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Non-small cell lung carcinoma subtyping in conventional cytology: Results of the IASLC Cytology Working Group survey to determine specific cytomorphological criteria for adenocarcinoma and squamous cell carcinoma

Jain, Deepali; Nambirajan, Aruna; Chen, Gang; Geisinger, Kim; Hiroshima, Kenzo; Layfield, Lester; Minami, Yuko; Moreira, Andre L; Motoi, Noriko; Papotti, Mauro; Rekhtman, Natasha; Russell, Prudence A; Prince, Spasenija Savic; Schmitt, Fernando; Yatabe, Yasushi; Eppenberger-Castori, Serenella; Bubendorf, Lukas
INTRODUCTION/BACKGROUND:Accurate subtyping of non-small cell lung carcinomas (NSCLC) into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) is the cornerstone of NSCLC diagnosis. Cytology samples show higher rates of classification failures, i.e., subtyping as non-small cell carcinoma, not otherwise specified (NSCC-NOS), as compared to histology. This study aims to identify specific algorithms based on known cytomorphological features that aid accurate and successful subtyping of NSCLC on cytology. METHODS:Thirteen expert cytopathologists participated anonymously in an online survey to subtype 119 NSCLC cytology cases (gold standard diagnoses being LUAD in 80 and LUSC in 39) enriched for non-keratinising LUSC. They selected from 23 pre-defined cytomorphological features that they used in subtyping. Data were analysed using machine learning algorithms based on Random Forest Method and regression trees. RESULTS:From 1474 responses recorded, concordant cytology typing was achieved in 53.7% (792/1474) responses. NSCC-NOS rates on cytology were similar among gold standard LUAD (36%) and LUSC (38%) cases. Misclassification rates were higher in gold standard LUSC (17.6%) than gold standard LUAD (5.5%; P<0.0001). Keratinisation, when present, recognised LUSC with high accuracy. In its absence, the ML algorithms developed based on experts' choices were unable to reduce cytology NSCC-NOS rates without increasing misclassification rates. CONCLUSION/CONCLUSIONS:Suboptimal recognition of LUSC in the absence of keratinisation remains the major hurdle in improving cytology subtyping accuracy with such cases either failing classification (NSCC-NOS) or misclassifying as LUAD. NSCC-NOS appears to be an inevitable morphological diagnosis emphasizing that ancillary IC is necessary to achieve accurate subtyping on cytology.
PMID: 35331963
ISSN: 1556-1380
CID: 5206762

Deep learning and pathomics analyses reveal cell nuclei as important features for mutation prediction of BRAF-mutated melanomas

Kim, Randie H; Nomikou, Sofia; Coudray, Nicolas; Jour, George; Dawood, Zarmeena; Hong, Runyu; Esteva, Eduardo; Sakellaropoulos, Theodore; Donnelly, Douglas; Moran, Una; Hatzimemos, Aristides; Weber, Jeffrey S; Razavian, Narges; Aifantis, Iannis; Fenyo, David; Snuderl, Matija; Shapiro, Richard; Berman, Russell S; Osman, Iman; Tsirigos, Aristotelis
Image-based analysis as a method for mutation detection can be advantageous in settings when tumor tissue is limited or unavailable for direct testing. Here, we utilize two distinct and complementary machine learning methods of analyzing whole slide images (WSI) for predicting mutated BRAF. In the first method, WSI of melanomas from 256 patients were used to train a deep convolutional neural network (CNN) in order to develop a fully automated model that first selects for tumor-rich areas (Area Under the Curve AUC=0.96) then predicts for mutated BRAF (AUC=0.71). Saliency mapping was performed and revealed that pixels corresponding to nuclei were the most relevant to network learning. In the second method, WSI were analyzed using a pathomics pipeline that first annotates nuclei and then quantifies nuclear features, demonstrating that mutated BRAF nuclei were significantly larger and rounder nuclei compared to BRAF WT nuclei. Lastly, we developed a model that combines clinical information, deep learning, and pathomics that improves the predictive performance for mutated BRAF to AUC=0.89. Not only does this provide additional insights on how BRAF mutations affect tumor structural characteristics, machine learning-based analysis of WSI has the potential to be integrated into higher order models for understanding tumor biology.
PMID: 34757067
ISSN: 1523-1747
CID: 5050512

The "Great Debate" at Melanoma Bridge 2021, December 2nd-4th, 2021

Ascierto, Paolo A; Warner, Allison Betof; Blank, Christian; Caracò, Corrado; Demaria, Sandra; Gershenwald, Jeffrey E; Khushalani, Nikhil I; Long, Georgina V; Luke, Jason J; Mehnert, Janice M; Robert, Caroline; Rutkowski, Piotr; Tawbi, Hussein A; Osman, Iman; Puzanov, Igor
The Great Debate session at the 2021 Melanoma Bridge virtual congress (December 2-4) featured counterpoint views from experts on seven important issues in melanoma. The debates considered the use of adoptive cell therapy versus use of bispecific antibodies, mitogen-activated protein kinase (MAPK) inhibitors versus immunotherapy in the adjuvant setting, whether the use of corticosteroids for the management of side effects have an impact on outcomes, the choice of programmed death (PD)-1 combination therapy with cytotoxic T-lymphocyte-associated antigen (CTLA)-4 or lymphocyte-activation gene (LAG)-3, whether radiation is needed for brain metastases, when lymphadenectomy should be integrated into the treatment plan and then the last debate, telemedicine versus face-to-face. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. Audiences voted both before and after each debate.
PMID: 35538491
ISSN: 1479-5876
CID: 5214372

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Kleffman, Kevin; Levinson, Grace; Rose, Indigo V L; Blumenberg, Lili M; Shadaloey, Sorin A A; Dhabaria, Avantika; Wong, Eitan; Galan-Echevarria, Francisco; Karz, Alcida; Argibay, Diana; Von Itter, Richard; Floristan, Alfredo; Baptiste, Gillian; Eskow, Nicole M; Tranos, James A; Chen, Jenny; Vega Y Saenz de Miera, Eleazar C; Call, Melissa; Rogers, Robert; Jour, George; Wadghiri, Youssef Zaim; Osman, Iman; Li, Yue-Ming; Mathews, Paul; DeMattos, Ronald; Ueberheide, Beatrix; Ruggles, Kelly V; Liddelow, Shane A; Schneider, Robert J; Hernando, Eva
Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (AB) for growth and survival in the brain parenchyma. Melanoma-secreted AB activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of AB decreases brain metastatic burden.
PMID: 35262173
ISSN: 2159-8290
CID: 5183542

Comparison of serum neurodegenerative biomarkers among hospitalized COVID-19 patients versus non-COVID subjects with normal cognition, mild cognitive impairment, or Alzheimer's dementia

Frontera, Jennifer A; Boutajangout, Allal; Masurkar, Arjun V; Betensky, Rebecca A; Ge, Yulin; Vedvyas, Alok; Debure, Ludovic; Moreira, Andre; Lewis, Ariane; Huang, Joshua; Thawani, Sujata; Balcer, Laura; Galetta, Steven; Wisniewski, Thomas
INTRODUCTION/BACKGROUND:Neurological complications among hospitalized COVID-19 patients may be associated with elevated neurodegenerative biomarkers. METHODS:Among hospitalized COVID-19 patients without a history of dementia (N = 251), we compared serum total tau (t-tau), phosphorylated tau-181 (p-tau181), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), and amyloid beta (Aβ40,42) between patients with or without encephalopathy, in-hospital death versus survival, and discharge home versus other dispositions. COVID-19 patient biomarker levels were also compared to non-COVID cognitively normal, mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia controls (N = 161). RESULTS:Admission t-tau, p-tau181, GFAP, and NfL were significantly elevated in patients with encephalopathy and in those who died in-hospital, while t-tau, GFAP, and NfL were significantly lower in those discharged home. These markers correlated with severity of COVID illness. NfL, GFAP, and UCHL1 were higher in COVID patients than in non-COVID controls with MCI or AD. DISCUSSION/CONCLUSIONS:Neurodegenerative biomarkers were elevated to levels observed in AD dementia and associated with encephalopathy and worse outcomes among hospitalized COVID-19 patients.
PMID: 35023610
ISSN: 1552-5279
CID: 5116752

Thymic Carcinomas - A Concise Multidisciplinary Update on Recent Developments from the Thymic Carcinoma Working Group of the International Thymic Malignancy Interest Group

Roden, Anja C; Ahmad, Usman; Cardillo, Giuseppe; Girard, Nicolas; Jain, Deepali; Marom, Edith M; Marx, Alexander; Moreira, Andre L; Nicholson, Andrew G; Rajan, Arun; Shepherd, Annemarie F; Simone, Charles B; Strange, Chad D; Szolkowska, Malgorzata; Truong, Mylene T; Rimner, Andreas
Thymic carcinomas are rare malignancies that in general arise in the prevascular (anterior) mediastinum. These tumors are usually invasive, often present at advanced stages, and typically behave aggressively. Studies are hampered by the paucity of these tumors, the large variety of carcinoma subtypes, and the lack of unique morphologic and immunophenotypic features. Despite these challenges, advances in diagnostic imaging, surgical approaches, systemic therapies, and radiation therapy techniques have been made. The World Health Organization classification of thymic epithelial tumors has been updated in 2021 and the 8th tumor nodal metastasis staging by the American Joint Committee on Cancer /Union for International Cancer Control included thymic carcinomas in 2017. Molecular alterations that provide more insight into the pathogenesis of these tumors and that potentially permit use of novel targeted therapies are increasingly being identified. New approaches to radiation therapy, chemotherapy, and immunotherapy are under evaluation. International societies including the International Thymic Malignancy Interest Group, European Society of Thoracic Surgeons, and Japanese, Chinese, and Korean thymic associations have been critical in organizing and conducting multi-institutional clinical studies. Herein we review contemporary multidisciplinary perspectives in diagnosis and management of thymic carcinoma.
PMID: 35227908
ISSN: 1556-1380
CID: 5174212

Assessing Pathologic Response in Resected Lung Cancers: Current Standards, Proposal for a Novel Pathologic Response Calculator Tool, and Challenges in Practice

Saqi, Anjali; Leslie, Kevin O; Moreira, Andre L; Lantuejoul, Sylvie; Shu, Catherine Ann; Rizvi, Naiyer A; Sonett, Joshua R; Tajima, Kosei; Sun, Shawn W; Gitlitz, Barbara J; Colby, Thomas V
The efficacy of neoadjuvant treatment for NSCLC can be pathologically assessed in resected tissue. Major pathologic response (MPR) and pathologic complete response (pCR), defined as less than or equal to 10% and 0% viable tumor cells, respectively, are increasingly being used in NSCLC clinical trials to establish them as surrogate end points for efficacy to shorten time to outcome. Nevertheless, sampling and MPR calculation methods vary between studies. The International Association for the Study of Lung Cancer recently published detailed recommendations for pathologic assessment of NSCLC after neoadjuvant treatment, with methodology being critical. To increase methodological rigor further, we developed a novel MPR calculator tool (MPRCT) for standardized, comprehensive collection of percentages of viable tumor, necrosis, and stroma in the tumor bed. In addition, tumor width and length in the tumor bed are measured and unweighted and weighted MPR averages are calculated, the latter to account for the varying proportions of tumor beds on slides. We propose sampling the entire visible tumor bed for tumors having pCR regardless of size, 100% of tumors less than or equal to 3 cm in diameter, and at least 50% of tumors more than 3 cm. We describe the uses of this tool, including potential formal analyses of MPRCT data to determine the optimum sampling strategy that balances sensitivity against excessive use of resources. Solutions to challenging scenarios in pathologic assessment are proposed. This MPRCT will facilitate standardized, systematic, comprehensive collection of pathologic response data with a standardized methodology to validate studies designed to establish MPR and pCR as surrogate end points of neoadjuvant treatment efficacy.
PMID: 35498382
ISSN: 2666-3643
CID: 5215842

Associations between TERT promoter mutations and survival in superficial spreading and nodular melanomas in a large prospective patient cohort

Chang, Gregory A; Robinson, Eric; Wiggins, Jennifer M; Zhang, Yilong; Tadepalli, Jyothirmayee S; Schafer, Christine N; Darvishian, Farbod; Berman, Russell S; Shapiro, Richard; Shao, Yongzhao; Osman, Iman; Polsky, David
Survival outcomes in melanoma, and their association with mutations in the telomerase reverse transcriptase (TERT) promoter, remain uncertain. In addition, few studies have examined whether these associations are affected by a nearby common germline polymorphism, or vary based on melanoma histopathological subtype. We analyzed 408 primary tumors from a prospective melanoma cohort for somatic TERT-124[C>T] and TERT-146[C>T] mutations, the germline polymorphism rs2853669, and BRAFV600 and NRASQ61 mutations. We tested the associations between these variants and clinicopathologic factors and survival outcomes. TERT-124[C>T] was associated with thicker tumors, ulceration, mitoses (>0/mm2), nodular histotype and CNS involvement. In a multivariable model controlling for AJCC stage, TERT-124[C>T] was an independent predictor of shorter recurrence-free survival (RFS) (HR=2.58, p=0.001), and overall survival (HR=2.47, p=0.029). Patients with the germline variant and TERT-124[C>T] mutant melanomas had significantly shorter RFS than those patients lacking either or both sequence variants (p<0.04). The impact of the germline variant appeared to be more pronounced in superficial spreading compared to nodular melanoma. No associations were found between survival and TERT-146[C>T], BRAF or NRAS mutations. These findings strongly suggest that TERT-124[C>T] mutation is a biomarker of aggressive primary melanomas, an effect that may be modulated by rs2853669.
PMID: 35469904
ISSN: 1523-1747
CID: 5205542

Diagnostic Challenges in the Cytology of Thymic Epithelial Neoplasms

Willner, Jonathan; Zhou, Fang; Moreira, Andre L
Thymic epithelial neoplasms are rare tumors that constitute the majority of anterior mediastinal masses. They are classified as thymomas, thymic carcinomas, and thymic neuroendocrine neoplasms. Biopsy diagnosis is not common, and most tumors are surgically resected. Biopsy, including cytology, is indicated when a non-surgical entity is suspected or in cases of locally advanced disease. Smears of thymomas consist of round or spindle epithelial cells admixed with varying amounts of lymphocytes depending on the type of thymoma. Smears of thymic carcinoma and thymic neuroendocrine neoplasms are often indistinguishable from corresponding tumor types from other organs. Accurate cytological diagnosis can be difficult due to the histological diversity of thymomas, as well as the morphological features that certain thymic tumors share with similar tumors from other organs. However, fine needle aspiration (FNA) of anterior mediastinal masses can provide clinically actionable information and can be used to determine whether lesions require surgical, systemic, or local noninvasive treatments. Ancillary studies, namely, immunocytochemical stains, flow cytometry, and radiology, are important tools in the evaluation of thymic aspirates. This review discusses the utility and limitations of thymic FNAs and illustrates the diagnostic features and pitfalls of these specimens.
PMID: 35454918
ISSN: 2072-6694
CID: 5218662

Integrated analysis of ovarian juvenile granulosa cell tumors reveals distinct epigenetic signatures and recurrent TERT rearrangements

Vougiouklakis, Theodore; Zhu, Kelsey; Vasudevaraja, Varshini; Serrano, Jonathan; Shen, Guomiao; Linn, Rebecca L; Feng, Xiaojun; Chiang, Sarah; Barroeta, Julieta E; Thomas, Kristen M; Schwartz, Lauren E; Shukla, Pratibha S; Malpica, Anais; Oliva, Esther; Cotzia, Paolo; DeLair, Deborah F; Snuderl, Matija; Jour, George
PURPOSE/OBJECTIVE:-truncating mutations. Conversely, the molecular underpinnings of the rare juvenile granulosa cell tumor (JGCT) have not been well elucidated. To this end, we applied a tumor-only integrated approach to investigate the genomic, transcriptomic, and epigenomic landscape of 31 JGCTs to identify putative oncogenic drivers. EXPERIMENTAL DESIGN/METHODS:Multipronged analyses of 31 JGCTs were performed utilizing a clinically validated next-generation sequencing (NGS)-panel targeting 580 cancer-related genes for genomic interrogation, in addition to targeted RNA NGS for transcriptomic exploration. Genome-wide DNA methylation profiling was conducted using an Infinium Methylation EPIC array targeting 866,562 CpG methylation sites. RESULTS:non-rearranged JGCTs under direct promoter control. Genome-wide DNA methylation rendered a clear delineation between AGCTs and JGCTs at the epigenomic level further supporting its diagnostic utility in distinguishing among these tumors. CONCLUSIONS:rearrangements in a subset of tumors. Our findings further offer insights into possible targeted therapies in a rare entity.
PMID: 35031544
ISSN: 1557-3265
CID: 5119182