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Tumours often contain B cells and plasma cells but the antigen specificity of these intratumoral B cells is not well understood1-8. Here we show that human papillomavirus (HPV)-specific B cell responses are detectable in samples from patients with HPV-positive head and neck cancers, with active production of HPV-specific IgG antibodies in situ. HPV-specific antibody secreting cells (ASCs) were present in the tumour microenvironment, with minimal bystander recruitment of influenza-specific cells, suggesting a localized and antigen-specific ASC response. HPV-specific ASC responses correlated with titres of plasma IgG and were directed against the HPV proteins E2, E6 and E7, with the most dominant response against E2. Using intratumoral B cells and plasma cells, we generated several HPV-specific human monoclonal antibodies, which exhibited a high degree of somatic hypermutation, consistent with chronic antigen exposure. Single-cell RNA sequencing analyses detected activated B cells, germinal centre B cells and ASCs within the tumour microenvironment. Compared with the tumour parenchyma, B cells and ASCs were preferentially localized in the tumour stroma, with well-formed clusters of activated B cells indicating ongoing germinal centre reactions. Overall, we show that antigen-specific activated and germinal centre B cells as well as plasma cells can be found in the tumour microenvironment. Our findings provide a better understanding of humoral immune responses in human cancer and suggest that tumour-infiltrating B cells could be harnessed for the development of therapeutic agents.
Assuntos
Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/virologia , Linfócitos do Interstício Tumoral/imunologia , Papillomaviridae/imunologia , Microambiente Tumoral/imunologia , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/genética , Linfócitos B/metabolismo , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/virologia , Separação Celular , Centro Germinativo/citologia , Centro Germinativo/imunologia , Neoplasias de Cabeça e Pescoço/sangue , Humanos , Imunidade Humoral , Imunoglobulina G/sangue , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Infecções por Papillomavirus/sangue , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Plasmócitos/imunologia , Plasmócitos/metabolismo , RNA-Seq , Análise de Célula Única , Hipermutação Somática de Imunoglobulina/genética , Hipermutação Somática de Imunoglobulina/imunologia , TranscriptomaRESUMO
T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer1,2. Here we studied CD8 T cells in patients with human papillomavirus (HPV)-positive head and neck cancer and identified several epitopes derived from HPV E2, E5 and E6 proteins that allowed us to analyse virus-specific CD8 T cells using major histocompatibility complex (MHC) class I tetramers. HPV-specific CD8 T cells expressed PD-1 and were detectable in the tumour at levels that ranged from 0.1% to 10% of tumour-infiltrating CD8 T lymphocytes (TILs) for a given epitope. Single-cell RNA-sequencing analyses of tetramer-sorted HPV-specific PD-1+ CD8 TILs revealed three transcriptionally distinct subsets. One subset expressed TCF7 and other genes associated with PD-1+ stem-like CD8 T cells that are critical for maintaining T cell responses in conditions of antigen persistence. The second subset expressed more effector molecules, representing a transitory cell population, and the third subset was characterized by a terminally differentiated gene signature. T cell receptor clonotypes were shared between the three subsets and pseudotime analysis suggested a hypothetical differentiation trajectory from stem-like to transitory to terminally differentiated cells. More notably, HPV-specific PD-1+TCF-1+ stem-like TILs proliferated and differentiated into more effector-like cells after in vitro stimulation with the cognate HPV peptide, whereas the more terminally differentiated cells did not proliferate. The presence of functional HPV-specific PD-1+TCF-1+CD45RO+ stem-like CD8 T cells with proliferative capacity shows that the cellular machinery to respond to PD-1 blockade exists in HPV-positive head and neck cancer, supporting the further investigation of PD-1 targeted therapies in this malignancy. Furthermore, HPV therapeutic vaccination efforts have focused on E6 and E7 proteins; our results suggest that E2 and E5 should also be considered for inclusion as vaccine antigens to elicit tumour-reactive CD8 T cell responses of maximal breadth.
Assuntos
Alphapapillomavirus/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/virologia , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Células-Tronco/citologia , Alphapapillomavirus/isolamento & purificação , Linfócitos T CD8-Positivos/classificação , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/imunologia , Diferenciação Celular , Proliferação de Células , Proteínas de Ligação a DNA/imunologia , Humanos , Linfócitos do Interstício Tumoral/classificação , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/metabolismo , Proteínas Oncogênicas Virais/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/imunologia , RNA-Seq , Receptores de Antígenos de Linfócitos T/imunologia , Análise de Célula Única , Células-Tronco/imunologia , Fator 1 de Transcrição de Linfócitos T/metabolismo , Linfócitos T/imunologia , Transcrição GênicaRESUMO
AIMS: The Milan system for reporting salivary gland cytopathology was developed by an international group of experts and first published in 2018 with the goal to standardise reporting of salivary gland aspirates. Seven categories with distinct risks of malignancy were proposed. Core needle biopsies (CNB) of salivary glands are also common, but reporting lacks standardisation. Here we explore the feasibility of a Milan-like reporting system on CNB of the parotid gland. METHODS AND RESULTS: Our laboratory information system was searched for parotid gland CNBs from 2010 to 2021. Reports were translated into a Milan-like reporting system. When available, CNB findings were correlated with cytology and resection specimens. In order to compare the performance of CNB with fine-needle aspirations (FNA), we established a second cohort of cases consisting of parotid FNA with surgical follow-up. The risk of neoplasia (RON) and risk of malignancy (ROM) was calculated for FNA and CNB Milan categories using cases with follow-up resection. We analysed 100 cases of parotid gland CNB. Of these cases, 32 underwent subsequent resection, while 52 had concurrent FNA. A total of 20 cases had concurrent FNA and underwent follow-up resection. In 63 (63%) cases, a specific diagnosis was provided on CNB, with 18 cases undergoing follow-up resection having an accuracy rate of 94%. CONCLUSIONS: This study confirms the feasible of using a Milan-like system in the setting of parotid gland CNB with differentiation in RON and ROM. CNB allows assessment of architectural features that may allow more specific diagnoses in some cases.
Assuntos
Glândula Parótida , Humanos , Biópsia com Agulha de Grande Calibre , Glândula Parótida/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Adulto , Biópsia por Agulha Fina , Neoplasias Parotídeas/patologia , Neoplasias Parotídeas/diagnóstico , Idoso de 80 Anos ou mais , Glândulas Salivares/patologia , Adulto Jovem , Citodiagnóstico/métodos , Adolescente , CitologiaRESUMO
AIMS: The phosphatase and tensin homologue (PTEN) hamartoma tumour syndrome (PHTS) is a genetic disorder with variable clinical presentation and increased lifetime risk of multiorgan malignancies. The thyroid gland is commonly affected with follicular nodular disease (FND) and follicular cell-derived carcinomas. Histopathological and immunohistochemical assessment of thyroid disease in PHTS is essential to identify patients at-risk. METHODS AND RESULTS: In all, 30 PHTS patients with available thyroidectomy specimen material (2000-2023) and 31 control patients with FND and "adenomatous nodules" were retrieved. Histologic criteria, including the frequency of adenomatous-type nodules versus hyperplastic-type nodules, background and nodular lipomatous metaplasia, chronic lymphocytic thyroiditis, cytoplasmic clearing of follicular cells in nodules, nodule-in-nodule appearance, and spectrum of nuclear atypia between nodules were evaluated in both cohorts and a Thyroid Histomorphologic PHTS Score (THiPS) system was established with a cutoff of 4 points or higher being considered concerning for PHTS. In all, 27 PHTS (90%) and five control (16.1%) cases had THiPS ≥4. A PTEN immunohistochemical stain was evaluated in 25 cases of each cohort and showed nuclear and cytoplasmic loss of expression in all or most of the nodules of 24/25 PHTS cases. In 3/25 control cases, two with THiPS ≥4, had loss of expression in one to multiple nodules. Conventional papillary thyroid carcinomas in PHTS patients retained PTEN cytoplasmic expression. CONCLUSIONS: Our study supports that, although not specific, the finding of multiple histologic features is found more frequently in patients with PHTS compared to the non-PHTS control group. The THiPS system has high sensitivity for thyroid specimens from patients with PHTS.
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BACKGROUND AND AIMS: Salivary duct carcinoma (SDC) is an aggressive salivary malignancy with multiple morphological subtypes. Primary salivary squamous cell carcinoma (SCC) requires exclusion of high-grade salivary malignancies and metastatic disease and is considered exceptionally rare. We report six cases of SDC with resemblance to SCC on account of variable, but often extensive, squamous differentiation. METHODS AND RESULTS: A retrospective review (2009-2023) at two institutions of SDC with histological and immunophenotypical evidence of squamous differentiation identified six cases. Medical charts and available glass slides were reviewed. There were five males and one female with a median age of 63 years, with tumours involving the parotid (five of six) and submandibular (one of six) glands. All six tumours showed a conventional SDC component comprising < 5-90% of viable tumour. Squamous differentiation comprised 10-95%+ (> 75% in three of six cases) of total viable tumour, and demonstrated CK5/6, p63 and/or p40 immunoexpression in all cases. A sarcomatoid component, comprising 10-60% of viable tumour, was present in three of six (50%) cases. All tumours were androgen receptor (AR)-positive, but only two of six (33.3%) retained AR immunoreactivity in the squamous component. Metastatic SDC to regional lymph nodes exhibited exclusive squamous differentiation in two of six (33.3%) cases. CONCLUSION: Squamous differentiation, histologically and immunophenotypically, can be extensive in SDC. AR expression may be lost in the squamous component and metastases may demonstrate only squamous differentiation. These findings cast further doubt on the existence of primary salivary SCC. SDC should be considered whenever encountering a carcinoma with squamous differentiation in major salivary glands or within cervical lymph nodes in the setting of a salivary mass.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas , Imunofenotipagem , Neoplasias das Glândulas Salivares , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias das Glândulas Salivares/patologia , Idoso , Carcinoma de Células Escamosas/patologia , Estudos Retrospectivos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal/patologia , Carcinoma Ductal/diagnóstico , Ductos Salivares/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
Salivary duct carcinoma (SDC) is aggressive with limited therapeutic options. A subset of SDC display human epidermal growth factor receptor 2 (HER2) protein overexpression by immunohistochemistry, and some show ERBB2 gene amplification. Guidelines for HER2 scoring are not firmly established. Recent advances in breast carcinoma have established a role for anti-HER2 therapies in lesions with low HER2 expression lacking ERBB2 amplification. Delineating HER2 staining patterns in SDC is critical for evaluating anti-HER2 treatments. In total, 53 cases of SDC resected at our institution between 2004 and 2020 were identified. Androgen receptor (AR) and HER2 immunohistochemistry and ERBB2 fluorescence in situ hybridization were performed in all cases. AR expression was scored for percentage positive cells and categorized as positive (>10% of cells), low positive (1%-10%), or negative (<1%). HER2 staining levels and patterns were recorded, scored using 2018 ASCO/CAP guidelines, and categorized into HER2-positive (3+ or 2+ with ERBB2 amplification), HER2-low (1+ or 2+ without ERBB2 amplification), HER2-very low (faint staining in <10% of cells), or HER2-absent types. Clinical parameters and vital status were recorded. Median age was 70 years, with a male predominance. ERBB2-amplified tumors (11/53; 20.8%) presented at lower pT stages (pTis/pT1/pT2; P = .005, Fisher exact test) and more frequently had perineural invasion (P = .007, Fisher exact test) compared with ERBB2 nonamplified tumors; no other pathologic features differed significantly by gene amplification status. In addition, 2+ HER2 staining by 2018 ASCO/CAP criteria was most common (26/53; 49%); only 4 cases (8%) were HER2-absent status; 3+ HER2 staining was found in 9 tumors, and all were ERBB2 amplified. Six patients with HER2-expressing tumors received trastuzumab therapy, including 2 with ERBB2-amplified tumors. Overall survival and recurrence-free survival did not differ significantly based on ERBB2 status. This work suggests that 2018 ASCO/CAP guidelines for HER2 evaluation in breast carcinoma could be applied to SDC. Our findings also show broad overexpression of HER2 in SDC raising the possibility that more patients may benefit from anti-HER2-directed therapies.
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Sinonasal biopsy specimens are a challenging area in anatomic pathology. The small, often fragmented or crushed nature of these biopsies can hinder morphologic assessment. Additionally, many of the tumors in this area are rare and share morphologic, and sometime immunophenotypic similarities. In many cases, immunohistochemistry is helpful if not necessary to reach a specific diagnosis. In other cases, a specific diagnosis is not possible and a differential diagnosis must be given on a biopsy specimen despite access to a well-equipped immunohistochemistry laboratory. This review article groups some of the more challenging entities in the sinonasal region based on morphologic patterns. These include low grade squamoid lesions such as sinonasal (Schneiderian) papilloma and DEK::AFF2 rearranged carcinoma, glandular neoplasms such as intestinal and non-intestinal type sinonasal adenocarcinoma, high-grade carcinomas such as HPV-related multiphenotypic sinonasal carcinoma, NUT carcinoma and SWI/SNF deficient carcinomas, small round blue cell tumors such as teratocarcinosarcoma, neuroendocrine carcinoma and olfactory neuroblastoma, and finally, low grade spindle cell neoplasms such as glomangiopericytoma, biphenotypic sinonasal sarcoma and solitary fibrous tumor.
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Carcinoma Neuroendócrino , Neoplasias dos Seios Paranasais , Seios Paranasais , Sarcoma , Humanos , Diagnóstico Diferencial , Seios Paranasais/patologia , Neoplasias dos Seios Paranasais/diagnóstico , Neoplasias dos Seios Paranasais/patologia , Biópsia , Biomarcadores TumoraisRESUMO
OBJECTIVES: The aim of the study was to investigate the association of surgical margin conditions, including positive specimen margins revised to negative relative to local recurrence, disease-free survival, and overall survival (OS) within a cohort of HPV-mediated oropharyngeal squamous cell carcinoma (OPSCC) who underwent en bloc resection via transoral robotic surgery (TORS). MATERIALS AND METHODS: Retrospective cohort of patients with untreated HPV-mediated OPSCC cT1 or T2 undergoing TORS resection between October 2014 and March 2020. The methodologic description of our interdisciplinary institutional approach, number of cut-through margins (CTMs) during intraoperative consultation, percentage of final positive margin cases, and disease-free survival and OS stratified by margin status and margin tumor-free distance is identified. RESULTS: 135 patients with primary cT1/T2 HPV-mediated OPSCC met inclusion criteria. Twenty-eight of 135 (20.7%) specimens revealed CTM and were revised during the same operative setting. Three of 135 (2.2%) surgical cases had positive final margin status. Local control rate was 97%. On univariate analysis, margin distance did not impact OS. CTM and final positive margins had lower OS than initially negative margins (p = 0.044). Pathologic N-stage significantly impacted OS (p < 0.001). CONCLUSIONS: High local control rate and low final positive margin status confound the study of specimen margin-based techniques in HPV-mediated OPSCC resected en bloc with TORS. Pathologic N-stage may impact OS more than margin status. Larger numbers are needed to confirm differences.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Procedimentos Cirúrgicos Robóticos , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Margens de Excisão , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologia , Neoplasias Orofaríngeas/cirurgia , Neoplasias Orofaríngeas/patologia , Procedimentos Cirúrgicos Robóticos/métodos , Estudos Retrospectivos , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/cirurgiaRESUMO
BACKGROUND: Radiographic concern for lymphatic extranodal extension (ENE) impacts upfront management decisions for patients with human papilloma virus (HPV) oropharyngeal squamous cell carcinoma (OPSCC). Therefore, we set out to evaluate the accuracy of preoperative contrast-enhanced computed tomography (CECT) to predict major ENE (> 2 mm). METHODS: Twenty-seven consecutive patients with HPV-associated OPSCC who presented at our institutional multidisciplinary tumor board were staged radiographically with positron emission tomography (PET/CT) and CECT, and underwent primary transoral robotic resection and neck dissection. CECT imaging results were correlated with pathologic ENE (pENE). RESULTS: CECT specificity for all pENE was 69 and 75% for radiologist 1 and 2, respectively. For pENE > 2 mm, the sensitivities were 88 and 100%, but specificities were 52.6 and 63.2%. Positive predictive values (PPV) were 43.8 and 53.3%; negative predictive values were 90.9 and 100%. On logistic regression analysis, only size ≥3 cm (OR 4.7-5.4, p < 0.02, 95% CI 1.3-44.0) demonstrated significant correlation with major ENE > 2 mm. CONCLUSIONS: Preoperative imaging for HPV-associated OPSCC had a PPV for pENE > 2 mm of 44-55%, based on any interruption in the capsule or invasion into the perinodal fat. The PPV is low and equipoise in treatment decision making for patients with HPV-associated OPSCC may require other imaging characteristics.
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Carcinoma de Células Escamosas/diagnóstico por imagem , Invasividade Neoplásica/diagnóstico por imagem , Neoplasias Orofaríngeas/diagnóstico por imagem , Infecções por Papillomavirus/complicações , Tomografia Computadorizada por Raios X , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Meios de Contraste , Humanos , Metástase Linfática/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Papillomaviridae , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Cuidados Pré-Operatórios , Prognóstico , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X/métodosRESUMO
Short interfering RNA (siRNA) is a promising molecular tool for cancer therapy, but its clinical success is limited by the lack of robust inâ vivo delivery systems. Rationally designed DNA nanoparticles (DNPs) have emerged as facile delivery vehicles because their physicochemical properties can be precisely controlled. Nonetheless, few studies have used DNPs to deliver siRNAs inâ vivo, and none has demonstrated therapeutic efficacy. Herein, we constructed a number of DNPs of rectangular and tubular shapes with varied dimensions using the modular DNA brick method for the systemic delivery of siRNA that targets anti-apoptotic protein Bcl2. The siRNA delivered by the DNPs inhibited cell growth both inâ vitro and inâ vivo, which suppressed tumor growth in a xenograft model that specifically correlated with Bcl2 depletion. This study suggests that DNPs are effective tools for the systemic delivery of therapeutic siRNA and have great potential for further clinical translation.
Assuntos
Antineoplásicos/administração & dosagem , DNA/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Humanos , Camundongos , Neoplasias/genética , Neoplasias/patologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Tamanho da Partícula , Proteínas Proto-Oncogênicas c-bcl-2/deficiência , RNA Interferente Pequeno/síntese química , RNA Interferente Pequeno/química , Propriedades de Superfície , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIMS: The data on the histological type of carcinomatous component and the extent of extracapsular invasion for salivary carcinomas ex pleomorphic adenoma (PA) are conflicting. We aimed to determine the prognostic value of extracapsular invasion in salivary duct carcinomas (SDC) ex PA. METHODS AND RESULTS: A total of 117 patients with SDC were identified retrospectively; 44 cases involving major salivary glands had pre-existing PA (44 of 117, 37%). The morphological spectrum of SDC ex PA was characterized. The primary endpoint was overall survival (OS). Most SDC ex PA were widely invasive at presentation (27 of 44; 61%). Five patients with intracapsular SDC ex PA experienced no disease progression. The assessment of extracapsular invasion was precluded in eight cases (e.g. positive margins of resection). The rate of lymph node involvement was similar in cases with extracapsular invasion of ≤2 mm (two of three) and >7 mm (22 of 26). Only pT correlated with OS [116 months, 95% confidence interval (CI) 22-210 months for pT1 versus 20 months (95% CI 6-34) for pT4; P = 0.013]. CONCLUSIONS: Intracapsular SDC ex PA are potentially indolent. SDC ex PA with extracapsular invasion of ≤2 mm are rare, and appear to be clinically aggressive. Several histological parameters preclude assessment of extracapsular invasion.
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Adenoma Pleomorfo/patologia , Carcinoma/patologia , Neoplasias das Glândulas Salivares/patologia , Adenoma Pleomorfo/mortalidade , Idoso , Idoso de 80 Anos ou mais , Carcinoma/mortalidade , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ductos Salivares/patologia , Neoplasias das Glândulas Salivares/mortalidadeRESUMO
Palisading adenocarcinoma is a morphologically distinct salivary gland neoplasm that has been recently described with predilection to the sublingual gland. We report our experience with this neoplasm to corroborate and enrich the literature and further clarify its phenotype.
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Adenocarcinoma , Humanos , Adenocarcinoma/patologia , Neoplasias das Glândulas Salivares/patologia , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Biomarcadores Tumorais/análiseRESUMO
BACKGROUND: Molecular triage of indeterminate thyroid aspirates offers the opportunity to stratify the risk of malignancy (ROM) more accurately. Here we examine our experience with ThyroSeq v3 testing. METHODS: We analyzed 276 of 658 (42%) fine needle aspiration samples classified as indeterminate thyroid nodules using ThyroSeq v3 (Sept 2017-Dec 2019). The test provides a ROM and detects specific mutations. Surgical diagnoses were reviewed. RESULTS: Of 276 ThyroSeq-tested cases, 42% (n = 116) harbored genetic alterations, whereas 64% (n = 74) had surgical follow-up. Notably, 79% cases within intermediate to higher risk mutations were highly associated with surgical intervention, resulting in a 77.5% ROM when including both cancer and noninvasive follicular thyroid neoplasia with papillary-like features (cancer+NIFTP) and 68% malignant diagnosis when excluding NIFTP. RAS-like alterations were most common (66%), exhibiting a 73.4% ROM and a 59% malignant diagnosis. Interestingly, this group included 24 encapsulated follicular variant papillary thyroid carcinomas (EFVPTCs), 1 infiltrative FVPTC, 9 follicular carcinomas, and 7 NIFTP. Additionally, three high-risk mutations and eight BRAF/V600E mutations had a 100% ROM, all diagnosed as classic-type papillary thyroid carcinoma (cPTC). Combined analysis of thyroid nodules from Bethesda III and IV categories revealed a 78.2% positive predictive value (PPV) and a 75.9% negative predictive value (NPV). CONCLUSION: ThyroSeq v3 effectively stratifies the ROM in indeterminate thyroid nodules based on specific genetic alterations, guiding appropriate surgical management. Notably, the BRAFV600E/high-risk group and RAS-like groups exhibited ROM of 100% and 77.5%, respectively, with promising predictive accuracy (PPV of 78.2% and NPV of 75.9%).
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Nódulo da Glândula Tireoide , Humanos , Nódulo da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/diagnóstico , Biópsia por Agulha Fina , Mutação , Feminino , Masculino , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico , Pessoa de Meia-Idade , Adulto , IdosoRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0238497.].
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BACKGROUND: Biphenotypic sinonasal sarcoma (BSS) is a low-grade, locally aggressive sarcoma unique to the sinonasal region. BSS is most common in middle aged patients and affects women more frequently than men. It is characterized by a bland spindled cell proliferation with neural and myogenic differentiation. BSS are usually associated with rearrangement t(2;4)(q35;q31.1) resulting in a PAX3::MAML3 fusion. Less commonly, other genes are found in combination with PAX3 and some cases reported in the literature have an unknown fusion partner. METHODS: A 54-year-old man presented with nasal mass. Endoscopic resection showed a low-grade spindle cell neoplasm with morphologic features of BSS and immunohistochemical and next generation sequencing were performed to confirm the diagnosis. RESULTS: The tumor was positive for S100 and smooth muscle actin but negative for SOX10. Next generation sequencing demonstrated a novel PAX3::FOXO6 gene fusion. CONCLUSIONS: Although a PAX3::FOXO6 gene fusion has never been reported, this finding combined with the morphologic and immunophenotypic features supports the diagnosis of supports the diagnosis of BSS.
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Neoplasias dos Seios Paranasais , Sarcoma , Neoplasias de Tecidos Moles , Pessoa de Meia-Idade , Masculino , Humanos , Feminino , Fator de Transcrição PAX3/genética , Imuno-Histoquímica , Fatores de Transcrição/genética , Neoplasias dos Seios Paranasais/patologia , Sarcoma/patologia , Neoplasias de Tecidos Moles/genética , Biomarcadores Tumorais/genética , Fatores de Transcrição ForkheadRESUMO
Anaplastic thyroid carcinoma (ATC) demonstrates a wide variety of morphologies and is characteristically associated with a differentiated thyroid carcinoma component. Heterologous differentiation is a rare, potentially challenging phenomenon in ATC, mostly observed as osteosarcomatous or chondrosarcomatous differentiation. We now describe a novel 'glomangiosarcoma-like' differentiation, review our archival experience from two institutions (UPMC, CC), and perform a systematic review for the prevalence of heterologous elements in ATC. The patient is a 57-year-old female who presented with 4.5 cm left thyroid, and 3.4 cm neck masses. Histologically, the thyroid demonstrated a differentiated high grade papillary thyroid carcinoma, tall cell and hobnail/micropapillary subtypes transitioning into an anaplastic component with spindled to ovoid cells with hemangiopericytoma-like vasculature showing CD34 positivity, variable muscle marker expression and pericellular lace-like type IV collagen deposition. The neck mass consisted solely of the latter morphology. Targeted next-generation sequencing was performed on high grade DTC and adjacent ATC from the thyroid as well as ATC from the neck metastasis. All three components shared BRAFV600E, TERT promoter, and PIK3CA mutations confirming a clonal origin. Archival (UPMC: n = 150, CC: n = 74) and literature review showed no prior examples. Systematic review and meta-analysis of prevalence showed a baseline pooled prevalence (generalized linear mixed model) of heterologous elements of any type to be 1.6% (95% confidence interval: 1.0-2.6%) for studies where this was specifically addressed. ATC with glomangiosarcoma-like heterologous differentiation is a rarity among an already rare morphologic category with unique diagnostic pitfalls.
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Adenocarcinoma , Sarcoma , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Feminino , Humanos , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide , Prevalência , Neoplasias da Glândula Tireoide/patologia , Carcinoma Anaplásico da Tireoide/patologia , Diferenciação Celular , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Ancillary and molecular testing of cytopathology specimens has emerged as a reliable and useful tool to provide diagnostic information and treatment-related biomarker status for the management of cancer patients. The cytology specimens obtained through minimally invasive means have proven suitable testing substrates for a variety of ancillary tests, including immunohistochemistry, fluorescence in situ hybridization, as well as polymerase chain reaction and next generation sequencing molecular techniques. By focusing specifically on the cytology specimen, this review provides an overview of basic testing considerations and assay selection in addition to updates on the ancillary testing of cytologic tumor specimens from the lung, salivary gland, and thyroid.
Assuntos
Glândulas Salivares , Glândula Tireoide , Humanos , Hibridização in Situ Fluorescente , Glândulas Salivares/patologia , Técnicas de Diagnóstico Molecular , PulmãoRESUMO
Depth of invasion (DOI) was added to the staging criteria for carcinoma of the lip and oral cavity in the 8th edition of the American Joint Committee on Cancer Staging Manual (AJCC8). However, there are multiple practical challenges to obtaining an accurate DOI measurement with limited data regarding interobserver variability in DOI measurement. The aim of this study was to investigate interobserver variability in DOI measurement and its effect on tumor stage. We performed an electronic medical record search for excisions of squamous cell carcinoma of the oral cavity between January 1, 2010 and December 25, 2017. All slides containing significant tumor were selected for independent blinded DOI measurement by four head and neck pathologists per AJCC8 guidelines. Pathologic stage was assigned in conjunction with reported tumor greatest dimension. Observers recorded the slide used for measurement and potential issues limiting assessment of DOI. Results were compared for reproducibility in DOI and tumor stage using intraclass correlation coefficient (ICC) analysis. A total of 167 cases of oral squamous cell carcinoma with available slides were included. The ICC score for DOI between observers was 0.91339 (> 0.9 considered excellent). Only 7.2% of cases had uniform DOI amongst observers. Increasing overall tumor size and average DOI correlated with increasing range in DOI amongst observers. Differences in DOI resulted in differences in pathologic tumor staging (pT) for 15% of tumors. Use of different slides for DOI measurements was significantly associated with different pT staging. In contrast, ulceration and exophytic growth did not correlate with higher DOI or pT variability. Despite the excellent ICC score, differences in DOI measurement resulted in variable pT staging for a considerable number of cases. We therefore recommend consensus for DOI in at least some cases in which potential differences in DOI could alter pT stage assignment.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Humanos , Estadiamento de Neoplasias , Reprodutibilidade dos TestesRESUMO
INTRODUCTION: High-risk human papillomavirus (HR-HPV) status is critical in the diagnosis of oropharyngeal squamous cell carcinoma, informing prognosis and choice of therapy. HR-HPV status additionally plays a key role in the evaluation of squamous cell carcinoma of unknown origin metastatic to cervical lymph nodes. Thus, HR-HPV testing of fine needle aspirate (FNA) specimens from the head and neck is invaluable for accurate diagnosis, prognostication, and treatment planning. MATERIALS AND METHODS: American Society of Cytopathology members were surveyed to understand the current state of HR-HPV testing on FNA samples from the head and neck. The survey focused on 3 main topic areas: practice setting of respondents, methods of collection and processing of aspirate specimens for HR-HPV testing, and validation of HR-HPV testing methodologies on aspirate samples. RESULTS: The survey reveals that laboratories employ various methods to detect HR-HPV in FNA samples, most commonly p16 immunohistochemical staining of cell block sections. Although some laboratories have independently validated their HR-HPV detection method, such validation is not universal. Finally, not all respondents currently have HR-HPV testing available, but approximately half of those without a testing method desire to make HR-HPV testing of FNA samples available. CONCLUSIONS: Survey responses highlight that various testing modalities are utilized for HR-HPV detection in aspirate samples. However, internal laboratory validation of HR-HPV testing for FNA specimens is not ubiquitous despite professional society recommendations.