Publications by authors named "Natasha Rekhtman"

135 Publications

Are there imaging characteristics that can distinguish separate primary lung carcinomas from intrapulmonary metastases using next-generation sequencing as a gold standard?

Lung Cancer 2021 Mar 25;153:158-164. Epub 2021 Jan 25.

Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Objectives: Distinguishing separate primary lung carcinomas (SPLCs) from intrapulmonary metastases (IPMs) in non-small cell lung cancer (NSCLC) patients is a challenging dilemma in clinical practice. Next-generation sequencing (NGS) was recently shown to represent a robust molecular method for clonal discrimination in this setting. In this study, using clonal relationships established by comprehensive NGS as the ground truth, we investigated whether NSCLC patients with SPLCs versus IPMs exhibit distinct imaging characteristics.

Material And Methods: This retrospective study included patients who underwent pre-treatment computed tomography (CT) and/or positron emission tomography/CT (PET/CT) imaging followed by surgical resection for >1 NSCLC. Nodular, parenchymal, pleural, and ancillary CT features, as well as maximum standardized uptake values (SUVs) on PET/CT were recorded. Rao-Scott chi-square, Wilcoxon rank-sum, and Fisher's exact tests were used in patient- and lesion-level comparisons.

Results: This study included 60 patients (median age = 69 years, 68 % female) with 127 individual tumors comprising 51 SPLC vs 23 IPM tumor pairs based on NGS profiling. SPLCs were associated with subsolid consistency (P = 0.005) and spiculated contours (P <  0.001), while IPMs were associated with greater difference of size between lesions (P = 0.017) or pure solid consistency of the smaller lesion (P = 0.011). Lymph node involvement was more frequent in IPMs than SPLCs (P = 0.036). SUV measurements were not useful for differentiation (P > 0.05).

Conclusion: Selected preoperative CT features are distributed differentially in SPLCs and IPMs, suggesting that imaging may have a role in distinguishing clonal relationships of tumors in patients with >1 NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2021.01.019DOI Listing
March 2021

Ultrarapid Mutation Screening Followed by Comprehensive Next-Generation Sequencing: A Feasible, Informative Approach for Lung Carcinoma Cytology Specimens With a High Success Rate.

JTO Clin Res Rep 2020 Sep 18;1(3). Epub 2020 Jul 18.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Introduction: For patients with advanced NSCLC, cytologic samples may be the only diagnostic specimen available for molecular profiling. Although both rapid and comprehensive assessment are essential in this setting, an integrated multitest approach remains an important strategy in many laboratories, despite the risks and challenges when working with scant samples. In this study, we describe our experience and high success rate in using a multitest approach, focusing on the clinical validation and incorporation of ultrarapid testing using the Idylla system followed by comprehensive next-generation sequencing (NGS).

Methods: Cytology samples received for routine molecular testing were included in this study. The performance characteristics of the Idylla assay were assessed; tissue suitability parameters and interpretation criteria to supplement automated mutation calling were established. The assay performance was monitored for 1 year, comparing the results with those of concurrent NGS testing by MSK-IMPACT (primarily) or MSK-AmpliSeq and MSK-Fusion solid panel in a subset of cases.

Results: Overall, 301 samples were studied; 83 samples were included in validation (60.2% [50 of 83] were positive for mutations). Concordance with the reference method was 96.4% (80 of 83) of the samples with excellent reproducibility. The limit of detection was variable depending on the total tissue input and the specific mutation tested. Unextracted tissue inputs that maintained total cycle of quantification at less than 23 allowed all mutations to be detected if present at greater than 5% variant allele frequency. Mutations could be detected at 1% variant allele frequency with total cycle of quantification of 18. During the clinical implementation phase, 218 NSCLC samples were tested by Idylla (24.3% [53 of 218] were mutation positive). Concurrent NGS testing was requested on 165 samples and successfully performed on 96.4% (159 of 165) of the samples. The Idylla automated results were concordant with those obtained by NGS in 96.2% (153 of 159) of cases and improved to 98.7% (157 of 159) after incorporation of manual review criteria to supplement automated calling, resulting in a diagnostic sensitivity of 95.6% (95% confidence interval: 84.9%-99.5%). In general, 9% (14 of 159) of the cases tested by NGS had mutations not covered by the Idylla assay, primarily insertions in exon 19 and 20 and minor mutations cooccurring with canonical sensitizing mutations.

Conclusions: Comprehensive molecular testing is feasible and has a high success rate in NSCLC cytology samples when using a multitest approach. Testing with the Idylla system enables rapid and accurate determination of the status without compromising subsequent NGS testing.
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http://dx.doi.org/10.1016/j.jtocrr.2020.100077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839984PMC
September 2020

A Genomic-Pathologic Annotated Risk Model to Predict Recurrence in Early-Stage Lung Adenocarcinoma.

JAMA Surg 2021 Feb 10;156(2):e205601. Epub 2021 Feb 10.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Recommendations for adjuvant therapy after surgical resection of lung adenocarcinoma (LUAD) are based solely on TNM classification but are agnostic to genomic and high-risk clinicopathologic factors. Creation of a prediction model that integrates tumor genomic and clinicopathologic factors may better identify patients at risk for recurrence.

Objective: To identify tumor genomic factors independently associated with recurrence, even in the presence of aggressive, high-risk clinicopathologic variables, in patients with completely resected stages I to III LUAD, and to develop a computational machine-learning prediction model (PRecur) to determine whether the integration of genomic and clinicopathologic features could better predict risk of recurrence, compared with the TNM system.

Design, Setting, And Participants: This prospective cohort study included 426 patients treated from January 1, 2008, to December 31, 2017, at a single large cancer center and selected in consecutive samples. Eligibility criteria included complete surgical resection of stages I to III LUAD, broad-panel next-generation sequencing data with matched clinicopathologic data, and no neoadjuvant therapy. External validation of the PRecur prediction model was performed using The Cancer Genome Atlas (TCGA). Data were analyzed from 2014 to 2018.

Main Outcomes And Measures: The study end point consisted of relapse-free survival (RFS), estimated using the Kaplan-Meier approach. Associations among clinicopathologic factors, genomic alterations, and RFS were established using Cox proportional hazards regression. The PRecur prediction model integrated genomic and clinicopathologic factors using gradient-boosting survival regression for risk group generation and prediction of RFS. A concordance probability estimate (CPE) was used to assess the predictive ability of the PRecur model.

Results: Of the 426 patients included in the analysis (286 women [67%]; median age at surgery, 69 [interquartile range, 62-75] years), 318 (75%) had stage I cancer. Association analysis showed that alterations in SMARCA4 (clinicopathologic-adjusted hazard ratio [HR], 2.44; 95% CI, 1.03-5.77; P = .042) and TP53 (clinicopathologic-adjusted HR, 1.73; 95% CI, 1.09-2.73; P = .02) and the fraction of genome altered (clinicopathologic-adjusted HR, 1.03; 95% CI, 1.10-1.04; P = .005) were independently associated with RFS. The PRecur prediction model outperformed the TNM-based model (CPE, 0.73 vs 0.61; difference, 0.12 [95% CI, 0.05-0.19]; P < .001) for prediction of RFS. To validate the prediction model, PRecur was applied to the TCGA LUAD data set (n = 360), and a clear separation of risk groups was noted (log-rank statistic, 7.5; P = .02), confirming external validation.

Conclusions And Relevance: The findings suggest that integration of tumor genomics and clinicopathologic features improves risk stratification and prediction of recurrence after surgical resection of early-stage LUAD. Improved identification of patients at risk for recurrence could enrich and enhance accrual to adjuvant therapy clinical trials.
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http://dx.doi.org/10.1001/jamasurg.2020.5601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758824PMC
February 2021

Rapid EGFR Mutation Detection Using the Idylla Platform: Single-Institution Experience of 1200 Cases Analyzed by an In-House Developed Pipeline and Comparison with Concurrent Next-Generation Sequencing Results.

J Mol Diagn 2021 Mar 18;23(3):310-322. Epub 2020 Dec 18.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Mutations in the epidermal growth factor receptor (EGFR) are the most common targetable alterations in lung adenocarcinoma. To facilitate rapid testing, the Idylla EGFR assay was incorporated as a screening method before next-generation sequencing (NGS). Validation and experience using an in-house developed analysis pipeline, enhanced with a manual review algorithm is described. Results are compared with corresponding NGS results. In all, 1249 samples were studied. Validation demonstrated 98.57% (69/70) concordance with the reference methods. The limit of detection varied from 2% to 5% variant allele frequency for total EGFR quantitation cycle between 20 and 23. Of the 1179 clinical cases, 23.41% were EGFR-positive by Idylla. Concurrent NGS was successfully performed on 94.9% (799/842) requests. Concordance of Idylla with NGS was 98.62% (788/799) and 98.50% (787/799) using our in-house and Idylla analysis pipelines, respectively. Discordances involved missed mutations by both assays associated with low tumor/low input. Incorporating a manual review algorithm to supplement automated calls improved accuracy from 98.62% to 99.37% and sensitivity from 94.68% to 97.58%. Overall reporting time, from receipt of material to official clinical report, ranged from 1 to 3 days. Therefore, Idylla EGFR testing enables rapid and sensitive screening without compromising subsequent comprehensive NGS, when required. Automated calling, enhanced with a manual review algorithm, reduces false-negative calls associated with low tumor/low input samples.
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http://dx.doi.org/10.1016/j.jmoldx.2020.11.009DOI Listing
March 2021

Bronchiolar Adenoma/Pulmonary Ciliated Muconodular Papillary Tumor.

Am J Clin Pathol 2020 Dec 14. Epub 2020 Dec 14.

Departments of Pathology.

Objectives: To describe the histologic features that are helpful in the diagnosis of the rare bronchiolar adenomas/ciliated muconodular papillary tumors (BAs/CMPTs) during intraoperative consultation.

Methods: Multi-institutional retrospective review of frozen sections of 18 BAs/CMPTs.

Results: In 14 of 18 cases, BA/CMPT was the primary reason for sublobar lung resection, and in 4 cases, BA/CMPT was an incidental finding intraoperatively for resections performed for carcinoma in other lobes. There were 11 proximal-type/classic BAs/CMPTs and 7 distal-type/nonclassic BAs/CMPTs. Only 3 (16.7%) of 18 were correctly diagnosed at the time of frozen section, all of which were proximal type/classic. The remainder were diagnosed as adenocarcinoma (n = 7); invasive mucinous adenocarcinoma (n = 1); non-small cell lung carcinoma (n = 1); cystic mucinous neoplasm, favor adenocarcinoma (either mucinous or colloid type) (n = 1); favor adenocarcinoma, cannot exclude CMPT (n = 1); atypical proliferation (n = 2); mucinous epithelial proliferation (n = 1); and mucous gland adenoma (n = 1).

Conclusions: BA/CMPT can potentially be misdiagnosed as carcinoma during intraoperative consultation. On retrospective review of the frozen sections, the presence of the following may help to avoid misdiagnosis: a mixture of bland ciliated columnar cells, mucinous cells, and, most important, a basal cell layer, as well as a lack of necrosis, significant atypia, and mitoses.
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http://dx.doi.org/10.1093/ajcp/aqaa194DOI Listing
December 2020

A Performance Comparison of Commonly Used Assays to Detect RET Fusions.

Clin Cancer Res 2021 Mar 3;27(5):1316-1328. Epub 2020 Dec 3.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Selpercatinib and pralsetinib induce deep and durable responses in patients with advanced fusion-positive lung and thyroid cancer. fusion testing strategies with rapid and reliable results are critical given recent FDA approval. Here, we assess various clinical assays in a large pan-cancer cohort.

Experimental Design: Tumors underwent DNA-based next-generation sequencing (NGS) with reflex to RNA-based NGS if no mitogenic driver or if a structural variant of unknown significance (SVUS) were present. Canonical DNA-level fusions and RNA-confirmed fusions were considered true fusions. Break-apart FISH and IHC performance were assessed in subgroups.

Results: A total of 171 of 41,869 patients with DNA NGS harbored structural variants, including 139 canonical fusions and 32 SVUS. Twelve of 32 (37.5%) SVUS were transcribed into RNA-level fusions, resulting in 151 oncogenic fusions. The most common fusion-positive tumor types were lung (65.6%) and thyroid (23.2%). The most common partners were (45%), (29.1%), and (13.3%). DNA NGS showed 100% (46/46) sensitivity and 99.6% (4,459/4,479) specificity. FISH showed 91.7% (44/48) sensitivity, with lower sensitivity for - (66.7%, 8/12). A total of 87.5% (7/8) of SVUS negative for RNA-level fusions demonstrated rearrangement by FISH. The sensitivity of IHC varied by fusion partner: sensitivity was highest (100%, 31/31), followed by (88.9%, 16/18) and (50%, 6/12). Specificity of RET IHC was 82% (73/89).

Conclusions: Although DNA sequencing has high sensitivity and specificity, RNA sequencing of SVUS is necessary. Both FISH and IHC demonstrated lower sensitivity for - fusions.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3208DOI Listing
March 2021

Concurrent Mutations in STK11 and KEAP1 Promote Ferroptosis Protection and SCD1 Dependence in Lung Cancer.

Cell Rep 2020 Dec;33(9):108444

Graduate Program in Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Concurrent loss-of-function mutations in STK11 and KEAP1 in lung adenocarcinoma (LUAD) are associated with aggressive tumor growth, resistance to available therapies, and early death. We investigated the effects of coordinate STK11 and KEAP1 loss by comparing co-mutant with single mutant and wild-type isogenic counterparts in multiple LUAD models. STK11/KEAP1 co-mutation results in significantly elevated expression of ferroptosis-protective genes, including SCD and AKR1C1/2/3, and resistance to pharmacologically induced ferroptosis. CRISPR screening further nominates SCD (SCD1) as selectively essential in STK11/KEAP1 co-mutant LUAD. Genetic and pharmacological inhibition of SCD1 confirms the essentiality of this gene and augments the effects of ferroptosis induction by erastin and RSL3. Together these data identify SCD1 as a selective vulnerability and a promising candidate for targeted drug development in STK11/KEAP1 co-mutant LUAD.
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http://dx.doi.org/10.1016/j.celrep.2020.108444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722473PMC
December 2020

Alterations in Ki67 Labeling Following Treatment of Poorly Differentiated Neuroendocrine Carcinomas: A Potential Diagnostic Pitfall.

Am J Surg Pathol 2021 01;45(1):25-34

Memorial Sloan Kettering Cancer Center, New York, NY.

Assessment of the Ki67 index is critical for grading well-differentiated neuroendocrine tumors (WD-NETs), which can show a broad range of labeling that defines the WHO grade (G1-G3). Poorly differentiated neuroendocrine carcinomas (PD-NECs) have a relatively high Ki67 index, >20% in all cases and commonly exceeding 50%. After anecdotally observing PD-NECs with an unexpectedly low and heterogeneous Ki67 index following chemotherapy in 5 cases, we identified 15 additional cases of treated high-grade neuroendocrine neoplasms (HG-NENs). The study cohort comprised 20 cases; 11 PD-NECs, 8 mixed adenoneuroendocrine carcinomas, and 1 WD-NET, G3 from various anatomic sites (gastrointestinal tract, pancreas, larynx, lung, and breast). The Ki67 index was evaluated on pretreatment (when available) and posttreatment samples. Topographic heterogeneity in the Ki67 index was expressed using a semi-quantitative score of 0 (no heterogeneity) to 5 (>80% difference between maximal Ki67 and minimal Ki67 indices). Relative to the pretreatment group (n=9, mean Ki67 of 86.3%, range 80% to 100%), the neoplasms in the posttreatment group (n=20, mean Ki67 of 47.7%, range 1% to 90%) showed a significantly lower Ki67 index (18/20 cases). Of the 18 cases with a relatively low Ki67 index, 15 showed heterogeneous labeling (mean heterogeneity score of 2.3, range 1 to 5) and in 3 cases it was a homogeneously low. This phenomenon was observed in all subtypes of HG-NENs. In 6 cases, the alterations in Ki67 index following treatment were sufficient to place these HG-NENs in the WHO G1 or G2 grade, erroneously suggesting a diagnosis of WD-NET, and in 9 cases there was sufficient heterogeneity in the Ki67 index to suggest that a limited biopsy may sample an area of low Ki67, even though hotspot regions with a Ki67 index of >20% persisted. In 7 cases, the alterations in the Ki67 index were accompanied by morphologic features resembling a WD-NET. These observations suggest that there is a potential for misinterpretation of previously treated PD-NECs as WD-NETs, or for assigning a lower grade in G3 WD-NETs. While the prognostic significance of treatment-associated alterations in Ki67 index is unknown, awareness of this phenomenon is important to avoid this diagnostic pitfall when evaluating treated NENs.
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http://dx.doi.org/10.1097/PAS.0000000000001602DOI Listing
January 2021

Exon 14-altered Lung Cancers and MET Inhibitor Resistance.

Clin Cancer Res 2021 Feb 10;27(3):799-806. Epub 2020 Nov 10.

Thoracic Oncology, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: MET tyrosine kinase inhibitors (TKIs) can achieve modest clinical outcomes in exon 14-altered lung cancers, likely secondary to primary resistance. Mechanisms of primary resistance remain poorly characterized and comprehensive proteomic analyses have not previously been performed.

Experimental Design: We performed hybrid capture-based DNA sequencing, targeted RNA sequencing, cell-free DNA sequencing, selected reaction monitoring mass spectrometry (SRM-MS), and immunohistochemistry on patient samples of exon 14-altered lung cancers treated with a MET TKI. Associations between overall response rate (ORR), progression-free survival (PFS), and putative genomic alterations and MET protein expression were evaluated.

Results: Seventy-five of 168 exon 14-altered lung cancers received a MET TKI. Previously undescribed (zygosity, clonality, whole-genome duplication) and known (copy-number focality, tumor mutational burden, mutation region/type) genomic factors were not associated with ORR/PFS ( > 0.05). In contrast, MET expression was associated with MET TKI benefit. Only cases with detectable MET expression by SRM-MS ( = 15) or immunochemistry ( = 22) responded to MET TKI therapy, and cancers with H-score ≥ 200 had a higher PFS than cancers below this cutoff (10.4 vs. 5.5 months, respectively; HR, 3.87; = 0.02).

Conclusions: In exon 14-altered cancers treated with a MET TKI, a comprehensive analysis of previously unknown and known genomic factors did not identify a genomic mechanism of primary resistance. Instead, MET expression correlated with benefit, suggesting the potential role of interrogating the proteome in addition to the genome in confirmatory prospective trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854494PMC
February 2021

Identification of Immunohistochemical Reagents for In Situ Protein Expression Analysis of Coronavirus-associated Changes in Human Tissues.

Appl Immunohistochem Mol Morphol 2021 01;29(1):5-12

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York.

We studied the suitability of commercially available monoclonal antibodies (mAbs) for the immunohistochemical (IHC) detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in standard archival specimens. Antibodies were screened on HEK293 cells transfected with viral nucleoprotein, S1 subunit and S2 subunit of spike protein and on untransfected cells, as well as a panel of normal tissue. Lung tissue with presence of SARS-CoV2 confirmed by in situ hybridization (ISH) was also used. A total of 7 mAbs were tested: (1) mAb 001 (Sino Biological, 40143-R001), (2) mAb 007 (Sino Biological, 40150-R007), (3) mAb 019 (Sino Biological, 40143-R019), (4) mAb 1A9 (GeneTex, GTX632604), (5) mAb ABM19C9 (Abeomics, 10-10007), (6) FIPV3-70 (Santa Cruz, SC-65653), and (7) mAb 6F10 (BioVision, A2060). Only 2 mAbs, clone 001 to the nucleoprotein and clone 1A9 to the S2 subunit spike protein displayed specific immunoreactivity. Both clones showed strong staining in the acute phase of COVID-19 pneumonia, mostly in areas of acute diffuse alveolar damage, but were not completely congruent. Viral protein was also found in kidney tubules, endothelia of multiple organs and a nasal swab of a patient with persistent SARS-CoV2 infection. The other tested reagents were either poorly reactive or demonstrated nonspecific staining in tissues and lesions not infected by SARS-CoV2. Our study demonstrates that rigid specificity testing is mandatory for the evaluation of mAbs to SARS-CoV2 and that clones 001 to nucleoprotein and 1A9 to S2 subunit spike protein are useful for the in situ detection of SARS-CoV2.
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http://dx.doi.org/10.1097/PAI.0000000000000878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713639PMC
January 2021

Percutaneous computed tomography guided biopsy of sub-solid pulmonary nodules: differentiating solid from ground glass components at the time of biopsy.

Clin Imaging 2021 Jan 25;69:332-338. Epub 2020 Jul 25.

Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States of America.

Introduction: This study assessed (i) the ability to identify the solid components of part-solid nodules (PSN) during computed tomography (CT) guided lung biopsy (CTGLB), (ii) the ability of CTGLB to assess the invasive nature of a nodule on pathology.

Materials And Methods: Sixty-nine nodules were studied in 68 patients who underwent CTGLB between 1/1/2014 and 10/31/2015. Diagnostic CT images and CTGLB images were reviewed. On diagnostic CT images, nodules were classified as ground glass nodules (GGN) or PSNs. Nodule size, location, and percentage of solid component were recorded. At the time of biopsy, the ability to visualize the solid component of a PSN, depth of lesion from skin, and ability to identify the needle within the solid component were recorded.

Results: There were 42 (61%) part-solid nodules and 27 (39%) GGNs. During biopsy, it was possible to differentiate the solid from the ground glass components in 35 (83%) PSNs. Fifty-nine (86%) nodules were neoplastic based on biopsy pathology (all non-small cell lung carcinoma). Thirty-nine (66%) were resected. In all cases biopsy pathology and surgical pathology agreed regarding the presence of lung carcinoma. In 6 (15%) cases biopsy pathology demonstrated purely lepidic growth but had some non-lepidic growth on surgical pathology, including 2 cases with acinar growth as a dominant pattern.

Conclusion: In most patients, the solid and ground glass components of a PSN were distinguishable when performing a CTGLB. In a minority of patients, discrepancy was noted between biopsy pathology and surgical pathology regarding the invasive nature of a nodule.
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http://dx.doi.org/10.1016/j.clinimag.2020.07.011DOI Listing
January 2021

SCLC Subtypes Defined by ASCL1, NEUROD1, POU2F3, and YAP1: A Comprehensive Immunohistochemical and Histopathologic Characterization.

J Thorac Oncol 2020 12 1;15(12):1823-1835. Epub 2020 Oct 1.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Introduction: Recent studies have identified subtypes of small cell lung carcinoma (SCLC) defined by the RNA expression of ASCL1, NEUROD1, POU2F3, and YAP1 transcriptional regulators. There are only limited data on the distribution of these markers at the protein level and associated pathologic characteristics in clinical SCLC samples.

Methods: The expression of ASCL1, NEUROD1, POU2F3, and YAP1 was analyzed by immunohistochemistry in 174 patient samples with SCLC. Subtypes defined by these markers were correlated with histologic characteristics, expression of classic neuroendocrine markers (synaptophysin, chromogranin A, CD56, INSM1), and other SCLC markers, including the neuroendocrine phenotype-associated markers TTF-1 and DLL3.

Results: ASCL1 and NEUROD1 expression had the following distribution: (1) 41% ASCL1+/NEUROD1-; (2) 37% ASCL1+/NEUROD1+; (3) 8% ASCL1-/NEUROD1+; and (4) 14% ASCL1-/NEUROD1-. On the basis of their relative expression, 69% of cases were ASCL1-dominant and 17% were NEUROD1-dominant. POU2F3 was expressed in 7% of SCLC and was mutually exclusive of ASCL1 and NEUROD1. YAP1 was expressed at low levels, primarily in combined SCLC, and was not exclusive of other subtypes. Both ASCL1-dominant and NEUROD1-dominant subtypes were associated with neuroendocrine marker/TTF-1/DLL3 profile, whereas POU2F3 and other ASCL1/NEUROD1 double-negative tumors were neuroendocrine marker/TTF-1/DLL3.

Conclusions: This is the first comprehensive immunohistochemical and histopathologic analysis of novel SCLC subtypes in patient samples. We confirm that ASCL1/NEUROD1 double-negative tumors represent a distinct neuroendocrine-low subtype of SCLC, which is either uniquely associated with POU2F3 or lacks a known dominant regulator. The expression profiles of these markers appear more heterogeneous in native samples than in experimental models, particularly with regard to the high prevalence of ASCL1/NEUROD1 coexpression. These findings may have prognostic and therapeutic implications and warrant further clinical investigation.
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http://dx.doi.org/10.1016/j.jtho.2020.09.009DOI Listing
December 2020

CNS Metastases in Patients With Exon 14-Altered Lung Cancers and Outcomes With Crizotinib.

JCO Precis Oncol 2020 27;4. Epub 2020 Jul 27.

Thoracic Oncology and Early Drug Development Services, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center; and Weill Cornell Medical College, New York, NY.

Purpose: Although exon 14 (ex14)-altered lung cancers were first identified more than a decade and a half ago, the frequency of CNS metastatic disease remains poorly defined. Furthermore, the seminal trial of crizotinib in these patients (PROFILE 1001) did not report patterns of CNS response or progression.

Patients And Methods: Patients with pathologically confirmed, advanced non-small-cell lung cancers (NSCLC) harboring a ex14 alteration by targeted DNA/RNA sequencing were studied. The incidence of brain metastases and the outcomes of MET inhibition with crizotinib were analyzed.

Results: Eighty-three patients with ex14-altered metastatic NSCLC were identified. The incidence of CNS metastases at diagnosis was 17% (95% CI, 10% to 27%). The lifetime incidence was 36% (95% CI, 26% to 47%); 83% of patients had parenchymal disease, and 17% had leptomeningeal disease. The probability of having brain metastasis at 1, 2, and 3 years was 24%, 35%, and 38%, respectively. Fifty-four patients received crizotinib. The median time to radiologic CNS progression was 5.8 months (range, 3.7-20.0 months). Patterns of crizotinib progression were as follows: intracranial only in 10% of patients, intracranial and extracranial in 12%, and extracranial only in 78%. In patients with brain metastases before treatment, the median time on crizotinib was 7.5 months (range, 7.2-11.7 months).

Conclusion: CNS metastases, including leptomeningeal disease, occurred in more than a third of patients with ex14-altered lung cancers. In crizotinib-treated patients with or without CNS metastases, CNS failure was seen in less than a quarter of patients on progression.
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http://dx.doi.org/10.1200/PO.20.00098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446485PMC
July 2020

The Genomic Landscape of Alterations and Associations with Outcomes in Patients with Lung Cancer.

Clin Cancer Res 2020 Nov 24;26(21):5701-5708. Epub 2020 Jul 24.

Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.

Purpose: mutations are among the most common recurrent alterations in non-small cell lung cancer (NSCLC), but the relationship to other genomic abnormalities and clinical impact has not been established.

Experimental Design: To characterize alterations in NSCLC, we analyzed the genomic, protein expression, and clinical outcome data of patients with alterations treated at Memorial Sloan Kettering.

Results: In 4,813 tumors from patients with NSCLC, we identified 8% ( = 407) of patients with -mutant lung cancer. We describe two categories of mutations: class 1 mutations (truncating mutations, fusions, and homozygous deletion) and class 2 mutations (missense mutations). Protein expression loss was associated with class 1 mutation (81% vs. 0%, < 0.001). Both classes of mutation co-occurred more frequently with , and mutations compared with wild-type tumors ( < 0.001). In patients with metastatic NSCLC, alterations were associated with shorter overall survival, with class 1 alterations associated with shortest survival times ( < 0.001). Conversely, we found that treatment with immune checkpoint inhibitors (ICI) was associated with improved outcomes in patients with -mutant tumors ( = 0.01), with class 1 mutations having the best response to ICIs ( = 0.027).

Conclusions: alterations can be divided into two clinically relevant genomic classes associated with differential protein expression as well as distinct prognostic and treatment implications. Both classes co-occur with , and mutations, but individually represent independent predictors of poor prognosis. Despite association with poor outcomes, -mutant lung cancers may be more sensitive to immunotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641983PMC
November 2020

Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.

Cancer Cell 2020 08 23;38(2):229-246.e13. Epub 2020 Jul 23.

Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cell and Developmental Biology, Weill-Cornell Medical College, New York, NY 10065, USA. Electronic address:

Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS.
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http://dx.doi.org/10.1016/j.ccell.2020.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745838PMC
August 2020

Multiple faces of pulmonary large cell neuroendocrine carcinoma: update with a focus on practical approach to diagnosis.

Transl Lung Cancer Res 2020 Jun;9(3):860-878

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive malignancy that is strongly linked to smoking and notoriously difficult to diagnose and treat. Recent molecular data reveal that it represents a biologically heterogeneous group of tumors, characterized by morphologic and genomic diversity that straddles small cell and non-small cell lung carcinomas (NSCLCs), and in a minority of cases atypical carcinoids. This review provides an update on recent molecular and clinical developments in LCNEC with the main focus on practical approach to pathologic diagnosis using illustrative examples of the main differential diagnostic considerations.
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http://dx.doi.org/10.21037/tlcr.2020.02.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354156PMC
June 2020

Insights into pathogenesis of fatal COVID-19 pneumonia from histopathology with immunohistochemical and viral RNA studies.

Histopathology 2020 Dec 16;77(6):915-925. Epub 2020 Oct 16.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Introduction: We describe post-mortem pulmonary histopathologic findings of COVID-19 pneumonia in patients with a spectrum of disease course, from rapid demise to prolonged hospitalisation.

Methods And Results: Histopathologic findings in post-mortem lung tissue from eight patients who died from COVID-19 pneumonia were reviewed. Immunohistochemistry (IHC) and next-generation sequencing (NGS) were performed to detect virus. Diffuse alveolar damage (DAD) was seen in all cases with a spectrum of acute phase and/or organising phase. IHC with monoclonal antibodies against SARS-CoV-2 viral nucleoprotein and spike protein detected virus in areas of acute but not organising DAD, with intracellular viral antigen and RNA expression seen predominantly in patients with duration of illness less than 10 days. Major vascular findings included thrombi in medium- and large-calibre vessels, platelet microthrombi detected by CD61 IHC and fibrin microthrombi.

Conclusions: Presence of SARS-CoV-2 viral RNA by NGS early in the disease course and expression of viral antigen by IHC exclusively in the acute, but not in the organising phase of DAD, suggests that the virus may play a major role in initiating the acute lung injury of DAD, but when DAD progresses to the organising phase the virus may have been cleared from the lung by the patient's immune response. These findings suggest the possibility of a major change during the disease course of COVID-19 pneumonia that may have therapeutic implications. Frequent thrombi and microthrombi may also present potential targets for therapeutic intervention.
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http://dx.doi.org/10.1111/his.14201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361244PMC
December 2020

The Newly Described Filigree Pattern Is an Expansion of the Micropapillary Adenocarcinoma Concept Rather Than a Proposed New Subtype.

J Thorac Oncol 2020 07;15(7):e121-e124

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2020.04.018DOI Listing
July 2020

Spread Through Air Spaces Is Prognostic in Neuroendocrine Lung Tumors and Can Be Distinguished From Artifacts.

J Thorac Oncol 2020 07;15(7):e118-e120

Thoracic Service, Department of Surgery, Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1016/j.jtho.2020.04.017DOI Listing
July 2020

Lung-only melanoma: UV mutational signature supports origin from occult cutaneous primaries and argues against the concept of primary pulmonary melanoma.

Mod Pathol 2020 11 24;33(11):2244-2255. Epub 2020 Jun 24.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Primary pulmonary melanoma (PPM) is an entity recognized by the thoracic WHO classification. However, given the absence of native melanocytes in the lung and the known phenomenon of regression of cutaneous melanomas, the existence of PPM has remained controversial. Herein we investigate clinicopathologic and genomic features of lung-only melanomas with the goal to clarify their site of origin. We identified 10 melanomas involving exclusively lung with no current or previous cutaneous, uveal, or mucosal primaries. Four patients had solitary lesions with mean size of 5.1 cm (range 3.0-10.1 cm), meeting the criteria of PPM. Four patients had 2-3 lesions and 2 patients had >10 lesions. All cases underwent targeted next-generation sequencing interrogating up to 468 cancer genes, which revealed mean tumor mutation burden of 42.6 per megabase (range 1.8 to 126) and frequent mutations involving BRAF, NRAS, NF1, KIT, and KRAS - a genomic profile typical of UV-associated cutaneous melanoma. Mutational signature was assessable for eight cases harboring >20 mutations. This revealed that all evaluable cases harbored a dominant UV signature. In addition, one nonevaluable case harbored a GG > AA TERT promoter variant that is highly specific for UV-mutagenesis. As control groups, using the same methodology, a dominant UV signature was identified in 97% (470/486) of cutaneous melanomas, whereas no lung adenocarcinoma (n = 291) exhibited this signature. Notably, the clinical and pathologic features of solitary melanomas, especially those with large size and epithelioid morphology, closely mimicked primary lung carcinomas, highlighting a major potential for misdiagnosis. In conclusion, presence of a UV signature provides direct evidence that nearly all lung-only melanomas in this series, including solitary lesions meeting the strict criteria of PPM, represent metastases from occult cutaneous melanomas. This suggests that lung-only melanomas should be considered as likely metastatic even in the absence of a known primary melanoma elsewhere.
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http://dx.doi.org/10.1038/s41379-020-0594-0DOI Listing
November 2020

Immune-Related Pneumonitis After Chemoradiotherapy and Subsequent Immune Checkpoint Blockade in Unresectable Stage III Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2020 09 9;21(5):e435-e444. Epub 2020 Mar 9.

Department of Pulmonary Medicine and Critical Care, Centre Hospitalier et Université de Bourgogne, Dijon, France.

Approximately one third of patients with non-small-cell lung cancer (NSCLC) present with stage III or locally advanced NSCLC. These patients have historically been managed with chemoradiotherapy. However, outcomes for these patients remain poor, with a 5-year survival rate between 15% and 32%. Immune checkpoint inhibitors have revolutionized the treatment of patients with NSCLC. One such agent, durvalumab, a selective high-affinity human immunoglobulin G1 monoclonal antibody that blocks programmed cell death ligand 1 binding to programmed cell death protein 1 and cluster of differentiation 80, was recently approved in the consolidation setting after completion of definitive platinum-based chemoradiotherapy and has become the current standard of care for patients with stage III locally advanced NSCLC. Immune checkpoint blockade is associated with increased risk of immunotherapy-related adverse events, which can be managed most effectively when detected early, ideally in the context of a multidisciplinary approach. Pneumonitis represents the potentially most severe and life-threatening of all reported immunotherapy-related adverse events, but it is further complicated in the context of recent prior therapies also known to cause pulmonary toxicity, such as radiotherapy. However, there are major gaps in our ability to identify immunotherapy-related pneumonitis and distinguish it from radiation pneumonitis. This review aims to define the key steps in the detection, diagnosis, and treatment of immunotherapy-related pneumonitis.
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http://dx.doi.org/10.1016/j.cllc.2020.02.025DOI Listing
September 2020

A Grading System for Invasive Pulmonary Adenocarcinoma: A Proposal From the International Association for the Study of Lung Cancer Pathology Committee.

J Thorac Oncol 2020 10 17;15(10):1599-1610. Epub 2020 Jun 17.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Introduction: A grading system for pulmonary adenocarcinoma has not been established. The International Association for the Study of Lung Cancer pathology panel evaluated a set of histologic criteria associated with prognosis aimed at establishing a grading system for invasive pulmonary adenocarcinoma.

Methods: A multi-institutional study involving multiple cohorts of invasive pulmonary adenocarcinomas was conducted. A cohort of 284 stage I pulmonary adenocarcinomas was used as a training set to identify histologic features associated with patient outcomes (recurrence-free survival [RFS] and overall survival [OS]). Receiver operating characteristic curve analysis was used to select the best model, which was validated (n = 212) and tested (n = 300, including stage I-III) in independent cohorts. Reproducibility of the model was assessed using kappa statistics.

Results: The best model (area under the receiver operating characteristic curve [AUC] = 0.749 for RFS and 0.787 for OS) was composed of a combination of predominant plus high-grade histologic pattern with a cutoff of 20% for the latter. The model consists of the following: grade 1, lepidic predominant tumor; grade 2, acinar or papillary predominant tumor, both with no or less than 20% of high-grade patterns; and grade 3, any tumor with 20% or more of high-grade patterns (solid, micropapillary, or complex gland). Similar results were seen in the validation (AUC = 0.732 for RFS and 0.787 for OS) and test cohorts (AUC = 0.690 for RFS and 0.743 for OS), confirming the predictive value of the model. Interobserver reproducibility revealed good agreement (k = 0.617).

Conclusions: A grading system based on the predominant and high-grade patterns is practical and prognostic for invasive pulmonary adenocarcinoma.
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http://dx.doi.org/10.1016/j.jtho.2020.06.001DOI Listing
October 2020

The Promises and Challenges of Tumor Mutation Burden as an Immunotherapy Biomarker: A Perspective from the International Association for the Study of Lung Cancer Pathology Committee.

J Thorac Oncol 2020 09 6;15(9):1409-1424. Epub 2020 Jun 6.

Carolinas Pathology Group, Atrium Health, Charlotte, North Carolina.

Immune checkpoint inhibitor (ICI) therapies have revolutionized the management of patients with NSCLC and have led to unprecedented improvements in response rates and survival in a subset of patients with this fatal disease. However, the available therapies work only for a minority of patients, are associated with substantial societal cost, and may lead to considerable immune-related adverse events. Therefore, patient selection must be optimized through the use of relevant biomarkers. Programmed death-ligand 1 protein expression by immunohistochemistry is widely used today for the selection of programmed cell death protein 1 inhibitor therapy in patients with NSCLC; however, this approach lacks robust sensitivity and specificity for predicting response. Tumor mutation burden (TMB), or the number of somatic mutations derived from next-generation sequencing techniques, has been widely explored as an alternative or complementary biomarker for response to ICIs. In theory, a higher TMB increases the probability of tumor neoantigen production and therefore, the likelihood of immune recognition and tumor cell killing. Although TMB alone is a simplistic surrogate of this complex interplay, it is a quantitative variable that can be relatively readily measured using currently available sequencing techniques. A large number of clinical trials and retrospective analyses, employing both tumor and blood-based sequencing tools, have evaluated the performance of TMB as a predictive biomarker, and in many cases reveal a correlation between high TMB and ICI response rates and progression-free survival. Many challenges remain before the implementation of TMB as a biomarker in clinical practice. These include the following: (1) identification of therapies whose response is best informed by TMB status; (2) robust definition of a predictive TMB cut point; (3) acceptable sequencing panel size and design; and (4) the need for robust technical and informatic rigor to generate precise and accurate TMB measurements across different laboratories. Finally, effective prediction of response to ICI therapy will likely require integration of TMB with a host of other potential biomarkers, including tumor genomic driver alterations, tumor-immune milieu, and other features of the host immune system. This perspective piece will review the current clinical evidence for TMB as a biomarker and address the technical sequencing considerations and ongoing challenges in the use of TMB in routine practice.
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http://dx.doi.org/10.1016/j.jtho.2020.05.019DOI Listing
September 2020

MET-dependent solid tumours - molecular diagnosis and targeted therapy.

Nat Rev Clin Oncol 2020 09 8;17(9):569-587. Epub 2020 Jun 8.

Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Attempts to develop MET-targeted therapies have historically focused on MET-expressing cancers, with limited success. Thus, MET expression in the absence of a genomic marker of MET dependence is a poor predictor of benefit from MET-targeted therapy. However, owing to the development of more sensitive methods of detecting genomic alterations, high-level MET amplification and activating MET mutations or fusions are all now known to be drivers of oncogenesis. MET mutations include those affecting the kinase or extracellular domains and those that result in exon 14 skipping. The activity of MET tyrosine kinase inhibitors varies by MET alteration category. The likelihood of benefit from MET-targeted therapies increases with increasing levels of MET amplification, although no consensus exists on the optimal diagnostic cut-off point for MET copy number gains identified using fluorescence in situ hybridization and, in particular, next-generation sequencing. Several agents targeting exon 14 skipping alterations are currently in clinical development, with promising data available from early-phase trials. By contrast, the therapeutic implications of MET fusions remain underexplored. Here we summarize and evaluate the utility of various diagnostic techniques and the roles of different classes of MET-targeted therapies in cancers with MET amplification, mutation and fusion, and MET overexpression.
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http://dx.doi.org/10.1038/s41571-020-0377-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478851PMC
September 2020

An update on touch preparations of small biopsies.

J Am Soc Cytopathol 2020 Sep - Oct;9(5):322-331. Epub 2020 Apr 21.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address:

Touch preparations (TPs) are being increasingly utilized in the era of personalized medicine. They fill a gap in cytopathology practice by providing a method to perform rapid onsite evaluation of small tissue samples such as core needle biopsies. However, there is a paucity of literature about how best to perform and interpret a TP. A high-quality TP can provide excellent diagnostic accuracy and good concordance with core needle biopsy histopathology findings. Although many of the cytomorphologic features of TPs overlap with fine needle aspirate smears, TP cytology is unique and differs from conventional smears in many aspects. It is important for cytologists to recognize these features, as well as potential pitfalls and artifacts in order to avoid misinterpretation. Core depletion of tumor cells is a notable drawback if TPs are performed too aggressively. TP slides are also valuable for ancillary testing because they often contain a cellular and pure population of whole tumor cells. This paper reviews all of the aspects of TPs including their clinical utility, proper slide preparation techniques, distinctive cytomorphologic characteristics, limitations, and potential pitfalls.
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http://dx.doi.org/10.1016/j.jasc.2020.04.004DOI Listing
April 2020

Regenerative lineages and immune-mediated pruning in lung cancer metastasis.

Nat Med 2020 02 10;26(2):259-269. Epub 2020 Feb 10.

Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.
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http://dx.doi.org/10.1038/s41591-019-0750-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021003PMC
February 2020

Pulmonary sclerosing pneumocytoma: Cytomorphology and immunoprofile.

Cancer Cytopathol 2020 06 5;128(6):414-423. Epub 2020 Feb 5.

Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Sclerosing pneumocytoma (SP) is a rare, benign pulmonary neoplasm. To the authors' knowledge, the current study is the first to evaluate the cytomorphology and immunoprofile of SP in a series.

Methods: A total of 9 fine-needle aspiration cases of SP (7 of which were computed tomography guided and 2 of which were endobronchial ultrasound guided) including histopathology and immunohistochemistry were collected from 5 institutions.

Results: The female-to-male ratio was 3.5:1, and the mean age of the patients was 54 years (range, 27-73 years). All cases presented as lung nodules, with a mean size of 2.2 cm (range, 1.1-5 cm), and were interpreted as atypical on rapid on-site evaluation. The final diagnoses were favor adenocarcinoma (1 case), well-differentiated lung adenocarcinoma (2 cases), low-grade epithelial neoplasm (2 cases), and sclerosing pneumocytoma (4 cases). Samples were moderately cellular, and consisted of round epithelioid cells with clear cell features, columnar cells, and spindle cells. A papillary arrangement with prominent hyalinized fibrovascular cores was the most common architectural pattern, followed by flat sheets and acinar formations. Tumor cells demonstrated mild, focally moderate nuclear pleomorphism with prominent nucleoli, hyperchromasia, nuclear elongation, nuclear overlap, and occasional nuclear inclusions and grooves. The background consisted of foamy macrophages (9 cases), hemosiderin pigment (6 cases), and lymphoid aggregates (3 cases) with no mitoses and/or necrosis. The surface cells and underlying round cells were positive for both thyroid transcription factor 1 and epithelial membrane antigen in all cases, which was the most notable immunohistochemical finding.

Conclusions: Cytomorphological findings of SP overlap with those of well-differentiated lung adenocarcinoma. Awareness of these cytomorphologic findings and the distinct immunoprofile of the 2 cell types found in SP should prevent a misdiagnosis and aggressive treatment.
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http://dx.doi.org/10.1002/cncy.22251DOI Listing
June 2020

"Napoleon Hat" Sign: A Distinctive Cytologic Clue to Reactive Pneumocytes.

Authors:
Natasha Rekhtman

Arch Pathol Lab Med 2020 04 23;144(4):443-445. Epub 2020 Jan 23.

From the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Various types of acute and subacute lung injury can cause severe reactive pneumocyte atypia, which may mimic malignant proliferations and present a major diagnostic pitfall. This particularly applies to cytologic preparations and frozen sections, where background inflammatory injury may be subtle or not apparent. Although several distinguishing morphologic features of reactive pneumocytes have been suggested, there is significant overlap with neoplastic proliferations. In this article, a highly distinctive but underrecognized feature of reactive pneumocytes is highlighted that can serve as a useful diagnostic clue. The feature refers to the distinctive pinched shape of reactive pneumocytes, for which the author has coined the term "Napoleon hat" sign to draw the analogy with the iconic headwear. The analogy vividly captures the distinctive shape of reactive pneumocytes, and can serve as a useful diagnostic and teaching tool in the interpretation of pulmonary specimens.
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http://dx.doi.org/10.5858/arpa.2019-0615-SADOI Listing
April 2020

Tumor Analyses Reveal Squamous Transformation and Off-Target Alterations As Early Resistance Mechanisms to First-line Osimertinib in -Mutant Lung Cancer.

Clin Cancer Res 2020 06 7;26(11):2654-2663. Epub 2020 Jan 7.

Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.

Purpose: Patterns of resistance to first-line osimertinib are not well-established and have primarily been evaluated using plasma assays, which cannot detect histologic transformation and have differential sensitivity for copy number changes and chromosomal rearrangements.

Experimental Design: To characterize mechanisms of resistance to osimertinib, patients with metastatic -mutant lung cancers who received osimertinib at Memorial Sloan Kettering Cancer Center and had next-generation sequencing performed on tumor tissue before osimertinib initiation and after progression were identified.

Results: Among 62 patients who met eligibility criteria, histologic transformation, primarily squamous transformation, was identified in 15% of first-line osimertinib cases and 14% of later-line cases. Nineteen percent (5/27) of patients treated with first-line osimertinib had off-target genetic resistance (2 amplification, 1 mutation, 1 fusion, and 1 fusion) whereas 4% (1/27) had an acquired mutation ( G724S). Patients with squamous transformation exhibited considerable genomic complexity; acquired mutation, chromosome 3q amplification, and amplification were all seen. Patients with transformation had shorter time on osimertinib and shorter survival compared with patients with on-target resistance. Initial sensitizing mutation, time on osimertinib treatment, and line of therapy also influenced resistance mechanism that emerged. The compound mutation S768 + V769L and the mutation H1094Y were identified and validated as resistance mechanisms with potential treatment options.

Conclusions: Histologic transformation and other off-target molecular alterations are frequent early emerging resistance mechanisms to osimertinib and are associated with poor clinical outcomes..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448565PMC
June 2020

Three-Dimensional Histologic, Immunohistochemical, and Multiplex Immunofluorescence Analyses of Dynamic Vessel Co-Option of Spread Through Air Spaces in Lung Adenocarcinoma.

J Thorac Oncol 2020 04 27;15(4):589-600. Epub 2019 Dec 27.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Introduction: Spread through air spaces (STAS) is a method of invasion in lung adenocarcinoma and is associated with tumor recurrence and poor survival. The spatial orientation of STAS cells in the lung alveolar parenchyma is not known. The aim of this study was to use high-resolution and high-quality three-dimensional (3D) reconstruction of images from immunohistochemical (IHC) and multiplex immunofluorescence (IF) experiments to understand the spatial architecture of tumor cell clusters by STAS in the lung parenchyma.

Methods: Four lung adenocarcinomas, three micropapillary-predominant and one solid predominant adenocarcinoma subtypes, were investigated. A 3D reconstruction image was created from formalin-fixed, paraffin-embedded blocks. A total of 350 serial sections were obtained and subjected to hematoxylin and eosin (100 slides), IHC (200 slides), and multiplex IF staining (50 slides) with the following antibodies: cluster of differentiation 31, collagen type IV, thyroid transcription factor-1, and E-cadherin. Whole slide images were reconstructed into 3D images for evaluation.

Results: Serial 3D image analysis by hematoxylin and eosin, IHC, and IF staining revealed that the micropapillary clusters and solid nests of STAS are focally attached to the alveolar walls, away from the main tumor.

Conclusions: Our 3D reconstructions found that STAS tumor cells can attach to the alveolar walls rather than appearing free floating, as seen on the two-dimensional sections. This suggests that the tumor cells detach from the main tumor, migrate through air spaces, and reattach to the alveolar walls through vessel co-option, allowing them to survive and grow. This may explain the higher recurrence rate and worse survival of patients with STAS-positive tumors who undergo limited resection than those who undergo lobectomy.
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http://dx.doi.org/10.1016/j.jtho.2019.12.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288352PMC
April 2020