Rare immune-related adverse events in a patient with metastatic melanoma: a case report highlighting sarcoidosis-like reactions triggered by immune-checkpoint inhibitors.

Pembrolizumab and ipilimumab/nivolumab (ipi/nivo) combination are FDA-approved immune checkpoint inhibitor (ICI) therapies for metastatic melanoma. ICIs could result in various inflammation responses known as immune-related adverse events (IRAEs). We report a patient with metastatic melanoma who developed multiple IRAEs including sarcoidosis-like reaction (SLR), diabetic ketoacidosis (DKA), and worsening hypothyroidism on ICIs. A 71-year-old man with stage IIIC melanoma and lymph node metastasis began adjuvant therapy with pembrolizumab in May 2021. A surveillance positron emission tomography-computed tomography (PET-CT) scan four months later showed diffuse nodal uptake indicating potential metastases although the patient remained asymptomatic. His treatment was temporarily switched to ipi/nivo before biopsy was obtained for definitive diagnosis, which revealed non-caseating granulomas consistent with SLR. After resuming pembrolizumab, he developed DKA and worsening hypothyroidism in November 2021, both of which were attributed to IRAEs. His surveillance PET scan in March 2022 again revealed new hypermetabolic activity in several bones, subcutaneous tissue, and the left inguinal lymph node. Left inguinal node biopsy showed disease recurrence, while biopsies of hypermetabolic subcutaneous nodules and bone demonstrated non-caseating granulomas. Our case described a patient on ICIs who developed several IRAEs. SLR is often asymptomatic but remains a diagnostic challenge due to its indistinguishable appearance on imaging studies compared to metastasis. Better understanding of IRAEs and improved surveillance strategies are needed for optimal patient outcomes.

Use of molecular testing results to analyze the overuse of atypia of undetermined significance in thyroid cytology.

INTRODUCTION: The suggested atypia of undetermined significance (AUS) rate for thyroid fine-needle aspiration biopsies is 10% or less. Prompted by a high institutional AUS rate, we examined using molecular testing results (MTR) as a potential quality metric tool to reduce the AUS rate. We correlated MTR with AUS cytologic findings, surgical pathology follow-up, and individual pathologist AUS rates. MATERIALS AND METHODS: Demographic data, cytologic diagnoses, MTR, and surgical pathology diagnoses were retrospectively obtained. MTR were classified as either positive or negative. AUS rates and MTR proportions were compared among pathologists. The cytomorphologic features of 143 AUS cases were assessed and correlated with MTR. RESULTS: Between 2017 and 2022, 710 of 3247 thyroid fine-needle aspirations were classified as AUS, with a yearly average rate of 22% (range = 19%-26%). AUS cases included: 331 (47%) with architectural atypia; 204 (29%) with oncocytic (Hürthle cell) atypia; 99 (14%) with combined architectural and cytologic atypia; and 76 (10%) with isolated cytologic atypia. Most AUS cases with molecular testing had negative MTR (360/492, 73%). AUS with cytologic atypia had higher positive MTR risk (logarithm of odds ratio = 1.27, 95% credible interval [0.5-2.04], P = 0.001). The average positive MTR rate by pathologist was 21.5% (range 0%-35%); higher positive MTR rates had better correlation with subsequent neoplastic/malignant histologic diagnoses. The MTR sensitivity for malignant disease was 89% and the negative predictive value was 91%. CONCLUSIONS: MTR analysis reveals the importance of cytologic atypia as a determinant of malignancy risk in AUS cases. Periodic analysis of MTR data alongside individual pathologist AUS rates can help refine diagnostic criteria and potentially reduce AUS overuse.

Large-scale validation study of an improved semiautonomous urine cytology assessment tool: AutoParis-X.

BACKGROUND: Adopting a computational approach for the assessment of urine cytology specimens has the potential to improve the efficiency, accuracy, and reliability of bladder cancer screening, which has heretofore relied on semisubjective manual assessment methods. As rigorous, quantitative criteria and guidelines have been introduced for improving screening practices (e.g., The Paris System for Reporting Urinary Cytology), algorithms to emulate semiautonomous diagnostic decision-making have lagged behind, in part because of the complex and nuanced nature of urine cytology reporting. METHODS: In this study, the authors report on the development and large-scale validation of a deep-learning tool, AutoParis-X, which can facilitate rapid, semiautonomous examination of urine cytology specimens. RESULTS: The results of this large-scale, retrospective validation study indicate that AutoParis-X can accurately determine urothelial cell atypia and aggregate a wide variety of cell-related and cluster-related information across a slide to yield an atypia burden score, which correlates closely with overall specimen atypia and is predictive of Paris system diagnostic categories. Importantly, this approach accounts for challenges associated with the assessment of overlapping cell cluster borders, which improve the ability to predict specimen atypia and accurately estimate the nuclear-to-cytoplasm ratio for cells in these clusters. CONCLUSIONS: The authors developed a publicly available, open-source, interactive web application that features a simple, easy-to-use display for examining urine cytology whole-slide images and determining the level of atypia in specific cells, flagging the most abnormal cells for pathologist review. The accuracy of AutoParis-X (and other semiautomated digital pathology systems) indicates that these technologies are approaching clinical readiness and necessitates full evaluation of these algorithms in head-to-head clinical trials.

Examining longitudinal markers of bladder cancer recurrence through a semiautonomous machine learning system for quantifying specimen atypia from urine cytology.

BACKGROUND: Urine cytology is generally considered the primary approach for screening for recurrence of bladder cancer. However, it is currently unclear how best to use cytological examinations for assessment and early detection of recurrence, beyond identifying a positive finding that requires more invasive methods to confirm recurrence and decide on therapeutic options. Because screening programs are frequent, and can be burdensome, finding quantitative means to reduce this burden for patients, cytopathologists, and urologists is an important endeavor and can improve both the efficiency and reliability of findings. Additionally, identifying ways to risk-stratify patients is crucial for improving quality of life while reducing the risk of future recurrence or progression of the cancer. METHODS: In this study, a computational machine learning tool, AutoParis-X, was leveraged to extract imaging features from urine cytology examinations longitudinally to study the predictive potential of urine cytology for assessing recurrence risk. This study examined how the significance of imaging predictors changes over time before and after surgery to determine which predictors and time periods are most relevant for assessing recurrence risk. RESULTS: Results indicate that imaging predictors extracted using AutoParis-X can predict recurrence as well or better than traditional cytological/histological assessments alone and that the predictiveness of these features is variable across time, with key differences in overall specimen atypia identified immediately before tumor recurrence. CONCLUSIONS: Further research will clarify how computational methods can be effectively used in high-volume screening programs to improve recurrence detection and complement traditional modes of assessment.

Uncovering additional predictors of urothelial carcinoma from voided urothelial cell clusters through a deep learning-based image preprocessing technique.

BACKGROUND: Urine cytology is commonly used as a screening test for high-grade urothelial carcinoma for patients with risk factors or hematuria and is an essential step in longitudinal monitoring of patients with previous bladder cancer history. However, the semisubjective nature of current reporting systems for urine cytology (e.g., The Paris System) can hamper reproducibility. For instance, the incorporation of urothelial cell clusters into the classification schema is still an item of debate and perplexity among expert cytopathologists because several previous works have disputed their diagnostic relevance. METHODS: In this work, an automated preprocessing tool for urothelial cell cluster assessment was developed that divides urothelial cell clusters into meaningful components for downstream assessment (ie, population-based studies, workflow automation). RESULTS: In this work, an automated preprocessing tool for urothelial cell cluster assessment was developed that divides urothelial cell clusters into meaningful components for downstream assessment (ie, population-based studies, workflow automation). Results indicate that cell cluster atypia (i.e., defined by whether the cell cluster harbored multiple atypical cells, thresholded by a minimum number of cells), cell border overlap and smoothness, and total number of clusters are important markers of specimen atypia when considering assessment of urothelial cell clusters. CONCLUSIONS: Markers established through techniques to separate cell clusters may have wider applicability for the design and implementation of machine learning approaches for urine cytology assessment.

Large-scale longitudinal comparison of urine cytological classification systems reveals potential early adoption of The Paris System criteria.

INTRODUCTION: Urine cytology is used to screen for urothelial carcinoma in patients with hematuria or risk factors (eg, smoking, industrial dye exposure) and is an essential clinical triage and longitudinal monitoring tool for patients with known bladder cancer. However, urine cytology is semisubjective and thus susceptible to issues including specimen quality, interobserver variability, and "hedging" towards equivocal ("atypical") diagnoses. These factors limit the predictive value of urine cytology and increase reliance on invasive procedures (cystoscopy). The Paris System for Reporting Urine Cytology (TPS) was formulated to provide more quantitative/reproducible endpoints with well-defined criteria for urothelial atypia. TPS is often compared to other assessment techniques to justify its adoption. TPS results in decreased use of the atypical category and better reproducibility. Previous reports comparing diagnoses pre- and post-TPS have not considered temporal differences between diagnoses made under prior systems and TPS. By aggregating across time, studies may underestimate the magnitude of differences between assessment methods. MATERIALS AND METHODS: We conducted a large-scale longitudinal reassessment of urine cytology using TPS criteria from specimens collected from 2008 to 2018, prior to the mid-2018 adoption of TPS at an academic medical center. RESULTS: Findings indicate that differences in atypical assignment were largest at the start of the period and these differences progressively decreased towards insignificance just prior to TPS implementation. CONCLUSIONS: This finding suggests that cytopathologists had begun to utilize the quantitative TPS criteria prior to official adoption, which may more broadly inform adoption strategies, communication, and understanding for evolving classification systems in cytology.

Pathologist-Patient Visits-Revisited.

Direct pathologist-patient encounters are infrequent, but there has been a modest movement toward such interactions in the past 2 decades. The present article places that movement in perspective. It includes a discussion of diverse factors-including congressional laws, the views of department chairs, and progress in artificial intelligence-that could promote pathologist-patient interactions and also reviews factors that might deter such encounters.

Using molecular testing to improve the management of thyroid nodules with indeterminate cytology: an institutional experience with review of molecular alterations.

INTRODUCTION: Molecular testing has helped clinicians and cytopathologists to further categorize indeterminate thyroid fine needle aspiration (FNA) specimens. The purpose of the present study was to evaluate the accuracy of commercially available molecular tests, review their effects on patient treatment, and correlate the molecular alterations with the histologic findings. MATERIALS AND METHODS: A pathology laboratory information system search identified thyroid FNAs performed at our institution between January 1, 2015 and June 30, 2020. The results of surgical follow-up and ancillary molecular testing were collected. We evaluated the accuracy of these tests and whether they could reduce the number of surgeries performed. RESULTS: Our laboratory information system search identified 510 cases reported as atypia of undetermined significance, 94 as suspicious for follicular neoplasm, and 44 as suspicious for follicular neoplasm, Hurthle cell type. Of the specimens, 343 had no ancillary molecular testing, 146 were sent for ThyGenX/ThyraMIR, and 136 were sent for ThyroSeq. Of the patients without molecular testing, 50.4% had undergone follow-up surgery compared with 30.8% after ThyGenX/ThyraMIR and 38.2% after ThyroSeq testing, resulting in 38.9% and 24.2% fewer surgeries and an odds ratio of 0.04 (95% confidence interval, 0.00-0.33) and 0.14 (95% confidence interval, 0.01-0.95), respectively. For ThyGenX/ThyraMIR testing, the risk of malignancy for high and moderate to high risk alterations was 80%, 28.6% for moderate and low to moderate risk alterations, and 23.1% for low risk alterations. For ThyroSeq, the risk of malignancy was 87.5% for high risk alterations, 36.8% for intermediate to high risk alterations, 27.3% for intermediate risk alterations, and 0% for low risk alterations. The areas under the curve for ThyGenX/ThyraMIR and ThyroSeq testing were 0.65 and 0.85, respectively. CONCLUSIONS: These findings suggest that, at our institution, both ThygenX/ThyraMIR and ThyroSeq can be used to effectively stratify cytology specimens based on the risk of malignancy and reduce the number of surgeries performed at our institution.

Cytologic features of a case of mixed medullary and follicular cell-derived thyroid carcinoma with review of the literature.

Mixed medullary and follicular cell-derived thyroid carcinoma (MMFTC) is a rare primary thyroid carcinoma with morphologic and immunophenotypic evidence of admixed parafollicular and follicular cell-derived tumor populations within the same tumor. We herein present the fine-needle aspiration biopsy (FNAB) cytology of a case of MMFTC that was diagnosed histologically and discuss potential clues to the diagnosis for cytologists. We also provide a literature review of this uncommon primary thyroid tumor. The patient was a 47-year-old man with a history of hypothyroidism who presented with ear and neck pain. Imaging demonstrated thyroid nodules with regional lymphadenopathy. FNAB samples of two thyroid nodules and an involved lymph node were diagnosed as papillary thyroid carcinoma (PTC). The subsequent total thyroidectomy specimen demonstrated classic-type PTC which transitioned to a morphologically and immunophenotypically distinct medullary thyroid carcinoma (MTC) component within the same lesion, indicative of MMFTC. The patient experienced recurrence of the medullary component 20 months later and received chemotherapy with subsequent external beam radiation. As in this case, the cytologic diagnosis of MMFTC is almost never made prospectively. Retrospective review of the preoperative FNAB samples showed subtle cytomorphologic features suggestive of MTC in two of three biopsies, an impression confirmed by calcitonin immunohistochemistry on cell block material. In the broader literature, most MMFTCs on FNAB have been diagnosed as MTC, which is usually the more aggressive component of the mixed neoplasm.

Implementation of an Emergency Use Authorization Test During an Impending National Crisis.

The laboratory response to the current severe acute respiratory syndrome coronavirus 2 pandemic may be termed heroic. From the identification of the novel coronavirus to implementation of routine laboratory testing around the world to the development of potential vaccines, laboratories have played a critical role in the efforts to curtail this pandemic. In this brief report, we review our own effort at a midsized, rural, academic medical center to implement a molecular test for the virus; and we share insights and lessons learned from that process, which might be helpful in similar situations in the future.