Special Issue "HPV in the Head and Neck Region".

Previously, human papillomaviruses were best known for causing diseases in the genital tract, where high-risk types may cause, e.g., cancer of the cervix uteri, while low risk types could cause condylomas [...].

Cervical lymphadenopathy following coronavirus disease 2019 vaccine: clinical characteristics and implications for head and neck cancer services.

OBJECTIVE: Patients with coronavirus disease vaccine associated lymphadenopathy are increasingly being referred to healthcare services. This work is the first to report on the incidence, clinical course and imaging features of coronavirus disease vaccine associated cervical lymphadenopathy, with special emphasis on the implications for head and neck cancer services. METHODS: This was a retrospective cohort study of all patients referred to our head and neck cancer clinics between 16 December 2020 and 12 March 2021. The main outcomes measured were the proportion of patients with vaccine-associated cervical lymphadenopathy, and the clinical and imaging characteristics. RESULTS: The incidence of vaccine-associated cervical lymphadenopathy referrals was 14.8 per cent (n = 13). Five patients (38.5 per cent) had abnormal-looking enlarged and rounded nodes with increased vascularity. Only seven patients (53.9 per cent) reported full resolution within an average of 3.1 ± 2.3 weeks. CONCLUSION: Coronavirus disease vaccine associated cervical lymphadenopathy can mimic malignant lymphadenopathy and therefore might prove challenging to diagnose and manage correctly. Healthcare services may encounter a significant increase in referrals.

Solitary cystic metastatic lymph node of occult human papillomavirus-related oropharyngeal cancer mimicking second branchial cleft cyst: A case report.

RATIONALE: Human papillomavirus (HPV)-related oropharyngeal cancer is becoming more common, the primary cancer AQ4 usually occult and appearing only as cystic cervical lymph node (LN) metastasis. Distinguishing between a benign cystic lesion and cystic LN metastasis is challenging given their similar radiologic and histologic appearances. PATIENT CONCERNS: A 54-year-old man presented with a bulging cystic mass measuring 6.4cm on the right side of neck. DIAGNOSES: Postexcision diagnosis was second branchial cleft cyst. After 2 years, the cystic mass recurred, and HPV-related tonsillar squamous cell carcinoma with cystic metastatic LNs was confirmed after wide tonsillectomy and neck dissection. The previous cystic lesion proved to be a cystic metastatic LN from the same malignancy with additional p16 immunostain. INTERVENTIONS: The patient was treated with adjuvant concurrent chemoradiation therapy. OUTCOMES: The patient was followed up in the outpatient department with no evidence of recurrence after 1 year. LESSONS: When an adult has a cystic mass in the upper neck, we must rigorously exclude it as a cystic metastatic LN of occult HPV-related oropharyngeal cancer. Additional p16 staining might be helpful.

Initial presentation of human papillomavirus-related head and neck cancer: A retrospective review.

OBJECTIVE: Human papillomavirus (HPV) has been identified as a risk factor for oropharyngeal squamous cell carcinoma (OPSCC) and a cause of the recent dramatic rise in the incidence of this disease. HPV-positive OPSCC typically affects a younger population and has no validated screening test. This study aims to outline the common presenting signs of HPV-positive OPSCC. METHODS: We conducted a retrospective single-institution review on 370 patients who were treated at the Icahn School of Medicine at Mount Sinai, New York City, between April 2007 and November 2015 for OPSCC. We included patients with newly diagnosed OPSCC and sufficient history and physical data in the final analysis. Univariate analysis was used to compare HPV-positive and HPV-negative cohorts for demographics, tumor location, tumor staging, initial presentation and symptoms, and physical exam findings. RESULTS: Two hundred and seven patients met the inclusion criteria. The most common initial symptoms for OPSCC were neck mass (51.7%) and sore throat (13.0%). The HPV-positive cohort was more likely to present with a chief complaint of neck mass compared to the HPV-negative cohort (56.1% vs. 22.2%; P = 0.0015). A positive neck exam was associated with HPV-positive status (73.9% vs. 40.7%; P = 0.0012). CONCLUSION: HPV-positive OPSCC is an incipient epidemic, poised to surpass cervical cancer as the most common HPV-related cancer by 2020. Initial presenting signs may often be mistaken for benign processes. This study provides physicians with a better understanding of initial presentation of patients with HPV-positive OPSCC, leading to earlier diagnosis and improved outcomes. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:877-882, 2019.

Human papillomavirus (HPV) is absent in branchial cleft cysts of the neck distinguishing them from HPV positive cystic metastasis.

BACKGROUND: Distinguishing branchial cleft cysts (BCCs) from cystic metastases of a human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) is challenging. Fine needle aspirates (FNAs) from cystic metastasis may be non-representative, while reactive squamous cells from BCC can be atypic. Based on cytology and with the support of HPV DNA positivity many centers treat cystic metastasis oncological and thus patients are spared neck dissection. To do so safely, one must investigate whether HPV DNA and p16INK4a overexpression is found exclusively in cystic metastases and not in BCC. PATIENTS AND METHODS: DNA was extracted from formalin fixed paraffin embedded (FFPE) surgically resected BCCs from 112 patients diagnosed 2007-2015 at Karolinska University Hospital and amplified by PCR. A multiplex bead-based assay used to detect 27 HPV-types and p16INK4a expression was analyzed by immunohistochemistry (IHC). RESULTS: All 112 BCCs were HPV DNA negative, and of 105 BCCs possible to evaluate for p16INK4a, none overexpressed p16INK4a. CONCLUSIONS: HPV DNA and p16INK4a overexpression were absent in BCCs. Lack of HPV DNA and p16 protein overexpression in BCCs is helpful to discriminate benign BCCs from HPV+ OPSCC metastasis. HPV testing definitely has a role in the diagnostics of cystic masses of the neck.

Unusual case of hemidiaphragmatic paralysis secondary to cervical herpes zoster.

Hemidiaphragmatic paralysis is usually caused by surgery, malignancy or trauma and rarely by viral infections. Herpes zoster (shingles) results in varied neurological complications, but peripheral motor involvement or diaphragmatic paralysis is rare. We report the case of an 87-year-old male who presented with worsening breathlessness soon after an episode of shingles, affecting his right neck and upper chest. He had no alarm symptoms, history of trauma or malignancy. Skin lesions resolved after a few weeks, but his breathing did not improve. Chest X-ray revealed a new finding of elevated right hemidiaphragm; diaphragmatic ultrasound confirmed paradoxical cranial movement of right hemidiaphragm on sniff testing. CT scan showed no lung mass and complete collapse of right lower lobe due to elevated right hemidiaphragm. Patient has required no treatment and is under regular follow-up with the ventilation clinic.

Incidence of contralateral-bilateral nodes in the human papillomavirus era.

OBJECTIVES/HYPOTHESIS: HPV-positive oropharyngeal squamous cell carcinoma has a more favorable prognosis when compared to HPV-negative disease, regardless of the presence of nodal metastases. However, the importance of contralateral neck treatment based on HPV status has not been well studied. Given the historically poor prognostic implications of cervical nodal metastases, this study sought to elucidate the relationship between HPV status and contralateral/bilateral nodal metastasis in patients with oropharyngeal squamous cell carcinoma. STUDY DESIGN: Retrospective cohort analysis. METHODS: Data were collected on patients with oropharyngeal squamous cell carcinoma from 2001 to 2014. Nodal status was determined by contrast-enhanced computed tomography, positron emission tomography, or surgical pathology when available. Survival rates and associations between HPV status and demographic/tumor characteristics were assessed. RESULTS: Of 178 total patients, 46 (26.0%) had contralateral/bilateral metastases. There was no significant difference in incidence of contralateral/bilateral nodal metastases between HPV-positive and HPV-negative patients (24.6% vs. 29.1%, P = .53). Tonsil primaries had significantly lower incidence of contralateral/bilateral nodal metastases compared to tongue base (20.9% vs. 34.3%, P = .048). On multivariate regression, tumor size was the only factor associated with contralateral/bilateral nodal metastases (T4 vs. T1-3 odds ratio = 5.15, 95% confidence interval: 2.4-11.2). Five-year overall survival among all patients with and without contralateral/bilateral nodal metastases was 45.4% and 65.2%, respectively (P = .007). CONCLUSIONS: Our results did not show a significantly different incidence of contralateral/bilateral nodal metastases between HPV-positive and HPV-negative patients. T4 stage and tongue base location, however, were associated with contralateral disease. These data suggest treatment of bilateral necks might be warranted in these cases, regardless of HPV status. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:1328-1333, 2017.

Outcomes of surgically treated human papillomavirus-related oropharyngeal squamous cell carcinoma with N3 disease.

OBJECTIVES/HYPOTHESIS: To evaluate outcomes for patients with pathological N3 (pN3) neck disease from human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) and determine variables predictive of survival. STUDY DESIGN: Retrospective case series with chart review. METHODS: This study was conducted between 1998 and 2013 and included patients with HPV-related OPSCC treated with surgery with or without adjuvant therapy and who had pN3 nodal disease. The primary outcome was disease-specific survival (DSS). Secondary outcomes included overall survival (OS), disease-free survival (DFS), adverse events, and gastrostomy tube rates. RESULTS: Thirty-nine patients were included, of whom 36 (90%) underwent adjuvant therapy. Median follow-up was 39 months (range, 2-147 months). Mean age was 56 years, and 87% were male. Seventeen patients (44%) underwent selective neck dissection, whereas six (15%) underwent radical (n = 2) or extended radical (n = 4) neck dissection. Ninety-two percent had extracapsular extension. Five-year Kaplan-Meier estimated DSS, OS, and DFS were 89% (95% confidence interval [CI]: 79%-99%), 87% (95% CI: 75%-99%), and 84% (95% CI: 72%-96%), respectively. The disease recurrence rate was 10% (5% regional, 5% distant metastasis). Patients with less than 5 pathologically positive lymph nodes (P = .041) had improved DFS. CONCLUSIONS: Patients with HPV-related OPSCC and pN3 nodal disease treated with surgery and adjuvant therapy have very favorable long-term survival and regional control. Patients with five or more pathologically positive lymph nodes may be at higher risk for recurrence. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2033-2037, 2017.

Challenges in establishing the diagnosis of human papillomavirus-related oropharyngeal carcinoma.

OBJECTIVES/HYPOTHESIS: To describe initial presentations and idiosyncrasies in establishing the diagnosis for human papillomavirus-related (HPV(+) ) compared to HPV-unrelated (HPV(-) ) oropharyngeal carcinoma (OPC). STUDY DESIGN: A single institution retrospective series derived from an institutional prospectively compiled database supplemented by chart review. METHODS: We reviewed consecutive OPC patients referred to an academic tertiary cancer center from 2009 to 2011. HPV status was evaluated by p16 staining. Signs/symptoms and procedures to establish diagnosis were recorded independently by two abstractors blinded to the HPV status during data retrieval. Initial presentations (signs/symptoms), interval, and the procedures to establish the diagnosis were compared between HPV(+) and HPV(-) OPC. RESULTS: The most common initial presentation was an asymptomatic nodal mass for HPV(+) patients (n = 208; 69% vs. 29%, P < .001) in contrast to dysphagia/odynophagia for HPV(-) (n = 96; 34% vs. 63%, P < .001). Protracted interval (>12 months) from onset of signs/symptoms to diagnosis was observed in 18 (9%) HPV(+) versus three (3%) HPV(-) patients (P = .058). More HPV(+) patients required repeated (≥2) biopsy procedures (56% vs. 10%, P < .001). Misattribution to other disease occurred in eight (4%) HPV(+) patients (seven were mistaken as having a "branchial cleft cyst" when there were cystic lymph nodes and one as having a "lymphoma") compared to none in HPV(-) . CONCLUSIONS: About two-thirds of HPV(+) patients present with an asymptomatic neck mass and often require multiple biopsy procedures to establish the diagnosis. Idiosyncrasies in appreciating the diagnostic setting (cystic lymph node, misattribution to other entities, or submucosal location of the tumor) or patient-related factors could delay the diagnosis of HPV(+) OPC. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2270-2275, 2016.

HPV Infection of the Head and Neck Region and Its Stem Cells.

The human papillomavirus (HPV) is an etiologic agent associated with the development of head and neck squamous carcinoma (HNSCC)-in particular, oropharyngeal squamous cell carcinoma. The HPV-positive HNSCC is characterized by genetic alterations, clinical progression, and therapeutic response, which are distinct from HPV-negative head and neck cancers, suggesting that virus-associated tumors constitute a unique entity among head and neck cancers. Malignant stem cells, or cancer stem cells, are a subpopulation of tumor cells that self-renew, initiate new tumors upon transplantation, and are resistant to therapy, and their discovery has revealed novel effects of oncovirus infection in cancer. In this review, we provide a virus-centric view and novel insights into HPV-positive head and neck pathogenesis. We discuss the influence of cancer stem cells, HPV oncoproteins, altered molecular pathways, and mutations in cancer initiation and cancer progression. We compiled a catalogue of the mutations associated with HPV-positive HNSCC, which may be a useful resource for genomic-based studies aiming to develop personalized therapies. We also explain recent changes in mass vaccination campaigns against HPV and the potential long-term impact of vaccinations on the prevention and treatment of HPV-positive head and neck cancers.

[Head and neck space infection presenting with Herpes Simplex virus]. / Bas boyun alan enfeksiyonu ile Herpes Simpleks virüs birlikteligi.

A six-year-old girl was admitted to our clinic with the complaints of swelling, trismus, pain in the submandibular, submental and masticator area and vesicular lesions on the mandibular branch of trigeminal nerve (C5, V3). We present this case of head and neck space infection presenting with Herpes Simplex virus, as it is rarely seen.

Secondary infections, expanded tissue tropism, and evidence for malignant potential in immunocompromised mice infected with Mus musculus papillomavirus 1 DNA and virus.

Papillomavirus disease poses a special challenge to people with compromised immune systems. Appropriate models to study infections in these individuals are lacking. We report here the development of a model that will help to address these deficiencies. The MmuPV1 genome was synthesized and used successfully to produce virus from DNA infections in immunocompromised mice. In these early studies, we have demonstrated both primary and secondary infections, expanded tissue tropism, and extensive dysplasia.

Oropharyngeal cancers: significance of HPV16 detection in neck lymph nodes.

BACKGROUND: An increasing proportion of oropharyngeal squamous cell carcinomas (OPSCCs) is associated with human papillomavirus (HPV) type 16 infection. Several authors have suggested that HR-HPV DNA could be used as a marker of metastases in cervical cancers. Although HPV16 DNA has been detected in neck lymph node (LN) metastases of HPV16-positive OPSCC, its significance remains controversial. Does this presence correlate to metastatic involvement or is it just the consequence of LN filter function? OBJECTIVES: This study aims to analyse the relationship between HPV16 detection in neck LNs of HPV16-positive OPSCC and their pathological status. STUDY DESIGN: HP16-viral load (VL) was quantified by real-time-polymerase-chain reaction in primary tumours and neck LNs, in 11 patients with HPV16-positive OPSCC and in three patients with HPV16-negative OPSCC. HPV16 in situ hybridisation and p16 immunohistochemistry were performed in all LNs. RESULTS: A total of 45 LN levels were assessed. HPV16 DNA was not identified in HPV16-negative OPSCC LNs. All metastatic LNs from HPV16-positive OPSCC had a high VL and the viral DNA was located within tumoural cells. Among 27 pathologically tumour-free LN (PTFLN) levels 16/27 had no detectable VL, whereas the VL was low or medium (<10(5)copies/million cells) in 8/27 and high (>10(5)copies/million cells) in 3/27 PTFLN. In the latter group, no metastatic cell was identified and the viral DNA was located in immune cells. CONCLUSION: HPV16 detection in LN is explained by its presence within either metastatic cells or immune cells. HPV16 detection in PTFLN is not necessarily correlated to occult LN metastases.

An unusual presentation of herpes infection in the head and neck.

Herpes simplex virus (HSV) is among a spectrum of viruses known to affect the upper aerodigestive tract. Gingivostomatitis and pharyngitis are the most common clinical manifestations of first-episode HSV infection, whereas recurrent herpes labialis is the most common clinical manifestation of reactivation HSV infection. Herpetic viral infections seldom attack the larynx. Laryngeal disorders provoked by the herpes virus are characterised by a large spectrum of presentations and polymorphisms, and can simulate mucous lesions such as an extensive laryngeal neoplasm (supraglottic tumour). We report a case of a 69-year-old woman, smoker, who presented with a large ulcerated supraglottic mass mimicking laryngeal cancer, requiring emergency tracheostomy for worsening stridor, which turned out to be an HSV laryngitis superimposed onto an underlying Streptococcus A lower respiratory tract infection. The patient was treated for Streptococcus A infection and her symptoms resolved following treatment. Patient's tracheotomy tube was removed on follow-up appointment.

Detección de VPH en boca y cérvix de pacientes con diagnóstico citológico sugestivo de infección genital / HPV detection in the mouth and cervix of patients with histological diagnosis suggestive of genital infection

En este trabajo se evaluó la presencia de VPH en la cavidad bucal (mediante oroscopia y citología oralexfoliativa) y su relación con la infección genital en mujeres con diagnóstico citológico sugestivo de infección por VPH. La muestra consistió en 60 pacientes a quienes se les realizó oroscopia, citología y determinación viral en boca y cérvix por PCR, utilizando los iniciadores genéricos MY09/MY11 y MPCR. Se detectó ADN de VPH en las mucosas oral y genital en 48,33 % y 73,3% de las pacientes, respectivamente, obteniéndose una concordancia de 44,2% (k=0,44 indicando grado de acuerdo moderado). Los tipos virales más frecuentes fueron de bajo riesgo, especialmente el tipo 6, encontrado en 86,2% de las muestras bucales y 65,9% de las muestras cervicales, solo o en combinación con otros tipos debajo (11) o de alto riesgo oncogénico (16, 18, 33), con una concordancia de 10,45% (k=0,1 indicando grado de acuerdo muy bajo); sin embargo, particularmente en relación al tipo 6, hubo una concordancia de 75,86% (k=0,7 indicando grado de acuerdo alto). La citología de la cavidad bucal tuvo una sensibilidad de 3,5 % y especificidad de 93,6 %. Para la oroscopia, la sensibilidad fue de 27,6 % y la especificidad de 74,2 %. Los resultados señalan que la infección por VPH en cavidad bucal de pacientes con infección genital pudiera ser frecuente. La baja concordancia global entre los tipos virales sugiere que la infección por VPH en boca y cérvix presenta un comportamiento biológico diferente(AU)

This work evaluated HPV infection in the oral cavity (using oroscopy and exfoliative oral cytology) and its relation to genital infection in women with cytological diagnosis suggestive of HPV infection. The sample consisted of 60 patients who underwent oroscopy, cytology and viral determination in mouth and cervix by PCR using generic primers MY09/MY11 and MPCR. HPV DNA was detected in oral and genital mucosa in 48.33% and73.3% of patients, respectively, yielding a concordance of 44.2% (k=0.44, moderate agreement). The most common viral types were low risk, especially type 6,found in 86.2% of oral samples and 65.9% of cervical specimens, alone or in combination with other types of low (11) or high oncogenic risk (16, 18, 33), with a concordance of 10.45% (k = 0.1, insignificant agreement). However, in relation to type 6, there was a concordance of 75.86% (k=0.7, high agreement). The cytology of the oral cavity had a sensitivity of 3.5% and a specificity of93.6%. For oroscopy, sensitivity was 27.6% and specificity was 74.2%. The results indicate that HPV infection in the oral cavity of patients with genital infection could be frequent. The low concordance between HPV types suggests that HPV infection in the mouth and cervix has a different biological behavior(AU)

Diagnóstico y manejo de infecciones profundas de cuello 2005-2009 / Deep neck infections diagnosis and management 2005-2009

Las infecciones profundas de cuello ameritan diagnóstico oportuno y terapéutica urgente, debido a potenciales complicaciones y mortalidad. El objetivo del presente estudio fue revisar nuestra experiencia en el manejo de pacientes con esta patología, conocer los gérmenes más frecuentes yanalizar los factores asociados a complicaciones y estancia hospitalaria. Materiales y métodos: Se analizaron retrospectivamente 46 pacientes que acudieron al Hospital “Carlos Andrade Marín” de Quito, Ecuador, desde enero 2005 a junio de 2009. Resultados: El 63 por ciento fueron hombres y la medianade edad fue 33 años. Tratamiento antibiótico previo recibió un 50 por ciento de pacientes. El espacio más afectado fue el submaxilar 68 por ciento; dos compartimentos se afectaron en 11 por ciento. El 13 por ciento de pacientes presentó co-morbilidades. En el 48 por ciento la causa se relacionó con patología dental. La sintomatología encontrada estuvo conformada de tumor cervical, dolor y fiebre. La tomografía axial computarizada se realizó en el 22 por ciento de casos. Los antibióticos utilizados fueron: B lactámicos + inhibidores de Blactamasa en el 65 por ciento y penicilina cristalina + clindamicina en el 17 por ciento. En el 28 por ciento se utilizó corticoterapia como tratamiento coadyuvante. La estancia hospitalaria fue 9 días. El abordaje quirúrgico se realizó en el 48 por ciento y ninguno necesito re-intervención. La bacteria aislada más frecuentemente fue el estafilococo aureus. Complicaciones se presentaron en el 33 por ciento y no hubo mortalidad. Conclusiones: La infección dental es nuestra principal etiología, lo cual tiene relación topográfica de los compartimentos afectados. El estafilococo aureus fue la bacteria más encontrada. El tratamiento antibiótico utilizado fue de gran eficacia y el uso de corticoide disminuyó la estancia hospitalaria. Encontramos pocas co-morbilidades en nuestros pacientes lo cual podría explicar la ausencia de mortalidad en nuestra serie.

Objective: Deep neck infections need urgent diagnostic and treatment because of potential complications and mortality. The aim of this study was to review our experience in the management of patients with this disease, know the most common germs and analyze the factors associated withcomplications and hospital stay. Methods: We retrospectively analyzed 46 patients who attended the Carlos Andrade Marín Hospital in Quito, Ecuador, from January 2005 to June 2009. Results: 63% were men and median age was 33 years. Previous antibiotic treatment received 50% of patients. The most affected area was the submaxilar 68%, two compartments were affected in 11%. 13% of patientshad co-morbidities. In 48% the cause was related to dental disease. The symptoms found were cervical tumor, pain and fever. Computed tomography was performed in 22% of cases. The antibiotics used were: B-lactamics + B-lactamase inhibitors in 65% and clindamycin + penicillin G in 17%. In 28%received corticosteroids as adjunctive therapy. The hospital stay was 9 days. The surgical approach was performed in 48%. The most frequently isolated bacterium was Staphylococcus aureus.Complications occurred in 33% and we had no mortality. Conclusions: Dental infection is our main etiology, which is related topographic compartments affected. The bacteria staphylococcus aureus was the most found. The antibiotic regimen used was highly effective and steroid use decreasedhospital stay. We found few co-morbidities in our patients which could explain the absence of mortality in our series.