The current state of digital cytology and artificial intelligence (AI): global survey results from the American Society of Cytopathology Digital Cytology Task Force.

INTRODUCTION: The integration of whole slide imaging (WSI) and artificial intelligence (AI) with digital cytology has been growing gradually. Therefore, there is a need to evaluate the current state of digital cytology. This study aimed to determine the current landscape of digital cytology via a survey conducted as part of the American Society of Cytopathology (ASC) Digital Cytology White Paper Task Force. MATERIALS AND METHODS: A survey with 43 questions pertaining to the current practices and experiences of WSI and AI in both surgical pathology and cytology was created. The survey was sent to members of the ASC, the International Academy of Cytology (IAC), and the Papanicolaou Society of Cytopathology (PSC). Responses were recorded and analyzed. RESULTS: In total, 327 individuals participated in the survey, spanning a diverse array of practice settings, roles, and experiences around the globe. The majority of responses indicated there was routine scanning of surgical pathology slides (n = 134; 61%) with fewer respondents scanning cytology slides (n = 150; 46%). The primary challenge for surgical WSI is the need for faster scanning and cost minimization, whereas image quality is the top issue for cytology WSI. AI tools are not widely utilized, with only 16% of participants using AI for surgical pathology samples and 13% for cytology practice. CONCLUSIONS: Utilization of digital pathology is limited in cytology laboratories as compared to surgical pathology. However, as more laboratories are willing to implement digital cytology in the near future, the establishment of practical clinical guidelines is needed.

Digital cytology part 1: digital cytology implementation for practice: a concept paper with review and recommendations from the American Society of Cytopathology Digital Cytology Task Force.

Digital cytology and artificial intelligence (AI) are gaining greater adoption in the cytopathology laboratory. However, peer-reviewed real-world data and literature are lacking regarding the current clinical landscape. The American Society of Cytopathology in conjunction with the International Academy of Cytology and the Digital Pathology Association established a special task force comprising 20 members with expertise and/or interest in digital cytology. The aim of the group was to investigate the feasibility of incorporating digital cytology, specifically cytology whole slide scanning and AI applications, into the workflow of the laboratory. In turn, the impact on cytopathologists, cytologists (cytotechnologists), and cytology departments were also assessed. The task force reviewed existing literature on digital cytology, conducted a worldwide survey, and held a virtual roundtable discussion on digital cytology and AI with multiple industry corporate representatives. This white paper, presented in 2 parts, summarizes the current state of digital cytology and AI practice in global cytology practice. Part 1 of the white paper presented herein is a review and offers best practice recommendations for incorporating digital cytology into practice. Part 2 of the white paper provides a comprehensive review of AI in cytology practice along with best practice recommendations and legal considerations. Additionally, the results of a global survey regarding digital cytology are highlighted.

Digital cytology part 2: artificial intelligence in cytology: a concept paper with review and recommendations from the American Society of Cytopathology Digital Cytology Task Force.

Digital cytology and artificial intelligence (AI) are gaining greater adoption in the cytology laboratory. However, peer-reviewed real-world data and literature are lacking in regard to the current clinical landscape. The American Society of Cytopathology in conjunction with the International Academy of Cytology and the Digital Pathology Association established a special task force comprising 20 members with expertise and/or interest in digital cytology. The aim of the group was to investigate the feasibility of incorporating digital cytology, specifically cytology whole slide scanning and AI applications, into the workflow of the laboratory. In turn, the impact on cytopathologists, cytologists (cytotechnologists), and cytology departments were also assessed. The task force reviewed existing literature on digital cytology, conducted a worldwide survey, and held a virtual roundtable discussion on digital cytology and AI with multiple industry corporate representatives. This white paper, presented in 2 parts, summarizes the current state of digital cytology and AI practice in global cytology practice. Part 1 of the white paper is presented as a separate paper which details a review and best practice recommendations for incorporating digital cytology into practice. Part 2 of the white paper presented here provides a comprehensive review of AI in cytology practice along with best practice recommendations and legal considerations. Additionally, the cytology global survey results highlighting current AI practices by various laboratories, as well as current attitudes, are reported.

The World Health Organization Reporting System for Lung Cytopathology.

The International Academy of Cytology has joined with the International Agency for Research on Cancer (IARC) to bring together a group of experts in lung cytopathology to develop a WHO Reporting System for Lung Cytopathology (WHO System). This WHO System defines five categories for reporting lung cytopathology, that is, "Insufficient"/"Inadequate"/"Non-diagnostic," "Benign," "Atypical," "Suspicious for malignancy," and "Malignant," each with a clear descriptive term for the category, a definition, a risk of malignancy and a suggested management algorithm. The key diagnostic cytopathology features of each of the lesions within each category have been established by consensus and will be presented more fully in a subsequent IARC e-book and published hard cover book.The WHO System provides the best practice application of ancillary testing, including immunocytochemistry and molecular pathology, and provides a review to guide sampling and processing techniques to optimize the handling and preparation of the cytopathology sample emphasizing the cytomorphological differential diagnosis to aid low-resourced settings. The authors recognize that local medical and pathology resources will vary, particularly in low- and middle-income countries, and have developed the WHO System to make it applicable worldwide based on cytomorphology with options for further diagnostic management of the patient.The online WHO System provides a direct link to the WHO Tumour Classification for Thoracic Tumours 5th Edition. It will raise the profile and use of cytopathology by increasing awareness of its current role and its potential role in the era of personalized medicine based on molecular pathology utilizing "small biopsies." Ultimately, the System will improve patient care and outcomes.This System aims to improve and standardize the reporting of cytopathology, facilitate communication between cytopathologists and clinicians and improve patient care. The System is based on the current role of lung cytopathology and synthesizes the existing evidence while highlighting areas requiring further research and the future potential role of lung cytopathology.

Melanotic medullary thyroid carcinoma: A case report with review of the literature.

Melanotic medullary thyroid carcinoma is morphologically defined by the presence of melanin deposits in the cytoplasm of tumor cells. It is an extremely rare variant with only 15 cases described in the literature to date and only one report of diagnosis by fine needle aspiration (FNA) biopsy. A 51-year-old woman presented with neck swelling. An ultrasound examination revealed a single solid nodule in the right thyroid lobe that measured 5.4 × 4.7 × 4.3 cm. Laboratory examination revealed elevated levels of serum calcitonin (8643.0 pg/ml), carcinoembryonic antigen (CEA) (86.2 ng/ml), and chromogranin A (123.2 ng/ml). An FNA biopsy of the thyroid nodule revealed predominantly single plasmacytoid cells with round to oval eccentric nuclei and dark brown intracytoplasmic granules. Immunohistochemical studies with Melan-A performed on a cell block slide confirmed that the granules contained melanin. The tumor cells were also positive for calcitonin, CEA, synaptophysin, AE1/AE3, CAM5.2, and HMB-45(focal); the tumor cells were negative for chromogranin, thyroglobulin, PAX8 and TTF-1. The diagnosis was reported as melanotic variant of medullary thyroid carcinoma. The patient underwent a total thyroidectomy which revealed tumor cell expression of insulinoma-associated protein 1 and confirmed neuroendocrine differentiation. Shortly after she presented with tumor recurrence in the thyroidectomy bed. The tumor cells were positive for only S100, SOX10, and Melan-A. Molecular analysis with the SEMA4 Solid Tumor Panel revealed mutations in the HRAS, PIK3CA, PIK3R1, MYC, and CCND3 genes. The final diagnosis was reported as melanocytic medullary thyroid carcinoma with high grade transformation and loss of epithelial and neuroendocrine expression.

A comparative study of the genotype profiles of high-risk human papillomavirus infection in male and female HIV-positive patients and their correlation with anal cytology and biopsy.

INTRODUCTION: Although anal cancer is more common in women, most of the studies on the role of high-risk human papillomavirus (hrHPV) infection in anal squamous lesions have focused on high-risk male patients. Therefore, we compared the genotype profile and clinicopathologic correlation of hrHPV infection in human immunodeficiency virus-positive (HIV+) men and women. MATERIALS AND METHODS: We retrospectively analyzed 2254 HIV+ patients (1931 men and 323 women) who had undergone anal Papanicolaou tests at our institution; 1189 of them also had follow-up biopsy data available. HPV genotyping was performed using the Roche Cobas system and correlated with the cytologic and histologic diagnosis. RESULTS: Compared with the HIV+ men, the HIV+ women had a significantly lower rate of hrHPV infection (67.5% versus 78.5%; P < 0.0001) but a significantly higher rate of high-grade squamous intraepithelial lesions (HSILs) on anal Papanicolaou tests (4.6% versus 2.5%; P < 0.05). Other high-risk HPV (ohrHPV), as a group, is much more common than HPV16 or HPV18 in both genders. HIV+ women had significantly lower HPV16 and ohrHPV infection rates than did HIV+ men. However, the HPV18 infection rates were similar between HIV+ women and HIV+ men. For both genders, the rates of HSILs or high-grade anal intraepithelial neoplasia (AIN2-3) were significantly increased when coinfection of ohrHPV with either HPV16 or HPV18 was present. CONCLUSIONS: Although both HIV+ men and HIV+ women have an increased risk of hrHPV infection, HIV+ women have different hrHPV genotype profiles and higher rates of high-grade lesions. Coinfection with different genotypes of hrHPV can significantly increase the risk of HSILs or AIN2-3 in both genders and could requires vigilant clinical and laboratory follow-up.

Building a smart FNA cart: When Google meets cytology.

BACKGROUND: The appropriate management of a fine needle aspiration (FNA) supply cart and equipment set up is essential to ensure the smooth and optimal operation of a busy FNA clinic. We applied Lean strategies such as value stream mapping (VSM), the 5S method (Sort, Set in order, Shine, Standardize, Sustain), and Kanban to remove waste and improve patient flow in an FNA clinic. METHODS: The workflow analysis suggested that existent problems such as suboptimal inventory management and unavailability of standard operating procedures (SOPs) caused a 10% to 85% increase in total procedure time. To improve inventory management, we created a 2-bin Kanban system. We used the "Scan to Web" app and a Google Drive form to create a cost-effective electronic inventory management system. We distributed the essential SOPs in the format of video clips using our YouTube channel and leveraged barcode technology to access the links. RESULTS: Upon completion of our process improvement project, we succeeded to eliminate the stock-out events and maintain a process cycle efficiency of 87%. The 5S audit checklist result increased from 6% to 100% implementation, which is consistent with focused improvement. The developed inventory system enabled us to track the supply usage, forecast demands, and improve the accuracy of orders. CONCLUSIONS: Lean methods such as VSM, 5S, and Kanban combined with open source technologies can be implemented to ensure material availability, track inventory, and provide immediate access to SOPs on demand. The developed system also led to increased efficiency and improved flow, as well as responsiveness to changes in demand.

Analytic inquiry: Molecular testing in lung cancer.

Non-small cell lung cancer is a different disease from what it was a decade ago. The last 10 years were based on remarkable advances in the understanding of key genetic alterations that function as oncogenic drivers and serve as therapeutic targets, thereby defining new molecular subsets. These changes have had an impact on clinical care, patient outcomes, and pathologic diagnosis and present new challenges in the approach of the cytopathologist to this still deadly disease. To meet these new challenges and appropriately train the next generation of cytopathologists, the complex molecular background underlying this disease and the implications that cytologic and histologic diagnoses have on treatment must be understood. Herein, the author reviews the background leading to this new approach and explains how, why, and what cytologists need to know to successfully contribute to the care of the patient with lung cancer. Cancer Cytopathol 2017;125(6 suppl):470-6. © 2017 American Cancer Society.

Morphologic Accuracy in Differentiating Primary Lung Adenocarcinoma From Squamous Cell Carcinoma in Cytology Specimens.

CONTEXT: -The National Cancer Care Network and the combined College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology guidelines indicate that all lung adenocarcinomas (ADCs) should be tested for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements. As the majority of patients present at a later stage, the subclassification and molecular analysis must be done on cytologic material. OBJECTIVE: -To evaluate the accuracy and interobserver variability among cytopathologists in subtyping non-small cell lung carcinoma using cytologic preparations. DESIGN: -Nine cytopathologists from different institutions submitted cases of non-small cell lung carcinoma with surgical follow-up. Cases were independently, blindly reviewed by each cytopathologist. A diagnosis of ADC or squamous cell carcinoma was rendered based on the Diff-Quik, Papanicolaou, and hematoxylin-eosin stains. The specimen types included fine-needle aspiration from lung, lymph node, and bone; touch preparations from lung core biopsies; bronchial washings; and bronchial brushes. A major disagreement was defined as a case being misclassified 3 or more times. RESULTS: -Ninety-three cases (69 ADC, 24 squamous cell carcinoma) were examined. Of 818 chances (93 cases × 9 cytopathologists) to correctly identify all the cases, 753 correct diagnoses were made (92% overall accuracy). Twenty-five of 69 cases of ADC (36%) and 7 of 24 cases of squamous cell carcinoma (29%) had disagreement (P = .16). Touch preparations were more frequently misdiagnosed compared with other specimens. Diagnostic accuracy of each cytopathologist varied from 78.4% to 98.7% (mean, 91.7%). CONCLUSION: -Lung ADC can accurately be distinguished from squamous cell carcinoma by morphology in cytologic specimens with excellent interobserver concordance across multiple institutions and levels of cytology experience.

Low interobserver agreement in cytology grading of mucinous pancreatic neoplasms.

BACKGROUND: Identifying high-grade features in patients with pancreatic mucinous neoplasms (MNs) is important for patient management. The reproducibility of MN cytology grading has been evaluated to a limited extent. In the current study, the authors evaluated interobserver variability in grading MNs and the identification of neoplastic mucin in endoscopic ultrasound-guided fine-needle aspiration specimens. METHODS: A 54-case grading set was created from histologically confirmed MNs (44 MNs) and nonmucinous lesions with abundant gastrointestinal contamination (10 nonmucinous lesions). Six observers received a tutorial, reviewed prescreened slides, and recorded: 1) a diagnosis according to a 6-tiered system (TS) (nondiagnostic, atypical [ATP], mucinous cyst low grade [MCLG], mucinous cyst high grade, suspicious for adenocarcinoma, and positive for adenocarcinoma); 2) the cyst fluid carcinoembryonic antigen diagnosis (CEADX); and 3) the presence of neoplastic musin. Interobserver agreement (IOA) was evaluated by calculation of kappa coefficients (Kappa). Diagnostic accuracy was not evaluated. RESULTS: The IOA was lowest for the 6-TS (Kappa, 0.13; P<.001). The CEADX was available for 18 cases (33%), including 6 of 24 MCLG cases (25%). CEADX modestly improved IOA for combined tiers of the 6-TS with ATP and MCLG as separate categories. The highest IOA was noted with a 3-TS (nondiagnostic, ATP/MCLG, and mucinous cyst high grade/suspicious for adenocarcinoma/positive for adenocarcinoma [Kappa, 0.28; P<.001]) and various 4-TS (Kappa, 0.22-0.23). IOA was found to be low for neoplastic mucin (Kappa = 0.15; P<.001). CONCLUSIONS: In a study using simulated cytology practice, observers demonstrated fair IOA for grading MNs and low IOA for identifying neoplastic mucin. Knowledge of the cyst fluid CEA level was found to modestly improve the IOA for low-grade lesions.

Imaging appearances of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.

OBJECTIVE: The objective of the study was to describe the imaging appearances of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) on computed tomography (CT). MATERIALS AND METHODS: Electronic medical records were searched for patients with pathology-proven DIPNECH who had a CT available for review. Eleven patients were included. RESULTS: The most common finding on CT was small pulmonary nodules which were present in all patients and were multiple (≥5) in 7/11 patients. Other CT findings included mosaic pattern attenuation and bronchial wall thickening/bronchiectasis. CONCLUSION: DIPNECH should be considered as a diagnostic possibility when multiple small pulmonary nodules are identified on CT, particularly if there is an associated carcinoid tumor.

Small-cell lung cancers in patients who never smoked cigarettes.

INTRODUCTION: We describe clinical, pathologic, and molecular characteristics of never-smoker patients with small-cell lung cancers (SCLCs). METHODS: We identified cases of SCLCs evaluated at our institution from 2005 to 2012. We collected smoking history, demographic, treatment, and survival data. EGFR, KRAS, PIK3CA, ALK testing, RB protein expression, and next generation sequencing were performed on available samples. RESULTS: Two percent (23 of 1040) of patients with SCLCs were never-smokers. Eighty-three percent (19 of 23) had de novo SCLCs, whereas 17% had SCLC transformation as acquired resistance to erlotinib after treatment for EGFR-mutant lung carcinomas. Median survival from SCLC diagnosis was 23 months. Of de novo SCLCs, ALK rearrangement, KRAS mutations, EGFR mutations, and RB loss were identified in zero of five, zero of eight, two of eight, and six of seven, respectively. Two de novo samples underwent next generation sequencing. One had mutations in p53 and RB1 with amplification in TERT, and a second had mutations in CBL and GNAS with amplification in MYCL1. CONCLUSIONS: Two percent of patients with SCLCs are never-smokers. Although transformation to SCLC can rarely occur in acquired resistance to erlotinib, 83% of never-smokers with SCLCs had de novo SCLC. RB loss was noted in 86% of cases. Multiplexed genotyping can be performed on tissues to identify potentially actionable oncogenic drivers.

Metastatic Medullary Thyroid Carcinoma and Cabozantinib: Case Series and Review of Literature.

Cabozantinib, a tyrosine kinase inhibitor, was approved by the US Food and Drug Administration in November 2012, for the treatment of metastatic medullary thyroid carcinoma. Although side effects typically include stomatitis, palmar-plantar erythrodysesthesia syndrome, hypertension and diarrhea, most patients are able to tolerate the recommended dose of 140 mg daily. Surgical resection is the primary treatment for medullary thyroid carcinoma. Patients with metastatic disease, who are not candidates for surgery, are considered candidates for systemic therapy. However, systemic chemotherapy has a limited role in metastatic disease. Our paper highlights not only the malignant potential of a medullary thyroid carcinoma, but also the role of cabozantinib in patients with progressive metastatic disease. We report two cases of patients with progressive metastatic medullary thyroid carcinoma (involving lung, lymph nodes, liver, pancreas, brain and spine) who responded well to therapy with cabozantinib.

Comparison of multiplanar reformatted CT lung tumor measurements to axial tumor measurement alone: impact on maximal tumor dimension and T stage.

OBJECTIVE: The purpose of this study was to compare measurements of lung tumor size between axial and multiplanar reformatted CT images, as well as to establish whether the difference between these measurements leads to a change in T stage. MATERIALS AND METHODS: Patients with lung tumors who underwent chest CT up to 31 days before lung resection between December 2010 and March 2012 were included. Axial, sagittal, and coronal CT images were evaluated by two independent readers (1 and 2) who were blinded to clinical data. In 89 patients, lung tumors categorized as T1a (54%), T1b (19%), T2a (24%), or T2b (3%) were analyzed. The longest tumor diameter using multiplanar reformatted CT was compared and correlated with axial CT alone and pathologic T stage. Statistical analysis included a Wilcoxon rank sum test to evaluate differences between measurements, intraclass correlation coefficient (ICC), and kappa statistic to assess agreement. RESULTS: Prediction of T stage using axial CT alone compared with multiplanar reformatted CT agreed in 82% of patients for reader 1 (κ = 0.660 [95% CI, 0.531-0.789]) and 80% of patients for reader 2 (κ = 0.695 [95% CI, 0.572-0.818]). Prediction of T stage using multiplanar reformatted CT resulted in upstaging in 18% and 20% of patients (for readers 1 and 2, respectively). Interobserver agreement (ICC [95% CI]) was 0.900 (0.803-0.954) for axial, 0.874 (0.772-0.946) for sagittal, and 0.754 (0.556-0.921) for coronal planes. CONCLUSION: Radiologic measurement of lung tumor T stage was higher using multiplanar reformatted CT as compared with axial CT alone. When available, multiplanar reformatted CT should be used to measure tumor dimension and thus assign an accurate lung cancer T stage.

The diagnosis of malignant mesothelioma in effusion cytology: a reappraisal and results of a multi-institution survey.

BACKGROUND: The diagnosis of malignant mesothelioma (MM) in effusion specimens is controversial. At the study institution (Northwestern University), a primary diagnosis of MM is made on fluid cytology specimens. In an effort to estimate the practice at other institutions, a survey was disseminated regarding cytologic diagnosis of MM. The authors also evaluated their own institution's experience with primary cytologic diagnosis of MM. METHODS: Patients with MM at the study institution were identified from 1992 through 2011. Fluid cytology specimens preceding histologic diagnoses were reviewed. A survey was sent to a number of cytology laboratories to assess practice patterns regarding the diagnosis of MM. RESULTS: At the study institution, 20 cases of MM had effusion specimens preceding the diagnostic histologic material. In 6 cases (30%), a definitive diagnosis of MM was rendered via cytology alone. There were no false-positive diagnoses of MM. Of 55 laboratories that responded to the survey, 36 reported making a definitive diagnosis of MM after cytologic analysis. Almost all laboratories (35) willing to diagnose MM in effusions reported performing immunohistochemistry to distinguish adenocarcinoma from MM. A smaller proportion (18) of these laboratories reported doing additional immunohistochemistry or fluorescence in situ hybridization for p16 to help distinguish benign from malignant mesothelial proliferations. Those who do not definitively diagnose MM in fluid specimens state inability to identify invasion and overlap with reactive mesothelial proliferation as factors supporting their practice. Most respondents (32) felt that the clinicians at their institution would manage a patient based on a cytologic diagnosis of MM. CONCLUSIONS: The majority of respondents reported making a definitive diagnosis of MM in effusion cytology specimens. The diagnosis of MM in effusions, although not sensitive, is extremely specific.

Lung cancer in the era of targeted therapy: a cytologist's perspective.

CONTEXT: The diagnosis and treatment of non-small cell lung cancer have changed dramatically in the past few years. The discovery of activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor and the use of drugs that successfully target those mutations are among the key advances that have led to a shift in the practice of oncology and pathology, with perhaps the greatest effect on the field of cytology. OBJECTIVES: To present the perspective of a practicing thoracic pathologist and cytopathologist on the developments that have changed practice and to place those changes in a broader context. DATA SOURCES: Literature review, studies undertaken or participated in by the author, and personal experience. CONCLUSIONS: Cytologists are in an ideal position to influence appropriate testing and treatment in the era of targeted therapy. Lung pathology has led the way in the era of targeted therapy, in no small part due to cytology.

Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.

PURPOSE: All patients with EGF receptor (EGFR)-mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been conducted. EXPERIMENTAL DESIGN: Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a rebiopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA, and FISH for MET and HER2. RESULTS: Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations [63%; 95% confidence interval (CI), 55%-70%] and four had small cell transformation (3%, 95% CI, 0%-6%). MET amplification was seen in 4 of 75 (5%; 95% CI, 1%-13%). HER2 amplification was seen in 3 of 24 (13%; 95% CI, 3%-32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS (0 of 88, 0%; 95% CI, 0%-4%). Overlap among mechanisms of acquired resistance was seen in 4%. CONCLUSIONS: This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, whereas MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR-TKIs.

Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas.

The discovery of RET fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes. In an unselected population of non-small cell lung carcinomas (NSCLCs), RET fusions are present in 1% to 2% of cases. This incidence increases substantially, however, in never-smokers with lung adenocarcinomas that lack other known driver oncogenes. Although preclinical data provide experimental support for the use of RET inhibitors in the treatment of RET fusion-positive tumors, clinical data on response are lacking. We report preliminary data for the first three patients treated with the RET inhibitor cabozantinib on a prospective phase II trial for patients with RET fusion-positive NSCLCs (NCT01639508). Confirmed partial responses were observed in 2 patients, including one harboring a novel TRIM33-RET fusion. A third patient with a KIF5B-RET fusion has had prolonged stable disease approaching 8 months (31 weeks). All three patients remain progression-free on treatment.