolution of confirmed BIA-ALCL. The epidemiology of the disease strongly suggests that the vast majority of cases are not a cancer that will inevitably progress without treatment. The findings presented in the manuscript provide supportive clinical evidence. Consequently, an alternative view of BIA-ALCL with implications for research, diagnosis and clinical management needs to be considered. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Multicenter analysis of treatment outcomes for well differentiated grade 3 neuroendocrine tumors (NET G3).

4607 Background: Well differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications from 2017 and 2019. Retrospective data suggest that commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Therefore, current treatment guidelines suggest alternative first-line treatment protocols like temozolomide-based (TEM), streptozotocin-based (STZ) and FOLFOX which have only been studied in second-line so far. The aim of this multicenter analysis was to evaluate treatment outcomes for NET G3 with a focus on the efficacy of different first-line regimens. Methods: We performed retrospective analysis of all patients with NET G3 in the NEN databases of 3 German cancer centers. All histopathological findings were reviewed by the investigators in order to comply with the most current WHO classification. Results: A total of 131 patients could be identified. Median Ki67 was 30 %, primary tumors were located in the pancreas in 71 % of cases, 20 patients had a history of prior NET G1/G2 diagnosis. Median overall survival (OS) was 138.1 months with a median follow-up of 20.4 months. 125 patients received palliative first-line therapy: PE n = 34, FOLFOX n = 36, TEM (mostly temozolomide+capecitabine) n = 21, STZ n = 19, other (including targeted agents, somatostatin analogues, PRRT and multimodal combination approaches) n = 15. Overall response (ORR) and disease control rate was 35.3 % and 67.6 % for PE, 52.8 % and 80.6 % for FOLFOX, 28.6 % and 66.7 % for TEM, 47.4 % and 68.4 % for STZ, 20.0 % and 73.3 % for other respectively. Median progression-free survival for PE was 5.2 months. Compared to PE, PFS in the other treatment groups was 6.0 months for FOLFOX (p = 0.164), 12.0 months for TEM (p = 0.059), 5.7 months for STZ (p = 0.519), 14.1 months for other (p = 0.003). All non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 vs. 5.2 months; p = 0.011). 89 patients received second-line systemic therapy with a median PFS of 5.3 months. Conclusions: In this first multicenter analysis of different treatment strategies for NET G3, patients receiving upfront treatment with non-PE regimens had a significantly prolonged PFS. Of the single defined protocols, FOLFOX showed the highest ORR, and TEM the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this newly defined tumor entity is needed.

Epitheliod sarcoma: Molecular insights into proximal versus classic variant.

e23552 Background: Epithelioid sarcoma (ES) is an ultra-rare sarcoma with distinctive pathologic and clinical features, marked by the loss of the expression of the SWI/SNF chromatin remodeling complex subunit SMARCB1. The current WHO classification recognizes two ES subtypes, different by morphology, clinical behavior and outcome: the “classic-type” and “proximal-type” ES. This study is aimed to better understand the molecular grounds sustaining this difference, and to identify new potential treatment targets to personalize therapy in this rare disease. Methods: RNA sequencing profiling was conducted on FFPE samples. Functional annotation enrichment was evaluated through over representation and gene set enrichment analyses (GSEA). Inference of immune contexture was obtained through deconvolution and single sample GSEA (ssGSEA) approaches. Results: Twelve samples from 5 proximal-type ES and 7 classic-type ES were profiled, 10 naïve and 2 pre-treated with chemotherapy. Proximal variant samples featured an overepresentation of MYC activity signatures and of other signatures impacting on cell cycle, protein synthesis and chromatin metabolism. Pathways enriched in the classic variant included NOTCH/HEDGEHOG and immune system regulation (e.g. inflammatory, interferon alpha and interferon gamma). Accordingly, deconvolution and ssGSEA approaches predicted an increased immune infiltration in classic subtype samples, essentially involving T cells, as well as increased expression of HLA class I molecules. Conclusions: Different regulatory networks seem to contribute to the different biologic and clinical behavior of proximal and classic ES. These preliminary data suggest a potential greater sensitivity of proximal type ES to drugs targeting the cell cycle, whilst immune checkpoint inhibitors might have some activity in classic variant ES. Further studies are ongoing to validate these preliminary observations.

Hürthle-cell neoplasms of the thyroid: An algorithmic approach to pathologic diagnosis in light of molecular advances.

Our understanding of neoplasia is evolving at a rapid pace in these exciting times, where recent molecular pathology advances are reinforcing and fine tuning morphological divisions and classification. Thyroid gland neoplasia in general, and Hürthle-cell neoplasms in particular, are no exception in the current era of histopathology-molecular biology paradigm. In this review paper, we discuss the rationale that led pathologists in the past to separate Hürthle-cell neoplasms into its own dedicated diagnostic category, and provide an algorithmic approach to the differential diagnosis of oncocytic lesions of the thyroid. This review will also shed light on the current WHO classification of Hürthle-cell neoplasms in light of molecular advances that justify histopathologic distinctions.

Practical Topics and Updates in Renal Pathology

Our understanding of neoplasia is evolving at a rapid pace in these exciting times, where recent molecular pathology advances are reinforcing and fine tuning morphological divisions and classification. Thyroid gland neoplasia in general, and Hürthle-cell neoplasms in particular, are no exception in the current era of histopathology-molecular biology paradigm. In this review paper, we discuss the rationale that led pathologists in the past to separate Hürthle-cell neoplasms into its own dedicated diagnostic category, and provide an algorithmic approach to the differential diagnosis of oncocytic lesions of the thyroid. This review will also shed light on the current WHO classification of Hürthle-cell neoplasms in light of molecular advances that justify histopathologic distinctions.

Machine learning applications in R for the differentiation of primary CNS tumors.

Primary Central Nervous System (CNS) malignancies consist of various groups of tumors. Each sub‐class results in distinct clinical decision and related outcomes. According to current WHO classification of brain tumors, the integration of both histomorphology and molecular features is critical for diagnosis including tumor grade, and directly impacts treatment approaches and prognosis. However, in the United States and worldwide, scarce resources are available to perform all the required tests.The aim of this work is to improve and standardize neuropathological diagnoses for brain cancer patients throughout the world, with a particular emphasis on resource‐poor diagnostic scenarios. To achieve this goal, we have developed a population model based on articles from the open resources of MEDLINE database and the latest version of WHO classification of CNS tumors. Our data frame is comprised of 50 primary brain tumor diagnoses. Data on clinical, histomorphology and molecular features were carefully sorted according to particularities of each individual CNS tumor type. To distinguish features with the highest value for accurate diagnosis prediction we used Boruta function (Figure 1) and Model Weights Extraction (Table 1). Both methods could not detect tentative features and showed that common clinical data (age and specific tumor location) have a high impact on diagnosis prediction. In our work we implemented modern machine learning (ML) classification algorithms, such as randomForest (RF), Support Vector Machine (SVM) and Naive Bayes (NB) after splitting the data into training and validation set. We discovered that models trained to predict diagnosis on the basis of top 6 Boruta and Weight selected features showed the highest diagnostic accuracy on the validation set even in the absence of molecular data. The accuracy for all 3 algorithms with the mentioned features was as follows: RF (92%); SVM (79%); NB (52%). We also observed that ki67 plays a key role in differentiating CNS tumors as its presence significantly increased the accuracy for each trained model independently of ML algorithm. Importantly, despite the obvious value in further clinical decisions, the inclusion of all molecular data (BRAFV600E, FISH codeletion 1p19q, EGFR amplification, MGMT status and etc.) did little to contribute to distinguishing between different primary CNS malignancies in our study. In fact, the molecular data managed to slightly improve the accuracy of our prediction models (only ~ 5–6 %) compared to data on ki67 alone (~37%), suggesting that the proliferation markers should be considered as a more reliable tool for accurate staging and morphological evaluation of CNS tumors.In conclusion, our results confirm that the implementation of open sources and computing platforms by pathologists in low resource environments in the US and abroad would allow to develop a reliable cost‐effective panel of markers and significantly improve the quality of neuropathological diagnoses.The value of features according to BorutaFigure 1 The value of features according to Weight Extraction Model ## names attribute_importance ## 32 site 1.790710364 ## 18 ki67 1.123777357 ## 1 Age 0.887462753 ## 34 solid.with.infiltration 0.553816679 ## 13 GFAP 0.454128477 ## 29 perivascular.pseudorosettes 0.442591199 ## 17 infiltrative.diffuse 0.436200109 ## 14 high.cellularity 0.398945890 ## 25 Necrosis 0.330965699 ## 26 nodular 0.318905215 ## 10 Endothelial.Proliferation 0.295229054 ## 19 low.cellularity 0.279927747 ## 5 chicken.wire 0.278482297 ## 7 desmoplasia 0.260748678 ## 8 dysplastic.neurons 0.246787762 ## 28 perivascular.lymphocytes 0.244935349 ## 11 eosinophil.granular.bodies 0.239584778 ## 30 pseudopapiliar.papillary 0.228171358 ## 33 Solid.discohesive 0.217511802 ## 20 medium.cellularity 0.216013780 ## 6 columns.cords 0.212469602 ## 15 idh1.2.mutation 0.201122902 ## 22 microcystic 0.199572761 ## 35 storiform 0.189573543 ## 24 myxoid.areas 0.186702316 ## 16 idh1.R132H 0.170479121 ## 4 calcifications 0.163422951 ## 36 FISH_codeletion_1p19q 0.158014816 ## 37 LOH_codeletion_1p19q 0.150564459 ## 27 p53 0.149535733 ## 21 MGMT 0.128631095 ## 3 BRAF.V600E.mutation 0.103997736 ## 2 ATRX.loss 0.100807078 ## 31 rosenthal.fibers 0.089142945 ## 9 EGFR.amplification 0.058714262 ## 12 Gender 0.022632343 ## 23 multilayered.rosettes 0.008671977

Histology, 12p status, and IMP3 expression separate subtypes in testicular teratomas

IntroductionTwo types of testicular teratomas are distinguished by the current WHO classification. Prepubertal-type teratomas are benign, while postpubertal-type teratomas are considered malignant with metastatic potential, and are associated with germ cell neoplasia in situ. Prepubertal-type cases have been reported in the adult testis potentially causing confusion and overtreatment. Demonstration of the absence of 12p abnormalities with fluorescence in situ hybridization may facilitate diagnosis. Recently, IMP3 has emerged as a potential marker of malignancy in this context.AimsThe aim of this study was to assess histological characteristics, IMP3 expression and the presence of 12p abnormalities of pure testicular teratomas.ResultsThirty-seven cases were studied, 7 patients were children and 30 were adults. Six out of 7 pediatric cases showed no 12p abnormality and were IMP3 positive. Seventy-four percent and 79% of adult cases showed 12p abnormalities and IMP3 expression, respectively. Negative cases were not associated with in situ neoplasia or metastasis, they were smaller (mean, 14 vs 39 mm), showed less histological diversity (2.4 vs 4.0 types of tissues on average) compared to positive cases.ConclusionOur study provides further evidence that prepubertal-type (type I) teratomas may appear in adult testes, thus teratomas in adults may be either benign (type I) or malignant (type II). IMP3 expression may aid the distinction between type I and type II teratomas of the postpubertal testis even when GCNIS and 12p status cannot be assessed.

Molecular-Genetic Features of Pancreatic Neuroendocrine Tumors

Neuroendocrine tumors (NETs) account for less than 3% of primary neoplasias of the pancreas. Despite success of the classification, the discovery of new methods of treatment, and innovations in the field of visualization, non-aeroendocrine neoplasms remain a clinically complex object, which is associated, among other things, with the lack of effective biomarkers for early diagnosis and monitoring of the course of the disease. This review is devoted to the analysis of current data on the molecular genetic features of pancreatic neuroendocrine tumors, taking into account the current WHO classification. The signaling pathways and individual markers that are being developed for the typing of NETs, the prognosis of the course of the disease, and the identification of potential targets for targeted therapy are discussed. The molecular bases of hereditary syndromes, which are associated with the development of NETs, are considered.

2020 challenges in diagnosis and staging of lung cancer

Pathology plays an important role in diagnosis and management of patients with non-small cell lung carcinoma (NSCLC). The current (2015) WHO classification of lung tumours includes histologic and immunophenotypic (IHC) criteria. Adenocarcinomas are the primary focus of shifting nomenclature, emphasising histologic patterns with clinical and biological relevance. Minimally invasive and lepidic-predominant non-mucinous adenocarcinomas represent well-differentiated tumours, while solid and/or micropapillary growth patterns signify poorly-differentiated adenocarcinomas. Poorly-differentiated carcinomas that cannot be classified on the basis of histology alone can instead be subclassified using a limited IHC panel targeting TTF-1 and p63/p40. For adenocarcinomas with non-invasive (lepidic) components, pT staging hinges on the size and extent of only the invasive component. Multifocal tumours are staged based on a combination of gross growth characteristics and histologic findings. Pathology’s role extends beyond diagnosis and staging in response to expectations that cells and tissues will be available for expanded biomarker testing in patients with advanced stage disease. Testing strategies for predictive biomarkers frequently include a combination of immunohistochemistry and increasingly comprehensive molecular profiling as single gene assays become less common. Panels are constructed to balance the number of actionable targets over and against our ability to test extremely small amounts of viable tumour.

Low-grade Apocrine Intraductal Carcinoma: Expanding the Morphologic and Molecular Spectrum of an Enigmatic Salivary Gland Tumor.

Intraductal carcinoma (IDC) is the current designation for a salivary gland neoplasm previously referred to as "low-grade salivary duct carcinoma" and "low-grade cribriform cystadenocarcinoma," among others. IDC is conceptually believed to be similar to ductal carcinoma in-situ of the breast. Although IDC is one entity in the current WHO Classification of Head and Neck Tumors, recent studies have suggested that at least three subtypes exist: a low-grade, intercalated duct-like variant with frequent RET rearrangements; a high-grade apocrine variant with complex, salivary duct carcinoma-like genetics; and a mixed variant. We sought to characterize an unusual form of low-grade, purely apocrine IDC. Three cases of apocrine-type IDC with low-grade histology were retrieved from the authors' consultation files. Immunohistochemistry for androgen receptor, GCDFP-15, S100, smooth muscle actin, and p40 was performed. A custom, targeted next generation sequencing (NGS) panel including 1425 cancer-related genes was also done on all cases. All three cases developed in the parotid glands of men, aged 51, 63, and 73years (mean, 62years). All cases consisted of large, rounded macrocysts surrounded by smaller nests which were lined by cells with abundant granular eosinophilic cytoplasm and large round nuclei with prominent nucleoli. Pleomorphism was mild, the mitotic rate was low, and necrosis was absent. No cases had any invasive foci or areas of intercalated duct-like morphology. By immunohistochemistry, all cases were diffusely positive for androgen receptor and GCDFP-15, surrounded entirely by an intact layer of small myoepithelial cells positive for S100, smooth muscle actin, and p40. Targeted NGS results were obtained from two cases: both harbored HRAS mutations and copy number losses in TP53, while one case each harbored mutations in PIK3CA, SPEN, and ATM. Fusions were absent in both cases. All three patients were treated by surgery alone, and are currently free of disease (follow up 12-190months). This study confirms the existence of a low-grade, purely apocrine form of IDC. In its pure form, i.e., without an intercalated duct-type component, low-grade apocrine IDC is genetically similar to high-grade salivary duct carcinoma, with frequent HRAS and PI3K pathway mutations. Despite its molecular similarities to the aggressive salivary duct carcinoma, low-grade apocrine IDC appears to behave in a very indolent manner, supporting is classification as a non-invasive neoplasm, and underscoring the need to distinguish these tumors from each other.