Artificial intelligence algorithm accurately assesses oestrogen receptor immunohistochemistry in metastatic breast cancer cytology specimens: A pilot study.

OBJECTIVE: The Visiopharm artificial intelligence (AI) algorithm for oestrogen receptor (ER) immunohistochemistry (IHC) in whole slide images (WSIs) has been successfully validated in surgical pathology. This study aimed to assess its efficacy in cytology specimens. METHODS: The study cohort comprised 105 consecutive cytology specimens with metastatic breast carcinoma. ER IHC WSIs were seamlessly integrated into the Visiopharm platform from the Image Management System (IMS) during our routine digital workflow, and an AI algorithm was employed for analysis. ER AI scores were compared with pathologists' manual consensus scores. Optimization steps were implemented and evaluated to reduce discordance. RESULTS: The overall concordance between pathologists' scores and AI scores was excellent (99/105, 94.3%). Six cases exhibited discordant results, including two false-negative (FN) cases due to abundant histiocytes incorrectly counted as negatively stained tumour cells by AI, two FN cases owing to weak staining, and two false-positive (FP) cases where pigmented macrophages were erroneously counted as positively stained tumour cells by AI. The Pearson correlation coefficient of ER-positive percentages between pathologists' and AI scores was 0.8483. Optimization steps, such as lowering the cut-off threshold and additional training using higher input magnification, significantly improved accuracy. CONCLUSIONS: The automated ER AI algorithm demonstrated excellent concordance with pathologists' assessments and accurately differentiated ER-positive from ER-negative metastatic breast carcinoma cytology cases. However, precision in identifying tumour cells in cytology specimens requires further enhancement.

Activation of the RAS pathway through uncommon BRAF mutations in mucinous pancreatic cysts without KRAS mutation.

Diagnostic testing of pancreatic cyst fluid obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has traditionally utilized elevated carcinoembryonic antigen (CEA) (≥192 ng/ml) and cytomorphologic examination to differentiate premalignant mucinous from benign pancreatic cystic lesions (PCLs). Molecular testing for KRAS/GNAS mutations has been shown to improve accuracy of detecting mucinous PCLs. Using a targeted next-generation sequencing (NGS) panel, we assess the status of PCL-associated mutations to improve understanding of the key diagnostic variables. Molecular analysis of cyst fluid was performed on 108 PCLs that had concurrent CEA and/or cytological analysis. A 48-gene NGS assay was utilized, which included genes commonly mutated in mucinous PCLs such as GNAS, KRAS, CDKN2A, and TP53. KRAS and/or GNAS mutations were seen in 59 of 68 (86.8%) cases with multimodality diagnosis of a mucinous PCL. Among 31 patients where surgical histopathology was available, the sensitivity, specificity, and diagnostic accuracy of NGS for the diagnosis of mucinous PCL was 88.5%, 100%, and 90.3%, respectively. Cytology with mucinous/atypical findings were found in only 29 of 62 cases (46.8%), with fluid CEA elevated in 33 of 58 cases (56.9%). Multiple KRAS mutations at different variant allele frequencies were seen in seven cases favoring multiclonal patterns, with six of them showing at least two separate PCLs by imaging. Among the 6 of 10 cases with GNAS + /KRAS- results, uncommon, non-V600E exon 11/15 hotspot BRAF mutations were identified. The expected high degree of accuracy of NGS detection of KRAS and/or GNAS mutations for mucinous-PCLs, as compared with CEA and cytological examination, was demonstrated. Multiple KRAS mutations correlated with multifocal cysts demonstrated by radiology. In IPMNs that lacked KRAS mutations, the concurring BRAF mutations with GNAS mutations supports an alternate mechanism of activation in the Ras pathway.

Intraocular metastases of lung origin: Case reports and cytology correlates.

Intraocular metastases from the lung are a common occurrence and an important differential for cytopathologists reading fine needle aspiration biopsies (FNAB). It is a particularly challenging diagnosis when the patient has had no previous diagnosis of lung cancer. We present two cases of intraocular metastases from lung primaries, and we discuss the clinical, radiological, and cytopathological features that help differentiate intraocular metastases of lung primary from other intraocular tumours, in the setting of FNAB. We also discuss the importance of recognising the spectrum of FNAB cases that can be seen specific to an institution, which may vary according to different patient populations. A thorough metastatic workup and ancillary testing, such as IHC or molecular genetics, ensures an accurate diagnosis.

MYH9 binds to lncRNA gene PTCSC2 and regulates FOXE1 in the 9q22 thyroid cancer risk locus.

A locus on chromosome 9q22 harbors a SNP (rs965513) firmly associated with risk of papillary thyroid carcinoma (PTC). The locus also comprises the forkhead box E1 (FOXE1) gene, which is implicated in thyroid development, and a long noncoding RNA (lncRNA) gene, papillary thyroid cancer susceptibility candidate 2 (PTCSC2). How these might interact is not known. Here we report that PTCSC2 binds myosin-9 (MYH9). In a bidirectional promoter shared by FOXE1 and PTCSC2, MYH9 inhibits the promoter activity in both directions. This inhibition can be reversed by PTCSC2, which acts as a suppressor. RNA knockdown of FOXE1 in primary thyroid cells profoundly interferes with the p53 pathway. We propose that the interaction between the lncRNA, its binding protein MYH9, and the coding gene FOXE1 underlies the predisposition to PTC triggered by rs965513.

The role of SMAD3 in the genetic predisposition to papillary thyroid carcinoma.

PURPOSE: To identify and characterize the functional variants, regulatory gene networks, and potential binding targets of SMAD3 in the 15q22 thyroid cancer risk locus. METHODS: We performed linkage disequilibrium (LD) and haplotype analyses to fine map the 15q22 locus. Luciferase reporter assays were applied to evaluate the regulatory effects of the candidate variants. Knockdown by small interfering RNA, microarray analysis, chromatin immunoprecipitation (ChIP) and quantitative real-time polymerase chain reaction assays were performed to reveal the regulatory gene network and identify its binding targets. RESULTS: We report a 25.6-kb haplotype within SMAD3 containing numerous single-nucleotide polymorphisms (SNPs) in high LD. SNPs rs17293632 and rs4562997 were identified as functional variants of SMAD3 by luciferase assays within the LD region. These variants regulate SMAD3 transcription in an allele-specific manner through enhancer elements in introns of SMAD3. Knockdown of SMAD3 in thyroid cancer cell lines revealed its regulatory gene network including two upregulated genes, SPRY4 and SPRY4-IT1. Sequence analysis and ChIP assays validated the actual binding of SMAD3 protein to multiple SMAD binding element sites in the region upstream of SPRY4. CONCLUSION: Our data provide a functional annotation of the 15q22 thyroid cancer risk locus.

Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer.

The [A] allele of SNP rs965513 in 9q22 has been consistently shown to be highly associated with increased papillary thyroid cancer (PTC) risk with an odds ratio of ∼1.8 as determined by genome-wide association studies, yet the molecular mechanisms remain poorly understood. Previously, we noted that the expression of two genes in the region, forkhead box E1 (FOXE1) and PTC susceptibility candidate 2 (PTCSC2), is regulated by rs965513 in unaffected thyroid tissue, but the underlying mechanisms were not elucidated. Here, we fine-mapped the 9q22 region in PTC and controls and detected an ∼33-kb linkage disequilibrium block (containing the lead SNP rs965513) that significantly associates with PTC risk. Chromatin characteristics and regulatory element signatures in this block disclosed at least three regulatory elements functioning as enhancers. These enhancers harbor at least four SNPs (rs7864322, rs12352658, rs7847449, and rs10759944) that serve as functional variants. The variant genotypes are associated with differential enhancer activities and/or transcription factor binding activities. Using the chromosome conformation capture methodology, long-range looping interactions of these elements with the promoter region shared by FOXE1 and PTCSC2 in a human papillary thyroid carcinoma cell line (KTC-1) and unaffected thyroid tissue were found. Our results suggest that multiple variants coinherited with the lead SNP and located in long-range enhancers are involved in the transcriptional regulation of FOXE1 and PTCSC2 expression. These results explain the mechanism by which the risk allele of rs965513 predisposes to thyroid cancer.

Ischemic neurons recruit natural killer cells that accelerate brain infarction.

Brain ischemia and reperfusion activate the immune system. The abrupt development of brain ischemic lesions suggests that innate immune cells may shape the outcome of stroke. Natural killer (NK) cells are innate lymphocytes that can be swiftly mobilized during the earliest phases of immune responses, but their role during stroke remains unknown. Herein, we found that NK cells infiltrated the ischemic lesions of the human brain. In a mouse model of cerebral ischemia, ischemic neuron-derived fractalkine recruited NK cells, which subsequently determined the size of brain lesions in a T and B cell-independent manner. NK cell-mediated exacerbation of brain infarction occurred rapidly after ischemia via the disruption of NK cell tolerance, augmenting local inflammation and neuronal hyperactivity. Therefore, NK cells catalyzed neuronal death in the ischemic brain.

Utility of different immunostains for diagnosis of metastatic breast carcinomas in both surgical and cytological specimens.

OBJECTIVE: A panel of immunostains is usually performed to confirm a metastatic carcinoma origin. GATA3 is a transcription factor and has been proven to be a useful marker for breast carcinoma. Other immunostains including mammaglobin (MGB), gross cystic disease fluid protein 15 (GCDFP-15), estrogen receptor (ER) and progesterone receptor (PR) are also used in diagnosing metastatic breast cancer. In this study, we aimed to compare the performance of these immunostains in the work up of metastatic breast carcinoma in both surgical and cytological specimens. STUDY DESIGN: This study cohort was composed of 242 metastatic breast carcinomas (142 surgical and 100 cytological specimens) during a study period from October 2013 to December 2015. Immunostain results of GATA3, CK7, MGB, GCDFP-15, ER and PR and their correlations were examined. RESULTS: In surgical specimens, GATA3 and CK7 were highly expressed (88% and 87%), but MGB and GCDFP-15 showed much lower positivity rates (43% and 29%). In cytological specimens, GATA3, CK7 and MGB showed similar positivity rates to those in surgical specimens; but GCDFP-15, ER and PR showed significantly lower positivity rates than those in surgical specimens. All ER-positive cases were positive for GATA3 in both surgical and cytological specimens; however, GATA3 positivity showed a significantly stronger correlation with ER positivity in surgical specimens than in cytological specimens. CONCLUSIONS: GATA3 and CK7 performed better than other immunostains to detect metastatic breast carcinoma in both surgical and cytological specimens. GATA3 expression was positively correlated with ER expression, and the correlation was stronger in surgical specimens than in cytological specimens.

Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis.

IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune-suppressive activity. Although IL-35 was demonstrated to be produced by regulatory T cells, gene-expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. To determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35-producing plasmacytoma J558 and B16 melanoma cells and observed that the expression of IL-35 in cancer cells does not affect their growth and survival in vitro, but it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the tumor microenvironment and, thereby, promotes tumor angiogenesis. In immune-competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor Ag-specific CD8(+) T cell activation, differentiation, and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity.

Automated imaging analysis of Ki-67 immunohistochemistry on whole slide images of cell blocks from pancreatic neuroendocrine neoplasms.

INTRODUCTION: Accurate grading of pancreatic neuroendocrine tumors (PanNETs) relies on the assessment of Ki-67 immunohistochemistry (IHC). While digital imaging analysis (DIA) has been employed for Ki-67 IHC assessment in surgical specimens, its applicability to cytologic specimens remains underexplored. This study aimed to evaluate an automated DIA for assessing Ki-67 IHC on PanNET cell blocks. MATERIALS AND METHODS: The study included 61 consecutive PanNETs and 5 pancreatic neuroendocrine carcinomas. Ki-67 IHC slides from cell blocks were digitally scanned into whole slide images using Philips IntelliSite Scanners and analyzed in batches using the Visiopharm Ki-67 App in a digital workflow. Ki-67 scores obtained through DIA were compared to pathologists' manual scores. RESULTS: The Pearson correlation coefficient of the percentage of Ki-67-stained nuclei between DIA reads and the originally reported reads was 0.9681. Concordance between DIA Ki-67 grades and pathologists' Ki-67 grades was observed in 92.4% (61/66) of cases with the calculated Cohen's Kappa coefficient of 0.862 (almost perfect agreement). Discordance between DIA and pathologists' consensus reads occurred in 5 PanNET cases which were upgraded from G1 to G2 by DIA due to contaminated Ki-67-stained inflammatory cells. CONCLUSIONS: DIA demonstrated excellent concordance with pathologists' assessments, with only minor grading discrepancies. However, the essential role of pathologists in confirming results is emphasized to enhance overall accuracy.

SOX17 is a highly sensitive and specific marker for metastatic ovarian and endometrial carcinomas in cytology cell block specimens.

BACKGROUND: SOX17 (SRY-box transcription factor 17) was recently identified as a highly sensitive and specific marker for ovarian and endometrial carcinomas in surgical specimens. In this study, validation of the utility of SOX17 immunohistochemistry (IHC) in diagnosing metastatic gynecologic carcinomas in cytology specimens was sought. METHODS: The study cohort included 84 cases of metastatic carcinomas that included 29 metastatic gynecologic carcinomas (24 ovarian high-grade serous carcinomas, two endometrial serous carcinomas, one low-grade serous carcinoma, one ovarian clear cell carcinoma, and one endometrial endometrioid carcinoma) and 55 cases of metastatic nongynecologic carcinomas (10 clear cell renal cell carcinomas, 10 papillary thyroid carcinomas, 11 gastrointestinal adenocarcinomas, 10 breast carcinomas, 10 lung adenocarcinomas, and four urothelial carcinomas). Cytology specimen types included peritoneal fluid (n = 44), pleural fluid (n = 25), and fine-needle aspiration (n = 15). SOX17 IHC was performed on the cell block sections. The intensity of staining and percent positivity of the tumor cells were evaluated. RESULTS: SOX17 was highly expressed in all tested metastatic gynecologic carcinomas with diffuse and strong nuclear expression (29 of 29; 100%). SOX17 was negative in other metastatic nongynecologic carcinomas (54 of 55; 98.18%) except for one papillary thyroid carcinoma that showed low positivity (<10%). CONCLUSIONS: SOX17 is a highly sensitive (100%) and specific (98.2%) marker for the differential diagnosis of metastatic gynecologic carcinomas in cytology specimens. Therefore, SOX17 IHC should be included in the workup of differential diagnosis of metastatic gynecologic carcinomas in cytology specimens.

Dichotomy effects of Akt signaling in breast cancer.

BACKGROUND: The oncogenic roles contributed by the Akt/PKB kinase family remain controversial and presumably depend on cell context, but are perceived to be modulated by an interplay and net balance between various isoforms. This study is intended to decipher whether distinct Akt kinase isoforms exert either redundant or unique functions in regulating neoplastic features of breast cancer cells, including epithelial-mesenchymal transition (EMT), cell motility, and stem/progenitor cell expansion. RESULTS: We demonstrate that overactivation of Akt signaling in nonmalignant MCF10A cells and in primary cultures of normal human mammary epithelial tissue results in previously unreported inhibitory effects on EMT, cell motility and stem/progenitor cell expansion. Importantly, this effect is largely redundant and independent of Akt isoform types. However, using a series of isogenic cell lines derived from MCF-10A cells but exhibiting varying stages of progressive tumorigenesis, we observe that this inhibition of neoplastic behavior can be reversed in epithelial cells that have advanced to a highly malignant state. In contrast to the tumor suppressive properties of Akt, activated Akt signaling in MCF10A cells can rescue cell viability upon treatment with cytotoxic agents. This feature is regarded as tumor-promoting. CONCLUSION: We demonstrate that Akt signaling conveys novel dichotomy effects in which its oncogenic properties contributes mainly to sustaining cell viability, as opposed to the its tumor suppressing effects, which are mediated by repressing EMT, cell motility, and stem/progenitor cell expansion. While the former exerts a tumor-enhancing effect, the latter merely acts as a safeguard by restraining epithelial cells at the primary sites until metastatic spread can be moved forward, a process that is presumably dictated by the permissive tumor microenvironment or additional oncogenic insults.

NOR-1 (NR4A3) immunostaining on cytologic preparations for the preoperative diagnosis of acinic cell carcinoma of the salivary gland.

INTRODUCTION: Acinic cell carcinoma of the salivary gland (ACC-SG) is characterized by recurrent rearrangements in the nuclear receptor subfamily 4 group A member 3 (NR4A3). Immunostaining using an antibody targeting this rearrangement, neuron-derived orphan receptor 1 (NOR-1), has been recently studied on surgical specimens and cell block material of fine-needle aspirates for the diagnosis of ACC-SG. Our goal was to evaluate whether NOR-1 immunostaining could reliably be performed on destained cytologic preparations. MATERIALS AND METHODS: This was a retrospective multi-institutional study. Immunostaining with the NOR-1 antibody (sc-393902 [H-7], Santa Cruz Biotechnology Inc.) was performed at a titer of 1:30 on destained cytologic preparations. ACC-SG cases (n = 17) were represented by twelve cases with alcohol-fixed preparations (n = 12), including direct smears and SurePath preparations, as well as 5 cases with air-dried preparations (n = 5). These were compared to 27 mimicker lesions (n = 27): normal acini (4), chronic sialadenitis (3), oncocytoma (2), pleomorphic adenoma (6), Warthin tumor (8), mucoepidermoid carcinoma (1), secretory carcinoma (2), and salivary duct carcinoma (1). RESULTS: The positivity of NOR-1 in ACC-SG cases was 100% on destained alcohol-fixed preparations (12/12) and 60% on air-dried preparations (3/5). All 27 mimicker lesions were negative for NOR-1 (0/27). Evaluation of 2 ACC-SG cases with both types of cytologic preparations showed that NOR-1 was positive on the alcohol-fixed slides but negative on the air-dried slides. CONCLUSIONS: NOR-1 immunostaining can reliably be performed on alcohol-fixed direct smears and liquid-based preparations for the diagnosis of ACC-SG. Air-dried preparations show a lower positivity rate and may be less suitable for diagnostic immunostaining.

Performance of specific morphologic features in distinguishing low-grade squamous intraepithelial lesions from high-grade squamous intraepithelial lesions in borderline cases: a College of American Pathologists Cytopathology Committee multiobserver study.

INTRODUCTION: Distinguishing between low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL) can be difficult on certain Papanicolaou (Pap) tests, hindering interobserver concordance. We investigated the variables influencing the interpretation of LSIL versus HSIL in Pap test slides rejected from the College of American Pathologists PAP education program. MATERIALS AND METHODS: Eleven cytologists, who were unaware of the reference interpretation, examined 21 Pap slides (11 submitted as LSIL and 10 as HSIL) rejected from the PAP education program and recorded the number of LSIL cells, HSIL cells, keratinized dysplastic cells, LSIL clusters with mixed HSIL cells, atypical squamous metaplasia, atypical glandular cells, the presence of inflammation or infectious organisms, and the overall interpretation (LSIL or HSIL). We evaluated the significance of these 11 variables using a nonlinear mixed model analysis. RESULTS: LSIL had greater concordance (92 of 121 responses; 76.0% concordance) than HSIL (68 of 110 responses; 61.8% concordance; P < 0.001). The only predictors of misclassified cases were the number of atypical squamous metaplastic cells and the number of HSIL cells (P < 0.001). The more of these cells identified, the more likely the reviewers were to classify the slide as HSIL. The reproducibility of the diagnosis was fair (Gwet's agreement coefficient, 0.33). CONCLUSIONS: Interobserver reproducibility is a challenge for a subset of cases with features intermediate between LSIL and HSIL. Atypical squamous metaplasia and dysplastic nuclei with a nuclear/cytoplasmic ratio greater than one half of the cell volume (HSIL) present on a Pap test influenced the likelihood that a reviewer would interpret the case as HSIL rather than LSIL.

An unusual Aspergillus, herpes and strongyloides triple infection in a patient with chronic pulmonary disease: A case report with literature review.

We report a case of a 75 year old non-known cancer or organ transplant male with an unusual concurrent triple infection of Aspergillus, strongyloides stercoralis and herpes simplex virus in a bronchoalveolar lavage. He presented to an outside hospital with worsening respiratory distress and an open tracheostomy was performed due to concern he would not extubate. Following tracheostomy, there was concern for a possible esophageal perforation. A bronchoalveolar lavage (BAL) were performed and Strongyloides, herpes viral cytopathic changes and aspergillus microorganisms were identified. The patient subsequently expired following discharge.

The reporting rates of high-grade squamous intraepithelial lesions and their human papillomavirus testing and histologic follow-up results: A comparison between ThinPrep and SurePath preparations.

BACKGROUND: Liquid-based cytology (LBC) tests SurePath (SP) and ThinPrep (TP) have largely replaced conventional Papanicolaou (Pap) tests for cervical cytology screening due to higher sensitivity. However, comparison between SP and TP test sensitivity and efficacy in detecting squamous abnormalities is lacking. Our study aims to compare high-grade squamous intraepithelial lesion (HSIL) reporting rates, human papillomavirus (HPV) positivity rates, and histologic outcome between these two LBC methods. MATERIALS AND METHODS: We performed a retrospective search of the period between January 2014 and June 2017, when both TP and SP were utilized at our institution, to identify HSIL cases and collect the HPV testing and histologic follow-up results for those cases. RESULTS: One hundred twenty-five HSILs were identified from the 15 382 TP specimens (0.81%) and 93 HSILs were identified from the 25 105 SP specimens (0.37%), a statistically significant difference (P < .0001). The corresponding HPV positivity rates were 95.6% and 89.7% in TP-HSILs and SP-HSILs, respectively, a statistically non-significant difference. Histologic follow-up showed HSILs or carcinomas were identified in 78% (49/63) of TP-HSILs and 79% (45/57) of SP-HSILs, with no statistically significant difference. CONCLUSION: TP demonstrated a higher HSIL detection rate than SP with no significant difference in follow-up HPV or histologic results.

Using Endoscopic Optical Coherence Tomography to Detect and Treat Early-Stage Pancreatic Cancers.

We developed a novel technology capable of detecting early-stage pancreatic cancers using high-resolution three-dimensional endoscopic optical coherence tomography (Endo-OCT), and treating them using high dose rate brachytherapy (HDR) under the Endo-OCT image guidance. This technology integrates our custom-built ultra-high resolution endoscopic three-dimensional OCT diagnostic imaging device with a commercial high dose rate brachytherapy system (HDR), resulting in a compact, portable, easy-to-operate, and low-cost Endo-OCT image-guided high dose rate brachytherapy (OCT-IGHDR) system. The system has the dual functions of diagnosis and treatment that can precisely detect and measure the location and size of the early-stage pancreatic cancer or premalignant lesions and then treat them from the inside of the pancreatic duct with an accurate and focused dose while greatly reducing the radiation toxicity to the neighboring tissues and organs. This minimally-invasive treatment technology could avoid the potential complications from surgery and reduces the high operation cost. This technology could also be applied to treat diseases of the esophagus, rectum, bronchus, and other aerodigestive organs that are suitable for use with an endoscopic device. In this article, we describe the concept of this technology and the preliminary experiments that could demonstrate the concept by using this homemade Endo-OCT machine to image the pancreatic duct for diagnosis of early-stage pancreatic cancer or premalignant lesions and to perform Endo-OCT image-guided brachytherapy.

Pembrolizumab in a Patient with Treatment-Naïve Unresectable BRAF-Mutation Negative Anaplastic Thyroid Cancer.

Immune check point inhibitor (ICI) therapy can be a potentially effective salvage treatment for anaplastic thyroid cancer (ATC) with progression despite standard of care therapies. We report a case of unresectable treatment-naïve ATC showing a dramatic and durable response to first-line pembrolizumab therapy. A 69-year-old male presented with a large, right-sided neck mass associated with compressive symptoms. A neck ultrasound showed a large, right-sided, and highly suspicious thyroid nodule. A fine needle aspiration (FNA) biopsy revealed tumor cells consistent with ATC that were positive for PD-L1, with an expression score of >95% and negative for the BRAF V600E mutation. Imaging studies were negative for distant metastases. The disease was declared surgically inoperable, and the patient declined chemotherapy/radiation therapy (XRT), but agreed to ICI therapy with intravenous pembrolizumab 200 mg every three weeks. The patient has received 25 doses of pembrolizumab to date, with rapid resolution of symptoms and a significant reduction in tumor size. He remains alive without disease progression 18 months since initial diagnosis.