Pathology Reports: Discrepancy Patterns of Second Opinions in a Referral Cancer Center.

OBJECTIVE: To evaluate the diagnostic mismatch (discrepancy) of pathology reports in consulted specimens referred for second opinion. MATERIALS AND METHODS: This cross-sectional study was conducted at a major cancer center, Omid Hospital. In this study, 350 primary pathology reports and 350 reviewed pathology reports were extracted from the archives of Omid Hospital from 2011 to 2020 and assessed in terms of the extent of discrepancy, by two pathologists and one oncologist. The required data for each sample were entered into a checklist and then statistically analyzed. Cases with the same diagnosis on both reports were assigned to the matched group and the rest were assigned to the minor or major mismatch (discrepancy) group. Minor mismatches included changes in diagnosis that did not lead to changes in treatment (may lead to changes in prognosis or provide additional information to the oncologist) and major mismatches included changes in diagnosis leading to changes in treatment or remedies. RESULTS: Two hundred seven cases (59.1%) out of three hundred fifty cases had concordant results between the diagnosis of the first pathologist and the reviewing pathologist. In one hundred forty-three cases (40.9%) mismatch (discrepancy) was observed, including eighty- two cases (23.4%) with minor mismatches (discrepancy) and sixty-one cases (17.4%) with major mismatches (discrepancy). In the major mismatch group, fifteen cases (4.3%) changed from malignant to benign, eighteen cases (5.1%) changed from benign to malignant, two cases (0.6%) changed from one stage to another stage of Disease and twenty-six cases (7.4%) had changes in the type of malignancy. In this study, it was found that there was no significant relationship between anatomical areas of sampling and diagnostic mismatch (p = 0.254). The study also found that the rate of diagnostic mismatch in specimens obtained by resection or excisional biopsy was greater than that of small biopsies (eighty cases (22.8%) and sixty-two cases (17.7%, respectively)). There was no significant relationship in this regard (p = 0.077). CONCLUSION: Compared to most similar studies, the present study reported the highest discrepancy between the diagnosis of the first pathologist and the reviewing pathologist (40.9%).

Role of regulatory miRNAs of the PI3K/AKT/mTOR signaling in the pathogenesis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the common malignant human tumors with high morbidity worldwide. Aberrant activation of the oncogenic phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling is related to clinicopathological features of HCC. Emerging data revealed that microRNAs (miRNAs) have prominent implications for regulating cellular proliferation, differentiation, apoptosis, and metabolism through targeting the PI3K/AKT/mTOR signaling axis. The recognition of the crucial role of miRNAs in hepatocarcinogenesis represents a promising area to identify novel anticancer therapeutics for HCC. The present study summarizes the major findings about the regulatory role of miRNAs in the PI3K/AKT/mTOR pathway in the pathogenesis of HCC.

Association of cyclin-dependent kinase inhibitor 2A/B with increased risk of developing breast cancer.

There is a growing body of data reporting the association of genetic alterations in chromosome 9P21 with the risk of developing cancer. In the current study, we studied the association of a genetic variant in CDKN2A/B, rs1333049, with the risk of developing breast cancer. A total of 339 participants with and without breast cancer entered to the study. Genotyping was done by the TaqMan real-time polymerase chain reaction (RT-PCR) method and gene expression analysis was ran by RT-PCR. Our data showed that the minor allele homozygote in the total population was 10%, whereas for heterozygote was 38%. The dominant genetic model demonstrated that individuals with breast cancer had advanced TNM classification. Moreover, the logistic regression revealed that individuals who had CC/CG genotypes might have an enhanced risk of developing breast cancer when compared to the holders of GG genotype (e.g., OR = 2.8; 95% CI,1.4-5.4; p = .001), after regulated for confounders; age and body mass index. Furthermore, our analysis showed that the CDKN2A/B gene was downregulated in patients (p < .001). We showed a meaningful relationship of CDKN2A/B with the risk of breast cancer, cancer, showing the importance of studies in great sample size and several centers for studying the value of the marker as a risk classification in the management of patients with breast cancer.

Thyroid fibromatosis: A case report.

OBJECTIVES: Fibromatosis is a rare tumor with a prevalence of 2-4 per million per year. Its occur-rence in the thyroid is very rare and to the best of our knowledge only five cases have been reported in the literature.Subject and Results. In this case report, we present a thirty-seven-year-old man without any significant past medical history, who presented with an anterior neck swelling and occasional cough for four months before admission. Sonographic-guided fine needle aspiration cytology studies reported a follicular neoplasm. Microscopic and immunohistochemical evaluation of the thyroidectomy specimen showed thyroid fibromatosis. The patient had no symptoms after surgery and no signs of recurrence after 2 years of follow-up.

Idiopathic granulomatous mastitis: Management and predictors of recurrence in 474 patients.

Idiopathic Granulomatous Mastitis (IGM) is an uncommon inflammatory disease of the breast, with similar presentations as breast cancer and a relatively high recurrence rate. We reviewed the demographics, clinical presentations, and treatment modalities of a large cohort of patients in Iran. Most of the patients had history of pregnancy and breastfeeding. The most common clinical finding was pain and a palpable mass, respectively. Most of the patients received medical treatment, and about half of the patients had surgery. The recurrence rate was 24.8%, and breast skin lesions were associated with a significantly higher odds of recurrence.

Clinical and prognostic value of the C-Met/HGF signaling pathway in cervical cancer.

Aberrant activation of the HGF/c-Met signalling pathway is reported to be associated with cell proliferation, progression, and metastasis features of several tumor types, including cervical cancer, suggesting that it may be of potential value as a novel therapeutic target. Furthermore, HPV-positive patients had a higher serum level of HGF or c-Met protein, compared with HPV-negative patients. c-Met or HGF overexpression in lesions of cervical cancer is reported to be related to a poorer prognosis, and hence this may be of value as a prognostic and predictive biomarker. Several approaches have been developed for targeting HGF and/or c-Met. One of these is crizotinib (a dual c-Met/ALK inhibitor). This has been approved by FDA for the treatment of lung-cancer. Further investigations are required to evaluate and optimize the use of c-Met inhibitors in cervical cancer or parallel targeting signalling pathway associated/activated via MET/HGF pathway. The main aim of current review was to give an overview of the potential of the c-Met/HGF pathway as a prognostic, or predictive biomarker in cervical cancer.

Genetic susceptibility in cervical cancer: From bench to bedside.

Cervical cancer (CC) is the third most common malignancy in women globally, and persistent infection with the oncogenic human papillomaviruses (HPV) is recognized as the major risk factor. The pathogenesis of CC relies on the interplay between the tumorigenic properties of the HPV and host factors. Host-related genetic factors, including the presence of susceptibility loci for cervix tumor is substantial importance. Preclinical and genome-wide association studies (GWAS) have reported the associations of genetic variations in several susceptibility loci for the development of cervical cancer. However, many of these reports are inconsistent. In this review, we discuss the findings to date of candidate gene association studies, and GWAS in cervical cancer. The associations between these genetic variations with response to chemotherapy are also discussed.

Clinical Significance and Prognosis Value of Wnt Signaling Pathway in Cervical Cancer.

Cervical cancer is among the most commonly diagnosed cancer in women, supporting the need for identification of novel prognostic and predictive biomarkers to predict the risk of developing of this malignancy or predict the prognosis of patients. Against this background, the activation of the Wingless-type (Wnt)/ß-catenin pathway has been suggested as the main dysregulated pathways, which is involved in the multistep process of cervical carcinogenesis, suggesting its value as a potential biomarker or therapeutic target. The aim of current review is to give an overview about the potential application of WNT pathway and its value which is differentially expressed in cervical cancer versus non-tumorigenic tissue as biomarker for risk stratification and predict the prognosis of patients with cervical cancer. J. Cell. Biochem. 118: 3028-3033, 2017. © 2017 Wiley Periodicals, Inc.

Uncommon presentation of transitional cell carcinoma: A case report of hand involvement.

It is uncommon to see bladder cancer metastases in the hand. A 65-year-old man had bladder cancer surgery 3 years ago. His axilla and wrist swelled after surgery. Final amputation was necessary as the cancer had spread to hand. Transitional cell carcinoma was detected by immunohistochemistry with GATA-3, CK7, CK20, and p63 positivity.

Primary extraperitoneal hydatid cyst, a rare differential diagnosis of subdiaphragmatic mass: A case report.

Key Clinical Message: Hydatid cyst is a sly disease that can manifest with a spectrum of symptoms in almost every part of the human body, so it is crucial to be familiar with different scenarios that a patient may present. Abstract: The echinococcus granulosus parasite causes hydatid disease and is common in areas with animal husbandry and agriculture. Here, we report a middle age woman who presented with abdominal pain that further investigation revealed a cyst in subdiaphragmatic area.

A systematic review of machine learning-based tumor-infiltrating lymphocytes analysis in colorectal cancer: Overview of techniques, performance metrics, and clinical outcomes.

The incidence of colorectal cancer (CRC), one of the deadliest cancers around the world, is increasing. Tissue microenvironment (TME) features such as tumor-infiltrating lymphocytes (TILs) can have a crucial impact on diagnosis or decision-making for treating patients with CRC. While clinical studies showed that TILs improve the host immune response, leading to a better prognosis, inter-observer agreement for quantifying TILs is not perfect. Incorporating machine learning (ML) based applications in clinical routine may promote diagnosis reliability. Recently, ML has shown potential for making progress in routine clinical procedures. We aim to systematically review the TILs analysis based on ML in CRC histological images. Deep learning (DL) and non-DL techniques can aid pathologists in identifying TILs, and automated TILs are associated with patient outcomes. However, a large multi-institutional CRC dataset with a diverse and multi-ethnic population is necessary to generalize ML methods.

Automated segmentation and morphological characterization of placental intervillous space based on a single labeled image.

In this study, a novel method of data augmentation has been presented for the segmentation of placental histological images when the labeled data are scarce. This method generates new realizations of the placenta intervillous morphology while maintaining the general textures and orientations. As a result, a diversified artificial dataset of images is generated that can be used for training deep learning segmentation models. We have observed that on average the presented method of data augmentation led to a 42% decrease in the binary cross-entropy loss of the validation dataset compared to the common approach in the literature. Additionally, the morphology of the intervillous space is studied under the effect of the proposed image reconstruction technique, and the diversity of the artificially generated population is quantified. We have demonstrated that the proposed method results in a more accurate morphological characterization of the placental intervillous space with an average feature relative error of 6.5%, which is significantly lower than the 11.5% error observed with conventional augmentation techniques. Due to the high resemblance of the generated images to the real ones, applications of the proposed method may not be limited to placental histological images, and it is recommended that other types of tissue be investigated in future studies.

Primary carcinoid or sex cord-stromal tumor of the testis: A case report.

Background: Carcinoid tumors of the testis are rare and orchiectomy is the preferred treatment. This type of testis tumors is rare and their differentiation from sex cord-stromal tumors is difficult. Case presentation: A 29­year­old man presented with right testicular mass and underwent radical orchidectomy. Histological examination showed neuroendocrine tumor, confirmed by immunohistochemistry and electron microscopy (Ethic code: IR.MUMS.REC.1400.237). Conclusion: Primary testicular neuroendocrine tumor is very rare. It is crucial to submit the entire gross specimen for histopathologic examination to rule out an existing of other germ cell elements. Our patient had a well-differentiated carcinoid tumor and after two years of follow-up (every three months), there was no recurrence or metastasis.

A staghorn kidney stone or extraskeletal osteosarcoma of the kidney? A case report and literature review.

Extraskeletal osteosarcoma (ESOS) is a very rare entity among renal malignancies. There are few reports of renal ESOS in the database. Renal ESOS was found to have a high rate of local recurrence and distant metastasis. In most reports, the overall survival of patients was less than 1 year. We present a 51-year-old man who presented with gross hematuria and a clinical diagnosis of a staghorn stone in the left kidney. He underwent radical nephrectomy. The pathologic diagnosis of osteosarcoma was evident.

Assessment of the Tumor-Stroma Ratio and Tumor-Infiltrating Lymphocytes in Colorectal Cancer: Inter-Observer Agreement Evaluation.

BACKGROUND: To implement the new marker in clinical practice, reliability assessment, validation, and standardization of utilization must be applied. This study evaluated the reliability of tumor-infiltrating lymphocytes (TILs) and tumor-stroma ratio (TSR) assessment through conventional microscopy by comparing observers' estimations. METHODS: Intratumoral and tumor-front stromal TILs, and TSR, were assessed by three pathologists using 86 CRC HE slides. TSR and TILs were categorized using one and four different proposed cutoff systems, respectively, and agreement was assessed using the intraclass coefficient (ICC) and Cohen's kappa statistics. Pairwise evaluation of agreement was performed using the Fleiss kappa statistic and the concordance rate and it was visualized by Bland-Altman plots. To investigate the association between biomarkers and patient data, Pearson's correlation analysis was applied. RESULTS: For the evaluation of intratumoral stromal TILs, ICC of 0.505 (95% CI: 0.35-0.64) was obtained, kappa values were in the range of 0.21 to 0.38, and concordance rates in the range of 0.61 to 0.72. For the evaluation of tumor-front TILs, ICC was 0.52 (95% CI: 0.32-0.67), the overall kappa value ranged from 0.24 to 0.30, and the concordance rate ranged from 0.66 to 0.72. For estimating the TSR, the ICC was 0.48 (95% CI: 0.35-0.60), the kappa value was 0.49 and the concordance rate was 0.76. We observed a significant correlation between tumor grade and the median of TSR (0.29 (95% CI: 0.032-0.51), p-value = 0.03). CONCLUSIONS: The agreement between pathologists in estimating these markers corresponds to poor-to-moderate agreement; implementing immune scores in daily practice requires more concentration in inter-observer agreements.

Molecular Status of BRAF Mutation in Epithelial Ovarian Cancer: An Analysis of 57 Cases in the Northeast of Iran.

Background & Objective: Epithelial ovarian cancer (EOC) is the most prevalent type of ovarian cancer. Previous studies have elucidated different pathways for the progression of this malignancy. The mutation in the B-Raf proto-oncogene, serine/threonine kinase (BRAF) gene, a member of the MAPK/ERK signaling pathway, plays a role in the development of EOC. The current study aimed to determine the frequency of the BRAF V600E mutation in ovarian serous and mucinous tumors, including borderline and carcinoma subtypes. Methods: A total of 57 formalin-fixed paraffin-embedded samples, including serous borderline tumors (SBTs), low-grade serous carcinomas (LGSCs), high-grade serous carcinomas (HGSCs), mucinous borderline tumors (MBTs), and mucinous carcinomas, and 57 normal ovarian tissues were collected. The BRAF V600E mutation was analyzed using polymerase chain reaction (PCR) and sequencing. Results: While 40% of the SBT harbor BRAF mutation, we found no BRAF mutation in the invasive serous carcinoma (P=0.017). Also, there was only 1 BRAF mutation in MBT and no mutation in mucinous carcinomas. In addition, we found no mutation in the control group. Conclusion: The BRAF mutation is most frequent in borderline tumors but not in invasive serous carcinomas. It seems that 2 different pathways exist for the development of ovarian epithelial neoplasms: one for borderline tumors and the other for high-grade invasive carcinomas. Our study supports this hypothesis. The BRAF mutation is rare in mucinous neoplasms.

Dual targeting of TGF-ß and PD-L1 inhibits tumor growth in TGF-ß/PD-L1-driven colorectal carcinoma.

Immunosuppressive factors within the tumor microenvironment (TME), such as Transforming growth factor beta (TGF-ß), constitute a crucial hindrance to immunotherapeutic approaches in colorectal cancer (CRC). Furthermore, immune checkpoint factors (e.g., programmed death-ligand 1 [PD-L1]) inhibit T-cell proliferation and activation. To cope with the inhibitory effect of immune checkpoints, the therapeutic value of dual targeting PD-L1 and TGF-ß pathways via M7824 plus 5-FU in CRC has been evaluated. Integrative-systems biology approaches and RNAseq were used to assess the differential level of genes associated with 88 metastatic-CRC patients. The level of PD-L1 and TGF-ß was evaluated in a validation cohort. The anti-proliferative, migratory, and apoptotic effects of PD-L1/TGF-ß inhibitor, M7824, were assessed by MTT, wound-healing assay, and flow cytometry. Anti-tumor activity was assessed in a xenograft model, followed by biochemical studies and histological staining, and gene/protein expression analyses by RT-PCR and ELISA/IHC. The result of differentially expressed genes (DEGs) analysis showed 1268 upregulated and 1074 downregulated genes in CRC patients. Among the highest scoring genes and dysregulated pathways associated with CRC, PD-L1, and TGF-ß were identified and further validated in 92 CRC patients. Targeting of PD-L1-TGF-ß inhibited cell growth and migration, associated with modulation of CyclinD1 and MMP9. Furthermore, M7824 inhibited tumor growth via targeting TGF-ß and PD-L1 pathways, resulting in modulation of inflammatory response and fibrosis via TNF-α/IL6/CD4-8 and COL1A1/1A2, respectively. In conclusion, our data illustrated that co-targeting PD-L1 and TGF-ß pathways increased the effect of Fluorouracil (5-FU) and reduced the tumor growth in PD-L1/TGF-ß expressing tumors, providing a new therapeutic option in the treatment of CRC.

Occult breast cancer metastasis to the thyroid gland: Case report.

Thyroid metastases of occult breast cancer are very rare. A 48-year-old female patient presented with chronic bone pain, bone, liver and thyroid nodules, and pleural effusion. Histopathological result of the thyroid showed poorly differentiated papillary thyroid carcinoma. However, clinical laboratory and immunohistochemistry studies showed breast origin of the thyroid lesion.

Direct Smear Versus Liquid-Based Cytology in the Diagnosis of Bladder Lesions.

BACKGROUND & OBJECTIVE: Urine cytology is an important diagnostic method for urinary tract cancers (especially carcinomas), which is suitable for follow-up of residual urothelial tumors after surgery of malignant bladder tumors. Liquid-based cytology (LBC) was used for the first time in cervical cytology Compared to direct smear cytology (DSC), LBC reduced background elements (including cellular debris, inflammatory cells, and blood cells), provided better cell preservation, and had a higher satisfaction rate. In this study, we performed two different methods (DSC and LBC) to detect bladder lesions; also, we determined the sensitivity and specificity of these methods. METHODS: A total of 146 samples were taken from patients with suspected bladder cancer and processed for direct smear and LBC. In both methods, findings were reported according to the Paris System. Then, patients underwent cystoscopy and biopsy. Next, the accuracy of cytology methods was evaluated according to biopsy reports. The sensitivity and specificity of these methods were also calculated. RESULTS: Credit indices obtained for the direct smear method included sensitivity (62.5%), specificity (89%), positive predictive value (89.5%), and negative predictive value (91.5%). For LBC methods, credit indices included sensitivity (85.7%), specificity (99%), positive predictive value (96%), and negative predictive value (96%). Agreement between the two methods was statistically significant (P<0.000) in negative biopsies but not in positive biopsies (P>0.05). CONCLUSION: This study showed that LBC has higher sensitivity and specificity than the direct smear.