The diverse malignant, stromal, and immune cells in tumors affect growth, metastasis, and response to therapy. We profiled transcriptomes of ∼6,000 single cells from 18 head and neck squamous cell ...carcinoma (HNSCC) patients, including five matched pairs of primary tumors and lymph node metastases. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined HNSCC subtypes by their malignant and stromal composition and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.
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•Single-cell RNA-seq reveals diverse malignant, stromal, and immune cells•Malignant cells vary in cell cycle, hypoxia, and epithelial expression programs•A partial EMT program (p-EMT) at leading edge is regulated by the microenvironment•Computational modeling refines TCGA subtypes, linking p-EMT to metastasis
Single-cell transcriptomic analysis in patients with head and neck squamous cell carcinoma highlights the heterogeneous composition of malignant and non-malignant cells in the tumor microenvironment and associates a partial EMT program with metastasis.
Primary thyroid neoplasms with actionable NTRK rearrangements are rare, and their clinical behavior, histologic characteristics, and molecular landscape are not well understood. We report an ...institutional series of eleven NTRK-rearranged thyroid carcinomas (NRTC) by performing clinicopathologic review and next-generation sequencing for targeted mutations and gene rearrangements. The NRTC encompass a histomorphologic spectrum of ten papillary thyroid carcinomas (PTC), including one with high-grade features, and one secretory carcinoma (SC), in ten adults and one adolescent. All NRTC were characterized by an unusual multinodular growth pattern, extensive lymphovascular invasion, and cervical lymph node metastases at initial presentation. Immunophenotypically, while most cases were positive for TTF1 and PAX8, the SC case was negative/weak for these markers and instead diffusely expressed GATA3, mammaglobin and S100. Observed gene rearrangements included ETV6-NTRK3 (n = 4, including the SC), TPR-NTRK1 (n = 2), RBPMS-NTRK3 (n = 2), SQSTM1-NTRK1 (n = 1), SQSTM1-NTRK3 (n = 1), and EML4-NTRK3 (n = 1). Mutation profiling revealed a concurrent TERT promotor mutation C228T in two (22%) patients and a novel frameshift MEN1 deletion in one. All patients received total thyroidectomy and radioactive iodine. Despite frequent development of persistent/recurrent disease (9 cases, 82%) and distant metastases (6 cases; 55%), no tumor-related death occurred over a median (range) follow-up of 44 (11 to 471) months. Three patients received NTRK inhibitor therapy, with the SC case showing complete resolution and two other patients experiencing 33% and 69.7% decrease of disease burden. Although the range of features is variable, NRTC appear to be clinically aggressive tumors with high metastatic rate but relatively low mortality with NTRK inhibitor therapy. The histologic findings of multinodular growth and extensive lymphovascular spread, seen in all NRTC, including PTC and SC, may serve as useful histomorphologic clues to prompt NTRK status testing. We also present the first report of concurrent TERT promotor activating mutation which did not appear to confer entrectinib resistance to NRTC.
Context Human papillomavirus (HPV) is a major cause of oropharyngeal squamous cell carcinomas, and HPV (and/or surrogate marker p16) status has emerged as a prognostic marker that significantly ...impacts clinical management. There is no current consensus on when to test oropharyngeal squamous cell carcinomas for HPV/p16 or on which tests to choose. Objective To develop evidence-based recommendations for the testing, application, interpretation, and reporting of HPV and surrogate marker tests in head and neck carcinomas. Design The College of American Pathologists convened a panel of experts in head and neck and molecular pathology, as well as surgical, medical, and radiation oncology, to develop recommendations. A systematic review of the literature was conducted to address 6 key questions. Final recommendations were derived from strength of evidence, open comment period feedback, and expert panel consensus. Results The major recommendations include (1) testing newly diagnosed oropharyngeal squamous cell carcinoma patients for high-risk HPV, either from the primary tumor or from cervical nodal metastases, using p16 immunohistochemistry with a 70% nuclear and cytoplasmic staining cutoff, and (2) not routinely testing nonsquamous oropharyngeal carcinomas or nonoropharyngeal carcinomas for HPV. Pathologists are to report tumors as HPV positive or p16 positive. Guidelines are provided for testing cytologic samples and handling of locoregional and distant recurrence specimens. Conclusions Based on the systematic review and on expert panel consensus, high-risk HPV testing is recommended for all new oropharyngeal squamous cell carcinoma patients, but not routinely recommended for other head and neck carcinomas.
Genetically engineered T cell therapy can induce remarkable tumor responses in hematologic malignancies. However, it is not known if this type of therapy can be applied effectively to epithelial ...cancers, which account for 80-90% of human malignancies. We have conducted a first-in-human, phase 1 clinical trial of T cells engineered with a T cell receptor targeting HPV-16 E7 for the treatment of metastatic human papilloma virus-associated epithelial cancers (NCT02858310). The primary endpoint was maximum tolerated dose. Cell dose was not limited by toxicity with a maximum dose of 1 × 10
engineered T cells administered. Tumor responses following treatment were evaluated using RECIST (Response Evaluation Criteria in Solid Tumors) guidelines. Robust tumor regression was observed with objective clinical responses in 6 of 12 patients, including 4 of 8 patients with anti-PD-1 refractory disease. Responses included extensive regression of bulky tumors and complete regression of most tumors in some patients. Genomic studies, which included intra-patient tumors with dichotomous treatment responses, revealed resistance mechanisms from defects in critical components of the antigen presentation and interferon response pathways. These findings demonstrate that engineered T cells can mediate regression of common carcinomas, and they reveal immune editing as a constraint on the curative potential of cellular therapy and possibly other immunotherapies in advanced epithelial cancer.
We aimed to investigate the validity of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) through meta-analysis.
All publications between January 1, 2008 and September 1, 2011 that ...studied TBSRTC and had available histological follow-up data were retrieved. To calculate the sensitivity, specificity and diagnostic accuracy, the cases diagnosed as follicular neoplasm, suspicious for malignancy and malignant which were histopathologically confirmed as malignant were defined as true-positive. True-negative included benign cases confirmed as benign on histopathology. The nondiagnostic category was excluded from the statistical calculation. The correlations between the 6 diagnostic categories were investigated.
The publications review resulted in a case cohort of 25,445 thyroid fine-needle aspirations, 6,362 (25%) of which underwent surgical excision; this group constituted the basis of the study. The sensitivity, specificity and diagnostic accuracy were 97, 50.7 and 68.8%, respectively. The positive predictive value and negative predictive value were 55.9 and 96.3%, respectively. The rates of false negatives and false positives were low: 3 and 0.5%, respectively.
The results of meta-analysis showed high overall accuracy, indicating that TBSRTC represents a reliable and valid reporting system for thyroid cytology.
The discovery of actionable kinase gene rearrangements has revolutionized the therapeutic landscape of thyroid carcinomas. Unsolved challenges include histopathologic recognition of targetable cases, ...correlation between genotypes and tumor behavior, and evolving resistance mechanisms against kinase inhibitors (KI). We present 62 kinase fusion-positive thyroid carcinomas (KFTC), including 57 papillary thyroid carcinomas (PTC), two poorly differentiated thyroid carcinomas (PDTC), two undifferentiated thyroid carcinomas (ATC), and one primary secretory carcinoma (SC), in 57 adults and 5 adolescents. Clinical records, post-operative histology, and molecular profiles were reviewed. Histologically, all KFTC showed multinodular growth with prominent intratumoral fibrosis. Lymphovascular invasion (95%), extrathyroidal extension, gross and microscopic (63%), and cervical lymph node metastasis (79%) were common. Several kinase fusions were identified: STRN-ALK, EML4-ALK, AGK-BRAF, CUL1-BRAF, MKRN1-BRAF, SND1-BRAF, TTYH3-BRAF, EML4-MET, TFG-MET, IRF2BP2-NTRK1, PPL-NTRK1, SQSTM1-NTRK1, TPR-NTRK1, TPM3-NTRK1, EML4-NTRK3, ETV6-NTRK3, RBPMS-NTRK3, SQSTM1-NTRK3, CCDC6-RET, ERC1-RET, NCOA4-RET, RASAL2-RET, TRIM24-RET, TRIM27-RET, and CCDC30-ROS1. Individual cases also showed copy number variants of EGFR and nucleotide variants and indels in pTERT, TP53, PIK3R1, AKT2, TSC2, FBXW7, JAK2, MEN1, VHL, IDH1, PTCH1, GNA11, GNAQ, SMARCA4, and CDH1. In addition to thyroidectomy and radioactive iodine, ten patients received multi-kinase and/or selective kinase inhibitor therapy, with 6 durable, objective responses and four with progressive disease. Among 47 cases with >6 months of follow-up (median range: 41 6–480 months), persistent/recurrent disease, distant metastasis and thyroid cancer-related death occurred in 57%, 38% and 6%, respectively. In summary, KFTC encompass a spectrum of molecularly diverse tumors with overlapping clinicopathologic features and a tendency for clinical aggressiveness. Characteristic histology with multinodular growth and prominent fibrosis, particularly when there is extensive lymphovascular spread, should trigger molecular testing for gene rearrangements, either in a step-wise manner by prevalence or using a combined panel. Further, our findings provide information on molecular therapy in radioiodine-refractory thyroid carcinomas.
The 2021 American Society of Clinical Oncology (ASCO) guideline for the management of salivary gland cancer offers 47 evidence‐based recommendations on preoperative evaluations, diagnostic and ...therapeutic surgical procedures, radiotherapy, systemic therapy, follow‐up evaluations, and recurrent metastatic disease. The ASCO guideline provides a framework and the best current evidence for managing the care of patients with salivary gland malignancies from diagnosis to treatment, and it endorses fine‐needle aspiration biopsy and the new Milan System for Reporting Salivary Gland Cytopathology.
The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) represents a standardized, evidence‐based reporting system for salivary gland fine‐needle aspiration (FNA). The role of FNA is ...well established for the preoperative evaluation of patients with salivary gland lesions; however, the lack of a uniform system for salivary gland FNA has limited its effectiveness. To address this, an international panel of experienced cytopathologists proposed a uniform reporting system in 2015 under the sponsorship of the American Society of Cytopathology and the International Academy of Cytology. The MSRSGC consists of 6 diagnostic tiers: 1) nondiagnostic, 2) non‐neoplastic, 3) atypia of undetermined significance, 4) neoplasm (subdivided into benign and salivary gland neoplasm of uncertain malignant potential), 5) suspicious for malignancy, and 6) malignant. On the basis of evidence from the literature, each category has a suggested risk of malignancy that ranges from 5% for the neoplasm‐benign category to >90% for the malignant category. The overall goal of the MSRSGC is to improve the effectiveness of salivary FNA by providing a uniform system with the ultimate result of better communication and improved patient care.
The role of FNA is well established for the pre‐operative evaluation of patients with salivary gland lesions; however, the lack of a uniform system for salivary gland FNA (SG FNA) has limited its effectiveness. To address this, an international panel of experienced cytopathologists in 2015 proposed a uniform reporting system under the sponsorship of the American Society of Cytopathology (ASC) and the International Academy of Cytology (IAC): the Milan system for reporting salivary gland cytopathology.
Salivary duct carcinoma (SDC) is an aggressive subtype of primary salivary gland carcinoma, often with an advanced stage at presentation and high rates of metastasis and recurrence. It most commonly ...arises in the parotid gland of older men and microscopically resembles high‐grade breast ductal carcinoma. While 50 years have lapsed since the first report of this entity, recent intensive studies have shed light on its biologic, genetic, and clinical characteristics. The diagnosis of SDC is aided by the immunohistochemical expression of androgen receptor (AR) coupled with its characteristic histomorphology. Fine‐needle aspiration typically reveals cytologic features of high‐grade carcinoma, and ancillary studies using cell block material can facilitate the specific diagnosis of SDC. In surgical specimens, certain histologic features are important prognostic factors, including nuclear pleomorphism, mitotic counts, vascular invasion, and the morphology at the invasion front. Several clinical studies have shown promising results using targeted therapy for AR and human epidermal growth factor receptor 2 (HER2), and the latest version of the National Comprehensive Cancer Network guidelines recommends the evaluation of AR and HER2 status before treatment. Recent molecular analyses have revealed multiple heterogeneous alterations in well‐known oncogenes and tumor suppressor genes, including TP53, HRAS, PIK3CA, PTEN, and BRAF. Clinical trials of drugs targeting these genes may broaden the treatment options for SDC in the near future.
Salivary duct carcinoma is the most aggressive subtype of primary salivary gland carcinoma. Recent studies have clarified the biology and clinicopathological features of this entity, in turn leading to the introduction of new therapies.
Summary
Background
The early detection of medullary thyroid carcinoma (MTC) can improve patient prognosis, because histological stage and patient age at diagnosis are highly relevant prognostic ...factors. As a consequence, delay in the diagnosis and/or incomplete surgical treatment should correlate with a poorer prognosis for patients. Few papers have evaluated the specific capability of fine‐needle aspiration cytology (FNAC) to detect MTC, and small series have been reported. This study conducts a meta‐analysis of published data on the diagnostic performance of FNAC in MTC to provide more robust estimates.
Research Design and Methods
A comprehensive computer literature search of the PubMed/MEDLINE, Embase and Scopus databases was conducted by searching for the terms ‘medullary thyroid’ AND ‘cytology’, ‘FNA’, ‘FNAB’, ‘FNAC’, ‘fine needle’ or ‘fine‐needle’. The search was updated until 21 March 2014, and no language restrictions were used.
Results
Fifteen relevant studies and 641 MTC lesions that had undergone FNAC were included. The detection rate (DR) of FNAC in patients with MTC (diagnosed as ‘MTC’ or ‘suspicious for MTC’) on a per lesion‐based analysis ranged from 12·5% to 88·2%, with a pooled estimate of 56·4% (95% CI: 52·6–60·1%). The included studies were statistically heterogeneous in their estimates of DR (I‐square >50%). Egger's regression intercept for DR pooling was 0·03 (95% CI: −3·1 to 3·2, P = 0·9). The study that reported the largest MTC series had a DR of 45%. Data on immunohistochemistry for calcitonin in diagnosing MTC were inconsistent for the meta‐analysis.
Conclusions
The presented meta‐analysis demonstrates that FNAC is able to detect approximately one‐half of MTC lesions. These findings suggest that other techniques may be needed in combination with FNAC to diagnose MTC and avoid false negative results.
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