RESUMEN
The diverse malignant, stromal, and immune cells in tumors affect growth, metastasis, and response to therapy. We profiled transcriptomes of â¼6,000 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.
Asunto(s)
Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/patología , Metástasis de la Neoplasia/patología , Carcinoma de Células Escamosas/genética , Células Cultivadas , Transición Epitelial-Mesenquimal , Perfilación de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Humanos , Masculino , Análisis de la Célula Individual , Microambiente TumoralRESUMEN
Mesenchymal tumors with GLI1 fusions or amplifications have recently emerged as a distinctive group of neoplasms. The terms GLI1-altered mesenchymal tumor or GLI1-altered soft tissue tumor serve as a nosological category, although the exact boundaries/criteria require further elucidation. We examined 16 tumors affecting predominantly adults (median age: 40 years), without sex predilection. Several patients had tumors of longstanding duration (>10 years). The most common primary site was soft tissue (n = 9); other sites included epidural tissue (n = 1), vertebra (n = 1), tongue (n = 1), hard palate (n = 1), and liver (n = 1). Histologically, the tumors demonstrated multinodular growth of cytologically uniform, ovoid-to-epithelioid, occasionally short spindled cells with delicate intratumoral vasculature and frequent myxoid stroma. Mitotic activity ranged from 0 to 8 mitoses/2 mm2 (mean 2). Lymphovascular invasion/protrusion of tumor cells into endothelial-lined vascular spaces was present or suspected in 6 cases. Necrosis, significant nuclear pleomorphism, or well-developed, fascicular spindle-cell growth were absent. Half demonstrated features of the newly proposed subset, "distinctive nested glomoid neoplasm." Tumors were consistently positive for CD56 (n = 5/5). A subset was stained with S100 protein (n = 7/13), SMA (n = 6/13), keratin (n = 2/9), EMA (n = 3/7), and CD99 (n = 2/6). Tumors harbored ACTB::GLI1 (n = 15) or PTCH1::GLI1 (n = 1) fusions. The assays used did not capture cases defined by GLI1 amplification. We also identified recurrent cytogenetic gains (1q, 5, 7, 8, 12, 12q13.2-ter, 21, and X). For patients with available clinical follow-up (n = 8), half were disease free. Half demonstrated distant metastases (lungs, bone, or soft tissue). Of cases without follow-up (n = 8), 2 were known recurrences, and 1 was presumed metastasis. Our results imply a more aggressive biological potential than currently reported. Given the possibility for metastasis and disease progression, even in cytologically bland, nested tumors, close clinical surveillance, akin to that for sarcoma management, may be indicated. The term GLI1-altered mesenchymal tumor with malignant potential is proposed.
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Neoplasias de los Tejidos Conjuntivo y Blando , Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Humanos , Proteína con Dedos de Zinc GLI1/genética , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Proteínas S100 , Sarcoma/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisisRESUMEN
Cytological specimens play a pivotal role in head and neck nodule/mass work up and diagnoses. The specimens´ importance has grown with the onset of personalized medicine and the routine use of molecular markers in the diagnostic work up. The Updates in Head and Neck Cytopathology Short Course ran during the 35th European Congress of Pathology held in Dublin, Ireland, in 2023 and brought together experts in cytopathology, pathology, and related fields to share their expertise and experience in the field of head and neck cytopathology and its future directions. Topics such as a one-stop clinic, the Milan System for Reporting Salivary Gland Cytopathology, next generation sequencing, and human papilloma virus detection in the head and neck area were covered during the short course. These topics are briefly summarized in the present review.
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Neoplasias de las Glándulas Salivales , Glándulas Salivales , Humanos , Biopsia con Aguja Fina , Glándulas Salivales/patología , Cabeza/patología , Cuello/patología , Irlanda , Neoplasias de las Glándulas Salivales/patología , Estudios RetrospectivosRESUMEN
The use of standardised reporting systems for non-gynaecologic cytopathology has made enormous gains in popularity during the past decade, including for thyroid fine-needle aspiration, urine cytology, serous effusions, pancreas, lymph nodes, lung and more. In February 2018, the first edition of the Atlas of the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was published. The MSRSGC defines six diagnostic fine-needle aspiration categories encompassing the spectrum of non-neoplastic, benign and malignant lesions of the salivary glands. The goal of the MSRSGC is to combine each diagnostic category with a defined risk of malignancy and a specific clinical and/or surgical management algorithm. Since its initial publication in 2018, more than 200 studies and commentaries have been published, confirming the role of the MSRSGC. The second edition of the MSRSGC, published in July 2023, includes refined risks of malignancy based on systematic reviews and meta-analyses, a new chapter summarising the use of salivary gland imaging, new advances in ancillary testing and updates in nomenclature.
Asunto(s)
Neoplasias de las Glándulas Salivales , Humanos , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales/patología , Biopsia con Aguja Fina , Citodiagnóstico/métodos , Algoritmos , Estudios RetrospectivosRESUMEN
Olfactory neuroblastoma (ONB, esthesioneuroblastoma) is a sinonasal cancer with an underdeveloped diagnostic toolkit, and is the subject of many incidents of tumor misclassification throughout the literature. Despite its name, connections between the cancer and normal cells of the olfactory epithelium have not been systematically explored and markers of olfactory epithelial cell types are not deployed in clinical practice. Here, we utilize an integrated human-mouse single-cell atlas of the nasal mucosa, including the olfactory epithelium, to identify transcriptomic programs that link ONB to a specific population of stem/progenitor cells known as olfactory epithelial globose basal cells (GBCs). Expression of a GBC transcription factor NEUROD1 distinguishes both low- and high-grade ONB from sinonasal undifferentiated carcinoma, a potential histologic mimic with a distinctly unfavorable prognosis. Furthermore, we identify a reproducible subpopulation of highly proliferative ONB cells expressing the GBC stemness marker EZH2, suggesting that EZH2 inhibition may play a role in the targeted treatment of ONB. Finally, we study the cellular states comprising ONB parenchyma using single-cell transcriptomics and identify evidence of a conserved GBC transcriptional regulatory circuit that governs divergent neuronal-versus-sustentacular differentiation. These results link ONB to a specific cell type for the first time and identify conserved developmental pathways within ONB that inform diagnostic, prognostic, and mechanistic investigation.
Asunto(s)
Estesioneuroblastoma Olfatorio , Neoplasias Nasales , Neoplasias de los Senos Paranasales , Humanos , Ratones , Animales , Estesioneuroblastoma Olfatorio/diagnóstico , Estesioneuroblastoma Olfatorio/metabolismo , Estesioneuroblastoma Olfatorio/patología , Neoplasias de los Senos Paranasales/patología , Neuronas/patología , Neoplasias Nasales/genética , Neoplasias Nasales/diagnóstico , Cavidad Nasal/metabolismo , Cavidad Nasal/patologíaRESUMEN
Human papillomavirus (HPV), most commonly HPV16, causes a growing subset of head and neck squamous cell carcinomas (HNSCCs), including the overwhelming majority of oropharynx squamous cell carcinomas in many developed countries. Circulating biomarkers for HPV-positive HNSCC may allow for earlier diagnosis, with potential to decrease morbidity and mortality. This case-control study evaluated whether circulating tumor HPV DNA (ctHPVDNA) is detectable in prediagnostic plasma from individuals later diagnosed with HPV-positive HNSCC. Cases were participants in a hospital-based research biobank with archived plasma collected ≥6 months before HNSCC diagnosis, and available archival tumor tissue for HPV testing. Controls were biobank participants without cancer or HPV-related diagnoses, matched 10:1 to cases by sex, race, age and year of plasma collection. HPV DNA was detected in plasma and tumor tissue using a previously validated digital droplet PCR-based assay that quantifies tumor-tissue-modified viral (TTMV) HPV DNA. Twelve HNSCC patients with median age of 68.5 years (range, 51-87 years) were included. Ten (83.3%) had HPV16 DNA-positive tumors. ctHPV16DNA was detected in prediagnostic plasma from 3 of 10 (30%) patients with HPV16-positive tumors, including 3 of 7 (43%) patients with HPV16-positive oropharynx tumors. The timing of the plasma collection was 19, 34 and 43 months before cancer diagnosis. None of the 100 matched controls had detectable ctHPV16DNA. This is the first report that ctHPV16 DNA is detectable at least several years before diagnosis of HPV16-positive HNSCC for a subset of patients. Further investigation of ctHPV16DNA as a biomarker for early diagnosis of HPV16-positive HNSCC is warranted.
Asunto(s)
Alphapapillomavirus , Carcinoma de Células Escamosas , ADN Tumoral Circulante , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Anciano , Anciano de 80 o más Años , Alphapapillomavirus/genética , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , ADN Viral/genética , Neoplasias de Cabeza y Cuello/diagnóstico , Humanos , Persona de Mediana Edad , Papillomaviridae/genética , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnósticoRESUMEN
BACKGROUND: New ultrasensitive methods for detecting residual disease after surgery are needed in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC). METHODS: To determine whether the clearance kinetics of circulating tumor human papillomavirus DNA (ctHPVDNA) is associated with postoperative disease status, a prospective observational study was conducted in 33 patients with HPV+OPSCC undergoing surgery. Blood was collected before surgery, postoperative days 1 (POD 1), 7, and 30 and with follow-up. A subcohort of 12 patients underwent frequent blood collections in the first 24 hours after surgery to define early clearance kinetics. Plasma was run on custom droplet digital polymerase chain reaction (ddPCR) assays for HPV genotypes 16, 18, 33, 35, and 45. RESULTS: In patients without pathologic risk factors for recurrence who were observed after surgery, ctHPVDNA rapidly decreased to <1 copy/mL by POD 1 (n = 8/8). In patients with risk factors for macroscopic residual disease, ctHPVDNA was markedly elevated on POD 1 (>350 copies/mL) and remained elevated until adjuvant treatment (n = 3/3). Patients with intermediate POD 1 ctHPVDNA levels (1.2-58.4 copies/mL) all possessed pathologic risk factors for microscopic residual disease (n = 9/9). POD 1 ctHPVDNA levels were higher in patients with known adverse pathologic risk factors such as extranodal extension >1 mm (P = .0481) and with increasing lymph nodes involved (P = .0453) and were further associated with adjuvant treatment received (P = .0076). One of 33 patients had a recurrence that was detected by ctHPVDNA 2 months earlier than clinical detection. CONCLUSIONS: POD 1 ctHPVDNA levels are associated with the risk of residual disease in patients with HPV+OPSCC undergoing curative intent surgery and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. LAY SUMMARY: Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) is increasing at epidemic proportions and is commonly treated with surgery. This report describes results from a study examining the clearance kinetics of circulating tumor HPV DNA (circulating tumor human papillomavirus DNA [ctHPVDNA]) following surgical treatment of HPV+OPSCC. We found that ctHPVDNA levels 1 day after surgery are associated with the risk of residual disease in patients with HPV+OPSCC and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. These findings are the first to demonstrate the potential utility of ctHPVDNA in patients with HPV+OPSCC undergoing surgery.
Asunto(s)
Alphapapillomavirus , ADN Tumoral Circulante , Neoplasias de Cabeza y Cuello , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Alphapapillomavirus/genética , ADN Tumoral Circulante/genética , Neoplasias de Cabeza y Cuello/complicaciones , Humanos , Cinética , Papillomaviridae/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/complicacionesRESUMEN
Viruses are the second leading cause of cancer worldwide, and human papillomavirus (HPV)-associated head and neck cancers are increasing in incidence in the United States. HPV preferentially infects the crypts of the tonsils rather than the surface epithelium. The present study sought to characterize the unique microenvironment within the crypts to better understand the viral tropism of HPV to a lymphoid-rich organ. Laser-capture microdissection of distinct anatomic areas (crypts, surface epithelium, and germinal centers) of the tonsil, coupled with transcriptional analysis and multiparameter immunofluorescence staining demonstrated that the tonsillar crypts are enriched with myeloid populations that co-express multiple canonical and noncanonical immune checkpoints, including PD-L1, CTLA-4, HAVCR2 (TIM-3), ADORA2A, IDO1, BTLA, LGALS3, CDH1, CEACAM1, PVR, and C10orf54 (VISTA). The resident monocytes may foster a permissive microenvironment that facilitates HPV infection and persistence. Furthermore, the myeloid populations within HPV-associated tonsil cancers co-express the same immune checkpoints, providing insight into potential novel immunotherapeutic targets for HPV-associated head and neck cancers.
Asunto(s)
Alphapapillomavirus/fisiología , Células Mieloides/patología , Células Mieloides/virología , Tonsila Palatina/patología , Tonsila Palatina/virología , Tropismo Viral/fisiología , Antígenos CD/metabolismo , Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Moléculas de Adhesión Celular/metabolismo , Epitelio/patología , Epitelio/virología , Centro Germinal/patología , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/virología , Humanos , Proteínas de Punto de Control Inmunitario/metabolismo , Captura por Microdisección con Láser , Monocitos/patología , Receptores Virales/metabolismo , Transcriptoma/genéticaRESUMEN
AIMS: Salivary gland intraductal carcinoma (IDC) is a complex ductal neoplasm surrounded by a layer of myoepithelial cells. Recent insights have shown that there are three different types: intercalated duct-like, with frequent NCOA4-RET fusions; apocrine, with salivary duct carcinoma-like mutations; and mixed intercalated duct-like/apocrine, with RET fusions, including TRIM27-RET. In addition, an oncocytic IDC has been described, but it remains unclear whether it represents a fourth variant or simply oncocytic metaplasia of another IDC type. Our aim was to more completely characterize oncocytic IDC. METHODS AND RESULTS: Six IDCs with oncocytic changes were retrieved from the authors' archives, from three men and three women ranging in age from 45 to 75 years (mean, 63 years). Five arose in the parotid gland, with one in an accessory parotid gland. Four patients with follow-up were free of disease after 1-23 months. Several immunostains (S100, mammaglobin, androgen receptor, and p63/p40) and molecular tools (RNA sequencing, RET fluorescence in-situ hybridisation, BRAF V600E VE1 immunohistochemistry, and Sanger sequencing) were applied. Histologically, the tumours were variably cystic with solid intracystic nodules often difficult to recognise as intraductal. In all, tumour ducts were positive for S100 and mammaglobin, negative for androgen receptor, and completely surrounded by myoepithelial cells positive for p63/p40. Molecular analysis revealed TRIM33-RET in two of six cases, NCOA4-RET in one of six cases, and BRAF V600E in two of six cases. One case had no identifiable alterations. CONCLUSIONS: Oncocytic IDC shares similarities with intercalated duct-like IDC. Although additional verification is needed, the oncocytic variant appears to be sufficiently unique to be now regarded as the fourth distinct subtype of IDC. Because of its indolent nature, oncocytic IDC should be distinguished from histological mimics.
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Carcinoma Intraductal no Infiltrante , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de las Glándulas Salivales , Factores de Transcripción/genética , Adulto , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Carcinoma Ductal/diagnóstico , Carcinoma Ductal/genética , Carcinoma Ductal/patología , Carcinoma Intraductal no Infiltrante/diagnóstico , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/patología , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Mutación , Fusión de Oncogenes , Células Oxífilas/patología , Neoplasias de las Glándulas Salivales/diagnóstico , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales/patología , Análisis de Secuencia de ARNRESUMEN
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.
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Proteínas de Fusión Oncogénica/genética , Receptor trkA/genética , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Femenino , Reordenamiento Génico , Humanos , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Fusión Oncogénica/metabolismo , Receptor trkA/metabolismo , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Adulto JovenRESUMEN
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.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma/genética , Fusión Génica , Reordenamiento Génico , Mutación , Proteínas Quinasas/genética , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Anciano , Antineoplásicos/uso terapéutico , Carcinoma/enzimología , Carcinoma/secundario , Carcinoma/terapia , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Humanos , Radioisótopos de Yodo/uso terapéutico , Masculino , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular , Terapia Molecular Dirigida , Recurrencia Local de Neoplasia , Fenotipo , Inhibidores de Proteínas Quinasas/uso terapéutico , Radiofármacos/uso terapéutico , Estudios Retrospectivos , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapia , Tiroidectomía , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: To determine if there is a biologic rationale for using checkpoint inhibitor drugs targeting programmed cell death ligand 1 (PD-L1) and PD-L2 in the treatment of adenoid cystic carcinoma of the orbit. METHODS: Twenty-three cases of adenoid cystic carcinoma involving the orbit (13 primary lacrimal gland, 5 secondarily extending into the orbit, and 5 unspecified) were examined histopathologically. Immunohistochemistry for PD-L1, PD-L2, and CD8 was performed. Charts were reviewed for clinical correlations. RESULTS: Expression of PD-L1 and of PD-L2 was overall low in adenoid cystic carcinoma (mean expression 1.4 ± 0.9 of 5 for PD-L1, mean 0.83 ± 1.1 of 5 for PD-L2), and tumor-infiltrating CD8-positive T-lymphocytes were sparse (mean 1.1 ± 0.51 of 3). Only 13 of the 23 (57%) cases expressed PD-L1 as a combined positive score ≥1 of cells. No associations were found between expression levels of these markers and patient sex, tumor site of origin, Tumor, Node, Metastasis stage, or patient outcome. A significant association was observed between stromal PD-L1 expression and tumor histopathologic subtype (p = 0.05), and between tumor PD-L1 expression and prior exposure to radiation (p = 0.03). CONCLUSIONS: Checkpoint inhibitor drugs may have limited impact in the treatment and clinical course of orbital adenoid cystic carcinoma based on the low frequency of CD8 infiltrate and low expression of PD-L1 and PD-L2. Pretreatment with radiation, however, may improve tumor response to checkpoint inhibitor drugs.
Asunto(s)
Carcinoma Adenoide Quístico , Antígeno B7-H1 , Biomarcadores de Tumor , Linfocitos T CD8-positivos , Carcinoma Adenoide Quístico/terapia , Humanos , Linfocitos Infiltrantes de Tumor , Órbita , Proteína 2 Ligando de Muerte Celular Programada 1RESUMEN
BACKGROUND: Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy without effective systemic therapies. Delineation of molecular profiles in ACC has led to an increased number of biomarker-stratified clinical trials; however, the clinical utility and U.S.-centric financial sustainability of integrated next-generation sequencing (NGS) in routine practice has, to our knowledge, not been assessed. MATERIALS AND METHODS: In our practice, NGS genotyping was implemented at the discretion of the primary clinician. We combined NGS-based mutation and fusion detection, with MYB break-apart fluorescent in situ hybridization (FISH) and MYB immunohistochemistry. Utility was defined as the fraction of patients with tumors harboring alterations that are potentially amenable to targeted therapies. Financial sustainability was assessed using the fraction of global reimbursement. RESULTS: Among 181 consecutive ACC cases (2011-2018), prospective genotyping was performed in 11% (n = 20/181; n = 8 nonresectable). Testing identified 5/20 (25%) NOTCH1 aberrations, 6/20 (30%) MYB-NFIB fusions (all confirmed by FISH), and 2/20 (10%) MYBL1-NFIB fusions. Overall, these three alterations (MYB/MYBL1/NOTCH1) made up 65% of patients, and this subset had a more aggressive course with significantly shorter progression-free survival. In 75% (n = 6/8) of nonresectable patients, we detected potentially actionable alterations. Financial analysis of the global charges, including NGS codes, indicated 63% reimbursement, which is in line with national (U.S.-based) and international levels of reimbursement. CONCLUSION: Prospective routine clinical genotyping in ACC can identify clinically relevant subsets of patients and is approaching financial sustainability. Demonstrating clinical utility and financial sustainability in an orphan disease (ACC) requires a multiyear and multidimensional program. IMPLICATIONS FOR PRACTICE: Delineation of molecular profiles in adenoid cystic carcinoma (ACC) has been accomplished in the research setting; however, the ability to identify relevant patient subsets in clinical practice has not been assessed. This work presents an approach to perform integrated molecular genotyping of patients with ACC with nonresectable, recurrent, or systemic disease. It was determined that 75% of nonresectable patients harbor potentially actionable alterations and that 63% of charges are reimbursed. This report outlines that orphan diseases such as ACC require a multiyear, multidimensional program to demonstrate utility in clinical practice.
Asunto(s)
Carcinoma Adenoide Quístico/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Técnicas de Diagnóstico Molecular/métodos , Femenino , Humanos , Masculino , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Therapeutic cancer vaccines have met limited clinical success. In the setting of cancer, the immune system is either tolerized and/or has a limited tumor-specific T cell repertoire. In this study, we explore whether intratumoral (IT) vaccination with an HPV vaccine can elicit quantitative and qualitative differences in immune response as compared to intramuscular (IM) vaccination to overcome immune resistance in established tumors. We report that IT administration of an HPV-16 E7 peptide vaccine formulated with polyinosinic-polycytidylic acid [poly(I:C)] generated an enhanced antitumor effect relative to IM delivery. The elicited anti-tumor effect with IT vaccination was consistent among the vaccinated groups and across various C57BL/6 substrains. IT vaccination resulted in an increased frequency of PD-1hi TILs, which represented both vaccine-targeted and non-vaccine-targeted tumor-specific CD8+ T cells. Overall, the CD8+/Treg ratio was increased within the tumor microenvironment using IT vaccination. We also assessed transcriptional changes in several immune-related genes in the tumor microenvironment of the various treated groups, and our data suggest that IT vaccination leads to upregulation of a broad complement of immunomodulatory genes, including upregulation of interferon gamma (IFNγ) and antigen presentation and processing machine (APM) components. IT vaccine delivery is superior to traditional IM vaccination routes with the potential to improve tumor immunogenicity, which has potential clinical application in the setting of accessible lesions such as head and neck squamous cell carcinomas (HNSCCs).
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeza y Cuello/terapia , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Experimentales/inmunología , Proteínas E7 de Papillomavirus/inmunología , Vacunas contra Papillomavirus/inmunología , Linfocitos T Reguladores/inmunología , Animales , Presentación de Antígeno/genética , Vacunas contra el Cáncer/inmunología , Carcinoma de Células Escamosas/inmunología , Células Cultivadas , Citotoxicidad Inmunológica , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/inmunología , Humanos , Inmunidad Celular/genética , Inyecciones Intramusculares , Interferón gamma/genética , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Poli I-C/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , VacunaciónRESUMEN
Fine needle aspiration (FNA) is a well-established procedure for the diagnosis and management of salivary gland lesions despite challenges imposed by their diversity, complexity, and cytomorphologic overlap. Until recently, the reporting of salivary gland FNA specimens was inconsistent among different institutions throughout the world, leading to diagnostic confusion among pathologists and clinicians. In 2015, an international group of pathologists initiated the development of an evidence-based tiered classification system for reporting salivary gland FNA specimens designated the "Milan System for Reporting Salivary Gland Cytopathology" (MSRSGC) that culminated with the publication of the MSRSGC Atlas in February 2018. The MSRSGC consists of 6 diagnostic categories, which incorporate the morphologic heterogeneity and overlap among various non-neoplastic, benign, and malignant lesions of the salivary glands. In addition, each diagnostic category is associated with a risk of malignancy and management recommendations. The main goal of the MSRSGC is to improve communication between cytopathologists and treating clinicians, while also facilitating cytologic-histologic correlation, sharing of data from different laboratories for quality control, and research. Herein, we review the current status of salivary gland cytology and the role of MSRSGC in providing a framework for reporting salivary gland lesions.
Asunto(s)
Biopsia con Aguja Fina , Transformación Celular Neoplásica/patología , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales/patología , Terminología como Asunto , Biopsia con Aguja Fina/normas , Consenso , Diagnóstico Diferencial , Humanos , Valor Predictivo de las Pruebas , Pronóstico , Neoplasias de las Glándulas Salivales/clasificación , Neoplasias de las Glándulas Salivales/terapiaRESUMEN
PURPOSE: Although the minor salivary gland biopsy (MSGB) is a major criterion for the diagnosis of Sjögren syndrome (SS), multiple studies have outlined difficulties in standardization. The purpose of this study was to answer the following question: in all patients referred for MSGB, did strict application of focus scoring criteria alter the sensitivity of and predictive value of the MSGB in the diagnosis of SS compared with the initial interpretation? MATERIALS AND METHODS: The authors designed a cross-sectional study of patients referred to the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery (Boston, MA) over a 5-year period for MSGB. The primary predictor variable was the MSGB focus score. The primary outcome variable was the SS diagnosis. The newly established SS diagnosis status results were compared with the initial SS diagnoses. Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were calculated. Other relevant variables of interest, such as size of glandular tissue harvested and associated signs and symptoms, also were documented. The primary predictor variable was the MSGB focus score and the primary outcome variable was the SS diagnosis (positive or negative). RESULTS: Seventy-three patients met the inclusion criteria. The mean age was 48.5 years (range, 19 to 71 yr) and 64 were women (87.6%). The authors' previous study using initial pathology reports yielded 80.0% sensitivity, 87.5% specificity, 57.1% PPV, and 95.5% NPV. The present review of the MSGB using strict focus scoring guidelines yielded 95.4% sensitivity, 76.4% specificity, 63.6% PPV, and 97.5% NPV. CONCLUSIONS: The MSGB is an important major criterion in establishing a diagnosis of SS. Application of strict focus scoring guidelines when reviewing the MSGB yielded a sensitivity far greater than initially reported in this group. Difficulties with interpretation are discussed. Future studies will focus on improvement of interpretation and immunohistochemical aids in diagnosis.
Asunto(s)
Glándulas Salivales Menores , Síndrome de Sjögren , Adulto , Anciano , Biopsia , Estudios Transversales , Femenino , Humanos , Persona de Mediana Edad , Glándulas Salivales Menores/patología , Síndrome de Sjögren/diagnóstico , Adulto JovenRESUMEN
BACKGROUND/AIMS: The importance of adjuvant radiotherapy in patients with close margin resections for mucoepidermoid carcinoma of the parotid gland remains unclear. METHODS: Patients who underwent parotidectomy for mucoepidermoid carcinoma with or without adjuvant radiotherapy at a single academic tertiary care center from 2000 to 2014 were identified. Included patients had negative but close (≤2 mm) surgical margins without other high-risk histopathological factors including advanced T-stage, positive nodal disease, lymphovascular or perineural invasion, or high-grade histology. RESULTS: Nineteen patients were identified, of whom 15 (79%) were observed postoperatively, while 4 (21%) underwent adjuvant radiotherapy. There were no significant differences in extent of parotidectomy, elective neck dissection, T staging, or tumor size between patients who were observed and those undergoing adjuvant radiation. There were no locoregional or distant recurrences in any patients at a mean follow up 74.3 months. Patients undergoing adjuvant radiation, however, had significantly more intermediate-grade as compared to low-grade histology (75% vs. 13%, difference 62%, 95% CI 4% to 100%). CONCLUSIONS: Patients with negative but close (≤2 mm) surgical margins without other high-risk histopathological factors have excellent long-term locoregional control with surgery alone. The effects of adjuvant radiotherapy for those who have intermediate-grade disease remain uncertain.
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Carcinoma Mucoepidermoide/patología , Carcinoma Mucoepidermoide/radioterapia , Neoplasias de la Parótida/patología , Neoplasias de la Parótida/radioterapia , Anciano , Carcinoma Mucoepidermoide/cirugía , Femenino , Humanos , Masculino , Márgenes de Escisión , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias de la Parótida/cirugía , Radioterapia Adyuvante , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: Sjögren syndrome (SS), although commonly associated with xerostomia and xerophthalmia, can present with extraglandular manifestations that make definitive diagnosis difficult. The 2 leading diagnostic classification systems include a positive minor salivary gland biopsy (MSGB) result as a major inclusion criterion. The purpose of this study was to better define the role of the MSGB in establishing a diagnosis of SS in a cohort of referred patients. MATERIALS AND METHODS: This is a retrospective cohort study of patients referred to the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery (Boston, MA) over a 5-year period to establish a diagnosis of SS. Inclusion criteria were complete information regarding presenting symptoms, reason for referral, and findings at MSGB. Incomplete records and referral for reasons other than presumptive SS resulted in exclusion. The MSGB and its role in definitive diagnosis based on accepted classification systems were evaluated for sensitivity, specificity, and positive and negative predictive values. Other variables of interest (demographics, pattern of referral, and symptomology) are described for the cohort. RESULTS: Eighty-seven patients met the inclusion criteria. The mean age was 48.3 years (range, 19 to 74 yr) and 75 were women (86.2%). Fifteen MSGB results (17.2%) were positive based on the focus score histologic criteria. In 12 of 15 cases, the positive MSGB result allowed for a definitive diagnosis (80%). In 3 cases, other criteria allowed diagnosis without the contribution of the MSGB (sensitivity of MSGB, 80.0%; specificity, 87.5%; positive predictive value, 57.1%; negative predictive value, 95.5%). CONCLUSION: The MSGB is an important contributor to a diagnosis of SS. When serology was negative, the MSGB often was the criterion that allowed the diagnosis to be established. It is the most frequently positive of the major criteria used by the 2 classification systems in current use.
Asunto(s)
Glándulas Salivales Menores/patología , Síndrome de Sjögren/diagnóstico , Adulto , Anciano , Biopsia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad , Síndrome de Sjögren/patologíaRESUMEN
PURPOSE: The purpose of this study was to assess the utility of intraoperative radiographs and frozen sections in achieving negative margins and preventing recurrence of mandibular ameloblastomas. MATERIALS AND METHODS: This was a retrospective cohort study of patients who underwent resection (≥1 cm) of mandibular ameloblastomas from 2005 through 2015. Patients were included if they had at least 1-year follow-up and complete records. Demographic variables included age, gender, and type of resection (segmental vs marginal). Predictor variables were type of margin assessment: 1) frozen section, 2) intraoperative ex vivo specimen radiograph, 3) both, or 4) none. The outcome variables were final margin status and recurrence rate. Accuracy of intraoperative radiographic margins was determined by comparison with histologic margin distance. Descriptive statistics were conducted with the Fisher exact test. RESULTS: The study sample consisted of 35 patients (47.5 ± 20.4 yr old; 16 men) who underwent 25 segmental and 10 marginal resections. Ten had frozen sections only, 3 had ex vivo specimen radiographs only, 10 had no intraoperative measurements, and 12 had both. There were no positive frozen sections. One patient had a positive posterior bony margin at final pathology despite negative frozen section histology. There was no difference in recurrence rate at latest follow-up among cohorts. The anterior radiographic margin was 11.8 ± 5.9 mm compared with 11.5 ± 7.5 mm by histology (P = .124). The posterior radiographic margin was 12.3 ± 5.3 mm compared with 9.8 ± 6.5 mm histologically (P = .546). Margin distances that were at least 5 mm when measured with specimen radiographs had histologic margin distances of at least 5 mm in 25 of 30 resection margins (83.3%). CONCLUSION: Resection of ameloblastoma with planned margins of at least 1 cm is sufficient to prevent recurrence of ameloblastoma. Achieving a radiographic margin of at least 5 mm provided a histologic margin of at least 5 mm 83.3% of the time.
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Ameloblastoma/cirugía , Neoplasias Mandibulares/cirugía , Adulto , Ameloblastoma/diagnóstico por imagen , Ameloblastoma/patología , Biopsia , Femenino , Secciones por Congelación , Humanos , Masculino , Neoplasias Mandibulares/diagnóstico por imagen , Neoplasias Mandibulares/patología , Márgenes de Escisión , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Neoplasia Residual/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: Robinson and Martinez established unicystic ameloblastoma (UA) as a distinct pathologic entity in 1977. Using their original description, the aims of this study were to compare the clinical presentation and outcomes of UA treated at Massachusetts General Hospital (MGH) with outcomes reported in the original article. PATIENTS AND METHODS: This was a retrospective cohort study of MGH patients treated for UA during a 15-year period. Patients were included if they had a confirmed clinical and histologic diagnosis of UA. The primary predictor variable was the source of the study sample (MGH vs Robinson and Martinez). Secondary variables included age, gender, radiographic appearance, treatment, and histologic subtype. The primary outcome variable was the number of recurrences over time comparing the 2 groups. RESULTS: There were 19 patients (10 female and 9 male patients) in the MGH group and 20 patients (10 female and 10 male patients) in the Robinson and Martinez study. The lesions were predominantly unilocular (13 in MGH group and 19 in Robinson and Martinez group), located in the mandible (18 in MGH group and 20 in Robinson and Martinez group), and tooth associated (12 in MGH group and 14 in Robinson and Martinez group). No statistically significant demographic differences were noted between the 2 groups. In the MGH group, 13 cases (68%) exhibited mural or intramural ameloblastic epithelium, 4 (21%) were luminal or intraluminal, and 2 were unknown. However, histologic configuration was not reported in the Robinson and Martinez group. MGH patients were treated by enucleation (n = 7, 37%) or resection (n = 12, 63%) compared with enucleation in 100% cases in the Robinson and Martinez group. Overall, the disease-free survival rate was higher in the Robinson and Martinez group, but the difference was not statistically significant (P = .089). Within the MGH group, 100% of recurrences occurred in patients with mural invasion treated by enucleation. CONCLUSIONS: The results of this study support UA as a distinct entity based on demographic, clinical, and radiographic criteria. Outcomes in the MGH group were influenced by the degree of ameloblastic epithelial invasion and suggest that this variable should be considered when planning treatment.