Guidance Navigation and Control

Cotta A., Carvalho E., da-Cunha-Júnior A.L., Antunes J.S., de Souza F.S., de Moura H.B., de Brito Pinto A.P., Valicek J., Navarro M.M., Godinho F., da Silveira E.B., Lima M.I., Cordeiro B.A., Cauhi A.F., Menezes M.M., et. al.

Abstract Background Limb Girdle Muscular Dystrophy is defined as a group of progressive autosomal recessive (85%, 28 genes) and autosomal dominant (15%, 5 genes) muscular dystrophies described in at least two unrelated families, affecting individuals that achieve independent walking, with predominant proximal muscles weakness at presentation, elevated serum creatine kinase activity, dystrophic changes on muscle biopsy, and degeneration on muscle imaging over the course of the disease. Main body The aims of this review are: (1) to show the recent Limb Girdle Muscular Dystrophy (LGMD) genetic classification illustrated with clinical and physiopathological characteristics, and cellular localization of the main gene products; (2) to present muscle radiophenotypes with an algorithm for differential diagnosis; (3) to show the role of muscle biopsy for phenotypic characterization, and pathogenicity confirmation in the era of surgical-molecular pathology. Conclusion Pathologists may be aware of clinical, neurophysiological, laboratorial, imaging, molecular, and muscle biopsy modalities to provide a precise phenotypic-genotypic diagnosis for adequate rehabilitation care, and genetic counselling.

Abdelsalam R.A., El-Shawaf I.M., Abdel-Aziz A., Bismar T.A., Yussif S.M.

Abstract Background Wnt/β-catenin pathway has an important role in hepatocarcinogenesis. It has been involved in progression, growth, epithelial mesenchymal transition and metastasis of hepatocellular carcinoma (HCC). This pathway may represent a potential target for evolving treatment strategies. β-catenin gene (CTNNB1) has been identified as an important oncogene involved in hepatocarcinogenesis in previous trials to understand the pathogenesis of HCC. This study aimed to spot light on the role of Wnt/ β-Catenin and CTNNB1 gene mutation in HCC development and its relation with different clinicopathological features. Patients and methods This study was conducted on 121 HCC cases that were obtained from liver explants from pathology laboratory at Mansoura Gastroenterology center retrospectively in the period between 2006-2017. Tissue Microarray (TMAs) were prepared. β-Catenin and Wnt immunohistochemical (IHC) staining was performed on these blocks. Detection and scoring of CTNNB1 gene mutation were done by Chromogenic In Situ Hybridization (CISH). The relation between aberrant β-Catenin, Wnt2 IHC staining and CTNNB1 mRNA expression and different clinicopathological characteristics was studied. Results A significant association was detected between aberrent β-catenin IHC staining and larger tumor size (p = 0.011), multiple tumor nodules (p = 0.021), higher stages of the tumor (p = 0.03) and with presence of lymphovascular emboli (LVE) (p = 0.034). However, no significant association was detected with tumor site, presence of lymph node spread, distant metastasis, tumor necrosis, local recurrence and alpha-fetoprotein level. No significant association was seen between Wnt2 IHC staining with either tumor site, tumor size, number of tumor nodules, presence of LVE, tumor necrosis, tumor grade, TNM stage or presence of local recurrence. A significant association was seen between CTNNB1 mRNA expression and larger tumor size (> 5 cm) (p = 0.041), higher tumor stages (Stages III and IV) (p = 0.005) and presence of distant metastasis (p = 0.008).). No significant association between CTNNB1 mRNA expression and LVE, tumor necrosis, tumor grade or occurrance of local recurrence. Conclusion Aberrant β-catenin IHC staining and CTNNB1 gene mutation in HCC correlate significantly with tumor size, number of tumor nodules, tumor stage and presence of LVE. All of these items confer poor prognosis in HCC. A highly significant correlation was detected between CTNNB1 gene mutation and aberrant β-catenin expression in HCC cases.

Bendari A., Ucar E., Bendari A., Hammoud H., Kiran F., Al-Refai R., Sham S., Kumar S.K., Jean R.D., Harshan M.

Abstract Introduction Local recurrence and distant metastasis after curative surgery and chemotherapy for colorectal cancer (CRC) is a serious complication and is considered a failure of the therapeutic strategy. The aim of this study is to identify the different prognostic factors associated with tumor recurrence and distant metastasis in CRC. Design An analytical cross-sectional design was employed, and our hospital clinical and pathology databases were queried for non-metastatic CRC (stage I-III). Patients were included if they underwent surgery and chemotherapy between 01/2016 to 12/2018 and demographic information, tumor characteristics and postoperative outcomes were extracted from each case. The data were entered into a database using SPSS version 21. Univariate analysis was initially performed, followed by a multivariate analysis to develop a prognostic model for tumor recurrence and distant metastasis in CRC. Result A total of 138 non-metastatic CRC patients were enrolled in this study. The demographic characteristics of all patients are summarized in Table 1. Our study included 65 male and 73 female patients with a Median (IQR) age of 69 (17.7) years. Among the cases, 91 (65.9%) patients had no recurrence, and 47 (34.1%) patients developed a recurrence during follow-up. Univariate analysis revealed that positive lymph nodes (p = 0.03) and tumor deposits ≥ 4 (p = 0.04) were significantly associated with colorectal tumor recurrence and/or metastasis. However, variables such as age, sex, smoking, alcohol consumption, family history of CRC, PNI, LVI, tumor size, and histological features like mucinous or signet ring cell morphology did not show any statistical significance (p > 0.05). Multivariate analysis adjusted for age, lymph node status, and tumor deposits, identified that tumor deposits ≥ 4 was the only predictor of tumor recurrence following colorectal surgery and chemotherapy. Conversely, positive lymph node status did not show statistical significance (p = 0.3). Further analysis revealed that patients who had tumor deposit number ≥ 4 tend to experience local recurrence/distant metastasis more than patients with tumor deposit number < 4. Conclusion In non-metastatic CRC patients, TD ≥ 4 is a strong predictor of local tumor recurrence and distant metastasis. Based on these findings, patients who have TDs in primary CRC resection should be subjected to enhanced surveillance.

Gedich E., Waters D.M., Gitto L.

AbstractTriple coronary artery thrombosis is a rare cause of acute myocardial infarction, and is associated with high mortality. Only a few cases of simultaneous multiple-vessel coronary thrombosis have been reported in the medical literature. This paper reports a unique case of sudden cardiac death in 36-year-old man without relevant risk factors who suffered from acute myocardial infarction due to simultaneous triple coronary artery thrombosis. Autopsy and histopathology examinations revealed near-total thrombotic occlusion in all three main coronary arteries. While the exact mechanism behind the simultaneous formation of these thrombi remains unclear, this paper discusses certain risk factors that may contribute to multiple coronary thrombosis. A review of previously reported cases of coronary thrombosis involving all three major coronary arteries in the literature is also provided to contribute to the understanding of this rare and potentially fatal condition. Obtaining a detailed medical and family history, collecting and saving blood samples for potential genetic analyses, and testing for Novel Coronavirus disease could be beneficial in cases of multiple coronary artery thrombosis to detect a potential underlying cause and provide prevention to family members at risk.

Verma D., Newaskar V., Balani S., Malik R., Khan A.

Abstract Background The International Academy of Cytology (I.A.C.) Yokohama System to report breast cytopathology can effectively categorize breast diseases into different cytological groups. Fine needle aspiration (FNAC) from the lesions in the breast has been regarded as a major method of diagnosing breast cancer, particularly in rural settings. The major purpose of this study was to validate the diagnostic accuracy of breast FNA utilizing the IAC Yokohama system in future endurances. Histopathological examination is considered the gold standard for diagnosing benign as well as malignant breast lesions and is compared with FNA results. Material and methods Research on patients getting a core-needle, incisional, or excisional biopsy of breast lesions between January 1st, 2021, and December 31st, 2021, was conducted at a tertiary care center in central India. 216 breast FNAs were recorded utilizing the IAC Yokohama system, and the most appropriate category was assigned for every case and correlated with histopathology to evaluate the effectiveness of IAC system. Results The new "International Academy of Cytology (IAC) Yokohama system" was used to categorize 216 patients into five categories based on the cytologic diagnosis. Those were C1: insufficient material (8.7%), C2: benign (65.7%), C3: atypical (1.8%), C4: suspicious of malignancy (2.7%), and C5: malignant (20.8%). FNACs were associated with ancillary testing and histological diagnosis to examine diagnostic accuracy. The overall Specificity, sensitivity, negative predictive value, positive predictive value, and accuracy were calculated with the risk of malignancy. Conclusion With high specificity and sensitivity for each type of situation, for all tumors, and for each analyzed BI-RADS category, the IAC Yokohama system provides excellent accuracy for breast FNA .

da Silveira H.G., Junior H.F., de Souza Campos L.D., Stall J., Blasius R., Kricheski C., Silva B.L., de França P.H., de Paula Alves Coelho K.M.

Abstract Background Preferentially expressed antigen in melanoma (PRAME) is a promising immunohistochemical marker for distinguishing benign from malignant melanocytic lesions in lymph node deposits. Objective To evaluate PRAME expression in metastatic melanomas and nevi found in the sentinel lymph nodes of patients with primary melanoma. Methods Thirty patients, comprising 15 nodal nevi and 15 metastatic melanomas, were immunohistochemically analyzed for PRAME expression. Nuclear expression was scored as 0–25%, > 25–50%, > 50–75% or > 75% in tumor cells. The sensitivity, specificity, and positive and negative predictive values were calculated considering nuclear expression of PRAME > 75% as positive cases. Results Cases previously diagnosed as nodal nevi were uniformly negative for PRAME. Conversely, all cases diagnosed as melanoma showed PRAME expression in more than 50% of the cells. Twelve cases showed expression above 75% of cells and were considered positive for calculations, resulting in sensitivity and specificity rates of 80% and 100%, respectively, with corresponding positive and negative predictive values of 100% and 83%. Conclusions A high level of PRAME immunoreactivity was identified in metastatic melanoma, suggesting that PRAME is a useful analytical tool for confirming the diagnosis of melanoma in a melanocytic nodal deposit.

Rana N., Thakur S., Thakur V., Chauhan A., Gulati A., Makhaik S.

Abstract Background The prevalence of breast cancer is increasing globally and its early detection is the need of hour for giving the patient a long disease-free meaningful life. The latest management regimes depend upon the biological behavior of the breast cancer that itself relies upon expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her 2) neu status for its molecular subtyping. Aim To determine the predictive value of mammographic parameters in identifying the estrogen and progesterone hormone receptor status, human epidermal growth factor receptor 2 (Her 2) neu expression and molecular subtypes of breast cancer. Methods A prospective observational study was conducted from January 2021 to September 2022 in a tertiary care institute. The study enrolled 51 females with histopathologically proven invasive breast carcinoma. The patients underwent digital mammography followed by tissue biopsy. Mammographic parameters were based on Breast Imaging-Reporting and Data System (BI-RADS) imaging features. The molecular subtypes of breast cancer were grouped into four subtypes based on St. Gallen International Expert Consensus Panel 2013. The mammographic features were then statistically correlated with molecular subtypes of breast cancer. Results Luminal type A was the most common molecular subtype in our study [ 17 (33.33%)] followed by triple negative type [10(19.61%)]. Tumors with non-circumscribed margins were predicted to be Luminal A or Luminal B subtype (p value < 0.02). Tumor with microcalcification was strongly predicted to be Her 2 subtype with a statistically significant association (p value < 0.001). Circumscribed tumors with absence of microcalcification were predicted to be triple-negative type of breast cancer. Conclusions Key features in mammography were significantly associated with breast cancer molecular subtypes. Knowledge of such correlations could help clinicians stratify breast cancer patients according to their likely molecular subtypes, potentially enabling earlier, more effective treatment or aiding in therapeutic decisions in countries where immunohistochemical (IHC) hormone receptor and Her 2 testing is not readily available.

Cotta A., Carvalho E., da-Cunha-Júnior A.L., Antunes J.S., de Souza F.S., de Moura H.B., de Brito Pinto A.P., Valicek J., Navarro M.M., Godinho F., da Silveira E.B., Lima M.I., Cordeiro B.A., Cauhi A.F., Menezes M.M., et. al.

Abstract Background Neuromuscular disorders are characterized by disturbances in any part of the neurologic pathways, including: the Central Nervous System, the motor neuron of the anterior horn of the spinal cord; the peripheral nerve, the neuromuscular junction, and the muscle. Neuromuscular disorders are considered rare affections but when the prevalences of all subtypes are analysed together they may be encountered by general neurologists and pathologists. Therefore, basic knowledge in this field is necessary to timely guide serologic, molecular, or muscle biopsy investigation for appropriate treatment and/or genetic counselling. Main body The aims of this review are: (1) to briefly describe the prevalence of common neuromuscular disorders; (2) to present basic concepts of topographic neuromuscular diagnosis; (3) to provide essential information for pathologists about the diagnostic approach of common neuromuscular disorders; (4) to present basic concepts of muscle imaging for myopathologists; (5) to provide muscle imaging, and biopsy examples of common neuromuscular disorders. Conclusion A multiprofessional integrated approach is essential for precise neuromuscular diagnosis. Detailed clinical examination with the formulation of phenotypic hypothesis is the basis for appropriate diagnosis in the Surgical-Molecular Pathology era. Clinical, epidemiological, neurophysiological, laboratorial, imaging, molecular, and physiopathologic aspects are essential for adequate neuromuscular diagnosis.

Elhassan E.A., Khalifa M.S., Ibrahim F., Mohammed S.A.

Abstract Background Every branch of surgery relies in some way on histology to obtain a conclusive diagnosis. Since precise and comprehensive information on the request form is crucial to the correct analysis and interpretation of test results, it is anticipated that all patient data and information for any requested test be provided. One of the most significant duties of the peri-operative team is the care and handling of intraoperative surgical specimens. Poor labeling and handling of surgical specimens can lead to unfavorable consequences such as misdiagnosis, incorrect or delayed therapy, and even the need for repeat surgery. The study’s. objective is to highlight the primary mistakes that occur in the pre analytical stage of histopathology request forms and specimens at two Khartoum-based histopathological institutions. Methods A prospective descriptive laboratory based cross-sectional study was carried out on 528 request forms and specimens sent to two histopathology centers between the period of May to August 2019 having gotten Ethical clearance from SMSB. Results A total of 528 laboratory request forms and specimens, Age was written in 75.6% (n 399), while the gender only was written only in 46.2% (n 244). No clinical history in 48.3% (n 255). The differential diagnosis found only in 29.5% (n156) of request forms. Regarding specimen 15.7% (83) were inadequate relative to the size of the container and only 5.3% (28) were not labeled with any information. 17.4% (92) were not sent in formalin but in normal saline. Marking of the specimen was not needed in 60% (317) and among the rest cases; 34.2% was not marked. Conclusion The study shows that laboratory request forms were not properly and thoroughly completed. Most of the specimens sent for histology had inadequate fixative and unsuitable containers, or they were mislabeled and not properly tagged. This for sure will have a detrimental effect on the quality of care.

Gallas L.F., Pacca A.M., de Andrade Natal R.

AbstractSarcomas are tumors of mesenchymal origin that remain with poor prognosis. This review highlights some emerging predictive biomarkers that could drive personalized therapy, focusing on KIT, TP53, MDM2, CDK4 mutations, PRAME, INI1 and NF1. Research shows that there is a role for imatinib in some gastrointestinal stromal tumors with KIT mutations, and the TP53 mutation may someday serve as a biomarker to assist decision-making for neoadjuvant chemotherapy. Amplifications of MDM2 and CDK4 are currently targets for new therapeutical drugs. For PRAME, there is perspective for tumors with high CTA expression with some T-cell mediated therapies. INI1 loss can be a target for tazemetostat treatment in patients with advanced epithelioid sarcoma, and studies have shown a role for Selumetinib in patients with NF1 mutations related tumors.

Morini M.A., da Cunha I.W.

AbstractMost pediatric kidney tumors clinically present as an abdominal mass, typically detected by the child’s caregivers and later confirmed through imaging tests. Malignant renal cancers account for approximately 5% of childhood kidney neoplasms, with Wilms tumors (WT) being the most common diagnosis in this category (90% of cases). Patients are treated according to two main protocols: the American protocol of the Children’s Oncology Group (COG) or the protocol from the Société Internationale d’Oncologie Pédiatrique (SIOP), which differ in terms of the timing of surgery (before or after chemotherapy). Grossly, pediatric kidney tumors are neoplasms that can vary significantly in size. After a correct histological diagnosis, the child will be treated according to the guidelines for that specific neoplasm. Therefore, the accurate diagnosis of the histological subtype is crucial for determining the appropriate treatment that can improve survival rates in children. Consequently, it is extremely important to recognize neoplasms that require differentiation from WT.

Nagel J., Paschoalini R.B., Barreto P.S., Credidio C.H., Paulino E., Del Pilar Estevez-Diz M.

AbstractEndometrial carcinoma (EC) is the most common gynecologic malignancy in high-income countries, with its incidence and mortality rising globally, particularly in countries undergoing rapid socioeconomic transitions. Over the past decade, the management of EC has shifted towards molecular classification and biomarker-driven therapies. This shift began in 2013 with the discovery of the 4 prognostic and molecular EC subgroups by The Cancer Genome Atlas (TCGA). Following the TCGA discovery, the Proactive Molecular Risk Classifiers for Endometrial Cancer (ProMisE) and the TransPORTEC initiative have provided 4 pragmatic molecular classifiers by combining next-generation sequencing (NGS) and surrogate immunohistochemical markers to TCGA’s categorization: Mismatch Repair Deficient (MMRd); p53-abnormal (p53abn); No Specific Molecular Profile (NSMP); and POLE-mutant (POLEmut). These subgroups not only provide insights into the biological behavior of EC but also have strong clinical relevance and prognostic implications. In line with these advancements, the World Health Organization (WHO) endorsed molecular classification in 2020, advocating for its integration into EC pathology reports. In 2023, the Federation of International Gynecology and Obstetrics (FIGO) proposed a new staging system that integrates histological parameters and molecular profiles into routine pathology practice. The use of complete molecular classification surrogates in all EC cases, whenever resources permit, is intended to promote prognostic risk-group stratification, data collection, Lynch Syndrome (LS) screening, and potentially influence adjuvant and systemic treatment decisions, as well as predict the efficacy of Immune Checkpoint Inhibitors (ICI). Consequently, the evolving landscape of predictive biomarkers in EC has gained importance in daily oncology practice, profoundly changing the role of pathologists. Pathologists are now crucial in interpreting molecular information and participating as members of multidisciplinary teams in therapeutic decisions. This review article aims to emphasize the importance of molecular classification in EC and encourage pathologists to become familiar with the use of predictive biomarkers in their daily anatomical pathology practice.

Campos A.H., Auresco L.C., Marins L.V., Divino P.H., Sabbaga J., Hoff P.M.

AbstractPredictive biomarkers of response to therapy are fundamental for the personalized therapeutic management of patients with colorectal carcinoma (CRC). The main predictive biomarkers related to CRC are the mismatch repair proteins/microsatellite instability status (MMR/MSI status), RAS/RAF mutation status and HER2 status. We discuss the scenarios in which these biomarkers are used and address different aspects that may affect the evaluation of each biomarker. We also address the increasingly recognized importance of circulating tumor DNA (ctDNA) testing in the management of stage II-III CRC as well as the role of the pathologist in this setting.

Nishimuni M., Claro L.C., Braghiroli M.I.

AbstractGastric cancer is the fifth most common cause of cancer-related deaths globally, with a decreasing but still high number of cases. Although there have been improvements in treatment choices, the expected survival rates have not yet been achieved. In addition to the challenges associated with developing effective therapies, there is an urgent need to establish diagnostic and predictive biomarkers to guide treatment selection. Therefore, this review summarizes key aspects of gastric cancer, including its epidemiology, associated risk factors, and underlying pathogenesis. It also discusses the main biomarkers involved in this disease, such as PD-L1, HER − 2, Epstein-Barr virus (EBV), Claudin 18.2, FGFR2, and the current standard and targeted therapies. Molecular testing for these changes is gaining significance in the context of gastric cancer. By incorporating detailed biomarker analysis into clinical practice, we can provide more effective and personalized treatment options, ultimately improving clinical management and enhancing survival rates for gastric cancer patients.

Ladan A., Aslanabadi S., Badebarin D., Jamshidi M., Farhadi E., Hasanzadeh N., Naghavi M., Moharrami Yeganeh P.

Abstract Introduction Hirschsprung’s disease (HD) is a neurogenic intestinal disorder attributed to incomplete neural crest cell migration during fetal intestinal development, leading to an aganglionic segment of the colon and functional obstruction. Associated malformations like intestinal atresia, hydronephrosis, and imperforate anus can accompany Hirschsprung’s disease. this study aims to evaluate the efficacy of Calretinin and Cajal cells (CD34 and CD117) immunohistochemical staining in improving HD diagnosis. Methods The study involved 70 pediatric patients suspected of Hirschsprung’s disease. Clinical, histopathological, and immunohistochemical analyses were conducted, focusing on calretinin, CD34, and CD117 markers to identify ganglion cells and Cajal cells. Data were statistically analyzed using SPSS software. Results In the examination of the samples, the calretinin marker exhibited a consistent accuracy of 100% in diagnosing Hirschsprung’s disease (with sensitivity and specificity both at 100%). Regarding the markers for Cajal cells in cases of Hirschsprung’s disease, an irregularity in the arrangement of Cajal cells was observed, which was absent in normal cases. These markers also demonstrated a specificity and sensitivity of 100% in diagnosing the disease. Conclusion Hirschsprung’s disease remains a complex condition with multifaceted pathophysiological mechanisms. Calretinin immunohistochemical staining offers enhanced diagnostic accuracy, while the debate surrounding ICC distribution underscores the need for advanced diagnostic techniques. Further research is warranted to unravel the intricacies of Hirschsprung’s disease and its associated complications.