Histopathology of Polyps and Cancer of Colorectum: A ten years study from a tertiary care center

Introduction and objectives: Polyps and colorectal cancer have overlapping clinical presentation and may be difficult to diagnose on clinical grounds alone and close clinicopathological correlation is required for correct diagnosis and management. This study was aimed to see the spectrum of polyps and cancer in colorectum, see the percentage of colorectal cancer in younger individuals, see association between histologic grade and pathologic stage at presentation and compare site of tumor and pathologic stage at presentation in younger and older age group. Methods: This study was carried out on 138 consecutive cases of polyps and malignant lesions of colorectum during a time period of 10 years from January 2011 to December 2020. Results: Age of the patients ranged from 2 – 90 years with mean 45.1 years and a male female ratio 2:1. There were 58 (42.0%) cases of polyps and 80 (58.0%) cases of malignancies. 37 (46.3%) malignancy cases were seen in individuals ≤ 50 years of age. Most common site of involvement was rectum in 80 (58.0%) cases. Most common non-neoplastic polyp was retention polyp comprising 25 (67.6%) and most common neoplastic polyp was adenoma comprising of 18 (85.7%) cases. Most common malignancy was adenocarcinoma comprising 75 (93.8%) cases. Conclusion: Significant number of malignancies is seen in younger individuals stressing the need for suspicion and surveillance in this age group. Histologic grade is an important prognostic parameter and there is no difference in site of tumor and stage at presentation between younger and older age group.

High Expression of Ubiquitin-Specific Protease 39 and Its Roles in Prognosis in Patients with Hepatocellular Carcinoma

Background. Ubiquitin-specific protease 39 is mainly involved in mRNA splicing and multiple kinds of tumors. Accumulating evidence has shown that USP39 participated in the proliferation and metastasis of hepatocellular carcinoma (HCC). The present study aimed to demonstrate the association between USP39 expression and clinical features and the diagnostic value in HCC based on the Cancer Genome Atlas (TCGA). Methods. A comprehensive analysis for expression of USP39 in HCC was conducted by using multiple databases. The mRNA level of USP39, clinical features, survival rate, and diagnostic value in HCC were analyzed using data from TCGA. The Gene Set Enrichment Analysis (GSEA) was conducted to analyze signaling pathways correlated with USP39 expression in HCC. Results. The mRNA level of USP39 was significantly elevated in HCC. The expression of USP39 showed significant correlation with T stage, pathologic stage, tumor status, age, and histologic grade. Logistic analysis demonstrated that high expression of USP39 was significantly associated with older age, tumor status, advanced pathologic stage, T stage, and higher histologic grade. Univariate Cox regression analysis showed that high expression of USP39 was significantly associated with advanced T stage, pathological stage, and tumor status. Multivariate Cox analysis confirmed the result that USP39 expression was an independent prognostic factor for overall survival (OS) in HCC. Results of Kaplan–Meier curves showed that high expression of USP39 had a significant association with poor OS, disease-free survival (DSS), and progress-free interval (PFI) in HCC. ROC analysis indicated that USP39 could be regarded as a promising marker for distinguishing HCC from nontumor. Conclusion. The increased USP39 might play roles in the progression, diagnosis, and prognosis of HCC.

High risk histopathological factors in retinoblastoma in upfront enucleated eyes: An experience from a tertiary care centre of Pakistan

Background & Objectives: The assessment of histopathological risk factors (HRFs) in retinoblastoma in upfront enucleated eyes is important in deciding treatment protocols. Limited data is available from the developing countries as very few studies were conducted on retinoblastoma. The study aims to report this data from Pakistan. Methods: This cross-sectional study included treatment naïve retinoblastoma patients who underwent upfront enucleation between 2017 to 2021. Various tumor characteristics i.e. laterality, size, histologic grade, anaplasia grade, growth pattern, extent and length of optic nerve invasion, pathologic staging, tumor involvement of ocular structures were assessed. High-risk factors such as involvement of anterior chamber, choroidal, scleral, extrascleral, and optic nerve were also noted. Results: A total number of 54 patients were enrolled, out of which 53.7% were females while remaining were males. Median age at presentation was 24 months. Unilateral tumor was seen in 92.6% cases. Most frequent histologic grade was G2 (64.7%) and moderate anaplasia was observed in 59.2% cases. Vitreous involvement was seen in (86.5%). Pathologic staging of most of the tumors was pT1 (39.2%). Assessment of high-risk factors revealed that optic nerve involvement (35.1%) was the most common finding with retrolaminar tumor invasion seen in 75% cases. Choroidal invasion (≤3mm) was seen in 55.6% of patients. Limited involvement of anterior chamber (3.8%), sclera (7.4%), and extrascleral (3.8%) tissue was also observed. Conclusion: The presence of high risk histopathological factors in enucleated eyes diagnosed with retinoblastoma are known to have a profound impact on the risk stratification as well as decision of future treatment plan. doi: https://doi.org/10.12669/pjms.38.ICON-2022.5787 How to cite this:Yaqoob N, Mansoor S, Aftab K, Kaleem B, Hamid A, Jamal S. High risk histopathological factors in retinoblastoma in upfront enucleated eyes: An experience from a tertiary care centre of Pakistan. Pak J Med Sci. 2022;38(2):369-374. doi: https://doi.org/10.12669/pjms.38.ICON-2022.5787 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Clinical Outcomes of Low Histologic Grade Follicular Lymphoma with High Proliferation Index

Background: Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma (NHL) accounting for ~35% of NHL and often have a clinically indolent course. PET/CT max SUV ≥10 and high proliferative index are associated with FL at high risk for transformation to aggressive lymphoma (Schöder, 2005; Rossi, 2020). A subset of patients (pts) with low histologic grade and high proliferation index (LG-HPI) have a more aggressive clinical course with inferior overall survival (OS) compared to low grade, low proliferation index (LG-LPI) FL patients (Wang, 2005). The aim of our study was to identify outcomes for patients with LG-HPI FL at our institution. Methods: We conducted a single center, retrospective study of FL diagnosed from 1/1/2015-1/1/2021. Demographic information, diagnoses, laboratory results, medications, pathology, and radiology reports were collected from pts' electronic medical records. Pathology specimens were de-identified and retrospectively reviewed by two pathologists. Review included comprehensive evaluation of histologic grade, proliferation index by Ki-67 percentage (Ki-67%), immunohistochemical staining, and c-MYC immunohistochemical staining. Biopsies were classified as LG-LPI if Grade 1-2 and Ki-67 was <30%, LG-HPI if Grade 1-2 and Ki-67 was ≥30%, and high grade (HG) if Grade 3A or 3B. The primary endpoint was progression free survival (PFS) defined as time from treatment until time of progression and last known follow up as determined by Kaplan-Meier method. OS was calculated from time of diagnosis to last follow up or death by Kaplan-Meier method. Comparisons were made using Log-rank model and Cox Proportional Hazards Model. Time to first treatment (TTFT) was calculated as time from diagnosis to first treatment. Receiver operating curve (ROC) was used to determine correlation between PET SUV values (defined as ≥10, or <10) and Ki-67%. Results: 152 pts were diagnosed with FL and included for analysis. Patient characteristics are summarized in Table 1. Median age at diagnosis for all pts was 65.9 years. Sixty-three pts had LG-LPI, 61 LG-HPI, and 28 HG pts. Ten pts transformed to DLBCL (2 LG-LPI, 5 LG-HPI, 3 HG). Treatment regimens included initial observation (n = 44), anti-CD20 therapy alone (n = 24), chemo-immunotherapy (n = 53), and other (n = 31). Median TTFT was 1.27 mo (range 0-115.2 mo). There was moderate correlation between SUV of biopsied lesion ≥10 and Ki-67 percentage (ROC Area 0.6175). Median PFS was longer for LG-LPI compared to LG-HPI (78.6 vs 57.8 mo, p = 0.04, HR 2.37) but not between LG-HPI and HG (57.8 vs 61.3 mo respectively, p = 0.32) (Figure 1A). Median OS was not reached in any cohort with median follow up of 29.5 mo. There was no difference in OS between LG-LPI vs LG-HPI (p = 0.53) (Figure 1B). Histologic grade, proliferation index, Ann Arbor Staging, FLIPI score, PET/CT SUV intensity (max or of biopsied lesion), presence of c-Myc staining, or initial treatment regimen were not associated with median PFS or OS in either subgroup on univariate analysis. Conclusions: In our cohort, PFS was shorter for LG-HPI compared to LG-LPI but with a similar trajectory to that of HG FL, consistent with prior reports. No differences were seen in OS between LG-HPI and LG-LPI, and no covariates of interest including histologic grade, proliferation index, Ann Arbor Staging, FLIPI score, PET/CT SUV intensity, presence of c-Myc staining, or initial treatment regimen were associated with differences in PFS or OS. Our study is limited by a short follow up time compared to prior published cohorts (29.5 vs 98.4 mo). PET/CT SUV values of ≥10 have moderate predictive value for higher proliferative disease and can aid in identifying patients with higher proliferative disease. Longer follow up is needed to determine if LG-HPI impacts OS. References: 1. SchöderH, et al. Intensity of 18fluorodeoxyglucose uptake in positron emission tomography distinguishes between indolent and aggressive non-Hodgkin's lymphoma. J Clin Oncol 2005;23:4643-51. 2. Rossi C, et al. Baseline SUVmaxis related to tumor cell proliferation and patient outcome in follicular lymphoma. Haematologica 2020;Online ahead of print. 3. Wang SA, et al. Low histologic grade follicular lymphoma with high proliferation index: morphologic and clinical features. Am J Surg Pathol2005;29:1490-6. Figure 1 Figure 1. Disclosures Allen: Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Other: Equity Ownership; Bristol Myers Squibb: Other: Equity Ownership; Alexon: Research Funding. Rhodes: Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support; AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant.

Assessment of Digital Pathology Imaging Biomarkers Associated with Breast Cancer Histologic Grade

Background: Evaluating histologic grade for breast cancer diagnosis is standard and associated with prognostic outcomes. Current challenges include the time required for manual microscopic evaluation and interobserver variability. This study proposes a computer-aided diagnostic (CAD) pipeline for grading tumors using artificial intelligence. Methods: There were 138 patients included in this retrospective study. Breast core biopsy slides were prepared using standard laboratory techniques, digitized, and pre-processed for analysis. Deep convolutional neural networks (CNNs) were developed to identify the regions of interest containing malignant cells and to segment tumor nuclei. Imaging-based features associated with spatial parameters were extracted from the segmented regions of interest (ROIs). Clinical datasets and pathologic biomarkers (estrogen receptor, progesterone receptor, and human epidermal growth factor 2) were collected from all study subjects. Pathologic, clinical, and imaging-based features were input into machine learning (ML) models to classify histologic grade, and model performances were tested against ground-truth labels at the patient-level. Classification performances were evaluated using receiver-operating characteristic (ROC) analysis. Results: Multiparametric feature sets, containing both clinical and imaging-based features, demonstrated high classification performance. Using imaging-derived markers alone, the classification performance demonstrated an area under the curve (AUC) of 0.745, while modeling these features with other pathologic biomarkers yielded an AUC of 0.836. Conclusion: These results demonstrate an association between tumor nuclear spatial features and tumor grade. If further validated, these systems may be implemented into pathology CADs and can assist pathologists to expeditiously grade tumors at the time of diagnosis and to help guide clinical decisions.

β-Catenin Expression and Its Association with Prognostic Factors in Hepatocellular Carcinoma: A Study on Alpha-fetoprotein, Histologic Grade, and Microvascular Invasion

Background. Hepatocellular carcinoma (HCC), the most common primary liver cancer. In addition to its high incidence, the disease burden is high due to its poor prognosis and high recurrence rate. Some of the currently known clinicopathologic prognostic factors include alpha-fetoprotein (AFP) level, histologic grade, and microvascular invasion. At the molecular level, β-catenin is one of the most common driver mutation found in HCC. The Wnt/β-catenin pathway regulates cellular processes related to initiation, growth, survival, migration, differentiation, and apoptosis. Although the underlying pathogenesis of hepatocarcinogenesis is known, clinical application warrants a greater understanding of the molecular characteristics and tumor phenotype, especially for determining the prognosis. This study aims to analyze the expression of β-catenin and its association with AFP, histologic grade, and microvascular invasion. Materials and methods. Thirty-five samples of surgically resected HCCs at Cipto Mangunkusumo National Referral Hospital were examined. Diagnoses were made based on histopathological and immunohistochemical findings followed by β-catenin staining. β-catenin expression was analyzed to determine difference between variables. Results and conclusions. Here we show that β-catenin expression is significantly associated with low serum alpha-fetoprotein and well to moderate differentiation Implications. Strong nuclear β-catenin expression implies better prognosis in HCC.

FAM83H and Nectin1 expression are related with survival and relapse of bladder urothelial carcinoma patients

Background FAM83H was originally reported to be essential for dental enamel formation. However, FAM83H has recently been implicated in tumorigenesis and tumor progression. Analysis of a publicly available gene expression database revealed a significant correlation between FAM83H and Nectin1 mRNA expression and bladder urothelial carcinoma (BUC). Therefore, we investigated the association between FAM83H and Nectin1 expression levels and the survival and recurrence of BUC in BUC patients using a tissue microarray. Methods We performed immunohistochemical staining of FAM83H and Nectin1 in 165 human BUC tissue sections, and analyzed the prognostic significance of FAM83H and Nectin1 expression. Results Both FAM83H and Nectin1 were mainly expressed in the cytoplasm, and their expression was significantly associated. FAM83H expression was significantly correlated with higher histologic grade, higher T stage, higher TNM stage, and recurrence. Nectin1 expression was significantly associated with higher histologic grade and recurrence. Univariate analysis showed FAM83H expression and Nectin1 expression were significantly associated with worse overall survival (OS) and shorter relapse-free survival (RFS) of BUC patients. In multivariate analysis, levels of FAM83H and Nectin1 were independent indicators of shorter survival of BUC patients. Conclusions Our results suggest that FAM83H and Nectin1 are important in the progression of BUC, and that expression patterns of these two proteins can be used as prognostic indicators of survival in BUC patients.

Multicenter retrospective study on the use of Curebest™ 95GC Breast for estrogen receptor-positive and node-negative early breast cancer

Background The benefits of postoperative chemotherapy in patients with estrogen receptor (ER)-positive breast cancer remain unclear. The use of tumor grade, Ki-67, or ER expression failed to provide an accurate prognosis of the risk of relapse after surgery in patients. This study aimed to evaluate whether a multigene assay Curebest™ 95GC Breast (95GC) can identify the risk of recurrence and provide more insights into the requirements for chemotherapy in patients. Methods This single-arm retrospective multicenter joint study included patients with ER-positive, node-negative breast cancer who were treated at five facilities in Japan and had received endocrine therapy alone as adjuvant therapy. The primary lesion specimens obtained during surgery were analyzed using the 95GC breast cancer multigene assay. Based on the 95GC results, patients were classified into low-risk (95GC-L) and high-risk (95GC-H) groups. Results The 10-year relapse-free survival rates were 88.4 and 59.6% for the 95GC-L and 95GC-H groups, respectively. Histologic grade, Ki-67, and PAM50 exhibited a significant relationship with the 95GC results. The segregation into 95GC-L and 95GC-H groups within established clinical factors can identify subgroups of patients using histologic grade or PAM50 classification with good prognosis without receiving chemotherapy. Conclusions Based on the results of our retrospective study, 95GC could be used to evaluate the long-term prognosis of ER-positive, node-negative breast cancer. Even though further prospective validation is necessary, the inclusion of 95GC in clinical practice could help to select optimal treatments for breast cancer patients and identify those who do not benefit from the addition of chemotherapy, thus avoiding unnecessary treatment.

Risk factors associated with suicide among esophageal carcinoma patients from 1975 to 2016

Throughout the world, esophageal cancer patients had a greater suicidal risk compared with ordinary people. Thus, we aimed to affirm suicide rates, standardized mortality rates, and underlying suicide-related risk factors of esophageal cancer patients. Patients suffering esophageal cancer were chosen from the Surveillance, Epidemiology, and End Results repository in 1975–2016. Suicide rates as well as standardized mortality rates in the patients were measured. Univariable and multivariable Cox regression had been adopted for establishing the latent suicide risk factors among patients suffering esophageal cancer. On multivariable Cox regression, gender (male vs. female, HR: 6.37), age of diagnosis (70–105 vs. 0–55, HR: 2.69), marital status, race (white race vs. black race, HR: 6.64; American Indian/Alaska Native, Asian/Pacific Islander vs. black race, HR: 8.60), histologic Grade (Grade III vs. Grade I, HR: 2.36), no surgery performed (no/unknown vs. yes, HR: 2.01), no chemotherapy performed were independent risk factors related to suicide in patients suffering esophageal cancer. Male sex, the older age, unmarried state, non-black race, histologic Grade III, no surgery performed, no chemotherapy performed were strongly related to suicide in patients suffering esophageal cancer.

Canine mammary cancer in overweight or obese female dogs is associated with intratumoral microvessel density and macrophage counts

Obesity is a major health condition owing to its effects on chronic diseases and cancers in humans, but little information is available regarding the role of obesity in canine mammary cancer (CMC). In the present study, we performed immunohistochemistry to investigate the effect of obesity on CMC by analyzing the number of tumor-associated macrophages, intratumoral microvessel density (iMVD), and the expression of prognostic factors including epidermal growth factor receptor (EGFR), cyclooxygenase 2 (COX-2), and Ki67 in CMC specimens. These data were compared in CMC specimens from lean or ideal body weight (Group 1) versus overweight or obese (Group 2) female dogs ( n = 60 for each group). Associations between obesity status and histologic characteristics, such as histologic subtype, grading, and lymphatic invasion, were also investigated. Compared with lean or ideal body weight dogs, TAM (tumor-associated macrophage) counts ( P < .005) and iMVD ( P < .001) were significantly higher in overweight or obese dogs. CMC specimens of dogs in the overweight or obese group also showed higher histologic grade ( P < .001). In addition, although no association was found between obesity status and either COX-2 or EGFR expression, Ki67 expression was greater in CMC specimens of overweight or obese dogs ( P < .005). The results of this study suggest that obesity may influence CMC development and progression, being associated with higher histologic grade, greater infiltration of TAMs, and increased tumor angiogenesis.