Fusion Oncogenes Are Associated With Increased Metastatic Capacity and Persistent Disease in Pediatric Thyroid Cancers

PURPOSE In 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes, RAS-like and BRAF-like, better reflects clinical behavior than sole reliance on pathologic classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer (DTC) and investigate whether mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC. METHODS Somatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized into RAS-mutant ( H-K-NRAS), BRAF-mutant ( BRAF p.V600E), and RET/ NTRK fusion ( RET, NTRK1, and NTRK3 fusions) to determine differences between subtype classification in regard to pathologic data (American Joint Committee on Cancer TNM) as well as response to therapy 1 year after initial treatment had been completed. RESULTS Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1 year. Patients with RET/ NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at 1 year than patients within RAS- or BRAF-mut subgroups. CONCLUSION Our data support that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathologic classification with patients with RET/ NTRK fusions having worse outcomes than those with BRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.

CD70 Expression in Mature T-Cell Lymphomas

Introduction Mature T-cell lymphomas (TCLs) represent about 15% of the non-Hodgkin lymphomas in U.S. and are a heterogeneous group of neoplasms. TCLs usually have poor outcomes and are resistant to conventional chemotherapy regimens. Therefore, there is a need for identifying biomarkers that could translate into effective novel treatments. CD70 is the TNF superfamily ligand of CD27 and it is being explored as a potential target in CAR-T therapy against TCLs and other neoplasms. Although CD70 expression has been documented in TCL cell lines, thus providing a potential rationale for its use as a therapeutic target, the expression of CD70 among the most frequent TCL subtypes in patient samples has not been previously evaluated. Methods Patients with de novo and/or relapsed mature TCLs diagnosed between 01/2010 and 06/2020 and with available tissue sections were included in the study. The assessment of CD70 expression was performed by immunohistochemistry (IHC) using a novel proprietary antibody developed by CRISPR Therapeutics. CD70 expression was scored using % of expression, intensity (negative, +1, +2, and +3) and H-score {H-score = [(%positive cells intensity 1+) x 1] + [(%positive cells intensity 2+) x 2] + [(%positive cells intensity 3+) x 3]} in neoplastic cells (Figure 1). Clinicopathologic characteristics were collected retrospectively and included age, sex, staging, biopsy site, WHO pathologic classification, immunophenotype, presence of other malignancies, treatment status, disease progression/relapsed, and follow-up. These characteristics were compared with CD70 expression using ANOVA or non-parametric analysis. Overall-survival (OS) was estimated using Kaplan-Meier method and compared using log-rank. A p< 0.05 was considered statistically significant. Results One hundred thirty-six patient samples representing the major subtypes of the 4 categories of mature TCLs were included [nodal TCLs (n=64; including PTCL Th1, and Th2 subtypes and angioimmunoblastic T cell lymphoma - AITL), extranodal (n=35; including primary intestinal lymphomas), cutaneous (n=24; including mycosis fungoides (MF) with large cell transformation), and leukemic (n=13; including adult T cell leukemia/lymphoma)]. Most patients were male (58.8%), in the 6 th or 7 th decade (47.1%), with advanced stage IV (55.7%), no previous malignancies (69.9%) and previously treated (57.2%); 59 of which (88%) received two or more lines of treatment. The median expression of CD70 was 40% (ranged from 0 to 100%) and the median H-score was 110 (ranged from 0 to 300) and was significantly higher (p= 0.006) in peripheral T-cell lymphoma, NOS, primary cutaneous TCLs (non-mycosis fungoides), and AITL (180, 150, and 150, respectively) (Figure 1). The expression of CD70 was more frequent in nodal and extranodal subtypes (including skin), compared to leukemic TCLs (p= 0.005). The expression of CD70 was associated with advanced age at the diagnosis (p= 0.003), CD2 expression (p= 0.01), CD3 expression (p= 0.001), CD16 negativity (p= 0.03), and absence of ALK-1 expression (p= 0.005). After a median follow-up of 19 months (range: 1 - 300 months), 42% of the patients died of disease. The median OS was 76 months (CI95, 38.5 - 113.4 months) and it was not associated with CD70 expression. Conclusions CD70 was highly expressed in most mature TCLs and it was negative in most ALK-positive ALCL. Its expression was associated with nodal and extranodal subtypes, advanced age, expression of CD2, CD3, and negativity for CD16. Therefore, CD70 can be used as a potential biomarker and a target in clinical trials of patients with mature TCLs. Figure 1 Figure 1. Disclosures Iyer: CRISPRX: Research Funding; Seattle Genetics: Research Funding; Rhizen: Research Funding; Merck: Research Funding; Legend: Research Funding; Innate: Research Funding; Spectrum: Research Funding; Trillium: Research Funding; Astra Zeneca: Research Funding; Yingli: Research Funding; Cyclacel: Research Funding. Sagert: CRISPR Therapeutics: Current Employment. Pham: CRISPR Therapeutics: Current Employment. Tipton: CRISPR Therapeutics: Current Employment. Vega: i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and the Society of Hematology Oncology: Research Funding; CRISPR Therapeutics and Geron: Research Funding.

Making Sense of a Complex Disease: A Practical Approach to Managing Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are a heterogeneous clinical entity with a broad range of grade, pace of disease, functional status, and primary sites. Pathologic classification, diagnostic modalities, and therapeutic options for NETs have evolved considerably in the past decade. In part driven by these advances, incidence and prevalence of NETs are rising in the United States and the practicing oncologist is likely to encounter these in the clinic. However, there are no clear lines of therapy for unresectable or metastatic NETs, and sequencing of systemic therapies depends on consideration of patient and tumor characteristics including extent of disease, grade, pace of growth, functional status, primary site, somatostatin receptor status, performance status, and comorbidities. Familiarity with ongoing clinical trials will guide therapeutic decision making as well. In this review, we seek to provide a framework to formulate and tailor an individualized treatment plan for each patient with a NET.

Invasive Fungal Sinusitis: Clinical Pathologic Characteristics of Acute vs. Chronic Infections

Introduction/Objective Invasive fungal sinusitis is a serious condition requiring early diagnosis and treatment. It has been classified into acute, chronic and granulomatous forms. This study aims to investigate clinical pathologic aspects such as a) Frequency of mass forming lesions, b) Frequency of granulomatous reaction, c) Frequency of acute inflammatory reaction and d) Frequency of angioinvasion, perineural invasion and necrosis, to determine if these factors allow a more meaningful clinical-pathologic classification. Methods/Case Report Cases of invasive fungal sinusitis with surgical pathology specimens available in our laboratory since January 1, 2006 to date were gathered. Electronic medical records, histopathologic diagnostic material and laboratory fungal identification results were reviewed. Results (if a Case Study enter NA) Thirty-one cases of invasive fungal sinusitis were found: Twenty-two were acute (< 4wk duration) and 9 chronic. Patient comorbidities in acute cases were malignancies: 45%, diabetes mellitus: 26% and solid organ transplant: 10%. Among patients with malignancies, 5 cases had relapsed/refractory acute myeloid leukemia with neutropenia < 1000/uL. Patients with diabetes mellitus exhibited an average HbA1c of 10.0%. Two out of 3 transplant patients had graft versus host disease. The most common causative fungi were species of Aspergillus, Candida and mucormycetes. By contrast, a third of the chronic cases had a history of recreational drug use and six presented with space occupying lesions seen on imaging studies. Upon histologic review, four of these showed granulomas and the majority of cases exhibited extensive necrosis. Among necrotic cases, perineural and vascular invasion by fungal organisms was identified. Conclusion We report the contrasting clinical pathologic characteristics of acute and chronic invasive fungal sinusitis in a series of cases treated at University affiliated tertiary/quaternary-care Hospitals. Acute invasive sinusitis is usually a complication of severe systemic diseases. Chronic cases are caused by various medical conditions including the use of recreational drug and may mimic neoplasms on imaging.

Defining and Treating High-grade B-cell lymphoma, NOS

High-grade B-cell lymphoma, not otherwise specified (HGBL, NOS) is a recently introduced diagnostic category for aggressive B-cell lymphomas. It includes tumors with Burkitt-like or blastoid morphology that do not have double-hit cytogenetics and that cannot be classified as other well-defined lymphoma subtypes. HBCL, NOS are rare and heterogeneous; most have germinal center B-cell phenotype, and up to 45% carry a single-hit MYC rearrangement, but otherwise they have no unifying immunophenotypic or cytogenetic characteristics. Recent analyses utilizing gene expression profiling (GEP) revealed that up to 15% of tumors currently classified as diffuse large B-cell lymphoma display a HGBL-like GEP signature, indicating a potential to significantly expand the HGBL category using more objective molecular criteria. Optimal treatment of HGBL, NOS is poorly defined due to its rarity and inconsistent diagnostic patterns. A minority of patients have early-stage disease which can be managed with standard RCHOP-based approaches with or without radiation. For advanced-stage HGBL, NOS, which often presents with aggressive, disseminated disease, high lactate dehydrogenase, and involvement of extranodal organs (including the central nervous system [CNS]), intensified Burkitt lymphoma-like regimens with CNS prophylaxis may be appropriate. However, many patients diagnosed at age > 60 years are not eligible for intensive immunochemotherapy. An improved, GEP and/or genomic-based pathologic classification that could facilitate HGBL-specific trials is needed to improve outcomes for all patients. In this review, we discuss the current clinicopathologic concept of HGBL, NOS, existing data on its prognosis and treatment, and delineate potential future taxonomy enrichments based on emerging molecular diagnostics.

Distinct subset of immune cells assessed by multiplex immunohistochemistry correlates with immune phenotype classified by an artificial intelligence-powered tissue analyzer in advanced non-small cell lung cancer.

e21012 Background: Pathologic classification of immune phenotype is challenging since there is no consensus on how to assess spatial relations of tumor-infiltrating lymphocyte (TIL) on cancer epithelium (CE) and cancer stroma (CS) in whole-slide images (WSI). We previously suggested that the artificial intelligence (AI)-powered tissue analyzer, Lunit SCOPE IO, can classify immune phenotype, and that its predictions are correlated with the clinical outcome of immune checkpoint inhibitor (ICI) in non-small cell lung cancer (NSCLC). In this study, we designed a pathologic validation of immune phenotype using multiplex immunohistochemistry. Methods: Lunit SCOPE IO was developed based on a 2.8 x 109 micrometer2 area of CE or CS, and 5.9 x 106 TILs from 3,166 H&E Whole-Slide Image (WSI) of multiple cancer types, annotated by board-certified pathologists. H&E WSIs were divided into 1 mm2-sized tiles, where we classified immune phenotype (IP) based on TIL density on CE and TIL density on CS. Representative IP was determined based on the overall proportion of tile-level IPs in each WSI. Multiplex immunohistochemistry (mIHC) staining with CD3, CD8, CD20, CD68, FOXP3, CK, and DAPI was performed in NSCLC tumor tissues (n = 99) treated with immune checkpoint inhibitors (ICI) at the Samsung Medical Center. A normalized number of cells expressing each marker was calculated by dividing the total number of marker-positive cells by the number of DAPI-positive cells in each WSI. Results: The proportions of inflamed IP, immune-excluded IP, and immune desert IP in the analysis set were 46.5%, 29.3%, and 24.2%. respectively. Median progression-free survival of ICI was 6.4 m in inflamed IP, 1.9 m in immune-excluded IP, and 1.6 m in immune-desert IP (hazard ratio of inflamed versus others: 0.43, confidence interval 0.27-0.68, P = 0.000188). Multiplex IHC results showed that the normalized CD3-positive cells and CD8-positive cells, which play a role of anti-tumor activity, were highly enriched in inflamed IP compared to those in other IPs (CD3: fold change [FC] 1.57, P = 0.0182; CD8: FC 1.24, P = 0.0697), whereas FOXP3-positive cells, linked to the immunosuppressive activity, were enriched in immune-excluded IP (FC 1.26, P = 0.0656). We also noted that CD68-positive cells were significantly enriched in immune-desert IP (FC 1.76, P = 0.00467). Conclusions: The immune cell subset in WSI is distinct according to the immune phenotype, as CD3- or CD8-positive cells are enriched in inflamed IP rather than immune-excluded IP as classified by AI-powered TIL analysis of H&E image.

Evaluation of cardiomyopathy diagnosis in heart transplant recipients: comparison of echocardiographic and pathologic classification

Background Definite diagnosis of cardiomyopathy types can be challenging in end-stage disease process. New growing data have suggested that there is inconsistency between echocardiography and pathology in defining type of cardiomyopathy before and after heart transplantation. The aim of the present study was to compare the pre-heart transplant echocardiographic diagnosis of cardiomyopathy with the results of post-transplant pathologic diagnosis. Results In this retrospective cross-sectional clinicopathological study, 100 consecutive patients have undergone heart transplantation in Masih-Daneshvari hospital, Tehran, Iran, between 2010 and 2019. The mean age of patients was 40 ± 13 years and 79% of patients were male. The frequency of different types of cardiomyopathy was significantly different between two diagnostic tools (echocardiography versus pathology, P < 0.001). On the other hand, in 24 patients, the results of echocardiography as regard to the type of cardiomyopathy were inconsistent with pathologic findings. Conclusion Based on the findings of the present study, it could be concluded that there is a significant difference between echocardiographic and pathologic diagnosis of cardiomyopathy; therefore, it is necessary to use additional tools for definite diagnosis of cardiomyopathy like advanced cardiac imaging or even endomyocardial biopsy before heart transplantation to reach an appropriate treatment strategy.

ADRENAL GLAND TUMOURS: A 2-YEAR TERTIARY CARE HOSPITAL BASED CASE SERIES

Introduction: Adrenal gland tumors are rare. Asymptomatic adrenal tumours are found in 2-10% of the population worldwide, out of which, adrenocortical carcinomas(ACC) have an incidence of 0.5-2 cases/million population/year. ACC accounts for 0.05% -0.2% of all malignancies with a bimodal age distribution, in the first two decades and then in the fifth decade. They can be asymptomatic and diagnosed as Incidentalomas or present with signs and symptoms of hormone imbalance. Materials and methods: In this 2 year hospital-based retrospective case series from June,2018 to May,2020 , 5 cases of adrenal gland tumors diagnosed in the Department of Pathology , GMCH, were retrieved from the archives and reviewed. Each case was analyzed with respect to age , sex, site and tumor characteristics. Results: In this 2-year period, 5 cases of adrenal tumors were found. The age range of the patients was 8-54 years. Out of 5 cases,2 cases were male and 3 cases were female. Out of 5 cases of , 4 were on the left side and 1 was on the right side.2 out of the 5 cases were diagnosed as Adrenocortical carcinoma(low grade), 1 as Phaeochromocytoma and 2 as Adrenocortical Adenoma. Conclusion: Adrenal gland tumors are rare, so the pathologic classification and determination of prognosis are very challenging.