Abstract:Mitoses are often assessed by pathologists to assist the diagnosis of cancer, and to grade malignancy, informing prognosis. Historically, this has been done by expressing the number of mitoses per n high power fields (HPFs), ignoring the fact that microscope fields may differ substantially, even at the same high power (×400) magnification. Despite a requirement to define HPF size in scientific papers, many authors fail to address this issue adequately. The problem is compounded by the switch to digital patholo… Show more
“…Poor reproducibility may result from various causes, including sampling (complete lymph node excision versus core needle biopsy), definition and recognition of centroblasts, and methods of enumeration. Since grading of FL is based on the enumeration of centroblasts per high-power field (HPF), one of the challenges is the lack of a consistent definition of a HPF using a 40x microscope objective (400x magnification), where the size of the microscopic field has changed over the years even at the same magnification [ 94 ]. Lack of consensus regarding the morphological spectrum of centroblasts and using conventional methods of counting further negatively impacts reproducibility [ 95 ].…”
Section: B-cell Lymphoid Proliferations and Lymphomasmentioning
We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.
“…Poor reproducibility may result from various causes, including sampling (complete lymph node excision versus core needle biopsy), definition and recognition of centroblasts, and methods of enumeration. Since grading of FL is based on the enumeration of centroblasts per high-power field (HPF), one of the challenges is the lack of a consistent definition of a HPF using a 40x microscope objective (400x magnification), where the size of the microscopic field has changed over the years even at the same magnification [ 94 ]. Lack of consensus regarding the morphological spectrum of centroblasts and using conventional methods of counting further negatively impacts reproducibility [ 95 ].…”
Section: B-cell Lymphoid Proliferations and Lymphomasmentioning
We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.
The new WHO classification of adrenal cortical proliferations reflects translational advances in the fields of endocrine pathology, oncology and molecular biology. By adopting a question–answer framework, this review highlights advances in knowledge of histological features, ancillary studies, and associated genetic findings that increase the understanding of the adrenal cortex pathologies that are now reflected in the 2022 WHO classification. The pathological correlates of adrenal cortical proliferations include diffuse adrenal cortical hyperplasia, adrenal cortical nodular disease, adrenal cortical adenomas and adrenal cortical carcinomas. Understanding germline susceptibility and the clonal-neoplastic nature of individual adrenal cortical nodules in primary bilateral macronodular adrenal cortical disease, and recognition of the clonal-neoplastic nature of incidentally discovered non-functional subcentimeter benign adrenal cortical nodules has led to redefining the spectrum of adrenal cortical nodular disease. As a consequence, the most significant nomenclature change in the field of adrenal cortical pathology involves the refined classification of adrenal cortical nodular disease which now includes (a) sporadic nodular adrenocortical disease, (b) bilateral micronodular adrenal cortical disease, and (c) bilateral macronodular adrenal cortical disease (formerly known primary bilateral macronodular adrenal cortical hyperplasia). This group of clinicopathological entities are reflected in functional adrenal cortical pathologies. Aldosterone producing cortical lesions can be unifocal or multifocal, and may be bilateral with no imaging-detected nodule(s). Furthermore, not all grossly or radiologically identified adrenal cortical lesions may be the source of aldosterone excess. For this reason, the new WHO classification endorses the nomenclature of the HISTALDO classification which uses CYP11B2 immunohistochemistry to identify functional sites of aldosterone production to help predict the risk of bilateral disease in primary aldosteronism. Adrenal cortical carcinomas are subtyped based on their morphological features to include conventional, oncocytic, myxoid, and sarcomatoid subtypes. Although the classic histopathologic criteria for diagnosing adrenal cortical carcinomas have not changed, the 2022 WHO classification underscores the diagnostic and prognostic impact of angioinvasion (vascular invasion) in these tumors. Microscopic angioinvasion is defined as tumor cells invading through a vessel wall and forming a thrombus/fibrin-tumor complex or intravascular tumor cells admixed with platelet thrombus/fibrin. In addition to well-established Weiss and modified Weiss scoring systems, the new WHO classification also expands on the use of other multiparameter diagnostic algorithms (reticulin algorithm, Lin–Weiss–Bisceglia system, and Helsinki scoring system) to assist the workup of adrenal cortical neoplasms in adults. Accordingly, conventional carcinomas can be assessed using all multiparameter diagnostic scheme...
“…For example, in 2017 the cut-off was clarified such that cases with an index less than 3.0 (including 2.99), which were previously unclear as to which grade this belonged, now clearly included Grade 1 9 . Naturally, as in any grading and staging system that assesses a continuous variable, the Ki-67 index-based system is imperfect 54 . For example, it can be expected that cases with 2.99 (now in G1) and 3.0 (now in G2) will be similar in biological behavior.…”
Section: Discussionmentioning
confidence: 99%
“…In this review, we chose to focus on PanNENs. However, the topic of manual vs. digital pathology scoring of Ki-67 is also certainly of importance for NENs at many other anatomic sites 54 , as well as for other neoplasms in which DIA-based systems are being leveraged to assess biomarkers. In 2015, Joseph et al studying a cohort of 48 lung carcinoids, demonstrated an overall similarity of manual counting vs. DIA; although Ki-67 estimation resulted in slightly higher results than manual counting 59 .…”
Section: Discussionmentioning
confidence: 99%
“…More recently, some investigators have shown that they are able to predict Ki-67 positive cells directly from H&E images using AI-based methods 51 . Another important pending issue that needs to be addressed for improving Ki-67 assessment in PanNENs is related to standardizing hotspot size and number to be evaluated 41 , 54 . Hotspots are defined as tumor areas with higher Ki-67 nuclear staining.…”
Ki-67 assessment is a key step in the diagnosis of neuroendocrine neoplasms (NENs) from all anatomic locations. Several challenges exist related to quantifying the Ki-67 proliferation index due to lack of method standardization and inter-reader variability. The application of digital pathology coupled with machine learning has been shown to be highly accurate and reproducible for the evaluation of Ki-67 in NENs. We systematically reviewed all published studies on the subject of Ki-67 assessment in pancreatic NENs (PanNENs) employing digital image analysis (DIA). The most common advantages of DIA were improvement in the standardization and reliability of Ki-67 evaluation, as well as its speed and practicality, compared to the current gold standard approach of manual counts from captured images, which is cumbersome and time consuming. The main limitations were attributed to higher costs, lack of widespread availability (as of yet), operator qualification and training issues (if it is not done by pathologists), and most importantly, the drawback of image algorithms counting contaminating non-neoplastic cells and other signals like hemosiderin. However, solutions are rapidly developing for all of these challenging issues. A comparative meta-analysis for DIA versus manual counting shows very high concordance (global coefficient of concordance: 0.94, 95% CI: 0.83–0.98) between these two modalities. These findings support the widespread adoption of validated DIA methods for Ki-67 assessment in PanNENs, provided that measures are in place to ensure counting of only tumor cells either by software modifications or education of non-pathologist operators, as well as selection of standard regions of interest for analysis. NENs, being cellular and monotonous neoplasms, are naturally more amenable to Ki-67 assessment. However, lessons of this review may be applicable to other neoplasms where proliferation activity has become an integral part of theranostic evaluation including breast, brain, and hematolymphoid neoplasms.
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