Arch Gynecol Obstet DOI 10.1007/s00404-014-3187-7

Case Report

HPV‑related cervical disease and oropharyngeal cancer Virginia Lozza · Annalisa Pieralli · Serena Corioni · Manuela Longinotti · Claudia Bianchi · Daniela Moncini · Maria Grazia Fallani 

Received: 10 January 2014 / Accepted: 12 February 2014 © Springer-Verlag Berlin Heidelberg 2014

Abstract  Human papillomavirus (HPV), especially HPV 16, is associated with the development of both cervical and oral cancer. We show the case of a woman affected by HPVrelated cervical disease and oropharyngeal squamous cell carcinoma (OPSCC). A 41-year-old woman arrived at our Colposcopy Center following an abnormal Pap smear result (ASC-H) and a diagnosis of moderate cervical dysplasia obtained by a cervical biopsy. She underwent a colposcopy that showed a cervical abnormal transformation zone grade 2. A laser conization was performed in November 2010. Histology reported a moderate/severe dysplasia. The cone resection margins were free. Follow-up colposcopy and cytology were negative. The HPV testing showed an infection by HPV 16. In October 2012, the patient presented to the Head–Neck ER after episodes of hemoptysis; a lesion was found in the left tonsillar lodge. A biopsy was performed with a result of squamous cell carcinoma with low-grade differentiation. The HPV testing detected a high-risk HPV and the immunohistochemical analysis was positive for p16. She was treated by chemotherapy and brachytherapy. She was followed at the head–neck center with monthly visits with oral visual inspection that showed complete absence of mucosal abnormalities. HPV-related OPSCC and cervical precancerous/cancerous lesions have significant similarities in terms of pathogenesis. They are both caused largely by HPV 16, as in the present case. In conclusion, because of this association found in V. Lozza (*) · A. Pieralli · S. Corioni · M. Longinotti · C. Bianchi · M. G. Fallani  Maternal and Child Department, Careggi University Hospital Florence, Largo Brambilla 3, 50134 Florence, Italy e-mail: [email protected] D. Moncini  Department of Biomedicine, Careggi University Hospital Florence, Largo Brambilla 3, 50134 Florence, Italy

literature and in our case, we think that women with HPV cervical lesions should have regular surveillance for oropharyngeal cancer, whereas women with OPSCC should be encouraged to have diligent cervical screening. Keywords  HPV · Tonsil · Cancer · Head and neck

Introduction Head and neck cancer (HNC) is the fifth most common cancer worldwide [1]. Within this heterogeneous group of tumors the most common histological types are squamous cell carcinomas (HNSCC) [2]. The relationship between human papilloma virus (HPV) and anogenital cancers in both genders is well known. More recently, the same virus has been recognized as the cause of several oropharyngeal tumors [3]. Over the last few years, an increasing number of oropharyngeal squamous cell carcinomas (OPSCC) have been diagnosed, mainly involving the tonsils and the base of tongue. The recent increase in the incidence of OPSCC is related to the growing number of HPV-related OPSCC (HPV-OPSCC) [4, 5]. A recent IARC review estimated that 25.6 % of oropharyngeal cancers worldwide are associated with HPV infection [6, 7]. Indeed, both HPV-OPSCC and cervical cancer share not only some risk factors, such as the number of lifetime sexual partners, but also the predominant etiological agent: the high-risk type HPV 16 [8]. In fact, over 90 % of HPV-associated head and neck squamous cell cancers are caused by HPV 16, the same genotype that is the primary cause of anogenital cancers [9]. Although cervical cancer and OPSCC show common aspects and causes, an epidemiologic association and the best clinical management of patient with HPV-associated HNC has not yet been defined.

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There are several detection methods of HPV in tumor tissue, but recently the importance of immunohistochemistry (IHC) for p16 protein as a potential screening marker has been highlighted [10]. p16 is a cyclin-dependent kinase inhibitor. p16 gene is overexpressed in most HPV-associated cancer precursors including cervical high-grade squamous intraepithelial lesion, adenocarcinoma in situ, squamous cell carcinoma, adenocarcinoma and also HNSCC [11, 12]. To emphasize the role of the identification of p16 in tumoral tissue, recent studies have shown that p16 expression correlates with better survival in patients with HNSCC [13, 14]. Here, we present the case of a woman treated for moderate cervical dysplasia, who developed an HPV-related OPSCC a few years later.

Case report A 41-year-old woman presented at our Colposcopy Center with an abnormal Pap smear indicating an ASC-H (atypical squamous cells not excluding HSIL) and a diagnosis of moderate cervical dysplasia after a cervical biopsy. The patient was a mild smoker, had underwent tonsillectomy in childhood and suffered from lupus-like disease. During the first visit she underwent a colposcopy that showed a cervical abnormal transformation zone grade 2. We programmed a laser conization that was performed in November 2010. Histology reported a moderate/severe dysplasia. The HPV testing showed an infection by HPV 16 and the immunohistochemical analysis was positive for p16 (Fig. 1). The cone resection margins were free of disease. No complications occurred during and after the treatment. The patient follow-up included colposcopy and Pap smear performed every 6 months for the first 2 years.

Arch Gynecol Obstet

Colposcopy and cytology were always negative for HPVrelated disease. In October 2012, the patient presented to the Head–Neck emergency room after episodes of hemoptysis; a suspicious lesion was found at the level of the left tonsillar lodge. A biopsy from the mucosa of the left tonsillar pillar and lodge was performed and resulted in a squamous cell carcinoma with low-grade differentiation. Given the previous cervical disease of the patient, HPV testing was performed and was positive for high-risk HPV. The immunohistochemical analysis was positive for p16 (Fig. 2). The patient underwent a face and neck MRI, which showed a solid swelling of the left tonsillar lodge that measured 23 × 22 × 27 mm and enhanced after the intravenous administration of gadolinium. The lesion appeared in contact with the base of tongue, with the inner face of the medial pterygoid muscle and posteriorly with the wall of the internal carotid artery, without recognizable cleavage plane. There were no pathological lymph nodes in both lateral cervical lymphatic chains. Positron emission tomography (PET) showed an intense hypermetabolism of the left tonsillar lodge. Additional sites of hypermetabolism were not detected. The patient was treated with chemotherapy (six cycles of cisplatin) and brachytherapy (33 sessions) at the dose of 60 Gy. She was followed at the head–neck center with monthly visits with oral visual inspection for mucosal abnormalities. In January 2013 the patient came back to our colposcopy center to continue follow-up for cervical HPV-related disease. The colposcopy and Pap test were negative for recurrence of HPV-related disease. She underwent a PET in April 2013 and a face and neck MRI in October 2013 which was completely negative for relapse.

Fig. 1  Cervical cone: hematoxylin–eosin coloring and immunohistochemistry for p16

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Fig. 2  Tonsillar lodge: hematoxylin–eosin coloring and immunohistochemistry for p16

Discussion Up to now, head and neck HPV-related disease has a very high prevalence that is rapidly increasing worldwide. In the USA the incidence of HPV-associated oropharyngeal cancer is similar or even greater than that of cervical cancer [15]. The epidemiology, biology and natural history of oropharyngeal HPV infection as well as the best clinical management of patients with HPV-related head and neck squamous cell tumors are still not well understood [16, 17]. Although HPV has been long known to be an important cause of anogenital cancer, only in recent years it has been recognized as one of the primary causes of OPSCC [16]. HPV-associated head and neck squamous cell carcinoma (HNSCC) seems to be a distinct clinical entity with better prognosis than HPV-negative oropharyngeal cancer. Findings of retrospective analyses suggest that individuals with HPV-positive oropharyngeal cancer have higher response rates to chemotherapy and radiotherapy and increased survival rate if compared with those with HPV-negative OPSCC [16]. Tumor HPV status is the most important prognostic factor for overall survival and progression-free survival in OPSCC and might also be a predictive marker of response to treatment [16, 18]. Because of the prognostic advantage of patients with tumors etiologically linked to HPV, the use of less aggressive treatment regimens in such patients is currently being evaluated and prospective trials may lead to stratified therapies based on tumor HPV status. Due to their better prognosis, patients with HPV-positive OPSCC may benefit from a different, possibly less aggressive treatment regimen and they could be spared excess treatment toxicity and therefore experience improved quality of life [18, 19]. This necessitates the development of sensitive, specific and

clinically relevant markers for the detection of patients with HPV-positive OPSCC [18]. p16 overexpression is proposed by various studies as a suitable surrogate marker of HPV infection, with high potential of impacting the standard of care. p16 is a cellular protein involved in cell cycle control; it represents a surrogate marker of HPV E7-mediated functional inactivation of retinoblastoma gene protein (pRB). p16 protein is consistently overexpressed in cervical precancerous and cancerous lesions. In addition, it is overexpressed in about 90–95 % HPV DNA-positive cases of OPSCC and its overexpression correlates well with HPV DNA and RNA presence in the analyzed specimens. p16 immunostaining, alone or in combination with HPV testing, represents a specific, sensitive and clinically accessible method for the identification of OPSCC patients who have a considerably better prognosis [10, 18]. From a systematic review of literature we found several studies that analyze the incidence and prevalence of oral HPV infection [3, 4, 6, 15–17], but only a few studies showing that OPSCC has a significant association with cervical cancer [20–22]. These are all recent studies, published in the last years. A study by Biron et al. published in 2011 demonstrated an increased risk of developing a cervical cancer in OPSCC patients compared with the general population. The authors state that overall, the incidence of cervical cancer in OPSCC is at least 25 times greater in comparison to the general population [20]. To our knowledge, this is the first study demonstrating an elevated risk of cervical cancer in OPSCC patients. Two previous studies examined the inverse association by investigating the rate of second primary tumors in a large cohort of women with cervical cancer. In these patients, the risk of developing an OPSCC was increased compared with women in the general population [21, 22].

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Chaturvedi and colleagues, using data from 104.760 1-year survivors of cervical cancers, reported 13 populationbased cancer registries in Denmark, Norway, Sweden, Finland and the USA, calculated standardized incidence ratio (SIRs) for second cancers overall and cancers at particular sites among women with cervical cancer. In these women, the calculated SIR of developing second primary tumors in the head and neck was significant for the pharynx (2.28) and the mouth (1.98) [21]. Balamurugan et al. also examined the incidence of second primary tumors in cervical cancer patients and observed a slightly elevated SIR (1.96) for oral cavity and pharynx [22]. The index cancer was cervical in 75 % of patients and OPSCC in 20 %, with synchronous lesions present in 5 % of women [20]. Women with OPSCC and cervical cancer more commonly presented tonsillar region tumors (55 %), as in the present case, followed by tumor of the base of tongue (25 %) [20]. The significantly elevated risk of cervical cancer in OPSCC patients and the inverse correlation between OPSCC and cervical cancer that were described in various studies may have several explanations. First of all, it is assumed that this epidemiologic association reflects coinfection of HPV between cervix and oropharynx through sexual behaviors; other possibilities include a genetic susceptibility to the oncogenic effects of HPV or common risk factors between cervical cancer and OPSCC, such as smoking [20]. HPV-OPSCC and cervical cancer show significant similarities in terms of pathogenesis and share carcinogenic mechanisms. Both entities are largely caused by HPV 16. Findings from various studies suggest similar molecular pathways in the pathogenesis of HPV-positive HNSCC and cervical cancer. HPV infection may act through a common mode of tumorigenesis, such as p53 tumour suppressor pathway [6, 20]. These data have important implications for women with OPSCC and cervical cancer. In our opinion, according to this proven association between cervical HPV disease and OPSCC, women with a diagnosis of oropharyngeal cancer should receive accurate counseling about the increased risk of developing HPVrelated cervical precancerous and cancerous lesions and should be encouraged to have diligent cervical screening by Pap test or HPV test; similarly, women with a cervical cancer or precancerous disease should have regular surveillance for oropharyngeal cancer [20]. The development of methods for primary and secondary prevention of cervical cancer with HPV vaccines and cytology-based or HPV-based screening, respectively, serves as a model for the prevention of HPV-associated non-cervical cancers. There are, however, current barriers

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to the development of analogous prevention strategies for HPV-positive OPSCC [6]. HPV vaccination could be useful because it may provide dual disease prevention for both HPV-related OPSCC and cervical cancer [20]; however, vaccine efficacy against oral HPV infection is still unknown, and therefore vaccination is not currently recommended for the primary prevention of oropharyngeal cancer [17]. An analysis of US cancer registry data recently showed that the number of HPV-positive oropharyngeal cancers diagnosed each year will surpass that of invasive cervical cancers by the year 2020: for this reason such vaccine trials are warranted [17]. Assuming an efficacy against oral HPV infections equivalent to that for cervical infection, a high proportion of HPV-caused oropharyngeal cancers could be prevented with current generation vaccines, because the attributable fraction for HPV 16 is 90–95 % [6]. Vaccine trials would also analyse the benefits of HPV vaccination of males, given the higher prevalence of oral HPV infection demonstrated as well as the higher incidence of HPV-positive OPSCC among men [6, 17]. Regarding secondary prevention, in contrast to cervical cancer, neither an established screening method nor a clear understanding of precancerous lesions exists for head and neck cancer. Currently, there are no widely validated screening methods for OPSCC [6]. The conventional visual and tactile examination (CVTE) is the current gold standard for OPSCC surveillance. The CVTE is often confounding, however, because oropharyngeal premalignant lesions and early cancers can be subtle in appearance and may mimic common reactive/inflammatory lesions. The addition of adjunctive screening tests to the CVTE may increase the sensitivity and specificity for precancerous lesions and early OPSCC. However, data on the ability of these tests to improve diagnostic accuracy are limited [23]. Fakhry et al. tried to determine the diagnostic utility of a “Pap test equivalent” for detecting premalignancy and early OPSCC in high-risk individuals, using a commercially available cytobrush. The data from this study suggest that an oropharyngeal “Pap test equivalent” may not be a practical and effective screening method for tonsillar OPSCC. The limitation of this test is due to the anatomy of the tonsils, the site of most HPV-related OPSCC. The cervix is covered by a flat and uniform layer of stratified squamous epithelium. Because of this characteristic, the cytobrush is able to obtain an adequate and representative collection of cells from cervical mucosa and the detection of cytologic abnormalities via brush-based cytology is highly successful. Unlike the cervix, however, the architecture of the tonsillar epithelium is not arranged as a flat mucosal surface. Rather, the tonsillar epithelium contains numerous invaginations that plunge into the lymphoid tissue of the tonsil,

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forming deep crypts, and it is believed that most tonsillar precancerous and cancerous lesions develop within these crypts below the mucosal surface. Tonsillar crypt epithelium cannot be reached by the cytobrush and for this reason the brush-based cytology has shown scarce results for OPSCC screening [23, 24]. The lack of a validated HPV-associated OPSCC screening test is an important obstacle that must be overcome. A major challenge for the future is to develop a screening test for OPSCC with sufficient diagnostic accuracy to detect both premalignant and early malignant lesions. Although the prognosis of HPV-associated OPSCC seems to be considerably better than that of the classic forms of the disease, HPV-associated OPSCC is still often diagnosed at an advanced stage. New screening strategies are needed that could be effective in reducing OPSCC morbidity and mortality as already happened for cervical cancer. Meanwhile, it is important to vaccinate as much as possible boys and girls who will likely benefit from vaccination for the prevention of both genital tumors and head and neck cancer. Acknowledgments  We thank DEKA M.E.L.A. S.r.l. for technical support. Conflict of interest  We declare that we have no conflict of interest.

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HPV-related cervical disease and oropharyngeal cancer.

Human papillomavirus (HPV), especially HPV 16, is associated with the development of both cervical and oral cancer. We show the case of a woman affect...
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