Mitotic Count Research Articles

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

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. 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. 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. 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.

RETROSPECTIVE STUDY CORRELATION BETWEEN GRADE AND AMOUNT OF MITOSIS WITH ER, PR, AND HER2 EXPRESSION IN INVASIVE BREAST CARCINOMA OF NO SPECIAL TYPE

Background: In 2018 there were about 24.2% new cases of breast carcinoma worldwide. Molecular breast carcinoma, like expression estrogen receptor (ER), progesterone receptor (PR), and Human Epidermal Growth Factor Receptor2 (HER2) have a higher sensitivity than morphological feature, like tumour grade and mitotic count as prognostic factors. The grade of the tumor reflects how similar these cells are to normal breast epithelial cells. The dominant growth pathway in normal breasts predominantly involves ER and PR, so tumours with ER and PR positivity show lower grade and proliferation activity. In contrast, tumours with ER and PR negativity often have more severe mutation, like overexpression of HER2. Objective: To analyze the correlation between grade and mitotic count with ER, PR, and HER2 expression. Methods: Analytical observational study with a retrospective design. This study used medical record data from ER, PR, and HER2 immunohistochemical examinations as well as histopathological grade and mitotic data for invasive breast carcinoma of no special type in the Anatomical Pathology Laboratory of Dr. Soetomo Surabaya for the period January 1, 2017 - December 31, 2019. Furthermore, the analysis of the relationship between grade and mitotic count was carried out with the expression of ER, PR, and HER2. Results: There was a significant negative relationship between grade and ER with rs = -0.170 (p = 0.000), the number of mitosis and ER with rs = -0.010 (p = 0.001), grade and PR with rs = -0.168 (p = 0.000), and the number of mitosis and PR with rs = -0.110 (p = 0.000). There was no significant relationship between grade and HER2 (p = 0.470) and the number of mitosis and HER2 (p = 0.279). Conclusion: There is a negative significant relationship between grade and amount of mitosis with ER and PR expression. There is no significant relationship between grade and amount of mitosis with HER2 expression.

Combining FORGE Score and Histopathological Diagnostic Criteria of Atypical Meningioma Enables Risk Stratification of Tumor Progression.

More than 50% of atypical meningiomas regrow within 5 years after surgery. FORGE score is a newly created tool to estimate the MIB-1 index in cranial meningiomas. In this investigation, we aimed to assess the predictive value of the FORGE score in combination with major diagnostic criteria of atypical meningioma (brain invasion, mitotic count ≥ 4) regarding recurrence in atypical meningiomas. We included patients operated on primary atypical meningiomas in our center from 2011 to 2019. The study included 71 patients (58% women, median age 63 years). ROC curves revealed a superiority of FORGE score combined with histopathological diagnostic criteria of atypical meningioma (AT-FORGE) in the prediction of tumor progression compared to FORGE score only (AUC: 0.72; 95% CI: 0.54–0.91, cut-off: ≥5/<5, sensitivity: 75%, specificity: 78%). Patients with an AT-FORGE score ≥ 5 had a shorter time to tumor progression (32.8 vs. 71.4 months, p < 0.001) in the univariable analysis. Multivariable cox regression analysis revealed significant predictive value of Simpson grade > II, presence of multiple meningiomas and AT-FORGE score ≥ 5 for tumor progression. The combination of histopathological diagnostic criteria for atypical meningioma with FORGE score might facilitate an effective identification of patients with an atypical meningioma who have an increased risk of tumor progression.

The first case of BRG (SMARCA4)/INI Deficient Tracheal Carcinoma: A Case Report and Review of the Literature

Abstract Introduction/Objective Primary tumors of the trachea are rare, they account for less than 0.1% of tumors in humans. In adults, 90% of primary tracheal tumors are malignant, with squamous cell carcinoma and adenoid cystic carcinoma accounting for two-thirds, with other forms occurring less frequently. The BRG (SMARCA4)/INI deficient tumor is a relatively new defined entity which is recently introduced in the WHO Classification of Tumors, 5th edition, 2021. The gene SMARCA4 is located at 19p13. Loss of SMARCA4 has been reported in several aggressive tumors with high- grade undifferentiated rhabdoid morphology but has not been reported in the trachea. Hence, we report the first case of BRG (SMARCA4)/ INI deficient tracheal carcinoma. Methods/Case Report We present a 60-year-old male with a history of tobacco abuse, shortness of breath, and a tracheal mass on chest imaging. Bronchoscopy was performed and showed a fleshy friable lesion at the anterior trachea with evidence of blood dripping into the distal airways. Results (if a Case Study enter NA) Microscopic examination showed a high grade, poorly differentiated carcinoma with tumor necrosis, high mitotic counts, and marked nuclear pleomorphism. Immunohistochemical stains were performed. The tumor cells were strongly and diffusely positive for CK-7 and weakly positive for synaptophysin, negative for pan-cytokeratin, TTF-1, CK-20, p40, CK5/6, and chromogranin. Then BRG (SMARCA4) and INI 1 (BAR47) were performed and showed negative staining on BRG expression, while INI 1 is intact (nuclear expression). These features are consistent with BRG (SMARCA4)/ INI deficient carcinoma. Conclusion BRG (SMARCA4)/ INI deficient carcinoma is a new entity in the trachea, which is very aggressive with a poor prognosis. Targeted therapy or clinical trials may be available as additional cases are diagnosed in the future.

Evaluation of NAB2-STAT6 Fusion Variants and Other Molecular Alterations as Prognostic Biomarkers in a Case Series of 83 Solitary Fibrous Tumors.

Simple SummaryA solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that can arise at any body location. Local or distant recurrences occur in a significant proportion of cases, but these recurrences are difficult to predict using clinical or pathological features. A specific genetic alteration, the gene fusion NAB2-STAT6, is considered to be the defining driver mutation, and different fusion variants seem to account for specific clinical and pathological features, but their prognostic value remains controversial. We inspected a series of 83 SFTs with a high rate of recurrence to evaluate the clinical significance of several potential biomarkers in addition to gene fusion. Our findings confirm previous observations and uncover novel associations of molecular alterations with clinical features, adding additional evidence for their potential application as molecular biomarkers that are helpful to predict the course of the disease.Risk stratification of solitary fibrous tumor (SFT) patients based on clinicopathological features has limited efficacy, especially in predicting late relapse or metastasis. The hallmark alteration of SFT is the gene fusion NAB2-STAT6, whose prognostic value remains controversial. As biological knowledge of this entity has increased in recent years, new molecular alterations have emerged that could be helpful to refine current risk models. Here, we evaluated NAB2-STAT6 fusion variants and other molecular alterations in a series of 83 SFTs that are enriched in progressing cases. Gene fusion variants were identified by targeted RNA-seq in the whole series, whereas TERT promoter (pTERT) mutations were inspected by Sanger sequencing in a subset of 18 cases. Immunohistochemical assays were performed to assess BCOR and NTRK expression as well as P53 mutation status in 45, 44, and 44 cases, respectively. While confirming the associations of gene fusion variants with clinicopathological parameters, our results do not prove their prognostic value. Pan-TRK immunoexpresion correlated with recurrence/progression, P53 staining associated with higher mitotic counts, and pTERT mutations were enriched in cases with fatal outcome. An intriguing correlation was found for BCOR protein expression with gene fusion variants, size, and tumor location.

Tumor-infiltrating lymphocytes (TILs) in feline melanocytic tumors: A preliminary investigation

The presence and the role of tumor-infiltrating lymphocytes (TILs) in different types of tumors, but particularly in melanoma, has become more and more investigated during the last decade, both in human and veterinary medicine. Melanocytic tumors are quite rare in cats, with diffuse iris melanoma being the most commonly diagnosed in this species.The aim of this study was to characterize the lymphocytic infiltration in feline melanocytic tumors and to analyze their association with the histological features of malignancy recognized in these tumors, as well as with the expression of the most commonly used immunohistochemical markers.Thirty-eight feline melanocytic tumors were retrospectively selected; histological and immunohistochemical characterization of the tumors (histologic criteria of malignancy; S100, Melan A, and PNL2 expression) and of TILs (presence/absence, density, distribution, and grade; CD3, CD20 expression) were performed and associations between them tested.Results showed that TILs grade increased with cellular pleomorphism (P < 0.05) and, within the group of cutaneous melanocytic tumors, also with the mitotic count (P < 0.05). On the other hand, TILs grade was inversely associated with the percentage of neoplastic cells positive for Melan A (P < 0.05) and PNL2 (P < 0.05). Both CD3+ and CD20+ lymphocytes increased significantly with TILs grade and in association with mitotic count, when stratified in low/high quantity.This preliminary study suggests that TILs in feline melanoma may be associated with histologic features of malignancy and loss of melanocytic-specific markers, such as Melan A and PNL2. Further studies, with a larger cohort and follow-up information, are recommended.

Novel architecture with selected feature vector for effective classification of mitotic and non-mitotic cells in breast cancer histology images

The paper focuses on the detection of mitosis in breast cancer. Detection methods in vogue rely heavily on visual inspection and assessment of histology images by trained pathologists, so the validation of results is a time-consuming process. Even accuracy wise, there remains room for improvement. This calls for high accuracy automated systems to replace manual assessments. Mitotic count is important because it provides us information about the aggressiveness of the tumour cells i.e. how rapidly it is spreading in the human body. To address this research gap, the current study is devoted to construct a novel framework utilizing neural network-based concepts along with reduced feature vectors and multiple machine learning techniques to classify the mitotic and non-mitotic cells. The dominant features in the detection of mitosis are texture features, therefore the texture of cells is used to derive the efficient reduced feature vectors which plays a significant role in identifying cancerous cells. During the feature engineering process, the features that distinguish a cancer cell from the normal cells were identified. Using these features as the base features, extraction with multiple techniques like GLCM, LBP and LTP along with classification algorithms like SVM, Naive Bayes and Random Forest were applied to the source dataset of the images, whose ground truth reference was available. Inspiring from Neural Networks, the proposed architecture allocates different weights to different features which increases the productivity of the model. The proposed framework is a new and intelligent version of ensemble learning which makes ensemble learning a more powerful tool for accurate and high-throughput results. The proposed method outperforms techniques already reported in the literature for the detection of mitotic cells in MITOS-12, AMIDA 13, MITOS-14 and TUPAC16.

616 Rare KIT gene mutation in a recurrent GIST: Case Report

Abstract Introduction The diagnosis and treatment of Gastro-intestinal stromal tumours (GISTs) has been revolutionized by molecular pathology and targeted therapy. Description This patient was diagnosed with locally advanced gastric GIST in 2009. He was initially treated neoadjuvantly with imatinib from 2009- 2010. He underwent laparoscopic resection in 2010. Pathology showed almost complete response with only 1.5mm focus of viable tumour. He did not receive adjuvant imatinib as this was not established practice in 2010. Recurrent disease was resected in 2011. Mitotic count was 200/50hpf. Adjuvant imatinib was given for 5 years then discontinued in 2016. Imaging showed no recurrence over this time period. Molecular testing showed Kit Exon 11 mutation- this is common in GISTs and associated with response to imatinib. Recurrent disease was diagnosed 2018 with a 10x9cm mass between residual stomach and liver– he recommenced imatinib with partial response (maximal response was reached in 2020, but a new 3cm lesion was noted) He underwent further resection of the residual stomach and liver segmentectomy in 2020. Histology showed acellular areas of myxoid degeneration, indicating treatment response however viable tumour remained. Sequencing was performed. This showed the expected mutation in exon 11 but also a mutation in exon 13 of KIT- this has been shown recently to confer resistance to imatinib. Discussion Over 90% of GISTs harbour mutations in c-KIT. Recent work has demonstrated that some tumours acquire secondary mutations conferring resistance, following prolonged TKI therapy. Radiological and histopathological features correlate with such events and assist in deciding surgical management.

S1552 A Rare Care of Pancreatic Neuroendocrine Tumor and Hyperammonemic Encephalopathy

Introduction: Hyperammonemic encephalopathy infrequently occurs as the presenting manifestation of a pancreatic neuroendocrine tumor (PNET) without associated hepatic failure. We present a rare case of a patient with neurologic decline requiring hospitalization who was diagnosed with a PNET and hyperammonemic encephalopathy without liver failure. Case Description/Methods: A 59-year-old male attorney with hypertension presented to his primary care physician with a bilateral intention tremor and 2 weeks later developed progressively worsening cognition. His medical history was otherwise unremarkable. Upon hospitalization, vital signs were normal. A neurologic exam showed 1/4 recall and impaired attention. Labs revealed an elevated ammonia (219 mg/dL) and total bilirubin of 5.9 mg/dL (indirect 4.1 mg/dL). His CBC, CMP, AST/ALT/Alkaline phosphatase, coagulation panel, heavy metal screen, B1, B6, B12, folate, HIV, TSH, RPR, Lyme, infectious evaluation (including COVID), and lumbar puncture were normal. A brain MRI showed nonspecific bilateral basal ganglia changes. A RUQ ultrasound showed a pancreatic mass. His mental status improved after 2 days of lactulose titrated to 3-4 soft bowel movements daily. A chest / abdominal / pelvic CT scan revealed an 11.3 cm heterogeneous pancreatic mass encasing the splenic artery and abutting greater than 50% of the superior mesenteric vein, without evidence of pulmonary or hepatic metastases. CA 19-9 was 13 U/mL. Ultrasound-guided biopsy revealed a well-differentiated neuroendocrine tumor (WHO Grade 2) positive for synaptophysin, Cam 5.2, Chromogranin A, Ki67 5%, and mitotic count < 2/5 mm 2. The patient underwent an open distal pancreatectomy and splenectomy;a liver nodule, positive for well-differentiated neuroendocrine cells, was found. 5/65 lymph nodes were positive for metastatic disease. Pathologic stage was T3N1M1a. A PET scan, done approximately a month after surgery, showed mild metabolic activity in the pancreatic body and multiple liver metastases not seen on CT scan. Currently, the patient is being followed by oncology and is receiving Lanreotide. Discussion: This case is unusual because the patient presented with encephalopathy without evidence of hepatic failure. It is postulated that the encephalopathy was the result of microvascular portosystemic shunting due to unrecognized hepatic metastases. This case study emphasizes the potential need for advanced imaging in patients with PNET and encephalopathy when initial studies suggest no evidence of hepatic failure.

The Ki-67 antigen in the new 2021 World Health Organization classification of lung neuroendocrine neoplasms.

SummaryProf. Rosai’s work has permeated the surgical pathology in many fields, including the 2017 World Health Organization classification on tumors of endocrine organs and pulmonary neuroendocrine cell pathology, with stimulating contributions which have also anticipated the subsequent evolution of knowledge. Among the many studies authored by Prof. Rosai, we would like to recall one of which whose topic has been encased in the new 2021 World Health Organization classification on lung tumors. This is an eminently practical paper dealing with the use of the proliferation antigen Ki-67 in lung neuroendocrine neoplasms. While these neoplasms are primarily ranked upon histologic features and Ki-67 labeling index does not play any role in classification, diagnostic dilemmas may however arise in severely crushed biopsy or cytology samples where this marker proves helpful to avoid misdiagnoses of carcinoids as small cell carcinoma. Another application of Ki-67 labeling index endorsed by the 2021 World Health Organization classification regards, alongside mitotic count, the emerging recognition of lung atypical carcinoids with increased mitotic or proliferation rates, whose biological boundaries straddle a subset of large cell neuroendocrine carcinoma.This article focuses on these two practical applications of the proliferation marker Ki-67 in keeping with the 2021 World Health Organization classification, which provides standards for taxonomy, diagnosis and clinical decision making in lung neuroendocrine neoplasm patients.

Surgical Approaches and Oncological Outcomes in the Management of Duodenal Gastrointestinal Stromal Tumors (GIST).

Background: Duodenal gastrointestinal stromal tumors (GIST) are a rare subset of GIST. Their surgical management in this anatomically complex region consists of varied approaches, and the administration of imatinib mesylate (IM) has not been clarified. Methods: We retrospectively reviewed patients with duodenal GIST treated during a 10-year-period. We analysed the clinicopathological characteristics and survival factors and evaluated the perioperative and long-term outcomes based on the extent of resection ((ocal-resection (LR) versus pancreaticoduodenectomy (PD)) and the IM-administration. The median follow-up period was 60 months (range, 12–140). Results: A total of thirteen patients (M:F = 7:6) with median age of 64 years (range, 42–77) underwent resection of duodenal GIST. Median tumor size was 5.2 cm (range, 1.5–13.3). Eight patients (61.5%) underwent LR and five patients (38.5%) PD. R0-resection was achieved in 92.5%. Neoadjuvant IM-therapy was administered in five patients leading to tumor downsizing and in 40% to less-extended resection. The PD group consisted of larger tumors with higher mitotic count, mostly located in D2 (p = 0.031). The PD group had longer operative time (p = 0.026), longer hospital stay (p = 0.016), and higher rate of postoperative complications (p = 0.128). The actuarial 1-, 3-, and 5-year overall survival were 92.5%, 84%, and 73.5%, respectively, whereas the disease-free survival rates at 1, 3, and 5 years were 91.5%, 83%, and 72%, respectively. A tendency towards increased risk of disease recurrence was demonstrated for patients with tumor >5 cm and high-risk potential. There was not statistic survival benefit for one or the other surgical approach. Conclusion: The type of resection depends on duodenal site of origin and tumor size. LR can be the treatment of choice for duodenal GIST whenever technically feasible. Recurrence of duodenal GIST is dependent on tumor biology rather than surgical approach. Administration of IM in neaodjuvant setting should be considered in cases with high-risk GIST scheduled for PD since it might facilitate less-extended resection.

Role of Trop2, Cyclin D1 and FOXP3 in bladder carcinoma in Egyptian patients: An immunohistochemical study

Background: In Egypt, Urinary bladder carcinoma is a common malignancy accounting for 14.3% of total malignancies in both sexes with a 3:1 M: F ratio. To reduce bladder cancer morbidity and mortality, identification of tumor markers specific enough for prognosis and can serve as an effective anti-cancer target is urgent. The purpose of this study is to evaluate the role of Trop2, Cyclin D1, FOXP3 and their relationship with the established clinicopathological parameters and overall survival of bladder cancer patients. Methods: Using the standard immunohistochemical technique in 80 primary bladder carcinomas and 20 specimens as non-neoplastic groups. The malignant group included 50 cases of muscle-invasive and 30 cases of non-muscle invasive bladder cancer. Results: significant association of overexpressed Trop2 and FOXP3 with high grade, advanced stage, lymph node involvement, and high mitotic count. On the other hand, Cyclin D1 displayed a favorable prognostic impact and an inverse relation with Trop2 and FOXP3. A direct correlation between both FOXP3 expression in malignant cells and peritumoral TIL FOXP3+ expression was displayed. Trop2, Cyclin D1, FOXP3 expression didn’t affect the overall survival of the studied sample. Conclusions: The inverse relation between Cyclin D1 and Trop2 proposes the consumption of Cyclin D1 by Trop2 as a ligand in the urinary bladder carcinogenesis. A synergistic role and a cross-talk between TIL FOXP3+ and tumoral FOXP3 + cells are anticipated. Trop2 and FOXP3 could be a promising potential biomarkers for identifying patients with poor prognostic factors in bladder cancer serving as potential targets for cancer therapy

Significance of circulating tumor cell monitoring in targeted therapy for gastrointestinal stromal tumors

Objective: To explore the significance of circulating tumor cell (CTC) monitoring in evaluating the efficacy of targeted therapy for gastrointestinal stromal tumor (GIST). Methods: A prospective cohort study was performed. The data of patients with locally advanced GIST or liver metastasis who were admitted to The Affiliated Hospital of Nantong University from August 2013 to December 2018 were collected. Inclusion criteria: (1) patients aged older than 18 years; (2) patients who were diagnosed with GIST based on pathology; (3) patients without surgery, whose preoperative imaging evaluation of GIST found the violations of the surrounding organs or partial transfer of an estimated difficulty to achieve R0 resection, or the maximum diameter of the tumor > 10 cm, or the liver metastasis, or the expectation of higher risk of surgical complications; (4) patients who were treated with the imatinib 400 mg/d for the first time; (5) Eastern Cooperative Oncology Group (ECOG) score of 0-2. Exclusion criteria: (1) genetic testing revealed a D842V mutation in exon 18 of the PDGFRA gene; (2) alanine aminotransferase and/or aspartate aminotransferase > 2.5 times the normal upper limit; (3) serum total bilirubin >1.5 times of normal upper limit; (4) neutrophil count < 1.5×10(9)/L, or platelet count < 75×10(9)/L, or hemoglobin < 60 g/L; (5) creatinine > normal upper limit; (6) patients had serious cardiovascular and cerebrovascular diseases within 12 months before enrollment; (7) female patients were pregnant or lactating; (8) patients suffered from other serious acute and chronic physical or mental problems, and were not suitable for participating in this study judged by researchers. The patients who could not tolerate treatment regimen, or developed serious adverse reactions and did not follow the medication scheme after enrollment were excluded. Before imatinib treatment and 1-month and 2-month after treatment, quantitative PCR was used to detect the DOG-1 expression of monocytes in peripheral blood, and the ratio of DOG-1/β-actin > 3×10(-5) was used as the CTC positive threshold of GIST. The positive rate of CTC, the efficacy of imatinib treatment (complete response, partial response, stable disease, progressive disease, and occurrence of adverse reactions), and the relationship between CTC positive rate and clinicopathological characteristics of patients were analyzed. Furthermore, the ratio of DOG-1 decrease/baseline DOG-1 after 1-month of treatment was used as an indicator to evaluate whether targeted therapy was effective. The receiver operating characteristic (ROC) curve was rendered, and the area under the curve (AUC) was calculated. Results: A total of 68 GIST patients were enrolled in this study, including 39 cases of locally advanced GIST and 29 cases with liver metastases, 32 males and 36 females with the mean age of (51.2±11.8) (range 31 to 74) years. After 2-month of imatinib treatment, 43 cases were evaluated as partial response, 11 cases as stable disease, and 14 cases as progressive disease, with an effective rate of 79.4% (54/68). During the treatment of imatinib, the incidence of grade 3 or higher adverse reactions was 22.1% (15/68), including 12 cases of grade 3 neutropenia and 3 of grade 4 drug eruption, which were all relieved after conservative treatment. The positive rates of CTC in 68 patients before treatment, 1-month and 2-month after treatment were 66.2% (45/68), 41.2% (28/68) and 23.5% (16/68), respectively. The positive rate of CTC was associated with tumor size, liver metastasis, mitotic count and risk level (all P<0.05). By analyzing the effective group and the ineffective group of targeted therapy, it was found that the positive rate of CTC in the effective group showed a decreasing trend, while the positive rate of CTC in the ineffective group showed an increasing trend. The AUC of predicting the efficacy of targeted therapy for GIST was 0.823 by detecting the change trend of CTC 1-month after treatment (P<0.001). When the DOG-1 content decreased by more than 57.5% 1-month after treatment, it can be used as an indicator to judge the effectiveness of the treatment, whose sensitivity was 72.2% and specificity was 100%. Conclusion: The detection of peripheral blood CTC can evaluate the efficacy of targeted therapy in GIST patients and can provide decision-making basis for further clinical treatment.

Definition of tumor rupture in gastrointestinal stromal tumor

Tumor rupture is a common clinical event in the process of tumorigenesis, progression, diagnosis and treatment of gastrointestinal stromal tumor, which is closely associated with tumor recurrence, metastasis and poor prognosis. Tumor rupture may be associated with some intrinsic biological aggressiveness qualities, such as large tumor size, high mitotic count, and KIT exon 11 deletion mutations involving codons 557 and 558, and may be relatively more frequent with small intestine GIST and excellent response to imatinib neoadjuvant therapy resulting in tumor tissue rapid liquefacient and necrosis. The triggering factors involve sudden increase in abdominal pressure, external pressure, collision and improper surgical operation, etc. Tumor rupture is considered as an important risk factor of recurrence after macroscopically complete resection of tumor, and an indication for determining interval or even lifelong adjuvant therapy with imatinib according to guidelines. However, there is no consensus or universally accepted definition of tumor rupture, and, consequently, its incidence varies greatly across reported series and lacks detailed epidemiological data. Without pre-defined criteria, it is difficult to assess the clinical significance of rupture. We reviewed the relevant literature and international guidelines, and generally divided tumor rupture into spontaneous rupture and iatrogenic rupture. Based on the Oslo criteria, we proposed the following six definitions for tumor rupture: (1) tumor fracture or spillage; (2) blood-stained ascites; (3) gastrointestinal perforation at the tumor site; (4) microscopic infiltration of an adjacent organ; (5) intralesional dissection or piecemeal resection; (6) incisional biopsy. The following types of minor defects of tumor integrity should not be defined as rupture: (1) mucosal defects or spillage contained within the gastrointestinal lumen; (2) microscopic tumor penetration of the peritoneum or iatrogenic damage only to the serosa; (3) uncomplicated transperitoneal needle biopsy; (4) R1 resection. In addition, we further emphasize the importance of identifying risk factors of tumor rupture, prevention and positive intervention.

Assessment of proliferation in breast cancer: cell cycle or mitosis? An observational study.

Proliferation is an important indicator of breast cancer (BC) prognosis, but is assessed using different approaches. Not all cells in the cell cycle are committed to division. This study aimed to characterise quantitative differences between BC cells in the cell cycle and those in mitosis and assess their relationship with other pathological parameters. A cohort of BC sections (n = 621) was stained with haematoxylin and eosin and immunohistochemistry for Ki-67. The proportion of mitotic cells and Ki-67-positive cells was assessed in the same areas. The Cancer Genome Atlas (TCGA) BC cohort was used to assess MKI-67 transcriptome level and its association with the mitotic counts. The mean proportion of BC cells in the cell cycle was 24% (range = 1-90%), while the mean proportion of BC cells in mitosis was 5% (range = 0-73%). A low proportion of mitoses to whole cycling cells was associated with low histological grade tumours and the luminal A molecular subtype, while tumours with a high proportion of mitoses to the overall cycling cells were associated with triple-negative subtype, larger tumour size, grade 3 tumours and lymph node metastasis. The high mitosis/low Ki-67-positive cells tumours showed a significant association with variables of poor prognosis, including high-grade and triple-negative subtypes. The proportion of BC cells in the cell cycle and mitosis is variable. We show that not only the number of cells in the cell cycle or mitosis, but also the difference between them, provides valuable information on tumour aggressiveness.

Diagnosis on Excision Biopsy of Breast Tissues Labeled As Fibroepithelial Tumors on Trucut Samples in a Developing Country.

Introduction: Fibroadenomas (FAs) and phyllodes tumors (PTs) are less prevalent but allied to have malignant transformation in many instances. It is a challenge to diagnose the phyllodes by conventional trucut biopsy technique.Objective: To evaluate the histological characteristics of tumors labeled as fibroepithelial lesions of breast tissues on trucut biopsy and compare with a diagnosis on excision biopsy.Methods and materials: It was a descriptive cross-sectional study that was carried out in Shaukat Khanum Memorial Hospital and Research Centre within six years from January 2015 to January 2021. In trucut samples, stromal cellularity, stromal cell nuclear atypia, mitotic count, stromal overgrowth, the enhancement of stromal cellularity adjacent to epithelium were scrutinized. In each category, the activity was seen as absent, mild, moderate, or severe. Mitotic activity was graded as 0-1, 0-5, 5-10, >10.Results: A total of 125 patients were registered for the study. The mean age of patients in our study was 33.86 ± 9.95 years. The mean size was 41.02 ± 27.38 mm with a mean lump duration of 7.52 ± 5.34 months. In the FA group, the trucut sampling report showed the stromal cellularity as mild in 62 (69.7%) and stromal cell nuclear atypia as absent in 68 (76.4%) cases. But in the phyllodes tumor group, the stromal cellularity was severe in 10 (27.8%) patients and stromal cell nuclear atypia was severe in five (13.9%). The ultimate outcome showed that 89 (71.2%) patients had FA and 36 (28.8%) had PT at excision.Conclusion: Assessment of tumor size, stromal cellularity, mitoses, and enhancement of stromal cellularity adjacent to epithelium are useful markers for diagnosing the PT in trucut needle biopsy.

Piloleiomyosarcoma in cats: Histological and immunohistochemical features.

This study describes the histomorphology and immunohistochemical profile of 9 cases of feline piloleiomyosarcoma. Cats ranged in age from 7 to 16 years (mean 10), and tumors were 7 to 24 mm in diameter (mean 15). Tumors were composed of fusiform cells that were haphazardly arranged or in variably sized interwoven bundles. Neoplastic cells had eosinophilic and fibrillar cytoplasm, and elongated blunt-ended nuclei. Entrapment of hair follicles and absence of vascular components support an origin from the smooth muscle cells of the arrector pili. Additional findings included bizarre nuclei and giant cells (7/9 cases), atypical mitoses (7/9 cases), ulceration (3/9 cases), and intratumoral necrosis (6/9 cases). Neoplastic cells expressed calponin, desmin, α-smooth muscle actin, and vimentin, but not CD18, CD31, cytokeratins, glial fibrillary acidic protein, neuron-specific enolase, Melan A, p63, or S-100 protein. Surgical excision was curative in 6/9 cases, with local recurrence in 2/9 cases and metastasis to local lymph nodes in 1/9 case. Clinical outcome was influenced by mitotic count, infiltration of subcutaneous tissue, and intensity of nuclear immunolabeling for p53.

Adaptive NK Cell Therapy Modulated by Anti-PD-1 Antibody in Gastric Cancer Model.

Recently, adaptive NK cell therapy has become a promising treatment but has limited efficacy as a monotherapy. The identification of immune checkpoint inhibitor (ICI) molecules has opened a new horizon of immunotherapy. Herein, we aimed to demonstrate the cytotoxic effects of a polytherapy consisting of ex vivo expanded IL-2-activated NK cells combined with human anti-PD-1 antibody as an important checkpoint molecule in a xenograft gastric cancer mouse model. EBV-LCL cell is used as a feeder to promote NK cell proliferation with a purity of 93.4%. Mice (NOG, female, 6–8 weeks old) with xenograft gastric tumors were treated with PBS, ex vivo IL-2-activated NK cells, IL-2-activated NK cell along with human anti-PD-1 (Nivolumab), and IL-2-activated pretreated NK cells with anti-PD-1 antibody. The cytotoxicity of ex vivo expanded NK cells against MKN-45 cells was assessed by a lactate dehydrogenase (LDH) assay. Tumor volume was evaluated for morphometric properties, and tumor-infiltrating NK cells were assessed by immunohistochemistry (IHC) and quantified by flow cytometry. Pathologic responses were considered by H and E staining. Ex vivo LDH evaluation showed the cytotoxic potential of treated NK cells against gastric cancer cell line. We indicated that the adoptive transfer of ex vivo IL-2-activated NK cells combined with anti-PD-1 resulted in tumor growth inhibition in a xenograft gastric cancer model. Mitotic count was significantly decreased (*p < 0.05), and the tumor was associated with improved infiltration of NK cells in the NK-anti-PD-1 pretreated group (*p < 0.05). In conclusion, the combination approach of activated NK cells and anti-PD-1 therapy results in tumor growth inhibition, accompanied by tumor immune cell infiltration in the gastric tumor model.

PSlugS158 immunohistochemistry is a novel promising mitotic marker for FFPE samples: a pilot study.

Slug is a transcription factor belonging to the slug/snail superfamily. The protein is involved in embryonic development and epithelial-mesenchymal transition of tumors. Slug is also under temporal regulation during cell cycle. Here, we examined relationship between pSlugS158 (site-specific phosphorylation) and the cell cycle, and checked whether its phosphorylation level reflects mitotic activity in tissue specimens. Cell cycle analysis was performed after cell synchronization. To evaluate pSlugS158 identifying mitotic figures, we performed immunohistochemistry (IHC) for pSlugS158 in various formalin-fixed paraffin-embedded tissues; in addition, mitotic counts were compared with those in sections stained with hematoxylin and eosin (HE) and IHC for PHH3, a mitotic marker. We found that the level of pSlugS158 protein increased specifically at M phase and decreased at the G1/S phases in vitro. In almost all tested tissues, nuclear stain of pSlugS158 was identified in the cell with mitotic figures. There was no significant difference in mitotic counts between HE- and pSlugS158-stained sections. In conclusion, pSlugS158 may be a novel and practical immunohistochemical marker for detecting mitotic figures in human tissues.

A molecularly integrated grade for meningioma.

BackgroundMeningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management.MethodsWe evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms.ResultsWe developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score.ConclusionWe propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.