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1.
Cancer ; 130(3): 410-420, 2024 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-37751180

RESUMEN

BACKGROUND: For oral cavity squamous cell carcinoma (OSCC), extent of extranodal extension (ENE) (minor, ≤2 mm; major, >2 mm) is differentially prognostic, whereas limitations exist with the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N-classification (TNM-8-N). METHODS: Resected OSCC patients at four centers were included and extent of ENE was recorded. Thresholds for optimal overall survival (OS) discrimination of lymph node (LN) features were established. After dividing into training and validation sets, two new N-classifications were created using 1) recursive partitioning analysis (RPA), and 2) adjusted hazard ratios (aHRs) and were ranked against TNM-8-N and two published proposals. RESULTS: A total of 1460 patients were included (pN0: 696; pN+: 764). Of the pN+ cases, 135 (18%) had bilateral/contralateral LNs; 126 (17%) and 244 (32%) had minor and major ENE, and two (0.3%) had LN(s) >6 cm without ENE (N3a). LN number (1 and >1 vs. 0: aHRs, 1.92 [95% confidence interval (CI), 1.44-2.55] and 3.21 [95% CI, 2.44-4.22]), size (>3 vs. ≤3 cm: aHR, 1.88 [95% CI, 1.44-2.45]), and ENE extent (major vs. minor: aHR, 1.40 [95% CI, 1.05-1.87]) were associated with OS, whereas presence of contralateral LNs was not (aHR, 1.05 [95% CI, 0.81-1.36]). The aHR proposal provided optimal performance with these changes to TNM-8-N: 1) stratification of ENE extent, 2) elimination of N2c and 6-cm threshold, and 3) stratification of N2b by 3 cm threshold. CONCLUSION: A new N-classification improved staging performance compared to TNM-8-N, by stratifying by ENE extent, eliminating the old N2c category and the 6 cm threshold, and by stratifying multiple nodes by size.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Estadificación de Neoplasias , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/patología , Pronóstico , Ganglios Linfáticos/patología , Neoplasias de Cabeza y Cuello/patología , Estudios Retrospectivos
2.
Br J Cancer ; 130(12): 1936-1942, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38714747

RESUMEN

BACKGROUND: Gut microbiome modulation to boost antitumor immune responses is under investigation. METHODS: ROMA-2 evaluated the microbial ecosystem therapeutic (MET)-4 oral consortia, a mixture of cultured human stool-derived immune-responsiveness associated bacteria, given with chemoradiation (CRT) in HPV-related oropharyngeal cancer patients. Co-primary endpoints were safety and changes in stool cumulative MET-4 taxa relative abundance (RA) by 16SRNA sequencing. Stools and plasma were collected pre/post-MET-4 intervention for microbiome and metabolome analysis. RESULTS: Twenty-nine patients received ≥1 dose of MET-4 and were evaluable for safety: drug-related adverse events (AEs) occurred in 13/29 patients: all grade 1-2 except one grade 3 (diarrhea). MET-4 was discontinued early in 7/29 patients due to CRT-induced toxicity, and in 1/29 due to MET-4 AEs. Twenty patients were evaluable for ecological endpoints: there was no increase in stool MET-4 RA post-intervention but trended to increase in stage III patients (p = 0.06). MET-4 RA was higher in stage III vs I-II patients at week 4 (p = 0.03) and 2-month follow-up (p = 0.01), which correlated with changes in plasma and stool targeted metabolomics. CONCLUSIONS: ROMA-2 did not meet its primary ecologic endpoint, as no engraftment was observed in the overall cohort. Exploratory findings of engraftment in stage III patients warrants further investigation of microbiome interventions in this subgroup.


Asunto(s)
Quimioradioterapia , Microbioma Gastrointestinal , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Humanos , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/microbiología , Neoplasias Orofaríngeas/virología , Masculino , Femenino , Persona de Mediana Edad , Quimioradioterapia/métodos , Anciano , Infecciones por Papillomavirus/complicaciones , Estudios Prospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/microbiología , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Adulto , Heces/microbiología
3.
Histopathology ; 84(2): 387-398, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37849332

RESUMEN

AIMS: Recently, HMGA2::WIF1 fusion has been reported in pleomorphic adenoma (PAs) originating from the parotid gland with a characteristic canalicular adenoma (CAA)-like pattern. However, it is unclear whether HMGA2::WIF1 fusion may occur in salivary gland carcinoma or tumours originating from the minor salivary glands. We herein conducted a detailed clinicopathological review of eight salivary gland tumours harbouring HMGA2::WIF1 fusions. METHODS AND RESULTS: The reviewed diagnoses of salivary gland neoplasms with HMGA2::WIF1 fusion were PA (n = four), myoepithelioma (n = one), myoepithelial carcinoma ex PA (n = two) and high-grade carcinoma with basaloid features (n = one). Two tumours originated from the minor salivary glands. Six tumours (80%) contained areas reminiscent of CAA characterised by interconnected trabeculae/canaliculi of monotonous oncocytic or cuboidal tumour cells associated with a hypocellular, hyalinised to myxoid stroma. Areas typical of PA were seen in four (50%) cases. All tumours showed diffuse S100 and CK7 immunopositivity. Adverse events were detected in two cases, including local recurrence in a patient with PA, and local and distant recurrences and disease-related death in a patient with a high-grade carcinoma of the minor salivary gland of the buccal space, showing tumour necrosis and perineural invasion. CONCLUSION: Salivary gland neoplasms with HMGA2::WIF1 fusion are predominantly characterised by CAA/striated duct adenoma-like histology and a S100+/CK7+ immunoprofile. These tumours are not always benign, as among all reported cases approximately 20% showed malignancy (six of 28) and adverse outcome (three of 15), including recurrence, distant metastasis and disease-specific mortality.


Asunto(s)
Adenoma Pleomórfico , Carcinoma , Neoplasias de las Glándulas Salivales , Humanos , Proteínas Adaptadoras Transductoras de Señales , Adenoma Pleomórfico/patología , Glándula Parótida/patología , Neoplasias de las Glándulas Salivales/patología
4.
Histopathology ; 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38708903

RESUMEN

BACKGROUND AND AIM: Head and neck nuclear protein of testis carcinoma (HN-NUT) is a rare form of carcinoma diagnosed by NUT immunohistochemistry positivity and/or NUTM1 translocation. Although the prototype of HN-NUT is a primitive undifferentiated round cell tumour (URC) with immunopositivity for squamous markers, it is our observation that it may assume variant histology or immunoprofile. METHODS: We conducted a detailed clinicopathological review of a large retrospective cohort of 30 HN-NUT, aiming to expand its histological and immunohistochemical spectrum. RESULTS: The median age of patients with HN-NUT was 39 years (range = 17-86). It affected the sinonasal tract (43%), major salivary glands (20%), thyroid (13%), oral cavity (7%), larynx (7%), neck (7%) and nasopharynx (3%). Although most cases of HN-NUT (63%) contained a component of primitive URC tumour, 53% showed other histological features and 37% lacked a URC component altogether. Variant histological features included basaloid (33%), differentiated squamous/squamoid (37%), clear cell changes (13%), glandular differentiation (7%) and papillary architecture (10%), which could co-exist. While most HN-NUT were positive for keratins, p63 and p40, occasional cases (5-9%) were entirely negative. Immunopositivity for neuroendocrine markers and thyroid transcription factor-1 was observed in 33 and 36% of cases, respectively. The outcome of HN-NUT was dismal, with a 3-year disease specific survival of 38%. CONCLUSIONS: HN-NUT can affect individuals across a wide age range and arise from various head and neck sites. It exhibits a diverse spectrum of histological features and may be positive for neuroendocrine markers, potentially leading to underdiagnosis. A low threshold to perform NUT-specific tests is necessary to accurately diagnose HN-NUT.

5.
Mod Pathol ; 36(11): 100305, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37595638

RESUMEN

Polymorphous adenocarcinoma (PAC) is a common, usually low-grade salivary gland carcinoma. While conventional PACs are most associated with PRKD1 p.E710D hotspot mutations, the cribriform subtype is often associated with gene fusions in PRKD1, PRKD2, or PRKD3. These fusions have been primarily identified by fluorescence in situ hybridization (FISH) analysis, with a minority evaluated by next-generation sequencing (NGS). Many of the reported fusions were detected by break-apart FISH probes and therefore have unknown partners or were negative by FISH altogether. In this study, we aimed to further characterize the fusions associated with PAC with NGS. Fifty-four PACs (exclusively cribriform and mixed/intermediate types to enrich the study for fusion-positive cases) were identified and subjected to NGS. Fifty-one cases were successfully sequenced, 28 of which demonstrated gene fusions involving PRKD1, PRKD2, or PRKD3. There were 10 cases with the PRKD1 p.E710D mutation. We identified a diverse group of fusion partners, including 13 novel partners, 3 of which were recurrent. The most common partners for the PRKD genes were ARID1A and ARID1B. The wide variety of involved genes is unlike in other salivary gland malignancies and warrants a broader strategy of sequencing for molecular confirmation for particularly challenging cases, as our NGS study shows.


Asunto(s)
Adenocarcinoma , Neoplasias de las Glándulas Salivales , Humanos , Hibridación Fluorescente in Situ , Adenocarcinoma/genética , Adenocarcinoma/patología , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Mutación , Fusión Génica
6.
Genes Chromosomes Cancer ; 61(12): 701-709, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35766997

RESUMEN

The mammalian Vestigial-like (VGLL) transcriptional cofactor family of proteins VGLL1-4 has recently emerged as an important player in the tumorigenesis of diverse neoplasms. The role of VGLL3 in soft tissue tumors is exemplified by its amplification in myxoinflammatory fibroblastic sarcoma and its rearrangement (fused to CHD7, CHD9, or MAMLD1) in hybrid schwannoma-perineurioma. This study characterizes a distinctive low-grade myogenic neoplasm with a striking predilection for the head and neck, characterized by VGLL3 fusions. The study includes five males and one female patient, aged 30-71 years (median, 56). Three tumors originated in the tongue, with one case each in the nasopharynx, oral cavity, and oropharynx. The VGLL3 fusion partners included TCF12 (n = 3), EP300 (n = 2), and PPARGC1A (n = 1). The tumor size range was 0.8-1.6 cm (all, but one, was <1 cm). Histologically, all tumors displayed bland spindle to ovoid cells arranged into vague fascicular and diffuse patterns. Mitotic activity ranged from 1 to 7 per 10 HPFs. Five tumors were muscle-centered and infiltrative, and one was centered beneath nasopharyngeal mucosa. Immunohistochemistry revealed consistent expression of desmin (diffuse in four and patchy in two cases) associated with patchy smooth muscle actin expression (4/6), and focal reactivity for myogenin (5/6) and myoD1 (1/3). All patients were managed surgically; one patient each received adjuvant radio- or chemotherapy. Three patients with follow-up were without disease at 8, 19, and 60 months and one was alive with unknown disease status at 24 months. All VGLL3 fusions were in-frame and involved exon 2, fused with either TCF12 exon 16, EP300 exon 31, or PPARGC1A exon 5, respectively. This series characterizes a distinctive subset of spindle cell rhabdomyosarcoma (RMS) with a predilection for the head and neck in adults, defined by VGLL3 fusions, likely indolent behavior and limited rhabdomyoblastic differentiation. Further delineation of this entity and differentiation from more aggressive molecular subtypes of spindle cell RMS is mandatory to define the most appropriate therapeutic strategy and avoid overtreatment.


Asunto(s)
Rabdomiosarcoma , Neoplasias de los Tejidos Blandos , Factores de Transcripción , Actinas , Adulto , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proteínas de Unión al ADN , Desmina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miogenina/genética , Rabdomiosarcoma/química , Rabdomiosarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Factores de Transcripción/genética
7.
Cancer ; 128(15): 2908-2921, 2022 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-35588085

RESUMEN

BACKGROUND: The objective of this study was to describe the clinical presentation and outcomes of human papillomavirus (HPV)-positive nasopharyngeal cancer (NPC) versus Epstein-Barr virus (EBV)-positive NPC and HPV-positive oropharyngeal cancer (OPC). METHODS: Clinical characteristics and presenting signs/symptoms were compared between patients who had viral-related NPC versus viral-related OPC treated with intensity-modulated radiotherapy from 2005 to 2020 and who were matched 1:1 (by tumor and lymph node categories, smoking, age, sex, histology, and year of diagnosis). Locoregional control (LRC), distant control (DC), and overall survival (OS) were compared using the 2005-2018 cohort to maintain 2 years of minimum follow-up. Multivariable analysis was used to evaluate the cohort effect. RESULTS: Similar to HPV-positive OPC (n = 1531), HPV-positive NPC (n = 29) occurred mostly in White patients compared with EBV-positive NPC (n = 422; 86% vs. 15%; p < .001). Primary tumor volumes were larger in HPV-positive NPC versus EBV-positive NPC (median volume, 51 vs. 23 cm3 ; p = .002), with marginally more Level IB nodal involvement. More patients with HPV-positive NPC complained of local pain (38% vs. 3%; p = .002). The median follow-up for the 2005-2018 cohort was 5.3 years. Patients who had HPV-positive NPC (n = 20) had rates of 3-year LRC (95% vs. 90%; p = .360), DC (75% vs. 87%; p = .188), and OS (84% vs. 89%; p = .311) similar to the rates in those who had EBV-positive NPC (n = 374). Patients who had HPV-positive NPC also had rates of LRC (95% vs. 94%; p = .709) and OS (84% vs. 87%; p = .440) similar to the rates in those who had HPV-positive OPC (n = 1287). The DC rate was lower in patients who had HPV-positive disease (75% vs. 90%; p = .046), but the difference became nonsignificant (p = .220) when the analysis was adjusted for tumor and lymph node categories, smoking, and chemotherapy. CONCLUSIONS: HPV-positive NPC and EBV-positive NPC seem to be mutually exclusive diseases. Patients who have HPV-positive NPC have greater local symptom burden and larger primary tumors but have similar outcomes compared with patients who have EBV-positive NPC or HPV-positive OPC.


Asunto(s)
Alphapapillomavirus , Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , ADN Viral , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/epidemiología , Herpesvirus Humano 4/genética , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/epidemiología , Neoplasias Nasofaríngeas/terapia , América del Norte , Papillomaviridae/genética , Infecciones por Papillomavirus/complicaciones , Pronóstico
8.
Mod Pathol ; 35(11): 1587-1595, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35701667

RESUMEN

DEK::AFF2 carcinoma of the sinonasal tract is an emerging entity. The tumor is typically characterized by papillary proliferation of non-keratinizing squamous epithelial cells with monotonous cytologic features, which may mimic other sinonasal tumors. The confirmation of this gene fusion has thus far relied solely on next-generation sequencing, fluorescence in situ hybridization (FISH), or reverse transcription polymerase chain reaction (RT-PCR). This current study aimed to validate an immunohistochemical assay for AFF2 C-terminus as an ancillary marker. We first analyzed publicly available RNA sequencing data of sinonasal tumors from the national center for biotechnology information (NCBI) sequence read archive and identified 3 DEK::AFF2 carcinomas out of 28 sinonasal tumors. The gene expression of AFF2 was significantly higher in the fusion-positive cases compared to the wild-type tumors (p < 0.001), while DEK was not. We then optimized an immunohistochemical assay with an anti-AFF2 C-terminus antibody for ancillary diagnosis. Seventeen DEK::AFF2 carcinomas, including 11 cases with predominantly low-grade morphology and one showing glandular differentiation, as well as 78 DEK FISH-negative sinonasal tumors were evaluated by AFF2 immunohistochemistry (IHC). Sixteen of the 17 DEK::AFF2 carcinomas showed nuclear AFF2 expression in ≥30% of tumor cells, including one decalcified case that failed FISH and RT-PCR confirmation. The one case that was negative for AFF2 IHC in the tumor cells also lacked expression in the internal positive control. It was thus considered a failure of the IHC rather than a truly negative case and was excluded from the statistical analysis. All DEK FISH-negative sinonasal tumors were negative for nuclear AFF2 expression. The nuclear expression of AFF2 IHC showed 100% sensitivity and specificity for DEK::AFF2 carcinoma. Accordingly, AFF2 IHC is a highly sensitive and specific ancillary marker that distinguishes DEK-AFF2 carcinoma from the other sinonasal tumors with overlapping morphological features and may be an especially useful alternative for decalcified specimens.


Asunto(s)
Carcinoma , Senos Paranasales , Humanos , Hibridación Fluorescente in Situ , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Carcinoma/diagnóstico , Carcinoma/genética , Carcinoma/patología , Inmunohistoquímica , Senos Paranasales/química , Senos Paranasales/patología , Proteínas de Unión a Poli-ADP-Ribosa/genética , Proteínas Cromosómicas no Histona/genética , Proteínas Oncogénicas/genética , Proteínas Nucleares/genética
9.
Genes Chromosomes Cancer ; 60(1): 49-53, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32951290

RESUMEN

Nasopharyngeal adenocarcinoma is a rare malignancy that is classified into conventional/surface- and salivary-types. Herein we report the case of a 52-year-old male who presented with a right nasopharyngeal mass and right-sided hearing loss. Diagnostic imaging revealed a circumscribed 1.7 cm mass centred in the right antero-lateral aspect of the nasopharynx. A biopsy showed a gland-forming neoplasm that was in continuity with the surface epithelium. The tumor exhibited a nested to micro-papillary architecture, with mild cytologic atypia. Immunohistochemistry demonstrated diffuse staining for CK7, SOX10, and p16; the abluminal layer was highlighted by CK5 and p63, while the luminal cells expressed CD117. The tumor was not amenable to subclassification and was diagnosed as a low-grade nasopharyngeal adenocarcinoma, not otherwise specified (NOS). Subsequent RNA sequencing was performed which identified a novel GOLGB1-BRAF fusion product. Based on its unique morphology and molecular findings, this is presumed to represent a novel subtype of nasopharyngeal adenocarcinoma. In addition to being of diagnostic relevance, this fusion may ultimately represent a potential therapeutic target.


Asunto(s)
Adenocarcinoma/genética , Proteínas de la Matriz de Golgi/genética , Neoplasias Nasofaríngeas/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas B-raf/genética , Adenocarcinoma/patología , Proteínas de la Matriz de Golgi/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/patología , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Proto-Oncogénicas B-raf/metabolismo
10.
Genes Chromosomes Cancer ; 60(10): 695-708, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34176176

RESUMEN

Salivary gland tumors represent a diverse group of neoplasms that occasionally pose a diagnostic challenge for pathologists, particularly with limited sampling. Gene fusions, which may reflect genetic drivers, are increasingly recognized in a subset of these neoplasms, and can be leveraged for diagnostic purposes. We performed a retrospective analysis on a cohort of 80 benign and malignant salivary gland tumors, enriched for subtypes known to harbor recurrent fusion events, to validate the diagnostic use of a targeted RNA sequencing assay to detect fusion transcripts. Testing identified fusion genes in 71% (24/34) of pleomorphic adenoma and carcinoma-ex-pleomorphic adenoma, with 56% of cases showing rearrangement of PLAG1 and 15% HMGA2. In addition to confirming known partners for these genes, novel PLAG1 fusion partners were identified, including DSTN, NTF3, and MEG3; CNOT2 was identified as a novel fusion partner for HMGA2. In adenoid cystic carcinoma, 95% of cases (19/20) were positive for a fusion event. MYB was rearranged in 60% (12/20), MYBL1 in 30% (6/20), and NFIB in 5% (1/20); two tumors exhibited novel fusion products, including NFIB-TBPL1 and MYBL1-VCPIP1. Fusion genes were identified in 64% (9/14) of cases of mucoepidermoid carcinoma; MAML2 was confirmed to partner with either CRTC1 (43%) or CRTC3 (21%). One salivary duct carcinoma was found to harbor a novel RAPGEF6-ACSL6 fusion gene. Finally, as anticipated, gene fusions were not detected in any of the five acinic cell carcinomas included in the cohort. In summary, targeted RNA sequencing represents a diagnostically useful ancillary technique for identifying a variety of existing, and novel, fusion transcripts in the classification of salivary gland neoplasms.


Asunto(s)
Adenoma Pleomórfico/patología , Biomarcadores de Tumor/genética , Carcinoma Adenoide Quístico/patología , Regulación Neoplásica de la Expresión Génica , Proteínas de Fusión Oncogénica/genética , Neoplasias de las Glándulas Salivales/patología , Análisis de Secuencia de ARN/métodos , Adenoma Pleomórfico/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Adenoide Quístico/genética , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Neoplasias de las Glándulas Salivales/genética , Adulto Joven
11.
Br J Cancer ; 124(9): 1543-1551, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33750907

RESUMEN

BACKGROUND: Oral and gut microbiomes have emerged as potential biomarkers in cancer. We characterised the oral and gut microbiomes in a prospective observational cohort of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) patients and evaluated the impact of chemoradiotherapy (CRT). METHODS: Saliva, oropharyngeal swabs over the tumour site and stool were collected at baseline and post-CRT. 16S RNA and shotgun metagenomic sequencing were used to generate taxonomic profiles, including relative abundance (RA), bacterial density, α-diversity and ß-diversity. RESULTS: A total of 132 samples from 22 patients were analysed. Baseline saliva and swabs had similar taxonomic composition (R2 = 0.006; p = 0.827). Oropharyngeal swabs and stool taxonomic composition varied significantly by stage, with increased oral RA of Fusobacterium nucleatum observed in stage III disease (p < 0.05). CRT significantly reduced the species richness and increased the RA of gut-associated taxa in oropharyngeal swabs (p < 0.05), while it had no effect in stool samples. These findings remained significant when adjusted by stage, smoking status and antibiotic use. CONCLUSIONS: Baseline oral and gut microbiomes differ by stage in this HPV+ cohort. CRT caused a shift towards a gut-like microbiome composition in oropharyngeal swabs. Stage-specific features and the transitions in oral microbiome might have prognostic and therapeutic implications.


Asunto(s)
Quimioradioterapia/efectos adversos , Microbioma Gastrointestinal , Mucosa Bucal/microbiología , Neoplasias Orofaríngeas/terapia , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/complicaciones , Saliva/microbiología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/virología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Mucosa Bucal/efectos de los fármacos , Mucosa Bucal/efectos de la radiación , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/virología , Pronóstico , Estudios Prospectivos , Saliva/efectos de los fármacos , Saliva/efectos de la radiación
12.
Mod Pathol ; 34(10): 1820-1830, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34108636

RESUMEN

A novel DEK-AFF2 fusion has been recently identified in four cases of basaloid to nonkeratinizing squamous cell carcinoma (SCC) in the sinonasal tract and middle ear with high-grade morphology. The exceptional response to immune checkpoint inhibitor in the first reported case highlights the potential clinical importance of identifying tumors with DEK-AFF2 fusions. We herein reported the first series of seven cases of DEK-AFF2 fusion-associated sinonasal SCC with deceptively bland morphology, including four cases of low-grade papillary Schneiderian carcinoma, which is a recently described tumor type with unknown molecular underpinnings. The DEK gene rearrangement was confirmed by DEK break-apart fluorescence in situ hybridization and DEK-AFF2 fusion transcripts were detected by reverse transcription polymerase chain reaction. In contrast to the previously reported DEK-AFF2 fusion-positive high-grade carcinomas, these tumors had a monotonous and bland morphology and were all initially diagnosed as sinonasal papilloma (SP) of various types, with or without dysplasia or carcinoma in situ. The tumor was characterized by mixed exophytic and inverted patterns, broad papillary fronds, acantholytic change, cellular monotony, dense neutrophilic infiltrates, and peripheral palisading. All tumors were diffusely positive for p40 or p63 and negative for NUT and p16. Molecular drivers associated with SP, including EGFR and KRAS mutations and both high and low-risk human papillomavirus infection, were negative in all cases. Although there was no overt stromal invasion or desmoplastic reaction in the initial specimens, these tumors tended to progress locoregionally through a prolonged clinical course and occasionally develop lymph node metastases, high-grade transformation, or extensively local destruction eventually leading to death. These justify more aggressive clinical management. Therefore, we propose the new terminology "DEK-AFF2 fusion-associated papillary SCC of the sinonasal tract" to better describe this clinicopathologically and molecularly distinct entity.


Asunto(s)
Carcinoma Papilar/genética , Proteínas Cromosómicas no Histona/genética , Neoplasias Nasofaríngeas/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Oncogénicas/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Adulto , Anciano , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patología , Proteínas Cromosómicas no Histona/metabolismo , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Proteínas Nucleares/metabolismo , Proteínas Oncogénicas/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología
13.
Mod Pathol ; 33(1): 65-73, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31492931

RESUMEN

Polymorphous adenocarcinoma (PAC) and cribriform adenocarcinoma of (minor) salivary gland (CASG) are salivary gland tumors with overlapping spectrum of morphology. Whether these represent distinct entities or a histologic spectrum of the same tumor remains contentious. PACs harbor recurrent PRKD1 E710D hotspot mutations in >70% of cases, whereas 80% of CASGs display rearrangements involving PRKD1, PRKD2, or PRKD3 (PRKD1/2/3). We studied the molecular and morphologic features of 37 PACs/CASGs, seeking to identify the associations among genotype, histologic phenotype, and classification. DNA was subjected to Sanger sequencing analysis of the PRKD1 hotspot locus. Fluorescence in situ hybridization (FISH) analysis for PRKD1/2/3 was performed using dual-color break-apart probes. Tumors were classified into four categories as described previously: PAC, CASG, tumor with indeterminate features (TIF), and tumor with a predominant papillary pattern (TPPP). PRKD1 E710D hotspot mutations were identified in 56%, 20%, 43% and 0% of PACs, CASGs, TIFs, and TPPPs, respectively. FISH demonstrated PRKD1/2/3 rearrangements in 13%, 78%, 36%, and 75% of PACs, CASGs, TIFs, and TPPPs, respectively. Histologically, fusion-positive tumors were associated with a high percentage of papillary growth, low percentage of single filing arrangement, a propensity of base of tongue location, and frequent (50%) lymph node metastasis, compared with the mutation-related tumors which had negligible nodal metastasis risk. Our results demonstrated that (1) PACs/CASGs are underpinned by genetic alterations affecting PRKD genes; (2) despite the associations between PAC and PRKD1 hotspot mutations and CASG and PRKD1/2/3 fusion, such distinction is not absolute; and (3) there is of a novel genotypic-phenotypic association whereby fusion-positive tumors are usually located in the base of the tongue, show papillary architecture and have a high risk of nodal metastasis. Genetic analysis of PRKD genes appears to be useful characterizing this spectrum of tumors, not only histologically but also clinically identifying those tumors with high risk of nodal metastasis.


Asunto(s)
Adenocarcinoma/genética , Adenocarcinoma/patología , Proteína Quinasa C/genética , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Adulto Joven
14.
Int J Gynecol Pathol ; 39(4): 391-399, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31274700

RESUMEN

Vulvar squamous cell carcinomas (VSCC) represent the most common carcinoma of the female external genitalia, with increasing incidence. Although high-risk human papillomavirus (HPV) infection has long been implicated in the majority of cervical and anal squamous cell carcinomas, there is uncertainty about its prevalence and prognostic impact in VSCC. In this study, we conducted a retrospective integrated morphologic and multimodal HPV analysis of a cohort of 114 VSCC cases treated at the Princess Margaret Cancer Centre/University Health Network, Toronto, Canada between 2000 and 2010. VSCC histology was reviewed. We analyzed the cohort for HPV using polymerase chain reaction based method, and tissue microarray DNA and RNA in situ hybridization (ISH), and p16 immunohistochemistry. Among the 114 cases (age 70±16 yr), 36.7% of cases were classified as having histomorphology of HPV infection. HPV was detected in 31.9% (polymerase chain reaction), 14.0% (DNA ISH), and 27.3% (RNA ISH) of cases. p16 immunohistochemistry was positive in 37.8% of cases. On univariate analysis, HPV morphology (P=0.009), p16+ (P=0.00013), DNA ISH+ (P=0.021), and RNA ISH+ (P=0.00061) were associated with better 5-yr progression-free survival. DNA ISH+ (P=0.049) was associated with better 5-yr overall survival. On multivariate analysis, HPV morphology (P=0.033), p16+ (P=0.01), and RNA ISH+ (P=0.035) were associated with better 5-yr progression-free survival. In conclusion, a subset of VSCC is associated with HPV, which correlates with better outcome. Relatively inexpensive tests such as histomorphologic evaluation, p16 immunohistochemistry, and HPV RNA ISH can be used to predict outcome in VSCC. Therefore, routine reporting of HPV status in VSCC is recommended.


Asunto(s)
Carcinoma de Células Escamosas/diagnóstico , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/diagnóstico , Neoplasias de la Vulva/diagnóstico , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/patología , Estudios de Cohortes , Femenino , Humanos , Inmunohistoquímica , Hibridación in Situ , Persona de Mediana Edad , Ontario/epidemiología , Papillomaviridae/genética , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/patología , Reacción en Cadena de la Polimerasa , Pronóstico , Supervivencia sin Progresión , ARN Viral/genética , Estudios Retrospectivos , Neoplasias de la Vulva/epidemiología , Neoplasias de la Vulva/patología
15.
Genes Chromosomes Cancer ; 58(10): 705-712, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31008539

RESUMEN

Fibroblastic/myofibroblastic neoplasms represent a broad, and occasionally diagnostically challenging, category of soft tissue neoplasms. A subset of these tumors defy conventional classification. However, with the advent of next-generation sequencing, the identification of disease-defining molecular alterations is gradually improving their subclassification. Following identification of two index cases of a distinctive fibroblastic neoplasm with a fusion gene involving PRRX1 and NCOA1, we performed a retrospective review to further characterize this entity. We identified two additional cases, including one with a fusion between PRRX1 and NCOA2. The average patient age was 38 years, and three patients were female. Two tumors occurred on the neck, and the others involved the groin and thigh. Tumors were centered in the subcutis and ranged from 2.3 to 14.0 cm (average 5.8 cm). Morphologically, they were predominantly hypocellular, with focal hypercellularity. They were composed of monomorphic spindle-stellate cells with a vague fascicular pattern. The nuclei were bland with only rare mitotic activity, and occasional multinucleation. The intervening stroma was typically abundant and ranged from myxoid to collagenous, with frequent rope-like collagen bundles. Three of the cases had a prominent vasculature ranging from numerous small curvilinear vessels to ectatic and branching staghorn-like vessels. Immunohistochemistry was negative for desmin, smooth muscle actin, S100, CD34, keratin, and epithelial membrane antigen. Each of the patients was treated by simple excision and none of the tumors were associated with local recurrence or metastasis. Based on their unique morphological and molecular attributes, we believe this represents a novel fibroblastic tumor for which we have tentatively proposed the name "PRRX-NCOAx-rearranged fibroblastic tumor."


Asunto(s)
Proteínas de Homeodominio/genética , Coactivador 1 de Receptor Nuclear/genética , Coactivador 2 del Receptor Nuclear/genética , Fusión de Oncogenes , Neoplasias de los Tejidos Blandos/genética , Adulto , Núcleo Celular/metabolismo , Núcleo Celular/patología , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de los Tejidos Blandos/patología
16.
J Proteome Res ; 17(6): 2045-2059, 2018 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-29681158

RESUMEN

Bidirectional communication between cells and their microenvironment is crucial for both normal tissue homeostasis and tumor growth. During the development of oral tongue squamous cell carcinoma (OTSCC), cancer-associated fibroblasts (CAFs) create a supporting niche by maintaining a bidirectional crosstalk with cancer cells, mediated by classically secreted factors and various nanometer-sized vesicles, termed as extracellular vesicles (EVs). To better understand the role of CAFs within the tumor stroma and elucidate the mechanism by which secreted proteins contribute to OTSCC progression, we isolated and characterized patient-derived CAFs from resected tumors with matched adjacent tissue fibroblasts (AFs). Our strategy employed shotgun proteomics to comprehensively characterize the proteomes of these matched fibroblast populations. Our goals were to identify CAF-secreted factors (EVs and soluble) that can functionally modulate OTSCC cells in vitro and to identify novel CAF-associated biomarkers. Comprehensive proteomic analysis identified 4247 proteins, the most detailed description of a pro-tumorigenic stroma to date. We demonstrated functional effects of CAF secretomes (EVs and conditioned media) on OTSCC cell growth and migration. Comparative proteomics identified novel proteins associated with a CAF-like state. Specifically, MFAP5, a protein component of extracellular microfibrils, was enriched in CAF secretomes. Using in vitro assays, we demonstrated that MFAP5 activated OTSCC cell growth and migration via activation of MAPK and AKT pathways. Using a tissue microarray of richly annotated primary human OTSCCs, we demonstrated an association of MFAP5 expression with patient survival. In summary, our proteomics data of patient-derived stromal fibroblasts provide a useful resource for future mechanistic and biomarker studies.


Asunto(s)
Fibroblastos Asociados al Cáncer/química , Proteínas Contráctiles/fisiología , Glicoproteínas/fisiología , Neoplasias de Cabeza y Cuello/patología , Comunicación Paracrina , Proteómica , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Biomarcadores , Fibroblastos Asociados al Cáncer/metabolismo , Movimiento Celular , Proliferación Celular , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Péptidos y Proteínas de Señalización Intercelular , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Análisis de Supervivencia , Neoplasias de la Lengua
17.
Cancer ; 122(20): 3136-3144, 2016 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-27379604

RESUMEN

BACKGROUND: The authors hypothesized that histogenetic classification of salivary duct carcinoma (SDC) could account for de novo tumors and those with morphologic or molecular evidence (pleomorphic adenoma gene 1 [PLAG1], high-mobility group AT hook 2 [HMGA2] rearrangement, amplification) of pleomorphic adenoma (PA). METHODS: SDCs (n = 66) were reviewed for morphologic evidence of PA. PLAG1 and HMGA2 alterations were detected by fluorescence in situ hybridization (FISH). PLAG1-positive tumors were tested by FISH for fibroblast growth factor receptor 1 (FGFR1) rearrangement. Thirty-nine tumors were analyzed using a commercial panel for mutations and copy number variations in 50 cancer-related genes. RESULTS: On the basis of combined morphologic and molecular evidence of PA, 4 subsets of SDC emerged: 1) carcinomas with morphologic evidence of PA but intact PLAG1 and HMGA2 (n = 22); 2) carcinomas with PLAG1 alteration (n = 18) or 3) HMGA2 alteration (n = 12); and 4) de novo carcinomas, without morphologic or molecular evidence of PA (n = 14). The median disease-free survival was 37 months (95% confidence interval, 28.4-45.6 months). Disease-free survival and other clinicopathologic parameters did not differ for the subsets defined above. Combined Harvey rat sarcoma viral oncogene homolog/phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit α (HRAS/PIK3CA) mutations were observed predominantly in de novo carcinomas (5 of 8 vs 2 of 31 tumors; P = .035). Erb-B2 receptor tyrosine kinase 2 (ERBB2) copy number gain was not observed in de novo carcinomas (0 of 8 vs 12 of 31 tumors; P = .08). Tumor protein 53 (TP53) mutations were more common in SDC ex pleomorphic adenomas than in de novo carcinomas (17 of 31 vs 1 of 8 tumors; P = .033). CONCLUSIONS: The genetic profile of SDC varies with the absence or presence of pre-existing PA and its cytogenetic signature. Most de novo SDCs harbor combined HRAS/PIK3CA mutations and no ERBB2 amplification. Cancer 2016;122:3136-44. © 2016 American Cancer Society.


Asunto(s)
Adenoma Pleomórfico/diagnóstico , Biomarcadores de Tumor/genética , Carcinoma Ductal/diagnóstico , Proteínas de Unión al ADN/genética , Reordenamiento Génico , Variación Genética/genética , Proteína HMGA2/genética , Neoplasias de las Glándulas Salivales/diagnóstico , Adenoma Pleomórfico/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal/clasificación , Carcinoma Ductal/genética , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Neoplasias de las Glándulas Salivales/clasificación , Neoplasias de las Glándulas Salivales/genética , Tasa de Supervivencia
18.
Invest New Drugs ; 34(5): 575-83, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27289242

RESUMEN

Background Curative-intent, non-surgical treatment options for locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) include radiotherapy with/without chemotherapy or radiotherapy with cetuximab. This single institution phase I dose escalation trial tested the pan-human epidermal growth factor receptor (HER) oral tyrosine kinase inhibitor, dacomitinib, in combination with standard cisplatin-based chemoradiotherapy. Methods Patients received oral dacomitinib once daily at 3 protocol-defined dose levels (15 mg, 30 mg, and 45 mg). Cisplatin was given intravenously at 100 mg/m(2) every 3 weeks. Radiotherapy was delivered using intensity modulated radiation therapy (IMRT) to a dose of 70Gy in 35 daily fractions to the primary and nodal disease. Dose escalation was performed using a standard 3 + 3 design. Results Twelve patients with LA-SCCHN were enrolled between January 2013 and August 2014. No dose limiting toxicities (DLTs) were observed in the 15 mg and 30 mg dose levels. In the 45 mg dose level, one of four evaluable patients developed a DLT with intolerable grade 2 diarrhea requiring discontinuation of therapy. Adverse events (AEs) attributed to dacomitinib alone include diarrhea, hypertension, and acneiform and maculopapular rash. The most common non-hematological AEs include weight loss, diarrhea, dry mouth, mucositis, nausea, hypoalbuminemia, and hyponatremia. Frequency and severity of AEs did not increase with increasing dose levels of dacomitinib. All patients completed the full course of radiotherapy on schedule and the median dose of cisplatin was 200 mg/m(2), which is comparable to historical standards. Of the 10 patients evaluable for response, 1 patient relapsed with metastatic disease. Conclusions The triple combination has a tolerable side effect profile and dose levels 15 mg and 30 mg were cleared safely. The addition of dacomitinib did not preclude delivery of standard chemoradiotherapy. Studies testing the addition of other HER-targeted therapies to platinum-based concurrent chemo-radiotherapy in LA-SCCHN have failed to demonstrate improved patient outcomes and have reported trends towards excessive toxicities. These results generated uncertainty regarding the future of these agents in combination with chemo-radiation for the treatment of LA-SCCHN, which ultimately led to the early termination of this study.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/terapia , Quimioradioterapia , Cisplatino/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Neoplasias de Cabeza y Cuello/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinonas/uso terapéutico , Adulto , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia/efectos adversos , Cisplatino/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Quinazolinonas/efectos adversos , Carcinoma de Células Escamosas de Cabeza y Cuello
19.
Histopathology ; 68(7): 1055-62, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26426580

RESUMEN

AIMS: Polymorphous low-grade adenocarcinoma (PLGA) is the second most common intra-oral salivary gland malignancy. The vast majority of PLGAs harbour a PRKD1 E710D hot-spot somatic mutation or somatic rearrangements of PRKD1, PRKD2 or PRKD3. Given the kinase domain homology among PRKD1, PRKD2 and PRKD3, we sought to define whether PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements would be driven by somatic mutations affecting the kinase domains of PRKD2 or PRKD3. METHODS AND RESULTS: DNA was extracted from eight microdissected PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements. Samples were thoroughly centrally reviewed, microdissected and subjected to Sanger sequencing of the kinase domains of the PRKD2 and PRKD3 genes. None of the PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements harboured somatic mutations in the kinase domains of the PRKD2 or PRKD3 genes. CONCLUSION: PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements are unlikely to harbour somatic mutations in the kinase domains of PRKD2 or PRKD3. Further studies are warranted to define the driver genetic events in this subgroup of PLGAs.


Asunto(s)
Adenocarcinoma/genética , Proteína Quinasa C/genética , Neoplasias de las Glándulas Salivales/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/enzimología , Adenocarcinoma/patología , Adulto , Anciano , Secuencia de Aminoácidos , Femenino , Reordenamiento Génico , Genotipo , Humanos , Masculino , Microdisección , Persona de Mediana Edad , Mutación , Dominios Proteicos , Neoplasias de las Glándulas Salivales/diagnóstico , Neoplasias de las Glándulas Salivales/enzimología , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales/patología , Alineación de Secuencia , Análisis de Secuencia de ADN
20.
Mol Cell Proteomics ; 13(12): 3572-84, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25271301

RESUMEN

HPV-positive oropharyngeal carcinoma (OPC) patients have superior outcomes relative to HPV-negative patients, but the underlying mechanisms remain poorly understood. We conducted a proteomic investigation of HPV-positive (n = 27) and HPV-negative (n = 26) formalin-fixed paraffin-embedded OPC biopsies to acquire insights into the biological pathways that correlate with clinical behavior. Among the 2,633 proteins identified, 174 were differentially abundant. These were enriched for proteins related to cell cycle, DNA replication, apoptosis, and immune response. The differential abundances of cortactin and methylthioadenosine phosphorylase were validated by immunohistochemistry in an independent cohort of 29 OPC samples (p = 0.023 and p = 0.009, respectively). An additional 1,124 proteins were independently corroborated through comparison to a published proteomic dataset of OPC. Furthermore, utilizing the Cancer Genome Atlas, we conducted an integrated investigation of OPC, attributing mechanisms underlying differential protein abundances to alterations in mutation, copy number, methylation, and mRNA profiles. A key finding of this integration was the identification of elevated cortactin oncoprotein levels in HPV-negative OPCs. These proteins might contribute to reduced survival in these patients via their established role in radiation resistance. Through interrogation of Cancer Genome Atlas data, we demonstrated that activation of the ß1-integrin/FAK/cortactin/JNK1 signaling axis and associated differential regulation of activator protein 1 transcription factor target genes are plausible consequences of elevated cortactin protein levels.


Asunto(s)
Carcinoma/genética , Cortactina/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Orofaríngeas/genética , Infecciones por Papillomavirus/genética , Factor de Transcripción AP-1/genética , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Carcinoma/complicaciones , Carcinoma/mortalidad , Carcinoma/patología , Ciclo Celular/genética , Estudios de Cohortes , Cortactina/metabolismo , Replicación del ADN , Femenino , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata/genética , Integrina beta1/genética , Integrina beta1/metabolismo , Masculino , Persona de Mediana Edad , Proteína Quinasa 8 Activada por Mitógenos/genética , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Neoplasias Orofaríngeas/complicaciones , Neoplasias Orofaríngeas/mortalidad , Neoplasias Orofaríngeas/patología , Papillomaviridae/fisiología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/mortalidad , Infecciones por Papillomavirus/patología , Purina-Nucleósido Fosforilasa/genética , Purina-Nucleósido Fosforilasa/metabolismo , Transducción de Señal , Análisis de Supervivencia , Factor de Transcripción AP-1/metabolismo
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