Undifferentiated carcinoma of the oropharynx: a human papillomavirus-associated tumor with a favorable prognosis

Abstract

Undifferentiated carcinoma (undifferentiated carcinoma, nasopharyngeal type, or lymphoepithelial carcinoma) is an uncommon and histologically distinct tumor in the oropharynx, which in Western countries, has been clearly shown not to harbor Epstein Barr virus (EBV). We sought to analyze these tumors for human papillomavirus (HPV) and to examine their clinical outcomes. All cases of oropharyngeal carcinoma diagnosed as 'undifferentiated' or 'lymphoepithelial' were retrieved from the department files at Barnes-Jewish Hospital. After consensus review by all three study pathologists, 16 were found to have diagnostic histological features and to lack distinguishing characteristics of other oropharyngeal cancers. Immunohistochemistry for p16 and p53 and in-situ hybridization for HPV and EBV encoded small RNA were performed. p16-positive but HPV in situ hybridization-negative cases were analyzed by polymerase chain reaction for high-risk HPV types. The results were correlated with pathological findings and clinical follow up. There were 16 patients. The average age was 59.2 years, 14 patients (88%) were smokers, and 13 (81%) had nodal metastases. In all, 14 cases (88%) were p16 positive and 15 (94%) were HPV positive by in situ hybridization and/or polymerase chain reaction. All cases were negative for EBV, and p53 was overexpressed in five (33%), four of which were HPV positive. Disease recurred in only three patients and two of these died with disease at 38 and 136 months, respectively. Three year overall, disease-free, and disease-specific survival rates were 54, 78, and 100%, respectively. In summary, in our patient population, the majority of oropharyngeal undifferentiated carcinomas harbor transcriptionally active HPV but not EBV. Almost all overexpress p16, and few have p53 overexpression. Disease-specific survival is comparable to published rates for other HPV-related oropharyngeal squamous cell carcinoma variants and is better than that of HPV-negative carcinomas.

Use of In Situ Hybridization for HPV in Head and Neck Tumors: Experience from a National Reference Laboratory

“…Although there is some data suggesting importance of high risk HPV in sinonasal cancers and undifferentiated carcinoma of oropharynx, it is generally accepted that prognostic significance of HPV is confined to SCC of the oropharynx [8,15,16]. Testing the HPV status of benign epithelial lesions of the upper respiratory tract and oral cavity, including solitary squamous papillomas, is of limited clinical utility as solitary squamous papillomas are thought to be unrelated to HPV and are usually cured by simple excision.…”

“…In recent years, HPV-related head and neck SCC have been dramatically increasing, affecting middle to older aged men with no history of smoking or drinking. HPV positive SCC represents a subset of head and neck tumors classically showing non-keratinizing squamous cell morphology [4]; however, a variety of other morphologies (papillary, adenosquamous, lymphoepithelial-like) have also been described in HPV-related carcinomas [5][6][7][8]. HPV-related head and neck SCC are associated with high risk HPVs (most commonly type 16) and even in the setting of a clinically undetectable primary may present with large metastatic lymph nodes in the neck.…”

Human Papillomavirus-16 Associated Adenocarcinoma NOS of Base of Tongue

“…The recent reports describing the presence of HPV in oropharyngeal neuroendocrine carcinomas [15,16], adenosquamous carcinomas [14], and undifferentiated carcinomas [17,18], and now adenocarcinoma-raise the possibility that HPV is involved in the carcinogenesis of, not only squamous cell carcinoma, but other uncommon carcinomas of the region. This situation resembles the role played by HPV in the carcinogenesis of uterine cervix where HPV is found not only in squamous cell carcinoma [30], but also in adenocarcinomas [31], and neuroendocrine carcinomas [32,33].…”

“…Pathologically, most HPV-positive OSCCs exhibit non-keratinizing or basaloid morphology [10][11][12][13]. Recently, HPV has also been found in adenosquamous carcinomas [14], neuroendocrine carcinomas [15,16] and undifferentiated ''lymphoepithelioma-like'' carcinomas of the oropharynx [17,18]. Although the number of cases described is still small, HPV-associated neuroendocrine carcinomas of the oropharynx are aggressive malignancies [15,16].…”

When is surgical therapy for head and neck malignant epithelial tumors not indicated?

“…Oropharyngeal cancers, particularly those with poorly and undifferentiated carcinoma histology, are frequently associated with human papillomavirus (HPV); these tumors often exhibit strong p16 protein expression and have low rates of p53 mutations [4]. With regard to HPV status, a site-specific analysis shows that patients with HPV-positive oropharyngeal tumors have a 28 % reduced risk of death in comparison to patients with HPV-negative oropharyngeal tumors.…”