Human Papillomavirus-related Carcinoma Research Articles

Human papillomavirus-related carcinoma with adenoid cystic-like features of the sinonasal tract: Case report and literature review.

Introduction and importanceHPV-related carcinoma with adenoid cystic carcinoma-like features currently known as HPV-related multiphenotypic sinonasal carcinoma (HMSC) is a rare distinct head and neck high-risk HPV-related carcinoma. The high-risk HPV subtypes implicated are particularly type 33,35 and 56. So far this is the first reported rare case of a variant of sinonasal carcinoma in Tanzania.Case presentationWe present a 59-year old female who presented with a history of right-sided nasal obstruction and intermittent epistaxis for about one year and later on had ipsilateral proptosis. A provisional diagnosis of advanced right-sided malignant sinonasal tumor was made. Trans nasal biopsy revealed HMSC.Clinical discussionThe patient had a right sided fixed neck mass that measured about 7.5 × 8.2 cm. Magnetic resonance imaging (MRI) of the paranasal sinuses revealed a T1 weighted contrasted images that showed a huge extensive enhancing mass (estimated to measure 4.5 × 4.4) involving the nasal cavity, bilateral ethmoid sinuses, frontal and sphenoid sinuses and also the tumor exhibit intracranial extension (anterior cranial fossa) and tend to compress medial walls of both orbits though more marked on the right side. Histopathology and immunohistochemistry confirmed HPV-related multiphenotypic sinonasal carcinoma. The disease was staged to be T4bN3aM0 and the patient was referred for palliative chemoradiation.ConclusionAlthough HMSC presents at advanced stage in close to half of cases and has a high-grade histological appearance it paradoxically exhibits a relatively indolent manner with frequent local recurrences. Prompt histopathological diagnosis is important to prevent metastases and HMSC-related deaths.

Factors associated with metastatic presentation in HPV-related squamous cell carcinoma of the head and neck (SCCHN): A National Cancer Database (NCDB) analysis.

e18213 Background: Metastasis is an ominous sign in SCCHN. Human papillomavirus (HPV) infection-associated SCCHN cancers tend to have a distinct prognosis. Factors that are associated with metastatic disease at the time of presentation and diagnosis in patients with HPV-related SCCHN tumors were examined. Methods: NCDB was queried to assess 12,857 patients with HPV-related oropharyngeal carcinomas (HPVOPCA) and 952 patients with HPV related non-oropharyngeal carcinomas (HPVNOPCA) diagnosed between between 2010-2014 with non-missing survival or M stage. Rate of metastases at presentation was analyzed using clinical M stage. Multivariable analysis was performed evaluating race, ethnicity, sex, age, facility location, facility type, insurance status, income, education, urban/rural location, surgery, radiation, and chemotherapy using logistic regression. Results: In both HPVOPCA and HPVNOPCA, over 90% of patients were white. Private insurance was carried by 64% and 47% of patients with HPVOPCA and HPVNOPCA, respectively. HPVOPCA cancer was located in the tonsil in 47% of cases. Patients with HPVOPCA were more likely to present with advanced nodal disease than patients with HPVNOPCA. For both HPVOPCA and HPVNOPCA, there was no meaningful difference in the rate of distant metastasis at presentation in facility type or location, sex, race, Hispanic ethnicity, or urban rural location. For HPVOPCA, there were significantly lower odds of metastasis in privately insured patients vs. uninsured patients (HR: 0.35, 95% CI: 0.21-0.59, p < 0.001), and higher odds of metastasis for those living in census tracts with the lowest rates of high school graduates vs. those living in census tracts with the highest rates of high school graduates (HR: 1.82, 95% CI: 1.07-3.09, p = 0.026). For HPVNOPCA, patients living in census tracts with the lowest rates of high school graduates were less likely to develop metastasis compared to those living in census tracts with the highest rates of high school graduates (p = 0.031). Conclusions: This large retrospective analysis identifies likely modifiable risk factors for metastatic presentation in HPV-related SCCHN. Health policies and educational interventions may result in modifications of these patterns.

Human Papillomavirus-Related Carcinoma With Adenoid Cystic-like Features of the Sinonasal Tract (Also Known as Human Papillomavirus-Related Multiphenotypic Sinonasal Carcinoma).

Human papillomavirus (HPV)-related carcinoma with adenoid cystic-like features is a rare, recently recognized entity restricted to the sinonasal tract. By definition, it is associated with high-risk HPV infection, particularly with HPV type 33. In most cases, tumors are composed of dual cell populations, including predominant basaloid myoepithelial cells and usually inconspicuous ductal cells. Solid components with focal cribriform or tubular patterns, abrupt keratinization within tumor nests, and squamous dysplasia of the surface epithelium are characteristics of HPV-related carcinoma with adenoid cystic-like features. The immunohistochemistry of p16 followed by high-risk HPV testing may help in the differential diagnosis. Recent studies have demonstrated that the morphologic features of this entity are more diverse than initially believed. Surgical resection is the prime alternative for treatment. According to the limited data, the prognosis of this disease may be better than that of other sinonasal carcinomas.

Evaluation of therapeutic potency of human papillomavirus-16 E7 DNA vaccine alone and with interleukin-18 as a genetic adjuvant

AIMS: Despite the existence of effective preventive vaccines for human papillomavirus (HPV), therapeutic vaccines that trigger cell-mediated immune responses are required to treat established infections and malignancies. The aim of this study was to evaluate the therapeutic potency of HPV-16 E7 deoxyribonucleic acid (DNA) vaccine alone and with interleukin (IL)-18. METHODS: In vitro expressions of IL-18 were performed on human embryonic kidney 293 cells and confirmed it by Western blotting methods. DNA vaccine was available from a previous study. A total of 45 female C57BL/6 mice divided into five groups (DNA vaccine, DNA vaccine adjuvanted with IL-18, pcDNA3.1, and phosphate buffer saline) were inoculated with murine tissue culture-1 cell line of HPV related carcinoma, expressing HPV-16 E6/E7 antigens. They were then immunized subcutaneously twice at a seven-day interval. The antitumor and antigen specific-cellular immunity were assessed by lymphocyte proliferation (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide: MTT) assay, lactate dehydrogenase release assay, IL-4 assay and interferon-gamma (IFN-γ) assay. Tumor size was followed for 62 days.RESULTS: MTT assay, which measures the lymphocyte proliferation in response to the specific antigen, increased in the co-administration and the DNA vaccine groups as compared to control and genetic adjuvant groups (p<0.001). The mice immunized with the co-administration generated significantly more IFN-γ and IL-4 than other immunized mice (p<0.001). Reduction of the tumor size in the co-administration and the DNA vaccine groups was significantly more pronounced than in the control and genetic adjuvant groups (p<0.001), but no statistically significant difference between DNA vaccine and co-administration groups (p=0.15) occurred.CONCLUSIONS: IL-18 as a genetic adjuvant and E7 DNA vaccine alone enhanced immune responses in mouse model systems against cervical cancer. However, using of IL-18 as a genetic adjuvant with E7 DNA vaccine had no significant synergistic effect on the immune responses in vivo.

MAML2 Rearrangements in Variant Forms of Mucoepidermoid Carcinoma: Ancillary Diagnostic Testing for the Ciliated and Warthin-like Variants.

Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. Recent studies have shown that most MECs harbor gene fusions involving MAML2-an alteration that appears to be specific for MEC, a finding that could be diagnostically useful. While most cases of MEC are histologically straightforward, uncommon variants can cause considerable diagnostic difficulty. We present 2 variants of MEC for which MAML2 studies were crucial in establishing a diagnosis: a previously undescribed ciliated variant, and the recently described Warthin-like variant. All cases of ciliated and Warthin-like MEC were retrieved from the archives of The Johns Hopkins Hospital. Break-apart fluorescence in situ hybridization for MAML2 was performed on all cases. One ciliated MEC and 6 Warthin-like MECs were identified. The ciliated MEC presented as a 4.6 cm cystic lymph node metastasis originating from the tongue base in a 47-year-old woman. The Warthin-like MECs presented as parotid masses ranging in size from 1.2 to 3.3 (mean, 2.7 cm) in 4 women and 2 men. The ciliated MEC consisted of macrocystic spaces punctuated by tubulopapillary proliferations of squamoid cells and ciliated columnar cells. The Warthin-like MECs were comprised of cystic spaces lined by multilayered oncocytic to squamoid cells surrounded by a circumscribed cuff of lymphoid tissue with germinal centers. In these cases, the Warthin-like areas dominated the histologic picture. Conventional MEC, when present, represented a minor tumor component. MAML2 rearrangements were identified in all cases. Warthin-like MEC, and now a ciliated form of MEC, are newly described variants of a common salivary gland carcinoma. Unfamiliarity with these novel forms, unanticipated cellular features (eg, cilia), and morphologic overlap with mundane benign processes (eg, developmental ciliated cysts, Warthin tumor) or other carcinomas (eg, ciliated human papillomavirus-related carcinoma) may render these variants susceptible to misdiagnosis. These unusual variants appear to consistently harbor MAML2 fusions-a finding that establishes a clear link to conventional MEC and provides a valuable adjunct in establishing the diagnosis.

Human papillomavirus-related carcinoma with adenoid cystic-like features of the sinonasal tract: clinical and morphological characterization of six new cases.

Human papillomavirus (HPV) is known as causative for squamous cell carcinoma (SCC) of the oropharynx, but is also found not infrequently in carcinomas of the sinonasal tract. Recently, a subset of these carcinomas was recognized to harbour HPV33 and have a significant morphological overlap with adenoid cystic carcinoma (ACC), a rare and aggressive carcinoma originating in the minor salivary glands. Termed 'HPV-related carcinoma with ACC-like features', only nine cases have been reported. To clarify the occurrence of these tumours we screened a large material for the presence of HPV-related ACC-like carcinoma. The identified tumours were characterized immunohistochemically and with fluorescence in-situ hybridization, and clinicopathological information for all cases is presented. Forty-seven candidate cases were screened for presence of HPV. Six cases were identified and genotyped as HPV types 33, 35, and 56. All six cases had areas of dysplastic mucosal lining and showed remarkable heterogeneous morphologies. MYB, MYBL1, and NFIB genes were intact and, interestingly, staining for MYB protein was largely negative in contrast to what was found in ACC. One patient experienced a local recurrence 11 years after initial treatment and the remaining five patients were alive without evidence of disease. We report six new cases of HPV-related ACC-like carcinoma and found that, although in a small material, the prognosis for these patients seems more favourable than for ACC. For the distinction between ACC and HPV-related ACC-like carcinoma, p16, MYB immunohistochemistry or investigation of MYB, MYBL1 and NFIB gene status are valuable.

Investigation of the presence of HPV related oropharyngeal and oral tongue squamous cell carcinoma in Mozambique

BackgroundCervical cancer caused by the human papillomavirus (HPV) is endemic in East Africa. Recent, dramatic, increases in the incidence of oropharyngeal cancer in the United States and Europe are linked to the same high risk HPV genotypes responsible for cervical cancer. Currently, there is extremely limited data regarding the role of HPV in head and neck cancers in Africa. Evidence of HPV as an etiologic agent in head and neck cancers in Africa would have important prevention and treatment implications. MethodsA retrospective single institution review of oral tongue and oropharyngeal squamous cell carcinomas diagnosed between 2005 and 2013 was performed. Individual case data for 51 patients with biopsy proven squamous cell carcinoma (SCC) from the oropharynx (n=22) and oral tongue (n=29) were identified. Formalin fixed, paraffin embedded biopsy samples were obtained and evaluated for p16 by immunohistochemistry and HPV genotype 16 specific oncogenes, E6 and E7, by PCR. ResultsAll of the positive controls, but none of the oropharyngeal samples stained positively for p16. Two of the oral tongue samples stained positive for p16. None of the oropharyngeal or oral tongue cases demonstrated PCR products for HPV-16 E6 or E7. ConclusionsThough Mozambique has extremely high levels of HPV positive cervical cancer this study demonstrates an absence of HPV positive oropharyngeal or oral tongue squamous cell carcinoma within biopsy samples from a single referral hospital in Maputo, the capital of Mozambique.

Human papillomavirus-related carcinoma with adenoid cystic-like features of the inferior turbinate: a case report.

Sinonasal malignancies are uncommon, but are of many different histologic types. Recently, Human papillomavirus (HPV)-related carcinoma with adenoid cystic features was reported as a new histologic form. Although this histologic type resembles an adenoid cystic carcinoma, it differs from adenoid cystic carcinomas with regard to its association with HPV. Here, we present a case of HPV-related carcinoma with adenoid cystic features in the nasal cavity. We also review the histological characters of the tumor.

Do patients with head and neck human papillomavirus-related carcinoma need a different treatment approach?

We congratulate Mizumachi and colleagues [1] on their assessment of ‘‘Improved survival of Japanese patients with human papillomavirus-positive oropharyngeal squamous cell carcinoma’’. However, we would like to raise several points regarding the necessity of less intensive therapy for patients with human papillomavirus (HPV)associated carcinoma. Numerous case series have established that HPV-positive oropharyngeal cancers have unique demographic and clinical characteristics [2, 3]. The prevalence of HPVrelated oropharyngeal carcinoma is rising in Western Europe and the USA. However, this correlation (as Mizumachi et al. have shown) has not been fully evaluated in Japan [1]. Indeed, HPV-positive tumor status is an important prognostic factor associated with a favorable outcome. However, the optimal treatment for HPV-positive head and neck squamous cell carcinoma is not yet defined. Moreover, quality of life (QoL) is receiving increasing attention as a criterion for the assessment of different treatment modalities [4]. Broglie et al. recently reported that patients treated by either surgery alone or surgery with adjuvant radiotherapy complained significantly less about troubles with dry mouth, teeth and senses compared to the non-surgically treated group. Moreover, HPV-positive patients appeared to have a better QoL independent of treatment strategy. Therefore, the authors consider that these patients could tolerate more intensive treatment without impairment of QoL [4]. Nevertheless, Lassen et al. [5] have recently reported that long-term morbidity was influenced neither by fractionation schedule nor by tumor HPV/p16 status in patients undergoing accelerated fractionated radiotherapy. In our opinion, although HPV-positive patients may have a better treatment tolerance, ‘‘less-intensive treatment’’ should be administered based on an understanding of the treatmentrelated risk factors that are independently associated with late swallowing complications (such as the volume of pharynx irradiated and radiation dose) [6, 7]. For example, patients with low volume stage III–IV disease (T1–2 and N1–2a/b) could be spared from aggressive multimodal treatment. It would therefore be interesting to corroborate these results in Japan too. Mizumachi et al. [1] have interestingly shown that patients in Japan with HPV-positive oropharyngeal cancers have a better prognosis than those with HPV-negative carcinomas. These results are consistent with those obtained in Europe and North America. However, to date there is insufficient data to justify a change in the treatment strategies for HPV-positive oropharyngeal cancer outside of clinical trials. From this point of view, these authors mention that HPV status should at least be included as a stratification factor into future randomized controlled trials to optimize the treatment of patients with this type of cancer in Japan [1]. J. Cacicedo Fernandez de Bobadilla (&) P. Bilbao Radiation Oncology Department, Cruces University Hospital, c/Plaza de Cruces s/n, 48903 Barakaldo, Vizcaya (Basque Country), Spain e-mail: jon.cacicedofernandezbobadilla@osakidetza.net

Human Papillomavirus–related Carcinoma With Adenoid Cystic–like Features

Human papillomavirus (HPV)-related carcinomas of the head and neck are characterized by a predilection for the oropharynx, a nonkeratinizing squamous morphology, and infection with the HPV 16 type; but comprehensive HPV testing across all head and neck sites has shown that the pathologic features of HPV-related carcinoma may be more wide ranging than initially anticipated. In particular, a subset of sinonasal carcinomas are HPV positive, and these include a variant that is histologically similar to adenoid cystic carcinoma (ACC). Cases were identified by retrospective and prospective analyses of head and neck carcinomas with ACC features. HPV analysis was performed using p16 immunohistochemistry and high-risk HPV in situ hybridization. HPV-positive cases were confirmed and typed using HPV type-specific quantitative polymerase chain reaction and further characterized on the basis of their immunohistochemical profile and MYB gene status. HPV was detected in 8 carcinomas of the sinonasal tract, but it was not detected in any ACCs arising outside of the sinonasal tract. The HPV types were 33 (n=6), 35 (n=1), and indeterminate (n=1). Six patients were women, and 2 were men, ranging in age from 40 to 73 years (mean 55 y). The carcinomas were characterized by a nested growth, a prominent basaloid component showing myoepithelial differentiation and forming microcystic spaces, and a minor epithelial component with ductal structures. Squamous differentiation, when present, was restricted to the surface epithelium. The carcinomas were not associated with the MYB gene rearrangement that characterizes a subset of ACCs. These cases draw attention to an unusual variant of HPV-related carcinoma that has a predilection for the sinonasal tract. Despite significant morphologic overlap with ACC, it is distinct in several respects including an association with surface squamous dysplasia, absence of the MYB gene rearrangement, and an association with HPV, particularly type 33. As HPV positivity confers distinct clinicopathologic characteristics when encountered in the oropharynx, a more comprehensive analysis of risk factors, response to therapy, and clinical outcomes is warranted for HPV-related carcinomas of the sinonasal tract.

Human Papillomavirus-related Carcinomas of the Sinonasal Tract

High-risk human papillomavirus (HPV) is an established cause of head and neck carcinomas arising in the oropharynx. The presence of HPV has also been reported in some carcinomas arising in the sinonasal tract, but little is known about their overall incidence or their clinicopathologic profile. The surgical pathology archives of The Johns Hopkins Hospital were searched for all carcinomas arising in the sinonasal tract from 1995 to 2011, and tissue microarrays were constructed. p16 immunohistochemical analysis and DNA in situ hybridization for high-risk types of HPV were performed. Demographic and clinical outcome data were extracted from patient medical records. Of 161 sinonasal carcinomas, 34 (21%) were positive for high-risk HPV DNA, including type 16 (82%), type 31/33 (12%), and type 18 (6%). HPV-positive carcinomas consisted of 28 squamous cell carcinomas and variants (15 nonkeratinizing or partially keratinizing, 4 papillary, 5 adenosquamous, 4 basaloid), 1 small cell carcinoma, 1 sinonasal undifferentiated carcinoma, and 4 carcinomas that were difficult to classify but exhibited adenoid cystic carcinoma-like features. Immunohistochemistry for p16 was positive in 59/161 (37%) cases, and p16 expression strongly correlated with the presence of HPV DNA: 33 of 34 (97%) HPV-positive tumors exhibited high p16 expression, whereas only 26 of 127 (20%) HPV-negative tumors were p16 positive (P<0.0001). The HPV-related carcinomas occurred in 19 men and 15 women ranging in age from 33 to 87 years (mean, 54 y). A trend toward improved survival was observed in the HPV-positive group (hazard ratio=0.58, 95% confidence interval [0.26, 1.28]). The presence of high-risk HPV in 21% of sinonasal carcinomas confirms HPV as an important oncologic agent of carcinomas arising in the sinonasal tract. Although nonkeratinizing squamous cell carcinoma is the most common histologic type, there is a wide morphologic spectrum of HPV-related disease that includes a variant that resembles adenoid cystic carcinoma. The distinctiveness of these HPV-related carcinomas of the sinonasal tract with respect to risk factors, clinical behavior, and response to therapy remains to be clarified.

Human papillomavirus (HPV) related carcinomas of the upper aerodigestive tract.

Epidemiologic, clinical, morphologic and molecular evidence show that high risk HPV, particularly type 16, is a prerequisite for some carcinomas of the upper aerodigestive tract (UADT), particularly tonsil and base of tongue. Sexual transmission is an important mode of infection while tobacco use and excessive drinking are not considered risk factors. HPV + tumors are distinct clinically and pathologically. They are more common in young patients (<40 years) with a male to female ratio of 4:1. They usually present as a small or occult primary tumor with advanced neck disease. Microscopically they are non-keratinizing squamous cell carcinomas with basaloid features, excessive mitosis and comedo type necrosis. The tumors have a distinct immunohistochemical profile characterized by strong and diffuse p16 reactivity, low or negative p53 staining and high Ki67 labeling scores. HPV + carcinomas are more radio-sensitive and have a better prognosis than the classical keratinizing SCC of the UADT. An anti-HPV vaccine has recently been made available for prevention of cervical cancer. The impact of the vaccine on the prevalence of HPV related carcinomas of the UADT is currently not known but likely beneficial.