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Journal of Clinical Oncology : Official... Jan 2022Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely...
PURPOSE
Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading scheme. In 2020, two groups separately developed slightly different schemes (the Memorial Sloan Kettering Cancer Center and Sydney grade) on the basis of proliferative activity (mitotic index and/or Ki67 proliferative index) and tumor necrosis. Building on this work, we sought to unify and validate an internationally accepted grading scheme for MTC.
PATIENTS AND METHODS
Tumor tissue from 327 patients with MTC from five centers across the United States, Europe, and Australia were reviewed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria and blinded to other clinicopathologic features. After reviewing different cutoffs, a two-tiered consensus grading system was developed. High-grade MTCs were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm, Ki67 proliferative index ≥ 5%, or tumor necrosis.
RESULTS
Eighty-one (24.8%) MTCs were high-grade using this scheme. In multivariate analysis, these patients demonstrated decreased overall (hazard ratio [HR] = 11.490; 95% CI, 3.118 to 32.333; < .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327; = .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261; = .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193; = .032) survivals. This prognostic power was maintained in subgroup analyses of cohorts from each of the five centers.
CONCLUSION
This simple two-tiered international grading system is a powerful predictor of adverse outcomes in MTC. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of MTCs in line with other NETs and can be readily applied in routine practice. We therefore recommend grading of MTCs on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biopsy; Carcinoma, Neuroendocrine; Cell Proliferation; Child; Child, Preschool; Consensus; Europe; Female; Humans; Ki-67 Antigen; Male; Middle Aged; Mitotic Index; Necrosis; Neoplasm Grading; New South Wales; Predictive Value of Tests; Reproducibility of Results; Retrospective Studies; Risk Assessment; Risk Factors; Thyroid Neoplasms; United States; Young Adult
PubMed: 34731032
DOI: 10.1200/JCO.21.01329 -
World Journal of Clinical Cases Sep 2021Gastric neuroendocrine neoplasms (g-NENs) or neuroendocrine tumors are generally slow-growing tumors with increasing incidence. They arise from enterochromaffin like... (Review)
Review
Gastric neuroendocrine neoplasms (g-NENs) or neuroendocrine tumors are generally slow-growing tumors with increasing incidence. They arise from enterochromaffin like cells and are divided into four types according to clinical characteristic features. Type 1 and 2 are gastrin dependent, whereas type 3 and 4 are sporadic. The reason for hypergastrinemia is atrophic gastritis in type 1, and gastrin releasing tumor (gastrinoma) in type 2 g-NEN. The diagnosis of g-NENs needs histopathological investigation taken by upper gastrointestinal endoscopy. g-NENs are positively stained with chomogranin A and synaptophysin. Grading is made with mitotic index and ki-67 proliferation index on histopathological analysis. It is crucial to discriminate between types of g-NENs, because the management, treatment and prognosis differ significantly between subtypes. Treatment options for g-NENs include endoscopic resection, surgical resection with or without antrectomy, medical treatment with somatostatin analogues, netazepide or chemotherapy regimens. Follow-up without excision is another option in appropriate cases. The prognosis of type 1 and 2 g-NENs are good, whereas the prognosis of type 3 and 4 g-NENs are close to the prognosis of gastric adenocancer.
PubMed: 34621854
DOI: 10.12998/wjcc.v9.i27.7973 -
CytoJournal 2022The existence of precursor lesions for invasive cervical cancer has been recognized for more than 50 years. Our understanding of the pathobiology and behavior of... (Review)
Review
The existence of precursor lesions for invasive cervical cancer has been recognized for more than 50 years. Our understanding of the pathobiology and behavior of cervical cancer precursors has evolved considerably over the past five decades. Furthermore, the terminology used to classify pre-invasive lesions of the cervix has frequently changed. The realization that human papillomavirus (HPV) infections constitute a morphologic continuum has prompted efforts to include them within a single classification system, specifically the squamous intraepithelial lesions (SILs) which have now been embraced by the surgical pathologists. The reduced number of specific pathological categories has made clinical decision-making more straightforward. The generic criteria for SIL have two important histological parameters: Alterations in the density of superficial epithelial cells and superficial squamous atypia. The flat condyloma or cervical intraepithelial neoplasia (CIN) I is generally associated with intermediate and high-risk HPV types as against the low-risk viruses that cause exophytic/papillary growth patterns of condylomas. The diagnosis of low-grade SIL (LSIL) (flat and exophytic condylomas) requires first excluding benign mimics of LSIL and second to confirm the characteristic cytologic atypia. For high-grade SILs (HSILs), the extent and degree of atypia generally exceed the limits of that described in flat or exophytic condylomas (LSILs). Less maturation, abnormal cell differentiation, loss of cell polarity, and increased mitotic index with abnormal mitotic figures occupying increasing thickness of the epithelium define a lesion as CIN II or CIN III. Atypical immature metaplasia associated with inflammation and atrophy is a challenge in cervical biopsy interpretation. Careful attention to the growth pattern of the epithelium, the distribution of the atypia, nuclear spacing, and the degree of anisokaryosis and the presence of enlarged hyperchromatic nuclei help in differentiating a non-neoplastic from a neoplastic process. This chapter describes in depth the diagnostic difficulties in the interpretation of cervical biopsies. It also provides useful criteria in distinguishing benign mimics from true precancerous lesions and the role of biomarkers such as the p16ink4 and Ki-67 in the differential diagnosis of precursor lesions and the reactive and metaplastic epithelium.
PubMed: 35928531
DOI: 10.25259/CMAS_03_13_2021 -
Modern Pathology : An Official Journal... Sep 2021Mitoses are often assessed by pathologists to assist the diagnosis of cancer, and to grade malignancy, informing prognosis. Historically, this has been done by... (Review)
Review
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 pathology systems, where ×400 equivalent fields are rectangular and also vary in the area displayed. The potential for error is considerable, and at times this may affect patient care. This is easily solved by the use of standardized international (SI) units. We, therefore, recommend that features such as mitoses are always counted per mm, with an indication of the area to be counted and the method used (usually "hotspot" or "average") to obtain the results.
Topics: Humans; Microscopy; Mitotic Index; Neoplasms
PubMed: 34079071
DOI: 10.1038/s41379-021-00825-7 -
Cancers Mar 2023Pancreatic neuroendocrine tumors (PNETs) are relatively uncommon malignancies, characterized as either functional or nonfunctional secondary to their secretion of... (Review)
Review
Pancreatic neuroendocrine tumors (PNETs) are relatively uncommon malignancies, characterized as either functional or nonfunctional secondary to their secretion of biologically active hormones. A wide range of clinical behavior can be seen, with the primary prognostic indicator being tumor grade as defined by the Ki67 proliferation index and mitotic index. Surgery is the primary treatment modality for PNETs. While functional PNETs should undergo resection for symptom control as well as potential curative intent, nonfunctional PNETs are increasingly managed nonoperatively. There is increasing data to suggest small, nonfunctional PNETs (less than 2 cm) are appropriate follow with nonoperative active surveillance. Evidence supports surgical management of metastatic disease if possible, and occasionally even surgical management of the primary tumor in the setting of widespread metastases. In this review, we highlight the evolving surgical management of local and metastatic PNETs.
PubMed: 37046665
DOI: 10.3390/cancers15072006 -
Gynecologic Oncology Reports Apr 2023The leiomyosarcoma (LMS) subtype of uterine sarcoma accounts for 1-2 % of uterine neoplasia cases. The present study aimed to demonstrate that the gene and protein...
The leiomyosarcoma (LMS) subtype of uterine sarcoma accounts for 1-2 % of uterine neoplasia cases. The present study aimed to demonstrate that the gene and protein chondroadherin (CHAD) levels may serve as novel biomarkers for predicting prognosis and devising novel treatment models for LMS. A total of 12 patients diagnosed with LMS and 13 patients diagnosed with myomas were included in the study. The extent of tumour cell necrosis, cellularity and atypia and the mitotic index of each patient with LMS were determined. CHAD gene expression was significantly increased in cancerous tissues compared with that in fibroid tissues (2.17 ± 0.88 vs 3.19 ± 1.61; P = 0.047). The mean CHAD protein expression in tissues was higher in LMS cases but this was not statistically significant (217.38 ± 93.9 vs 177.13 ± 66.67;P = 0.226). Positive significant correlations were obtained between CHAD gene expression and mitotic index (r = 0.476; P = 0.008), tumour size (r = 0.385; P = 0.029) and necrosis (r = 0.455; P = 0.011). Furthermore, there were significant positive correlations between CHAD protein expression levels and tumour size (r = 0.360; P = 0.039) and necrosis (r = 0.377; P = 0.032). The present study was the first to demonstrate the significance of CHAD in LMS. The results suggested that, due to its association with LMS, CHAD has predictive value in determining the prognosis of patients with LMS.
PubMed: 36860591
DOI: 10.1016/j.gore.2023.101144 -
Cell Cycle (Georgetown, Tex.) Dec 2021Mitosis is a key process in development and remains critical to ensure homeostasis in adult tissues. Besides its primary role in generating two new cells, cell division...
Mitosis is a key process in development and remains critical to ensure homeostasis in adult tissues. Besides its primary role in generating two new cells, cell division involves deep structural and molecular changes that might have additional effects on cell and tissue fate and shape. Specific quantitative and qualitative regulation of mitosis has been observed in multiple morphogenetic events in different embryo models. For instance, during mouse embryo gastrulation, the portion of epithelium that undergoes epithelial to mesenchymal transition, where a static epithelial cell become mesenchymal and motile, has a higher mitotic index and a distinct localization of mitotic rounding, compared to the rest of the tissue. Here we explore the potential mechanisms through which mitosis may favor tissue reorganization in various models. Notably, we discuss the mechanical impact of cell rounding on the cell and its environment, and the modification of tissue physical parameters through changes in cell-cell and cell-matrix adhesion.
Topics: Animals; Epithelial Cells; Epithelial-Mesenchymal Transition; Gastrulation; Mice; Mitosis; Morphogenesis
PubMed: 34720062
DOI: 10.1080/15384101.2021.1992854 -
Journal of Comparative Pathology Nov 2021Gastrointestinal lymphomas are uncommon in dogs and little is known about their distinct subtypes or proliferation rate. The aim of this study was to stratify 33 canine...
Gastrointestinal lymphomas are uncommon in dogs and little is known about their distinct subtypes or proliferation rate. The aim of this study was to stratify 33 canine gastrointestinal lymphoma samples according to the latest World Health Organization classification and to determine the Ki67 proliferation index by manual counting, digital image analysis and visual estimation. The Ki67 index was then correlated with subtype, immunophenotype, mitotic index, grade and tumour location. The mitotic index correlated positively with the Ki67 index. A significantly higher number of Ki67-positive cells was found in enteropathy-associated T-cell lymphoma type I and in diffuse large B-cell lymphoma compared with enteropathy-associated T-cell lymphoma type II. There was also a significant difference in Ki67 immunolabelled cells between grade 1 and grade 2 lymphomas. Moderate agreement was found between the Ki67 index as obtained by manual counting and visual estimation, but there was strong agreement between manual counting and digital image analysis. The user-friendly digital imaging system used in this study could have potential for future determination of the Ki67 index in lymphoid neoplasms.
Topics: Animals; Cell Proliferation; Dog Diseases; Dogs; Gastrointestinal Neoplasms; Ki-67 Antigen; Lymphoma, Large B-Cell, Diffuse; Mitotic Index
PubMed: 34886989
DOI: 10.1016/j.jcpa.2021.10.003 -
Veterinary Medicine (Auckland, N.Z.) 2014Mast cell tumors (MCTs) are the most common malignant skin cancer in dogs, and significant variability exists in their biological behavior. Most MCTs are cured with... (Review)
Review
Mast cell tumors (MCTs) are the most common malignant skin cancer in dogs, and significant variability exists in their biological behavior. Most MCTs are cured with appropriate local therapy, but a subset shows malignant behavior with the potential to spread to lymph nodes, liver, spleen, and other areas and to thus become a systemic cancer. Because of this variable behavior, it is difficult to predict how any individual tumor is going to behave. The variability thus creates uncertainty in deciding what a particular dog's prognosis is, whether staging tests to assess for metastasis are needed, and even what treatments will be necessary for best outcome. In addition to controversies over the potential for development of systemic disease, or diffuse metastasis, controversies also exist over what treatment is needed to best attain local control of these tumors. This article will briefly discuss the diagnosis of MCTs in dogs and will summarize the literature in regards to the controversial topics surrounding the more aggressive form of this disease, with recommendations made based on published studies.
PubMed: 32670846
DOI: 10.2147/VMRR.S41005