International Medullary Thyroid Carcinoma Grading System: A Validated Grading System for Medullary Thyroid Carcinoma

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 mm2, 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; P < .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327; P = .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261; P = .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193; P = .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.

TBC1D9: An Important Modulator of Tumorigenesis in Breast Cancer

Triple-negative breast cancer (TNBC) is a major concern among the different subtypes of breast cancer (BC) due to the lack of effective treatment. In a previous study by our group aimed at understanding the difference between TNBC and non-TNBC tumors, we identified the gene TBC1 domain family member 9 (TBC1D9), the expression of which was lower in TNBC as compared to non-TNBC tumors. In the present study, analysis of TBC1D9 expression in TNBC (n = 58) and non-TNBC (n = 25) patient tumor samples validated that TBC1D9 expression can differentiate TNBC (low) from non-TNBC (high) samples and that expression of TBC1D9 was inversely correlated with grade and proliferative index. Moreover, we found that downregulation of the TBC1D9 gene decreases the proliferation marginally in non-TNBC and was associated with increased migratory and tumorigenic potential in both TNBC and luminal BC cell lines. This increase was mediated by the upregulation of ARL8A, ARL8B, PLK1, HIF1α, STAT3, and SPP1 expression in TBC1D9 knockdown cells. Our results suggest that TBC1D9 expression might limit tumor aggressiveness and that it has a differential expression in TNBC vs. non-TNBC tumors.

Treatment Strategies for Dopamine Agonist-Resistant and Aggressive Prolactinomas: A Comprehensive Analysis of the Literature

Despite most of the prolactinomas can be treated with endocrine therapy and/or surgery, a significant percentage of these tumors can be resistant to endocrine treatments and/or recur with prominent invasion into the surrounding anatomical structures. Hence, clinical, pathological, and molecular definitions of aggressive prolactinomas are important to guide for classical and novel treatment modalities. In this review, we aimed to define molecular endocrinological features of dopamine agonist-resistant and aggressive prolactinomas for designing future multimodality treatments. Besides surgery, temozolomide chemotherapy and radiotherapy, peptide receptor radionuclide therapy, estrogen pathway modulators, progesterone antagonists or agonists, mTOR/akt inhibitors, pasireotide, gefitinib/lapatinib, everolimus, and metformin are tested in preclinical models, anecdotal cases, and in small case series. Moreover, chorionic gonadotropin, gonadotropin releasing hormone, TGFβ and PRDM2 may seem like possible future targets for managing aggressive prolactinomas. Lastly, we discussed our management of a unique prolactinoma case by asking which tumors’ proliferative index (Ki67) increased from 5–6% to 26% in two subsequent surgeries performed in a 2-year period, exerted massive invasive growth, and secreted huge levels of prolactin leading up to levels of 1 605 671 ng/dl in blood.

Expression of Calretinin in Carcinoma Breast in Correlation with Various Histological and Molecular Subtypes

Breast carcinoma is the second most common cancer following lung cancer. The incidence of cancer accounts for 24.2% and cancer death is about 15% among females. There are various prognostic and predictive factors for assessing the patient encountering carcinoma breast. Among the various prognostic factors, histological subtype and molecular subtype play a key role. The calretinin expression in carcinoma breast was seen in high-grade breast carcinomas and basal like subtype of carcinoma breast. Calretinin expression was predominantly noted in high grade II and III carcinomas as in other studies and other histological subtypes like metastatic carcinomas which are considered high grade tumours. The present study aimed to correlate the various clinicopathological parameters with the calretinin expression. The expression of Calretinin was seen mainly in grade II and grade III IDC- NST and metaplastic carcinomas. Among the molecular subtypes, the Basal like subtype and the Luminal B subtype showed calretinin expression. The calretinin expression was associated with tumours with a high proliferative index with Ki67 index >14%. This implies the importance of prognostic significance of calretinin expression, as cases with a high proliferative index are likely to have poor prognosis.

A Study of Lesions of Upper Respiratory Tract

The development of the organ systems are highly regulated in physiological conditions and the development of nose and paranasal sinuses commences in the 3rd week of gestation, when the primordial structures first appear and continues until completion in early adulthood when sinus pneumatization and bony growth have ceased. Their misregulation lead to the development of many cancers and primitive nasal septum Squamous cell carcinoma (SCC) of the upper respiratory tract ranks as the sixth leading cause of cancer worldwide.In the current study, out of 31 cases, maximum cases were found to be moderately differentiated grade amounting to 64.5%, followed by well differentiated grade (22.6%) and poorly differentiated grade (12.9%). The present study also showed that poorly differentiated SCC had higher Ki 67 proliferative index and it could be a useful tool for determining the stages of tumors. Ki 67 proliferative index study of the tumor helps in better understanding of the tumor behavior so as to provide appropriate treatment and thereby increasing the survival rate of the patient.

Silver Dots – A Screening and Prognostic Aid in Oral Health

Proper histopathological grading and typing of a tumour plays a significant role in evaluating and assessing the clinical management and prognosis of the tumour. Microscopically sometimes it is difficult in categorizing a tumour into benign or malignant as histopathology does not depict all the features which are of diagnostic and prognostic value. The present study aims :To evaluate the proliferative index of the oral epithelial cells taken from a buccal smear. Materials and method : A total of 90 subjects were included with 30 subjects in each category of normal, smokers and tobacco chewers. The smears were collected from buccal mucosa and applied on the glass slides followed by fixation with alcohol for 30 min and staining of the slides with AgNOR staining as proposed by Bukhari et al (2007). Results: The AgNOR number where more in smokers when compared to normal subjects and was statistically significant. Similarly in chewers it was also comparatively higher when compared to normal and statistically significant. But the AgNOR counts between smoker and tobacco chewer, showed a mean difference of 0.6 and was not statistically significant.

C-MYC Protein Expression and High Ki-67 Proliferative Index are Predictives of Disease Relapse in Diffuse Large B Cell Lymphoma

Objective: To evaluate the status of C-MYC protein expression and Ki-67 proliferative index and to clarify their role in predicting relapse of diffuse large B cell lymphoma (DLBL). Materials and Methods: A retrospective study conducted on 50 cases diagnosed as DLBL in a 3 years’ time period from January 2014 till December 2016, collected from the archive of Pathology Departments of the National Cancer Institute Cairo - Egypt, Misr University for Science and Technology and private labs of authors. The diagnosis of DLBL for all cases, both nodal and extranodal, was confirmed by histopathologic examination and immunophenotyping. Automated immunohistochemical staining using antibodies against C-MYC protein and MIB-1 was used to evaluate the C-MYC expression in tumor cells and to assess their proliferative ability by calculating Ki-67 labelling index. The relation between the percentage of C-MYC protein expression, Ki-67 proliferative index, clinical data and the relapse status during the follow up period were analyzed. Results: A total of 50 cases of DLBL in both nodal and extra-nodal sites were included. Twenty-three cases (46%) were expressing the C-MYC protein, and 29 cases (58%) showed high Ki-67 proliferative index. Twenty-two cases (44%) relapsed during the follow-up period. Positive C-MYC protein expression was significantly associated with high Ki-67 proliferative index. C-MYC protein expression and high Ki-67 proliferative index were independently associated with disease relapses in 81.8% and 86.4% of cases respectively. Cases with combined C-MYC protein expression and high Ki-67 proliferative index showed statistical prediction of relapse in 81.8% of cases. Conclusion: C-MYC protein expression and high Ki-67 proliferative index were independently associated with relapse of diffuse large B cell lymphoma. Furthermore, the combined positive C-MYC protein expression and high Ki-67 proliferative index is better than a single positive test in predicting relapses among DLBL patients.