BACKGROUND: Thyroid cytopathology cases with suspicious for malignancy (SFM) diagnosis often result in resection. However, molecular testing offers details that may provide additional insights. In this study, the molecular profiles of SFM cases from two institutions that routinely used ThyroSeq v3 (TSV3) were examined.
METHODS: Following institutional review board approval, SFM thyroid cytopathology cases with TSV3 results were retrieved from the databases of two institutions. Molecular information including molecular-derived risk of malignancy (MDROM), cytologic-histologic correlation data, and other related parameters were calculated. Statistical comparisons were made with a p <.05 considered significant.
RESULTS: The core data set comprised 114 SFM cases that passed TSV3 quality assurance. All TSV3 results were reported as positive or negative for genomic alterations and all except five cases provided a probability of malignancy estimate. The overall combined baseline MDROM of 75.7% (95% CI, 70.0-81.4) was comparable to the risk of malignancy (74%) published in the Bethesda System. There was a statistically significant difference between the combined MDROMs of resected and unresected cohorts (79.0% vs 58.6%; p = .0153). Interestingly, the MDROMs of the resected cohorts from the two institutions were statistically different (75.0% vs 85.3%; p = .020). Cytologic-histologic correlation revealed malignant outcome in 88.5% of resected cases.
CONCLUSIONS: Molecular analyses of SFM cases demonstrated higher risk genomic alterations that were associated with histologically overt neoplasms, resulting in increased malignancy outcome compared to baseline. MDROM analysis revealed differences in the cytopathologic practice patterns regarding follicular-patterned neoplasms at the two institutions.

Ground breaking advances in medicine, driven in part by major technologic developments in molecular biology have led us to a new model for cancer care that has been termed personalized, or precision medicine. Precision medicine is a model for making medical decisions that employs an innovative clinical approach and advanced tumor testing methods that are tailored to understanding an individual patient\'s tumor biology and the molecular drivers of their disease. This medical model includes a combination of diagnostic testing and specific treatment options that can be offered to patients at presentation and in theory throughout the course of their disease as new mutations arise with the development of disease recurrence. Although the precision medicine model offers incredible potential to transform cancer care, these advances are only meaningful when they reach the correct patients. The evolving paradigm of precision medicine is changing the practice of pathology, and the pathology community needs to be mindful of these changes because every tissue specimen represents a patient\'s life, and those patients are depending on the pathology community to handle their tissue correctly. The diagnostic tests performed in the pathology laboratory for precision medicine are increasingly complex, and pathologists along with the entire laboratory and clinical communities need to take steps to ensure that the right diagnosis is given to the right patient to inform the right treatment options, at the right time, along every step of the continuum of care for cancer patients. While hormone receptors and human epidermal growth factor receptor 2 (HER2) overexpression and/or amplification have been the mainstay for risk-stratification, and treatment decision making in breast cancer since the early 2000\'s, the seminal work on gene expression by Perou and colleagues in the early 2000\'s opened the door for molecular testing in the prognostic and predictive assessment of breast cancer. Molecular testing is now part of the standard of care in the precision medicine model for breast cancer care. In this article, the reader will gain a better understanding of how the lack of standardization of pre-analytic factors has the potential to negatively impact the quality of the tissue specimen for downstream biomarker and molecular testing, which ultimately can negatively affect patient care. The reader will also gain insight into the current climate surrounding molecular testing in breast cancer.

The spectrum of clinical and radiographic presentations of lung adenocarcinoma is increasingly broad, including in the metastatic setting. Here, we report on a patient who initially presented with a mild chronic cough that remained stable over a decade, with serial CT scans showing gradual worsening of multifocal areas of consolidation and ground-glass opacities of the bilateral lungs. The patient was ultimately diagnosed with ROS1 rearranged lung adenocarcinoma and achieved a dramatic response with entrectinib. This case highlights the variable presentation of non-small cell lung cancer (NSCLC) and the importance of comprehensive molecular testing for newly diagnosed metastatic NSCLC.

Concepts in thyroid diagnostics are evolving. As cytopathologists, we benefit from understanding the changes taking place in cytopathology practice as well as intersecting areas that may have implications for us. In this review, we discuss recent changes to 1. Classification systems, 2. Ancillary molecular testing modalities, and 3. Key metrics that affect thyroid cytopathology. The recent World Health Organization, Bethesda Thyroid Cytopathology, and American Joint Committee on Cancer classification systems have aspects that are designed to harmonize the clinical, cytopathologic, histomorphologic, and molecular findings for improved communication and patient management. New terminologies such as thyroid follicular nodular disease and low-risk follicular cell-derived thyroid neoplasms are introduced to reflect the subtle biologic nuances involving benign non-neoplastic and low-grade neoplastic conditions. The Bethesda Thyroid Cytopathology System has simplified its terminology, updated risk of malignancy estimates, and expanded the discussions on molecular testing, clinical and imaging assessments, and pediatric cytopathology. There is now a single term for each of the 6 diagnostic categories. The American Joint Committee on Cancer has refined the staging criteria to provide improved stratification of patient prognostication. Molecular testing using next-generation technology now offers large panels of markers that are sensitive for detecting the wide range of thyroid neoplasms. These panels were developed in North America and whether other regions of the world will choose similar tests remain to be seen. Finally, metrics such as molecular-derived risk of malignancy and molecular risk group may be viewed as surrogates of resection information and used to complement diagnostics, management, and quality assurance.

The incidence of thyroid cancer has increased over recent years due to the fact that several diagnostic tools, such as neck ultrasound and fine-needle aspiration, are being ever more widely adopted. Lately, another modality which might provide significant information preoperatively on the aggressiveness of a thyroid tumor, its prognosis, and its recurrence rate is molecular testing. We reviewed the literature with regard to the role of preoperative molecular testing in patients with Bethesda V and Bethesda VI thyroid nodules and its impact on choice of the optimal treatment strategy. Several molecular mutations and alterations are associated with thyroid cancer and its biological behavior, such as BRAF-V600E, RET, and TERT promoter. Although the value of preoperative molecular testing for indeterminate nodules (Bethesda III and Bethesda IV) have been analyzed in numerous studies, the impact of preoperative molecular testing on Bethesda V and Bethesda VI thyroid nodules is not adequately described in the current literature. The preoperative recognition of specific molecular mutations, such as BRAFV600E and TERT promoter mutation, might provide more individualized management for thyroid cancer patients by altering the surgical approach and the extent of surgery for patients diagnosed with a more aggressive or iodine-resistant subtype of thyroid cancer.Thyroid cancer is characterized by multiple genetic mutations and alterations and, as a result, preoperative molecular testing of malignant nodules could be a very useful tool for surgeons, enabling them to decide on the most appropriate surgical approach for each patient.

OBJECTIVE: The management of indeterminate thyroid nodules remains a topic of ongoing debate, particularly regarding the differentiation of malignancy. Somatic mutation analysis offers crucial insights into tumor characteristics. This study aimed to assist the clinical management of indeterminate nodules with somatic mutation analysis.
METHODS: Aspiration samples from 20 indeterminate thyroid nodules were included in the study. A next-generation sequencing panel containing 67 genes was used for molecular profiling. The results were compared with pathology data from surgical material, which is considered the gold standard. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated.
RESULTS: Variants in six genes (NRAS, BRAF, TP53, TERT, PTEN, PIK3CA) were detected in 10 out of 20 samples. We identified nine Tier 1 or 2 variants in 10 (67 %) out of 15 malignant nodules (NRAS, BRAF, TP53, TERT, PTEN, PIK3CA) and one Tier 2 (PIK3CA) variant in one out of five benign nodules. The study demonstrated an NPV of 40 %, a PPV of 90 %, a specificity of 80 %, and a sensitivity of 60 %.
CONCLUSIONS: Based on the detected molecular markers, at least nine patients (45 %) could be managed correctly without needing a repeat FNAB attempt. This study underscores the clinical practicality of molecular tests in managing nodules with indeterminate cytology. Additionally, this study emphasizes the importance of considering the patient\'s age when determining the DNA- or RNA-based genetic testing method. Finally, we discussed the significance of the somatic mutation profile and its impact on the current pathological classification.

BACKGROUND: The efficacy of radiofrequency ablation (RFA) in treating thyroid nodules with indeterminate cytology remains less studied. The objective of this study was to determine the efficacy of RFA in treating nodules with Bethesda III that have been molecularly profiled benign (BIII-MPN).
METHODS: We included prospectively enrolled patients who underwent RFA for benign and BIII-MPN thyroid nodules. Primary outcome measures were volume reduction ratio (VRR), symptom score (range 0-10), and cosmetic score (range 0-3) at 1, 3, 6, and 12 months after RFA, as well as complication rates.
RESULTS: A total of 258 nodules in 192 patients were included (benign: 238 in 174; BIII-MPN: 20 in 18). The median VRR differed insignificantly, whereas symptom and cosmetic score improvements were similar between two cohorts. BIII-MPN thyroid nodules were associated with lower rates of infection and temporary voice change.
CONCLUSIONS: Our preliminary findings suggest that RFA may be a feasible management option for BIII-MPN thyroid nodules. However, appropriate will be important to address the important risk of potentially missed malignancies.

OBJECTIVE: Optimal management of indeterminate nodules remains a controversial area of endocrine surgery. The purpose of this study is to compare observation, molecular testing, and immediate thyroid surgery for the management of Bethesda Classes III and IV nodules in patients age 50 to 90 years.
METHODS: A decision analysis was performed from April 22, 2021, to September 29, 2023, using a Markov model constructed with TreeAgePro 2023. Model variables and ranges were selected based on literature review data.
METHODS: TreeAgePro.
METHODS: A 1-way sensitivity analysis was performed to evaluate the age threshold at which each management pathway, immediate thyroid surgery, additional molecular testing, or observation, would be favored. A Monte Carlo probabilistic sensitivity analysis was performed 5 times with model patients assigned starting ages of 50, 60, 70, 80, and 90 years to assess how age at diagnosis would impact model results. Outcomes were measured with quality-adjusted life-years and accounted for perioperative complications including permanent recurrent laryngeal nerve injury, permanent hypoparathyroidism, and medical complications.
RESULTS: In the study models, molecular testing was more beneficial than surgery and observation across all ages. The age threshold at which observation became more beneficial than surgery as the next best option was 83.1 years. However, the clinical difference between all 3 treatment algorithms was relatively minimal.
CONCLUSIONS: Decision-making regarding indeterminate thyroid nodules is complex. Given the clinically similar results across all 3 treatment algorithm, this study reinforces that treatment modalities should be individually tailored and based on shared physician-patient decision making.

Lymph node (LN) fine-needle aspiration cytology (FNAC) is a common diagnostic procedure for lymphadenopathies. Despite the qualities and potentialities of LN-FNAC, the number of possible pathologies and the variety of clinical contexts represent a challenge and require a continuous upgrading of the procedure according to the emerging clinical requests and new technologies. This study presents an overview of the current and future impact of LN-FNAC on the care of patients with lymphadenopathy.

Small biopsies of lung are routinely obtained by many methods, including several that result in cytologic specimens. Because lung cancer is often diagnosed at a stage for which primary resection is not an option, it is critical that all diagnostic, predictive, and prognostic information be derived from such small biopsy specimens. As the number of available diagnostic and predictive markers expands, cytopathologists must familiarize themselves with current requirements for specimen acquisition, handling, results reporting, and molecular and other ancillary testing, all of which are reviewed here.