RESUMEN
Undifferentiated round cell sarcomas (URCS) represent a diverse group of tumors, including conventional Ewing sarcoma, round cell sarcoma with EWSR1/FUS-non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR alterations. Since 2018, 3 cases of URCS with a novel CRTC1::SS18 gene fusion have been reported in the literature. Herein, we report 3 additional cases of CRTC1::SS18 sarcoma, thereby doubling the number of described cases and expanding the clinicopathologic features of this rare translocation sarcoma. Together with the previously reported cases, we show that the male-to-female ratio is 1:2 with a median age of 34 years (range, 12-42 years). Tumors occurred primarily in intramuscular locations involving the lower extremity. Histologically, all tumors contained uniform round-to-epithelioid cells with a moderate amount of eosinophilic cytoplasm growing in sheets and nests with prominent desmoplastic stroma reminiscent of desmoplastic small round cell tumor. Immunohistochemical results were nonspecific, demonstrating variable expression of CD99 (patchy), ALK, GATA3, and cyclin D1. RNA sequencing revealed CRTC1::SS18 gene fusions in all cases, involving exons 1 to 2 of CRTC1 (the 5' partner gene) on chromosome 19 and either exon 2 or exon 4 of SS18 (the 3' partner gene) on chromosome 18. The clinical course was variable. Although 1 previously reported case demonstrated aggressive behavior with a fatal outcome, 2 others had a relatively indolent course with gradual growth for 6 to 7 years prior to resection. Two cases developed metastatic disease, including 1 case with bilateral lung metastasis and 1 with locoregional spread to a lymph node. By analyzing the clinicopathologic features, we aimed to improve recognition of this rare translocation sarcoma to better understand its biologic potential, optimize patient management, and expand the current classification of URCS.
RESUMEN
Sinonasal tumors with neuroepithelial differentiation, defined by neuroectodermal elements reminiscent of olfactory neuroblastoma (ONB) and epithelial features such as keratin expression or gland formation, are a diagnostically challenging group that has never been formally included in sinonasal tumor classifications. Recently, we documented that most of these neuroepithelial neoplasms have distinctive histologic and immunohistochemical findings and proposed the term "olfactory carcinoma" to describe these tumors. However, the molecular characteristics of olfactory carcinoma have not yet been evaluated. In this study, we performed targeted molecular profiling of 23 sinonasal olfactory carcinomas to further clarify their pathogenesis and classification. All tumors included in this study were composed of high-grade neuroectodermal cells that were positive for pankeratin and at least 1 specific neuroendocrine marker. A significant subset of cases also displayed rosettes and neurofibrillary matrix, intermixed glands with variable cilia, peripheral p63/p40 expression, and S100 protein-positive sustentacular cells. Recurrent oncogenic molecular alterations were identified in 20 tumors, including Wnt pathway alterations affecting CTNNB1 (n = 8) and PPP2R1A (n = 2), ARID1A inactivation (n = 5), RUNX1 mutations (n = 3), and IDH2 hotspot mutations (n = 2). Overall, these findings do demonstrate the presence of recurrent molecular alterations in olfactory carcinoma, although this group of tumors does not appear to be defined by any single mutation. Minimal overlap with alterations previously reported in ONB also adds to histologic and immunohistochemical separation between ONB and olfactory carcinoma. Conversely, these molecular findings enhance the overlap between olfactory carcinoma and sinonasal neuroendocrine carcinomas. A small subset of neuroepithelial tumors might better fit into the superseding molecular category of IDH2-mutant sinonasal carcinoma. At this point, sinonasal neuroendocrine and neuroepithelial tumors may best be regarded as a histologic and molecular spectrum that includes core groups of ONB, olfactory carcinoma, neuroendocrine carcinoma, and IDH2-mutant sinonasal carcinoma.
Asunto(s)
Biomarcadores de Tumor , Proteínas de Unión al ADN , Estesioneuroblastoma Olfatorio , Neoplasias de los Senos Paranasales , Factores de Transcripción , Vía de Señalización Wnt , Humanos , Anciano , Persona de Mediana Edad , Masculino , Factores de Transcripción/genética , Femenino , Vía de Señalización Wnt/genética , Proteínas de Unión al ADN/genética , Estesioneuroblastoma Olfatorio/patología , Estesioneuroblastoma Olfatorio/genética , Estesioneuroblastoma Olfatorio/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Neoplasias de los Senos Paranasales/patología , Neoplasias de los Senos Paranasales/genética , Neoplasias de los Senos Paranasales/metabolismo , Adulto , Proteínas Nucleares/genética , Mutación , Anciano de 80 o más Años , Neoplasias Nasales/patología , Neoplasias Nasales/genética , Neoplasias Nasales/metabolismo , InmunohistoquímicaRESUMEN
Adamantinoma-like Ewing sarcoma (ALES) has traditionally been considered a variant of Ewing sarcoma because it generally harbors EWSR1::FLI1 fusions despite showing diffuse positivity for keratins and p40. However, it has become increasingly recognized that different tumors can have identical translocations, including shared fusions between carcinomas and sarcomas, raising questions as to whether ALES might represent a separate entity. Using methylation profiling, we further explored the relationship between Ewing sarcoma and ALES. The archives of multiple institutions were searched for candidate cases of ALES. DNA methylation profiling was performed and results were compared to corresponding data from conventional Ewing sarcoma. Twelve cases of ALES (5 previously reported) were identified in 10 men and 2 women (aged 20-72 years; median age, 41.5 years). Cases included tumors arising in the parotid gland (3), sinonasal cavity (2), submandibular gland (2), thyroid gland (1), neck (1), gingiva (1), hypopharynx (1), and mandible (1). Histologic review consistently showed sheets and nests of basaloid cells within a fibromyxoid or hyalinized stroma. All tumors were positive for at least 1 keratin and CD99 expression, whereas all 10 cases tested were positive for p63 or p40; S100 protein expression was noted in 2 cases. Cases harbored either EWSR1::FLI1 fusions (n = 6), FUS::FLI1 fusions (n = 1), and/or EWSR1 rearrangements (n = 6). Methylation profiling was successful in 11/12 cases evaluated. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) of DNA methylation data revealed a distinct methylation cluster for all 11 cases, including the tumor with the FUS::FLI1 fusion, which clearly segregated them from the conventional Ewing sarcoma. Follow-up (n = 11, 1-154 months) revealed that 4 patients experienced recurrence and 6 developed metastatic disease. ALES demonstrates a distinct methylation signature from conventional Ewing sarcoma. This finding adds to the distinctive immunoprofile of ALES, suggesting that these 2 tumors should be considered distinct entities rather than histologic extremes of the same disease.
Asunto(s)
Adamantinoma , Sarcoma de Ewing , Sarcoma , Masculino , Humanos , Femenino , Adulto , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Adamantinoma/genética , Adamantinoma/patología , Metilación de ADN , Proteína EWS de Unión a ARN/genética , Sarcoma/genética , Reordenamiento Génico , Proteínas de Fusión Oncogénica/genéticaRESUMEN
Mucoepidermoid carcinoma (MEC) is historically defined by a mix of squamoid, intermediate, and mucous cells, but we have recently encountered several cases lacking immunoreactivity for squamous markers p40, p63, and CK5/6 despite MAML2 fusions. This study will characterise these unique tumours. Ten MEC were collected arising from the parotid gland (n = 4), submandibular gland (n = 2), nasopharynx (n = 1), base of tongue (n = 1), bronchus (n = 1), and trachea (n = 1). Six tumours were low-grade, two intermediate-grade, one high-grade, and one demonstrated low-grade areas with high-grade transformation. Four cases were oncocytic, four had clear-cell features, two had spindle cell features, and one high-grade MEC had prominent solid, cord-like, and micropapillary features. The tumours were negative for p40 (10/10), p63 (10/10), and CK5/6 (9/9). Targeted RNA sequencing demonstrated CRTC1::MAML2 in five cases, CRTC3::MAML2 in two, and a novel MAML2::CEP126 in the unusual high-grade case. In two cases with insufficient RNA, MAML2 fluorescence in situ hybridisation (FISH) showed rearrangement. Genetically-confirmed MEC may lack overt squamous differentiation by histology and immunohistochemistry. While most cases harboured canonical fusions and fit within the spectra of MEC variants with oncocytic, clear cell, and/or spindle cell features, one had a novel MAML2::CEP126 fusion and unusual morphology. In MEC without squamoid cells, the use of immunohistochemistry may hinder, rather than aid, the correct diagnosis. In such cases, MAML2 analysis is most useful. The historical definition of MEC as a carcinoma with squamoid, intermediate and mucous cells should be revisited.
Asunto(s)
Carcinoma Mucoepidermoide , Carcinoma de Células Escamosas , Neoplasias de las Glándulas Salivales , Humanos , Carcinoma Mucoepidermoide/diagnóstico , Carcinoma Mucoepidermoide/genética , Inmunohistoquímica , Neoplasias de las Glándulas Salivales/diagnóstico , Neoplasias de las Glándulas Salivales/genética , Transactivadores/genéticaRESUMEN
Thyroblastoma is a novel thyroid malignancy included in the 5th Edition WHO Classification of Endocrine and Neuroendocrine Tumours. The majority of tumors now classified as thyroblastoma were originally regarded to be malignant thyroid teratomas. However, these neoplasms were recently recognized as a separate entity based on a distinctive constellation of primitive multilineage elements, including immature thyroid epithelium, undifferentiated or rhabdomyoblastic spindle cell proliferations, and neuroepithelial blastema, as well as recurrent DICER1 hotspot mutations. Thyroblastoma is an aggressive tumor that leads to death from disease in ~50% of patients, making it essential to differentiate this entity from a wide range of other thyroid tumors that show overlapping histologic features or DICER1 mutations. This review aims to provide a practical overview of the background, clinicopathologic features, molecular underpinnings, and differential diagnosis of this recently-described and molecularly-defined entity.
Asunto(s)
Tumores Neuroendocrinos , Teratoma , Neoplasias de la Tiroides , Humanos , Teratoma/genética , Teratoma/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Mutación , Ribonucleasa III/genética , ARN Helicasas DEAD-box/genéticaRESUMEN
BACKGROUND: Microsecretory adenocarcinoma (MSA) is a newly described salivary gland neoplasm characterized by MEF2C::SS18 fusions. MSA was previously thought to occur exclusively in salivary glands. Here, we expand the spectrum of known primary sites of this tumor by describing a series of cutaneous tumors with analogous findings. METHODS: We identified four cutaneous primary tumors with histopathologic features identical to MSA of the salivary glands. These cases were evaluated by immunohistochemistry, fluorescence in situ hybridization (FISH) for SS18 rearrangement and targeted RNA-sequencing. We also queried a pan-tumor database of advanced carcinomas for MEF2C::SS18. RESULTS: The cases occurred in men ranging from 61 to 74 years (mean, 68). They arose from the skin of the nose, chin, scalp, and external auditory canal. All included cords/microcysts of eosinophilic cells with bland oval nuclei and bluish mucin within fibromyxoid stroma. The scalp tumor also exhibited high-grade transformation (marked atypia, elevated mitotic rate, and necrosis), a feature unreported in salivary MSA. By immunohistochemistry, all cases were positive for S100. Two showed a myoepithelial component positive for p40 and smooth muscle actin or calponin. Three cases harbored MEF2C::SS18 by RNA sequencing, while one with limited tissue had SS18 rearrangement via FISH. Two patients had no evidence of recurrence or metastasis in limited follow-up (3 and 6 months). The pan-tumor database query also did not identify MEF2C::SS18 in any advanced cutaneous carcinomas. CONCLUSION: This report expands the sites that can be involved by MSA. Similar to salivary cases, MEF2C::SS18 represents a recurrent fusion in MSA of the skin. Unusual features in cutaneous cases not seen in salivary MSA include one case with high-grade transformation and two cases with a myoepithelial cell component. Identification of this fusion expands the spectrum of salivary-analog cutaneous tumors and aids in precise tumor classification.
Asunto(s)
Adenocarcinoma , Carcinoma , Neoplasias de las Glándulas Salivales , Neoplasias Cutáneas , Humanos , Hibridación Fluorescente in Situ , Biomarcadores de Tumor/genética , Adenocarcinoma/genética , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Carcinoma/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Mesenchymal chondrosarcoma (MCS) is a rare translocation-associated sarcoma, driven by a canonical HEY1::NCOA2 fusion. The tumors typically have a biphasic phenotype of primitive small blue round cells intermixed with hyaline cartilage. The head and neck (HN) region is a common site for MCS, accounting for 12-45% of all cases reported. AIMS: We assembled a relatively large cohort of 13 molecularly confirmed HN MCS for a detailed clinicopathologic analysis. The underlying fusion events were determined using fluorescence in situ hybridization and/or targeted RNA sequencing. RESULTS: The median age of presentation was 19 years. Five MCSs (39%) had an intraosseous presentation (skull, maxilla, palate, and mandible), while the remaining eight cases occurred in the brain/meninges, orbit, and nasal cavity. Microscopically, HN MCSs were characterized by primitive round cells arranged in a distinctive nested architecture and a rich staghorn vasculature. A cartilaginous component of hyaline cartilage islands and/or single chondrocytes were present in 69% cases. A combined immunoprofile of CD99(+)/SATB2(+)/CD34(-)/STAT6(-) was typically noted. As this immunoprofile is non-specific, the referral diagnoses in cases lacking a cartilaginous component included Ewing sarcoma family and osteosarcoma. Among the seven patients with follow-up data, three developed distant metastasis and one died of disease. CONCLUSION: HN MCS may arise at intra- or extra-osseous sites. The HN MCS appears to have a more prolonged survival compared other MCS sites. Testing for HEY1::NCOA2 fusion is recommended in HN tumors with nested round cell morphology and staghorn vasculature that lack a distinctive cartilaginous component.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Condrosarcoma Mesenquimal , Fusión Génica , Neoplasias de Cabeza y Cuello , Coactivador 2 del Receptor Nuclear , Adulto , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas de Ciclo Celular/genética , Niño , Condrosarcoma Mesenquimal/genética , Condrosarcoma Mesenquimal/patología , Femenino , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Hibridación Fluorescente in Situ , Masculino , Coactivador 2 del Receptor Nuclear/genética , Adulto JovenRESUMEN
BACKGROUND: Human papillomavirus (HPV) is responsible for a growing proportion of oropharyngeal squamous cell carcinomas (OPSCCs) among men and White individuals. Whether similar trends apply to women, non-Whites, and non-oropharyngeal squamous cell carcinomas (non-OPSCCs) is unknown. METHODS: This is a cross-sectional analysis combining 2 multi-institutional case series of incident head and neck squamous cell carcinoma (HNSCC) cases. Incident HNSCCs from 1995 to 2012 were enrolled retrospectively using banked tumor samples and medical record abstraction. Incident HNSCCs from 2013 to 2019 were enrolled prospectively. The prevalence of tumor HPV biomarkers was tested over 3 time periods (1995-2003, 2004-2012, and 2013-2019). Centralized testing was done for p16 immunohistochemistry (p16) and oncogenic HPV in situ hybridization (ISH). RESULTS: A total of 1209 incident cases of HNSCC were included. Prevalence of p16- and ISH-positive tumors increased significantly for oropharynx cancers over time. The majority were positive after 2013 for White patients (p16, 92%; P < .001; ISH 94%; P < .001), Black patients (p16, 72%; P = .021; ISH 67%; P = .011), and Hispanic patients (p16, 100%; P = .04; ISH 100%; P = .013). For women with OPSCC, the prevalence of p16- and ISH-positive tumors increased significantly to 82% (P < .001) and 78% (P = .004), respectively. For non-OPSCCs, there was increased p16 and ISH positivity overall with 24% p16 and 16% ISH positivity in the most recent time period (P < .001 for both). CONCLUSIONS: The majority of OPSCCs in US tertiary care centers are now p16 and ISH positive for all sex and race groups. In some populations in the United States, 91% of OPSCCs are now caused by HPV. Few non-OPSCCs are p16 and ISH positive.
Asunto(s)
Alphapapillomavirus , Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/patología , Estudios Transversales , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Femenino , Neoplasias de Cabeza y Cuello/epidemiología , Humanos , Masculino , Papillomaviridae/genética , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/epidemiología , Prevalencia , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/epidemiología , Centros de Atención Terciaria , Estados Unidos/epidemiologíaRESUMEN
Although low-grade non-intestinal-type sinonasal adenocarcinoma (SNAC) is formally a diagnosis of exclusion defined by the absence of salivary or intestinal differentiation, most tumors in this category comprise a distinctive histologic group that are increasingly thought to derive from seromucinous glands. However, the molecular underpinnings of SNAC remain poorly understood, and it is unclear if diverse genetic alterations recently reported in isolated cases should delineate separate subgroups. This study aims to perform comprehensive evaluation of gene fusions and mutations and their histologic correlates in low-grade SNAC to clarify its pathogenesis and classification. We identified 18 non-intestinal-type SNAC that all displayed characteristic tubulopapillary architecture and low-grade cytology, although several cases had other unique histologic features and 3 showed intermixed high-grade areas. Among tumors stained with S100 protein, SOX10, and DOG1, 86% expressed at least one of these seromucinous markers. Of 17 cases with sufficient RNA or DNA available for analysis, likely oncogenic molecular alterations were identified in 76% of cases, most notably including CTNNB1 p.S33F mutations in 2 cases, concomitant BRAF p.V600E and AKT1 p.E17K mutations in 2 cases, and ETV6::NTRK3, PRKAR1A::MET, FN1::NRG1, and DNAJB1::PRKACA fusions in 1 case each. While tumors with most genetic alterations were histologically indistinguishable, cases with CTNNB1 mutations had intermixed squamoid morules and cases with BRAF and AKT1 mutations showed a myoepithelial cell population and prominent papillary to micropapillary architecture. Overall, these findings confirm previous reports of frequent seromucinous differentiation in low-grade SNAC. However, these tumors display striking molecular diversity with involvement of multiple kinase fusions, leading to frequent activation of signaling cascades including the MAPK pathway. While most genetic alterations are not associated with sufficiently distinctive histologic features to suggest separate classification, biphasic tumors with BRAF p.V600E mutations are more unique and may represent a distinctive subgroup.
Asunto(s)
Adenocarcinoma , Neoplasias de los Senos Paranasales , Adenocarcinoma/patología , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Fusión Génica , Proteínas del Choque Térmico HSP40/genética , Humanos , Hiperplasia , Neoplasias de los Senos Paranasales/genética , Neoplasias de los Senos Paranasales/patología , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
AIMS: The sinonasal tract is a common extranodal site for Rosai-Dorfman disease (RDD). Recently, histiocytes with features of RDD were identified in the clinical setting of chronic sinusitis. This study evaluates whether this phenomenon should be considered part of the RDD spectrum or classified separately as RDD-like histiocytes. METHODS AND RESULTS: We prospectively collected 13 cases showing histological features of RDD in chronic sinusitis patients and identified 14 with similar findings (3.5%) via retrospective review of 403 sinus contents over 2 years. All 27 cases displayed nodular aggregates of eosinophilic histiocytes with intermixed lymphoplasmacytic inflammation, prominent eosinophils and emperipolesis. The histiocytes were positive for S100 protein and cyclin D1 and negative for CD1a and CD207. All patients presented with severe chronic sinusitis without tumour formation or systemic symptoms. Twelve patients with follow-up (55%) required repeat sinus surgery compared with just 43 other sinusitis patients evaluated (11%); features of RDD were present in their additional specimens. Two cases that underwent targeted next-generation sequencing (20%) had oncogenic mutations in NF1 and KEAP1. CONCLUSIONS: Overall, these findings confirm diagnostic histological and immunohistochemical features of RDD in a subset of chronic sinusitis specimens. While patients uniformly lack systemic involvement or tumefactive growth, they have a high risk of recurrent sinus disease. Although the relatively subtle nature of the findings raises consideration of separate classification, the presence of occasional oncogenic mutations and evidence of consistent MAPK/ERK pathway activation via cyclin D1 positivity suggests that this phenomenon represents a unique limited manifestation of RDD.
Asunto(s)
Histiocitosis Sinusal , Sinusitis , Ciclina D1/metabolismo , Histiocitosis Sinusal/diagnóstico , Histiocitosis Sinusal/patología , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Sinusitis/diagnósticoRESUMEN
BACKGROUND: Recursive partitioning analysis (RPA) from the Radiation Therapy Oncology Group (RTOG)-0129 has identified a low-risk group of patients with oropharynx cancer (OPC) who might benefit from therapeutic de-intensification. These risk groups have not yet been reproduced in an independent cohort treated heterogeneously. Therefore, the objective of this analysis was to validate the RPA risk groups and examine the prognostic impact of novel factors. METHODS: Patients with OPC were enrolled in a prospective study at 3 academic medical centers from 2013 to 2018. Medical record abstraction was used to ascertain clinical variables including staging and survival according to the 7th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. Human papillomavirus-positive tumor status was determined by p16 immunohistochemistry and/or HPV RNA in situ hybridization. Kaplan-Meier and log-rank methods were used to compare survival. Cox proportional hazards were used to generate univariate and multivariable hazard ratios (HRs). RESULTS: Median follow-up time was 3.2 years. The low-, intermediate-, and high-risk groups had significant differences in 2-year overall survival (OS, 99.1%; 95% CI, 94.4%-99.9% vs OS, 93.0%; 95% CI, 74.7%-98.2% vs OS, 80.0%; 95% CI, 40.9%-94.6%; Poverall = .0001) and 2-year progression-free survival (PFS, 97.5%; 95% CI, 92.4%-99.2% vs PFS, 89.3%; 95% CI, 70.3%-96.4% vs PFS, 80.0%; 95% CI, 40.9%-94.6%; Poverall < .002). After adjustment for age, sex, and level of educational attainment, OS and PFS were significantly lower for the intermediate- (OS adjusted hazard ratio [aHR], 5.0; 95% CI, 1.0-23.0; PFS aHR, 3.4; 95% CI, 1.0-11.5), and high- (OS aHR, 7.3; 95% CI, 1.4-39; PFS aHR, 5.0; 95% CI, 1.2-21.6) risk groups compared with the low-risk group. Lower education was also independently significantly associated with worse OS (aHR, 8.9; 95% CI, 1.8-44.3) and PFS (aHR, 3.1; 95% CI, 1.0-9.6). CONCLUSIONS: In patients with OPC, the RTOG-0129 RPA model is associated with OS and PFS in a heterogeneously treated cohort.
Asunto(s)
Neoplasias Orofaríngeas , Estudios de Cohortes , Humanos , Neoplasias Orofaríngeas/patología , Pronóstico , Modelos de Riesgos Proporcionales , Estudios ProspectivosRESUMEN
BACKGROUND: Case-control studies from the early 2000s demonstrated that human papillomavirus-related oropharyngeal cancer (HPV-OPC) is a distinct entity associated with number of oral sex partners. Using contemporary data, we investigated novel risk factors (sexual debut behaviors, exposure intensity, and relationship dynamics) and serological markers on odds of HPV-OPC. METHODS: HPV-OPC patients and frequency-matched controls were enrolled in a multicenter study from 2013 to 2018. Participants completed a behavioral survey. Characteristics were compared using a chi-square test for categorical variables and a t test for continuous variables. Adjusted odds ratios (aOR) were calculated using logistic regression. RESULTS: A total of 163 HPV-OPC patients and 345 controls were included. Lifetime number of oral sex partners was associated with significantly increased odds of HPV-OPC (>10 partners: odds ratio [OR], 4.3 [95% CI, 2.8-6.7]). After adjustment for number of oral sex partners and smoking, younger age at first oral sex (<18 vs >20 years: aOR, 1.8 [95% CI, 1.1-3.2]) and oral sex intensity (>5 sex-years: aOR, 2.8 [95% CI, 1.1-7.5]) remained associated with significantly increased odds of HPV-OPC. Type of sexual partner such as older partners when a case was younger (OR, 1.7 [95% CI, 1.1-2.6]) or having a partner who had extramarital sex (OR, 1.6 [95% CI, 1.1-2.4]) was associated with HPV-OPC. Seropositivity for antibodies to HPV16 E6 (OR, 286 [95% CI, 122-670]) and any HPV16 E protein (E1, E2, E6, E7; OR, 163 [95% CI, 70-378]) was associated with increased odds of HPV-OPC. CONCLUSION: Number of oral sex partners remains a strong risk factor for HPV-OPC; however, timing and intensity of oral sex are novel independent risk factors. These behaviors suggest additional nuances of how and why some individuals develop HPV-OPC.
Asunto(s)
Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/complicaciones , Conducta Sexual , Parejas Sexuales , Adolescente , Adulto , Distribución por Edad , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Relaciones Extramatrimoniales , Femenino , Papillomavirus Humano 16/inmunología , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Proteínas Oncogénicas Virales/análisis , Neoplasias Orofaríngeas/epidemiología , Proteínas Represoras/análisis , Riesgo , Factores de Riesgo , Conducta Sexual/estadística & datos numéricos , Fumar/efectos adversos , Factores Socioeconómicos , Factores de Tiempo , Estados Unidos/epidemiología , Sexo Inseguro , Adulto JovenRESUMEN
Approximately 15% of advanced head and neck squamous cell carcinomas (HNSCC) respond to anti-PD-(L)1 monotherapies. Tumor PD-L1 expression and human papillomavirus (HPV) status have been proposed as biomarkers to identify patients likely to benefit from these treatments. We aimed to understand the potential immune effects of HPV in HNSCC and to characterize additional potentially targetable immune-regulatory pathways in primary, treatment-naïve tumors. CD3, CD4, CD8, CD20, CD68, FoxP3, PD-1, PD-L2, LAG-3, IDO-1, and GITR cell densities were determined in 27 HNSCC specimens. IHC for PD-L1 assessed percentage of positive tumor cells and immune cells separately or as a combined positive score (CPS), and whether PD-L1 was expressed in an adaptive or constitutive pattern (i.e., PD-L1+ tumor cells juxtaposed to TILs or in the absence of TILs, respectively). HPV testing with p16 IHC was confirmed by HPV genotyping. When compared to HPV(-) tumors (n = 14), HPV+ tumors (n = 13) contained significantly higher densities of CD3+, CD4+, CD8+, CD20+, and PD-1+ cells (P < 0.02), and there was a trend towards increased density of FoxP3 + cells. PD-L1 expression patterns did not vary by tumor viral status, suggesting possible heterogeneous mechanisms driving constitutive vs adaptive PD-L1 expression patterns in HNSCC. IDO-1 expression was abundant (> 500 IDO-1+ cells/mm2 in 17/27 specimens) and was found on tumor cells as well as immune cells in 12/27 (44%) cases (range 5-80% tumor cells+). Notably, the studied markers varied on a per-patient basis and were not always related to the degree of T cell infiltration. These findings may inform therapeutic co-targeting strategies and raise consideration for a personalized treatment approach.
Asunto(s)
Alphapapillomavirus/fisiología , Neoplasias de Cabeza y Cuello/inmunología , Infecciones por Papillomavirus/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Estudios de Cohortes , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/virología , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Infecciones por Papillomavirus/virología , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Transcriptoma , Microambiente TumoralRESUMEN
BACKGROUND: Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy. Oncologic drivers of ocular sebaceous carcinoma are incompletely understood. METHODS: A retrospective search of our pathology archives for OA sebaceous carcinoma identified 18 primary resection specimens. Immunohistochemistry for p16 and ZEB1 and RNA in situ hybridization for high-risk human papillomavirus (HPV) subtypes were performed. RESULTS: High-risk HPV was demonstrated in 2/11 (18%) cases. p16 overexpression was observed in 10/11 (91%). No association between gender, age at presentation, tumor location, intraepithelial spread, tumor size, and T stage was observed between HPV-driven and nonviral cases. High expression of ZEB1 was observed in the intraepithelial component of 4/14 (28%) cases and in the subepithelial component of 1/13 (7%) cases. ZEB1 overexpression was not associated with HPV status, T stage, or tumor size. CONCLUSION: As previously described by others, our findings suggest that a subset of OA sebaceous carcinomas may arise via an HPV-dependent pathway. However, unlike high-risk HPV-driven carcinomas of the oropharynx, we did not identify an association between HPV-status and prognostic features. Furthermore, p16 expression was not a useful surrogate marker for HPV-driven disease. ZEB1 overexpression is not associated with HPV in our cohort of ocular sebaceous carcinoma.
Asunto(s)
Adenocarcinoma Sebáceo/diagnóstico , Neoplasias del Ojo/patología , Neoplasias de las Glándulas Sebáceas/patología , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Adenocarcinoma Sebáceo/genética , Adenocarcinoma Sebáceo/virología , Anciano , Anciano de 80 o más Años , Alphapapillomavirus/genética , Estudios de Cohortes , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , ADN Viral/genética , Neoplasias del Ojo/genética , Neoplasias del Ojo/virología , Femenino , Humanos , Inmunohistoquímica/métodos , Hibridación in Situ/métodos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Estudios Retrospectivos , Neoplasias de las Glándulas Sebáceas/genética , Neoplasias de las Glándulas Sebáceas/virologíaRESUMEN
PURPOSE: To examine the potential benefit of reevaluation of original slides and p16 immunohistochemistry (IHC) of tonsillectomy specimens for primary tumor identification in cases of human papillomavirus (HPV) positive squamous cell carcinoma (SCC) of the head and neck of unknown primary. MATERIALS AND METHODS: Through a retrospective review, we identified all patients 18 or older who presented at our institution from 2003 to 2015 with histologically confirmed HPV-positive SCC in a cervical lymph node with unidentified primary tumor after initial workup. For patients for whom specimens were available, an expert head and neck pathologist re-reviewed original hematoxylin and eosin (H&E) slides to confirm absence of tumor and performed p16 IHC and deep sectioning of tissue blocks to identify potential tumor foci. RESULTS: Among 735 patient records assessed, 80 were HPV-positive SCC with unknown primary, 28 of which did not have a primary tumor identified, and 20 with original specimens available. Upon re-review of 103 original H&E slides, invasive SCC was identified for 2 patients. Deep sectioning and p16 IHC did not identify additional primary tumors. CONCLUSION: Re-review of original slides by an expert head and neck pathologist, but not p16 staining or deeper H&E sections, was able to identify additional tumors.
Asunto(s)
Alphapapillomavirus , Biomarcadores de Tumor/análisis , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/virología , Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Primarias Desconocidas/virología , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/virología , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Femenino , Humanos , Inmunohistoquímica/métodos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
A 78-year-old Caucasian female presented with a painless mass in the right orbit that had progressively enlarged over several months. Computed tomography scan of the orbits showed a right lacrimal gland mass with no bony erosion. Histopathologic analysis of the biopsy specimen revealed invasive squamous cell carcinoma positive via in-situ hybridization for high-risk human papillomavirus. The patient underwent successful removal of the right lacrimal gland tumor en bloc, followed by adjuvant radiotherapy. This is an extremely rare case of primary squamous cell carcinoma of the lacrimal gland and the first report describing human papillomavirus positivity in this tumor location.
Asunto(s)
Alphapapillomavirus , Carcinoma de Células Escamosas , Neoplasias del Ojo , Enfermedades del Aparato Lagrimal , Aparato Lagrimal , Anciano , Carcinoma de Células Escamosas/terapia , Neoplasias del Ojo/terapia , Femenino , Humanos , Aparato Lagrimal/diagnóstico por imagenRESUMEN
PURPOSE: The high mobility group A1 (HMGA1) chromatin remodeling protein is required for metastatic progression and cancer stem cell properties in preclinical breast cancer models, although its role in breast carcinogenesis has remained unclear. To investigate HMGA1 in primary breast cancer, we evaluated immunoreactivity score (IRS) in tumors from a large cohort of Asian women; HMGA1 gene expression was queried from two independent Western cohorts. METHODS: HMGA1 IRS was generated from breast tumors in Korean women as the product of staining intensity (weak = 1, moderate = 2, strong = 3) and percent positive cells (< 5% = 0, 5-30% = 1, 30-60% = 2, > 60% = 3), and stratified into three groups: low (< 3), intermediate (3-6), high (> 6). We assessed HMGA1 and estrogen receptor (ESR1) gene expression from two large databases (TCGA, METABRIC). Overall survival was ascertained from the METABRIC cohort. RESULTS: Among 540 primary tumors from Korean women (181 ER-negative, 359 ER-positive), HMGA1 IRS was < 3 in 89 (16.5%), 3-6 in 215 (39.8%), and > 6 in 236 (43.7%). High HMGA1 IRS was associated with estrogen receptor (ER)-negativity (χ2 = 12.07; P = 0.002) and advanced nuclear grade (χ2 = 12.83; P = 0.012). In two large Western cohorts, the HMGA1 gene was overexpressed in breast cancers compared to non-malignant breast tissue (P < 0.0001), including Asian, African American, and Caucasian subgroups. HMGA1 was highest in ER-negative tumors and there was a strong inverse correlation between HMGA1 and ESR1 gene expression (Pearson r = - 0.60, P < 0.0001). Most importantly, high HMGA1 predicted decreased overall survival (P < 0.0001) for all women with breast cancer and further stratified ER-positive tumors into those with inferior outcomes. CONCLUSIONS: Together, our results suggest that HMGA1 contributes to estrogen-independence, tumor progression, and poor outcomes. Moreover, further studies are warranted to determine whether HMGA1 could serve as a prognostic marker and therapeutic target for women with breast cancer.
Asunto(s)
Neoplasias de la Mama/metabolismo , Proteína HMGA1a/genética , Proteína HMGA1a/metabolismo , Receptores de Estrógenos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/genética , Progresión de la Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , República de Corea , Análisis de Supervivencia , Regulación hacia Arriba , Adulto JovenRESUMEN
Nonepithelial tumors of the larynx are rare and represent a minority of all laryngeal neoplasms. Imaging has an important role in the diagnosis, treatment planning, and surveillance of these entities. However, unfamiliarity with these neoplasms can cause diagnostic difficulties for radiologists, especially because many of the imaging findings are nonspecific. By using a systematic approach based on clinical history, patient age and gender, lesion location, endoscopic results, and specific imaging findings, the differential diagnosis can often be narrowed. These tumors typically affect the submucosal layer, so if a tumor has an intact mucosa at endoscopy, a nonepithelial neoplasm is the most likely diagnosis. Nonepithelial tumors of the larynx can arise from the laryngeal cartilage or muscle or from the surrounding lymphoid tissue or blood vessels. Consequently, imaging findings typically correspond to the specific cell type from which it originated. Recognizing specific features (eg, metaplastic bone formation, macroscopic fat, or enhancement pattern) can often help narrow the differential diagnosis. In addition, identification of noncircumscribed borders of the lesion and invasion of the adjacent structures is key to diagnosis of a malignant process rather than a benign neoplasm. Understanding the pathologic correlation is fundamental to understanding the radiologic manifestations and is ultimately crucial for differentiation of nonepithelial laryngeal neoplasms. Online supplemental material is available for this article. ©RSNA, 2020.
Asunto(s)
Neoplasias Laríngeas/diagnóstico por imagen , Neoplasias Laríngeas/patología , Condroma/diagnóstico por imagen , Condroma/patología , Diagnóstico Diferencial , Granuloma de Células Gigantes/diagnóstico por imagen , Granuloma de Células Gigantes/patología , Tumor de Células de la Granulosa/diagnóstico por imagen , Tumor de Células de la Granulosa/patología , Humanos , Neoplasias Laríngeas/epidemiología , Linfoma/diagnóstico por imagen , Linfoma/patología , Neurilemoma/diagnóstico por imagen , Neurilemoma/patología , Plasmacitoma/diagnóstico por imagen , Plasmacitoma/patología , Sarcoma/diagnóstico por imagen , Sarcoma/patología , Neoplasias Vasculares/diagnóstico por imagen , Neoplasias Vasculares/patologíaRESUMEN
OBJECTIVE: Clinical practice for differentiated thyroid cancer is moving towards lobectomy rather than total thyroidectomy in patients at low risk of recurrence. However, recurrence risk assessment depends on post-operative findings, while the surgical decision is based on preoperative factors. We determined the preoperative predictors of occult higher-risk pathology and rates of completion thyroidectomy among surgical candidates with nonbenign thyroid nodules 10 to 40 mm and no evidence of extrathyroidal extension or metastasis on preoperative evaluation. METHODS: Thyroid surgery cases at a single institution from 2005-2015 were reviewed to identify those meeting American Thyroid Association (ATA) criteria for lobectomy. ATA-based risk stratification from postoperative surgical pathology was compared to preoperative cytopathology, ultrasound, and clinical findings. RESULTS: Of 1,995 thyroid surgeries performed for nonbenign thyroid nodules 10 to 40 mm, 349 met ATA criteria for lobectomy. Occult high-risk features such as tall cell variant, gross extrathyroidal invasion, or vascular invasion were found in 36 cases (10.7%), while intraoperative lymphadenopathy led to surgical upstaging in 13 (3.7%). Intermediate risk features such as moderate lymphadenopathy or minimal extrathyroidal extension were present in an additional 44 cases. Occult risk features were present twice as often in Bethesda class 6 cases (35%) as in lower categories (12 to 17%). In multivariable analysis, Bethesda class and nodule size, but not age, race, sex, or ultrasound features, were significant predictors of occult higher-risk pathology. CONCLUSION: Most solitary thyroid nodules less than 4 cm and with cytology findings including atypia of undetermined significance through suspicious for papillary thyroid cancer would be sufficiently treated by lobectomy. ABBREVIATIONS: ATA = American Thyroid Association; CND = central neck dissection; DTC = differentiated thyroid cancer; ETE = extrathyroidal extension; FNA = fine needle aspiration; FTC/HCC = follicular thyroid carcinoma/Hurthle cell carcinoma; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; OR = odds ratio; PTC = papillary thyroid cancer; US = ultrasound.
Asunto(s)
Adenocarcinoma Folicular , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias de la Tiroides , Nódulo Tiroideo , Humanos , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Factores de Riesgo , Neoplasias de la Tiroides/cirugía , Nódulo Tiroideo/cirugíaRESUMEN
Integrase interactor 1 (INI-1)-deficient carcinoma is a rare cancer characterized by the loss of the SWItch/Sucrose Non-Fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene (SMARCB1) and tends to follow an aggressive clinical course. There is no currently available standard therapy option, although a few promising treatment strategies, including enhancer of zeste homolog 2 (EZH2) inhibition, are under active investigation. This report describes a 30-year-old woman with INI-1-deficient carcinoma who progressed on combination chemotherapy and an EZH2 inhibitor. Next-generation-sequencing-based targeted cancer-related gene assay confirmed SMARCB1 loss and revealed other mutations in breast cancer 1 gene and checkpoint kinase 2 gene, which may have impacted her clinical course. After discussion at the molecular tumor board, she was offered alisertib, an aurora A kinase inhibitor, on a single-patient expanded-use program and achieved prolonged disease stabilization. Aurora A kinase inhibition may have an important role in the management of patients with INI-1-deficient tumors, warranting further evaluation in clinical studies. KEY POINTS: Loss of the SWItch/Sucrose Non-Fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene (SMARCB1), which encodes integrase interactor 1 (INI-1), is associated with various mesenchymal malignancies, but a few carcinomas with rhabdoid features have been recently described as a distinct entity.INI-1-deficient carcinoma can be very aggressive, and there is no known treatment option available.There are encouraging preliminary data with an enhancer of zeste homolog 2 inhibitor, tazematostat, in INI-1-deficient malignancies, including INI-1-deficient carcinomas.Loss of INI-1 can activate aurora A kinase (AurkA), and inhibition of AurkA by alisertib could be a viable option and warrants further investigation in this cancer.Clinical genomic profiling can confirm diagnosis of molecularly defined malignancy and provide insights on therapeutic options.