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Item Evaluation of an institutional series of low-grade oncocytic tumor (LOT) of the kidney and review of the mutational landscape of LOT(Springer, 2023) Ricci, Costantino; Ambrosi, Francesca; Franceschini, Tania; Giunchi, Francesca; Grillini, Alessia; Franchini, Eugenia; Grillini, Marco; Schiavina, Riccardo; Massari, Francesco; Mollica, Veronica; Tateo, Valentina; Bianchi, Federico Mineo; Bianchi, Lorenzo; Droghetti, Matteo; Maloberti, Thais; Tallini, Giovanni; Colecchia, Maurizio; Acosta, Andres Martin; Lobo, João; Trpkov, Kiril; Fiorentino, Michelangelo; de Biase, Dario; Pathology and Laboratory Medicine, School of MedicineThe 2022 WHO classification of urinary and male genital tumors introduced several novel kidney entities exhibiting eosinophilic/oncocytic features with specific mutational backgrounds. Thus, molecular techniques, such as next-generation sequencing (NGS), became more commonly used for their evaluation. We studied 12 low-grade oncocytic tumors (LOT) of the kidney (from 11 patients), identified in a cohort of 210 eosinophilic/oncocytic renal tumors, diagnosed in our institution between October 2019 and May 2023, which represented 5.7% (12/210) of all eosinophilic/oncocytic renal tumors during this period. We reviewed their clinicopathologic, histologic, and immunohistochemical features, as well as their mutational profiles. We also reviewed the literature on NGS-derived data of LOT, by selecting papers in which LOT diagnosis was rendered according to the criteria proposed initially. Median age was 65 years (mean: 63.5; range 43–79) and median tumor size was 2.0 cm (mean: 2.2; range: 0.9–3.1). All tumors were positive for PAX8, CK7, and GATA3, and negative or focally positive for CD117/KIT. We found the following gene mutations: MTOR ((6/11), 54.5%)), TSC1 ((2/11), 18.2%)), and 1 had both NOTCH1 and NOTCH4 ((1/11), 9.1%)). Wild-type status was found in 2/11 (18.2%) patients and one tumor was not analyzable. A review of 8 previous studies that included 79 LOTs revealed frequent mutations in the genes that regulate the mammalian target of rapamycin (mTOR) pathway: MTOR (32/79 (40.5%)), TSC1 (21/79 (26.6%)), and TSC2 (9/79 (11.4%)). Other mutated genes included PIK3CA, NF2, and PTEN, not typically known to affect the mTOR pathway, but potentially acting as upstream and downstream effectors. Our study shows that LOT is increasingly diagnosed in routine practice when applying the appropriate diagnostic criteria. We also confirm that the mTOR pathway is strongly implicated in the pathogenesis of this tumor mainly through MTOR, TCS1, and TSC2 mutations, but other genes could also be involved in the pathway activation, especially in LOTs without “canonical” mutations.Item Malakoplakia in the Urinary Bladder of 4 Puppies(Sage, 2021) Davis, Katelin L.; Cheng, Liang; Ramos-Vara, José; Sánchez, Melissa D.; Wilkes, Rebecca P.; Sola, Mario F.; Pathology and Laboratory Medicine, School of MedicineMalakoplakia in humans most often affects the urinary bladder and is characterized by inflammation with von Hansemann–type macrophages, with or without Michaelis-Gutmann bodies, and is frequently associated with Escherichia coli infection. We describe the microscopic features of malakoplakia in the urinary bladder of 4 puppies. In all cases, the lamina propria of the urinary bladder was markedly expanded by sheets of large, round to polygonal macrophages with intracytoplasmic, periodic acid-Schiff-positive granules and granular inclusions, and rare Prussian blue–positive inclusions. Macrophages were positive for CD18 and Iba1. In 2 cases, Michaelis-Gutmann bodies were detected with hematoxylin and eosin stain and were best demonstrated with von Kossa stain. E. coli infection was confirmed in 2 cases with bacterial culture or polymerase chain reaction (PCR) and sequencing of the bacterial 16S ribosomal RNA gene. Transmission electron microscopy of one case demonstrated macrophages with abundant lysosomes, phagolysosomes, and rod-shaped bacteria. Microscopic features were similar to human cases of malakoplakia. In dogs, the light microscopic characteristics of malakoplakia closely resemble granular cell tumors and histiocytic ulcerative colitis.Item Fatal eosinophilic myocarditis and submassive hepatic necrosis in lamotrigine induced DRESS syndrome(BMC, 2023-10-25) Doan, Khanh Duy; Akinsanya, Adeyinka; Kuhar, Matthew; Mesa, Hector; Pathology and Laboratory Medicine, School of MedicineDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a rare but severe and sometimes fatal adverse drug reaction that is known to occur with a number of antiepileptic drugs. It often follows a prolonged clinical course, which can worsen even after discontinuing the causative drug and administering steroid treatment. Failure to promptly identify the delayed involvement of vital organs, such as the heart and liver, may result in irreversible organ failure and death. We report a case of a presumed sudden death of a young woman who had a documented history of a protracted intermittent hypersensitivity reaction to lamotrigine. Postmortem examination revealed the presence of eosinophilic myocarditis and submassive hepatic necrosis diagnostic of fatal DRESS syndrome that progressed despite early discontinuation of the medication and improvement of dermatologic and hematologic symptoms following steroid therapy.Item Attenuated TGFB signalling in macrophages decreases susceptibility to DMBA-induced mammary cancer in mice(BMC, 2021-03-24) Sun, Xuan; Bernhardt, Sarah M.; Glynn, Danielle J.; Hodson, Leigh J.; Woolford, Lucy; Evdokiou, Andreas; Yan, Cong; Du, Hong; Robertson, Sarah A.; Ingman, Wendy V.; Pathology and Laboratory Medicine, School of MedicineBackground: Transforming growth factor beta1 (TGFB1) is a multi-functional cytokine that regulates mammary gland development and cancer progression through endocrine, paracrine and autocrine mechanisms. TGFB1 also plays roles in tumour development and progression, and its increased expression is associated with an increased breast cancer risk. Macrophages are key target cells for TGFB1 action, also playing crucial roles in tumourigenesis. However, the precise role of TGFB-regulated macrophages in the mammary gland is unclear. This study investigated the effect of attenuated TGFB signalling in macrophages on mammary gland development and mammary cancer susceptibility in mice. Methods: A transgenic mouse model was generated, wherein a dominant negative TGFB receptor is activated in macrophages, in turn attenuating the TGFB signalling pathway specifically in the macrophage population. The mammary glands were assessed for morphological changes through wholemount and H&E analysis, and the abundance and phenotype of macrophages were analysed through immunohistochemistry. Another cohort of mice received carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), and tumour development was monitored weekly. Human non-neoplastic breast tissue was also immunohistochemically assessed for latent TGFB1 and macrophage marker CD68. Results: Attenuation of TGFB signalling resulted in an increase in the percentage of alveolar epithelium in the mammary gland at dioestrus and an increase in macrophage abundance. The phenotype of macrophages was also altered, with inflammatory macrophage markers iNOS and CCR7 increased by 110% and 40%, respectively. A significant decrease in DMBA-induced mammary tumour incidence and prolonged tumour-free survival in mice with attenuated TGFB signalling were observed. In human non-neoplastic breast tissue, there was a significant inverse relationship between latent TGFB1 protein and CD68-positive macrophages. Conclusions: TGFB acts on macrophage populations in the mammary gland to reduce their abundance and dampen the inflammatory phenotype. TGFB signalling in macrophages increases mammary cancer susceptibility potentially through suppression of immune surveillance activities of macrophages.Item Splenic-vasculature involvement is associated with poor prognosis in resected distal pancreatic cancer(Oxford University Press, 2020-11-24) Yin, Feng; Saad, Mohammed; Lin, Jingmei; Jackson, Christopher R.; Ren, Bing; Lawson, Cynthia; Karamchandani, Dipti M.; Bernabeu, Belen Quereda; Jiang, Wei; Dhir, Teena; Zheng, Richard; Schultz, Christopher W.; Zhang, Dongwei; Thomas, Courtney L.; Zhang, Xuchen; Lai, Jinping; Schild, Michael; Zhang, Xuefeng; Xie, Hao; Liu, Xiuli; Pathology and Laboratory Medicine, School of MedicineBackground: Distal pancreatic carcinoma is one of the most lethal cancers largely due to its high incidence of distant metastasis. This study aims to assess the prognostic value of splenic-vasculature involvement in resected distal pancreatic carcinoma. Methods: In this retrospective study, we collected the clinicopathologic information of 454 patients with pancreatic cancer and performed univariate and multivariate analyses to identify factors associated with progression-free survival (PFS) and overall survival (OS), with an emphasis on the prognostic value of splenic-artery and -vein involvement. Results: Univariate analysis revealed that larger tumor size, non-intraductal papillary mucinous neoplasm (non-IPMN)-associated adenocarcinoma, poor differentiation, stage pT3, nodal metastasis, lymphovascular invasion, perineural invasion, and pathologic and radiographic evidence of splenic-vein invasion were significantly associated with shorter PFS and OS (all P < 0.05). Multivariate analysis confirmed non-IPMN-associated adenocarcinoma, stage pT3, stage pN1-2, and post-operative adjuvant chemotherapy as independent risk factors for both PFS and OS, and larger tumor size and radiographic evidence of splenic-artery invasion as predictors of PFS only. Conclusion: Guidelines should be developed for a uniform approach with regard to the examination and reporting of the status of the splenic vasculature when dealing with distal-pancreatic-cancer specimens.Item Inflammatory bowel disease in Hermansky–Pudlak syndrome: a retrospective single-centre cohort study(Wiley, 2021) O’Brien, K. J.; Parisi, X.; Shelman, N. R.; Merideth, M. A.; Introne, W. J.; Heller, T.; Gahl, W. A.; Malicdan, M. C. V.; Gochuico, B. R.; Pathology and Laboratory Medicine, School of MedicineBackground: Knowledge about inflammatory bowel disease (IBD) in patients with Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles, could provide insights into IBD in general. Objective: To expand the understanding of IBD in patients with HPS. Methods: Retrospective review of records from patients with HPS evaluated at the National Institutes of Health Clinical Center from 1995 to 2019 was conducted. Clinical features of IBD, genotyping results and histologic findings of colectomy specimens were analysed. Results: IBD affected 37 (14.2%; 12 male, 25 female) of 261 patients with HPS. Median age of onset was 17 years; range was 1 to 52 years. The most common symptoms of HPS IBD were hematochezia, abdominal pain and loose stools. Fistulae or extra-intestinal manifestations developed in 30% or 22%, respectively. Genotyping showed that patients with biallelic variants in HPS1, HPS3, HPS4 or HPS6 were diagnosed with IBD. Six children had very early-onset IBD. Patients with HPS-3 had mild manifestations of IBD. Medical therapy and bowel resection were utilized to treat 73% and 35% of patients with HPS IBD, respectively; 7 of 13 patients receiving anti-tumor necrosis factor alpha therapy had prolonged clinical responses. Active cryptitis, chronic inflammatory changes, granulomas and ceroid lipofuscinosis were histopathologic findings in three colectomy specimens. Conclusions: IBD resembling Crohn's disease affects some patients with HPS; genetic heterogeneity is a feature of HPS IBD. HPS3 is a new gene associated with human IBD. Very early-onset IBD can develop in HPS.Item A Large Open Access Dataset of Brain Metastasis 3D Segmentations with Clinical and Imaging Feature Information(Springer Nature, 2024-02-29) Ramakrishnan, Divya; Jekel, Leon; Chadha, Saahil; Janas, Anastasia; Moy, Harrison; Maleki, Nazanin; Sala, Matthew; Kaur, Manpreet; Cassinelli Petersen, Gabriel; Merkaj, Sara; von Reppert, Marc; Baid, Ujjwal; Bakas, Spyridon; Kirsch, Claudia; Davis, Melissa; Bousabarah, Khaled; Holler, Wolfgang; Lin, MingDe; Westerhoff, Malte; Aneja, Sanjay; Memon, Fatima; Aboian, Mariam S.; Pathology and Laboratory Medicine, School of MedicineResection and whole brain radiotherapy (WBRT) are standard treatments for brain metastases (BM) but are associated with cognitive side effects. Stereotactic radiosurgery (SRS) uses a targeted approach with less side effects than WBRT. SRS requires precise identification and delineation of BM. While artificial intelligence (AI) algorithms have been developed for this, their clinical adoption is limited due to poor model performance in the clinical setting. The limitations of algorithms are often due to the quality of datasets used for training the AI network. The purpose of this study was to create a large, heterogenous, annotated BM dataset for training and validation of AI models. We present a BM dataset of 200 patients with pretreatment T1, T1 post-contrast, T2, and FLAIR MR images. The dataset includes contrast-enhancing and necrotic 3D segmentations on T1 post-contrast and peritumoral edema 3D segmentations on FLAIR. Our dataset contains 975 contrast-enhancing lesions, many of which are sub centimeter, along with clinical and imaging information. We used a streamlined approach to database-building through a PACS-integrated segmentation workflow.Item Thymic Hyperplasia with Lymphoepithelial Sialadenitis (LESA)-Like Features: Strong Association with Lymphomas and Non-Myasthenic Autoimmune Diseases(MDPI, 2021-01-16) Porubsky, Stefan; Popovic, Zoran V.; Badve, Sunil; Banz, Yara; Berezowska, Sabina; Borchert, Dietmar; Brüggemann, Monika; Gaiser, Timo; Graeter, Thomas; Hollaus, Peter; Huettl, Katrin S.; Kotrova, Michaela; Kreft, Andreas; Kugler, Christian; Lötscher, Fabian; Möller, Burkhard; Ott, German; Preissler, Gerhard; Roessner, Eric; Rosenwald, Andreas; Ströbel, Philipp; Marx, Alexander; Pathology and Laboratory Medicine, School of MedicineThymic hyperplasia (TH) with lymphoepithelial sialadenitis (LESA)-like features (LESA-like TH) has been described as a tumor-like, benign proliferation of thymic epithelial cells and lymphoid follicles. We aimed to determine the frequency of lymphoma and autoimmunity in LESA-like TH and performed retrospective analysis of cases with LESA-like TH and/or thymic MALT-lymphoma. Among 36 patients (21 males) with LESA-like TH (age 52 years, 32-80; lesion diameter 7.0 cm, 1-14.5; median, range), five (14%) showed associated lymphomas, including four (11%) thymic MALT lymphomas and one (3%) diffuse large B-cell lymphoma. One additional case showed a clonal B-cell-receptor rearrangement without evidence of lymphoma. Twelve (33%) patients (7 women) suffered from partially overlapping autoimmune diseases: systemic lupus erythematosus (n = 4, 11%), rheumatoid arthritis (n = 3, 8%), myasthenia gravis (n = 2, 6%), asthma (n = 2, 6%), scleroderma, Sjögren syndrome, pure red cell aplasia, Grave's disease and anti-IgLON5 syndrome (each n = 1, 3%). Among 11 primary thymic MALT lymphomas, remnants of LESA-like TH were found in two cases (18%). In summary, LESA-like TH shows a striking association with autoimmunity and predisposes to lymphomas. Thus, a hematologic and rheumatologic workup should become standard in patients diagnosed with LESA-like TH. Radiologists and clinicians should be aware of LESA-like TH as a differential diagnosis for mediastinal mass lesions in patients with autoimmune diseases.Item Novel histotypes of sporadic Creutzfeldt–Jakob disease linked to 129MV genotype(BMC, 2023-08-31) Cracco, Laura; Puoti, Gianfranco; Cornacchia, Antonio; Glisic, Katie; Lee, Seong‑Ki; Wang, Zerui; Cohen, Mark L.; Appleby, Brian S.; Cali, Ignazio; Pathology and Laboratory Medicine, School of MedicineThe MV1 and MV2 subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) are linked to the heterozygous methionine (M)/valine (V) polymorphism at codon 129 of the prion protein (PrP) gene. MV2 is phenotypically heterogeneous, whereas MV1, due to its low prevalence, is one of the least well characterized subtypes. In this study, we investigated the biochemical properties of PrPSc and phenotypic expression of cases diagnosed as sCJD MV1 and MV2. We describe four MV2 histotypes: 2C, with cortical (C) coarse pathology; 2K, with kuru (K) plaque deposits; 2C-K, with co-existing C and K histotypic features; and the novel histotype 2C-PL that mimics 2C in the cerebral cortex and cerebellum, but exhibits plaque-like (PL) PrP deposits in subcortical regions (e.g., basal nuclei, thalamus and midbrain). Histotype prevalence is highest for 2C-K (55%), intermediate for 2C (31%), and lowest for 2C-PL and 2K (7%). Nearly every MV2 case expressed both PrPSc types, with T2 being the predominant type ("MV2-1"). MV1 cases typically show a rapid disease course (≤ 4 months), and feature the 1C histotype, phenotypically identical to sCJDMM1. Co-existing PrPSc types, with T1 significantly exceeding T2 ("MV1-2"), are detected in patients diagnosed as MV1 with longer disease courses. We observed four histotypes among MV1-2 cases, including two novel histotypes: 1V, reminiscent of sCJDVV1; 1C-2C, resembling sCJDMM1-2 with predominant MM1 histotypic component; and novel histotypes 1C-2PL and 1C-2K, overall mimicking 1C in the cerebral cortex, but harboring T2 and plaque-like PrP deposits in subcortical regions (1C-2PL), and T2 and kuru plaques in the cerebellum (1C-2K). Lesion profiles of 1C, 1V, and 1C-2C are similar, but differ from 1C-2PL and 1C-2K, as the latter two groups show prominent hippocampal and nigral degeneration. We believe that the novel "C-PL" histotypes are distinct entities rather than intermediate forms between "C" and "C-K" groups, and that 1C-2PL and 1C-2K histotypes may be characterized by different T1 variants of the same size.Item Transcriptional Signatures of Hippocampal Tau Pathology in Primary Age-Related Tauopathy and Alzheimer’s Disease(medRxiv, 2023-09-12) Stein-O’Brien, Genevieve L.; Palaganas, Ryan; Meyer, Ernest M.; Redding-Ochoa, Javier; Pletnikova, Olga; Guo, Haidan; Bell, William R.; Troncoso, Juan C.; Huganir, Richard L.; Morris, Meaghan; Pathology and Laboratory Medicine, School of MedicineBackground: Tau pathology is common in age-related neurodegenerative diseases. Tau pathology in primary age-related tauopathy (PART) and in Alzheimer's disease (AD) has a similar biochemical structure and anatomic distribution, which is distinct from tau pathology in other diseases. However, the molecular changes associated with intraneuronal tau pathology in PART and AD, and whether these changes are similar in the two diseases, is largely unexplored. Methods: Using GeoMx spatial transcriptomics, mRNA was quantified in CA1 pyramidal neurons with tau pathology and adjacent neurons without tau pathology in 6 cases of PART and 6 cases of AD, and compared to 4 control cases without pathology. Transcriptional changes were analyzed for differential gene expression and for coordinated patterns of gene expression associated with both disease state and intraneuronal tau pathology. Results: Synaptic gene changes and two novel gene expression signatures associated with intraneuronal tau were identified in PART and AD. Overall, gene expression changes associated with intraneuronal tau pathology were similar in PART and AD. Synaptic gene expression was decreased overall in neurons in AD and PART compared to control cases. However, this decrease was largely driven by neurons lacking tau pathology. Synaptic gene expression was increased in tau-positive neurons compared to tau-negative neurons in disease. Two novel gene expression signatures associated with intraneuronal tau were identified by examining coordinated patterns of gene expression. Genes in the up-regulated expression pattern were enriched in calcium regulation and synaptic function pathways, specifically in synaptic exocytosis. These synaptic gene changes and intraneuronal tau expression signatures were confirmed in a published transcriptional dataset of cortical neurons with tau pathology in AD. Conclusions: PART and AD show similar transcriptional changes associated with intraneuronal tau pathology in CA1 pyramidal neurons, raising the possibility of a mechanistic relationship between the tau pathology in the two diseases. Intraneuronal tau pathology was also associated with increased expression of genes associated with synaptic function and calcium regulation compared to tau-negative disease neurons. The findings highlight the power of molecular analysis stratified by pathology in neurodegenerative disease and provide novel insight into common molecular pathways associated with intraneuronal tau in PART and AD.