Collaborative workflow between pathologists and deep learning for evaluation of tumor cellularity in lung adenocarcinoma

Owing to the high demand for molecular testing, the reporting of tumor cellularity in cancer samples has become a mandatory task for pathologists. However, the pathological estimation of tumor cellularity is often inaccurate. We developed a collaborative workflow between pathologists and artificial intelligence (AI) models to evaluate tumor cellularity in lung cancer samples and prospectively applied it to routine practice. We also developed a quantitative model that we validated and tested on retrospectively analyzed cases and ran the model prospectively in a collaborative workflow where pathologists could access the AI results and apply adjustments (Adjusted-Score). The Adjusted-Scores were validated by comparing them with the ground truth established by manual annotation of hematoxylin-eosin slides with reference to immunostains with thyroid transcription factor-1 and napsin A. For training, validation, retrospective testing, and prospective application of the model, we used 40, 10, 50, and 151 whole slide images, respectively. The sensitivity and specificity of tumor segmentation were 97% and 87%, and the accuracy of nuclei recognition was 99%. Pathologists altered the initial scores in 87% of the cases after referring to the AI results and found that the scores became more precise after collaborating with AI. For validation of Adjusted-Score, we found the Adjusted-Score was significantly closer to the ground truth than non-AI-aided estimates (p<0.05). Thus, an AI-based model was successfully implemented into the routine practice of pathological investigations. The proposed model for tumor cell counting efficiently supported the pathologists to improve the prediction of tumor cellularity for genetic tests.

NKX2-1 re-expression induces cell death through apoptosis and necrosis in dedifferentiated thyroid carcinoma cells

NK2 homeobox 1 (NKX2-1) is a thyroid transcription factor essential for proper thyroid formation and maintaining its physiological function. In thyroid cancer, NKX2-1 expression decreases in parallel with declined differentiation. However, the molecular pathways and mechanisms connecting NKX2-1 to thyroid cancer phenotypes are largely unknown. This study aimed to examine the effects of NKX2-1 re-expression on dedifferentiated thyroid cancer cell death and explore the underlying mechanisms. A human papillary thyroid carcinoma cell line lacking NKX2-1 expression was infected with an adenoviral vector containing Nkx2-1. Cell viability decreased after Nkx2-1 transduction and apoptosis and necrosis were detected. Arginase 2 (ARG2), regulator of G protein signaling 4 (RGS4), and RGS5 mRNA expression was greatly increased in Nkx2-1-transducted cells. After suppressing these genes by siRNA, cell death, apoptosis, and necrosis decreased in RGS4 knockdown cells. These findings demonstrated that cell death was induced via apoptosis and necrosis by NKX2-1 re-expression and involves RGS4.

Growth hormone deficiency in a child with benign hereditary chorea caused by a de novo mutation of the TITF1/NKX2-1 gene

Objectives Benign Hereditary Chorea (BHC) (MIM 118700) is a rare childhood-onset movements disorder characterized by non-progressive chorea. It is usually caused by variants in the thyroid transcription factor 1 (TITF-1/NKX2-1) gene and it is associated with thyroid dysfunction and pulmonary symptoms in the brain–lung–thyroid syndrome. Case presentation We reported the clinical case of a toddler presenting with neurological symptoms (hypotonia, delayed motor milestones, and axial dystonia) and subclinical hypothyroidism in which we found a ‘de novo’ variant in the NKX2-1 gene. Conclusions The peculiarity of our case is that the mild alteration of thyroid-stimulating hormone (TSH) levels, hypotonia, and delayed motor milestones were associated with growth hormone deficiency.

Thyroid Transcription Factor-1: Structure, Expression, Function and Its Relationship with Disease

Thyroid transcription factor-1 (TTF-1/NKx2.1) is a member of the NKx2 tissue-specific transcription factor family, which is expressed in thyroid follicle, parathyroid gland, alveolar epithelium, and diencephalon which originated from ectoderm, and participates in the differentiation, development, and functional maintenance of the above organs. Recent studies have shown that the abnormal expression of TTF-1 is closely related to the occurrence of a variety of human diseases and can be used as a potential new target for the diagnosis and treatment of related diseases. In this article, in order to strengthen the systematic understanding of TTF-1 and promote the progress of related research, we reviewed the structure, expression regulation, biological functions of TTF-1, and its role in the occurrence and development of human-related clinical diseases. Meanwhile, we prospect the future research direction of TTF-1, which might ultimately contribute to the understanding of the pathogenesis of related clinical diseases and the development of new prevention and treatment strategies.

Cancer of unknown primary in a mare: case report and comparative pathology review

A 25-y-old Percheron mare was admitted to the teaching hospital because of lethargy and intractable dyspnea. Thoracoabdominal ultrasound examination identified severe peritoneal effusion, mild bilateral pleural effusion, and a diffuse pulmonary nodular pattern. Cytology of peritoneal fluid revealed a hypercellular sample with clusters of neoplastic polygonal cells and admixed macrophages. Euthanasia was followed by postmortem examination; marked bi-cavitary effusion was present, and innumerable up to 4-cm diameter, round-to-floriform nodules were diffusely evident throughout serosal surfaces as well as the pulmonary and hepatic parenchyma. Disseminated adenocarcinoma, predominantly affecting lung and liver with widespread serosal implantation, was confirmed on light microscopy. Neoplastic cells had strong immunolabeling for pancytokeratin and lacked immunoreactivity to vimentin, napsin A, and Pax8. Cytokeratin 7 and thyroid transcription factor-1 were non-contributory given absent and inconsistent internal control reactivity, respectively. Such results, combined with the lack of a major mass that would indicate a primary site, were supportive of carcinoma of unknown primary site, which remains a conundrum in human oncology, and is poorly explored in veterinary medicine, mainly as a result of clinical and diagnostic limitations.

Colon Cancer With Metastatic Involvement of the Thyroid Incidentally Found at Excision of Parathyroid Adenoma

Metastatic disease from primary colon cancer in the thyroid is rare. The authors have submitted such a case. What makes this case particularly unusual is that it was in a man. 80% of such cases are in women. It has been speculated that there may be a humoral component. What is even more unique in this case is that it was found during the workup of a symptomatic parathyroid adenoma. The diagnosis was confirmed with immunochemistry using markers Cytokeratin 20 (CK20), Cytokeratin 7 (CK7), and Thyroid Transcription Factor 1 (TTF-1) .