Over the past 15 years, human papillomavirus (HPV) has become a well-known etiologic factor in the development of squamous cell carcinoma of the head and neck, particularly of the oropharynx. Although current guidelines do not identify HPV-positivity as a factor to consider in determining treatment deintensification, recognition of HPV-positive squamous cell carcinomas as a distinct clinical entity with less risk for second primary tumors raises the question of the appropriateness of ipsilateral definitive surgery or radiotherapy in HPV-positive patients. We report the case of a man with an HPV-positive oropharyngeal SCC treated with definitive ipsilateral radiation who later developed a contralateral metachronous second primary tumor. This second primary tumor was treated with a neck dissection followed by adjuvant ipsilateral radiation and concurrent chemotherapy. This case demonstrates the importance of considering the phenomenon of second primary tumors in patients with HPV-positive head and neck squamous cell carcinoma and illustrates the utility of advanced radiation technologies in creating treatment plans allowing for minimal overlap if a contralateral treatment becomes necessary. In addition, as publications regarding this phenomenon are limited, this case also highlights the need for greater understanding of the etiology, pathogenesis, clinical behavior, and prognosis of second primary tumors in HPV-positive patients. We anticipate this will become an increasingly recognized phenomenon and clinical scenario for the modern-day radiation oncologist.
Keywords: Squamous Cell Carcinoma; Human Papillomavirus; Oropharynx; Radiation; Second Primary Tumor
HNSCC: Head and Neck Squamous Cell Carcinoma;
SPT: Second Primary Tumor;
IMRT: Intensity-Modulated Radiation Therapy;
HPV: Human Papillomavirus
Historically, squamous cell carcinoma of the head and neck (HNSCC) has been largely considered tobacco smoke and alcohol related with a high risk of metachronous second primary tumors (SPTs). This risk—estimated to be 36% over 20 years—is especially significant given that SPTs are the leading cause of mortality in patients with HNSCC [1, 2]. Importantly, past radiation technology lessened the risk of SPTs located in the head and neck—shown to occur in 12% of patients with primary HNSCC—by requiring treatment with opposed lateral fields resulting in bilateral prophylactic coverage of the laryngopharynx and bilateral cervical nodes. However, with the evolution of advanced radiation technologies such as intensity-modulated radiation therapy (IMRT), radiation can now be limited to the ipsilateral oropharynx and neck in select patients. This technique is considered in order to decrease toxicities and is often felt to be preferable in lateralized tumors with minimal invasion and ipsilateral lymph node involvement. In this patient population, the risk of developing SPTs is considered low enough to not function as a primary factor in treatment decision-making.
Over the past 15 years, human papillomavirus (HPV) has become a well-known etiologic factor in the development of HNSCC, particularly of the oropharynx. Indeed, from 1984 to 2004, the percentage of HPV-positive oropharyngeal SCCs in the United States increased from 16.9% to 71.9% with an overall increase in the incidence of 225%. Similar trends have also been observed in other European countries over similar time periods[5-7]. In contrast to patients with the HPV-negative disease, multiple reports have shown that patients with HPV-positive oropharyngeal SCC have longer overall and disease- specific survival—even after disease progression—as well as a much lower rate of developing SPTs: estimated to be only 2-3%[8-10]. Although current guidelines do not identify HPV-positivity as a factor to be used in determining suitability for ipsilateral radiation, recognition of HPV-positive HNSCCs as a distinct clinical entity with less risk for SPTs has led some providers to consider the benefits of ipsilateral radiation in HPV-positive patients. In evaluating such a treatment approach, it is important to recognize that patients with HPV-positive HNSCC are also typically younger, with fewer comorbidities and light, former, or never smokers. As a result, they often have longer life expectancies than their HPV-negative counterparts and have the potential to harbor toxicities of treatment for many decades.
Here, we report the case of a man with an HPV-positive SCC of the right tonsillar fossa treated with definitive ipsilateral IMRT to 6480cGy. Seven years later, he was found to have a metachronous SPT-discovered in a contralateral cervical node which was treated with left neck dissection followed by adjuvant ipsilateral IMRT to 6000cGy and concurrent chemotherapy. This case demonstrates the importance of considering the phenomenon of SPTs in patients with HPV-positive HNSCC and illustrates the utility of advanced radiation technologies in creating treatment plans allowing for minimal overlap if contralateral treatment becomes necessary.
In 2007, a 66-year-old Caucasian male with minimal alcohol use and a remote smoking history (20 pack years followed by 32 years of abstinence) presented with right-sided neck swelling. Neck CT scan showed a 2.3 x 1.9 cm right level II lymph node which was subsequently excised and found to be metastatic nonkeratinizing squamous cell carcinoma (see Figure 1, Panel A). PCR showed the tumor to be positive for HPV 16 (see Figure 1, Panel B). Direct laryngoscopy was performed with biopsies of the right tonsillar fossa showing nonkerati-nizing squamous cell carcinoma (see Figure 1, Panel C). PET/ CT scan showed FDG uptake within the right level II lymph node and right tonsillar fossa but was negative for other sites of FDG avidity (see Figure 2). Consequently, his clinical stage was determined to be stage III T1N1M0 (per AJCC 6th Edition Guidelines). He was treated with definitive ipsilateral IMRT to the right hemi-neck and oropharynx (6480 cGy) and did not receive chemotherapy at that time. He showed no evidence of disease during five years of follow-up.
Figure 1. Pathology of Primary and SPT Biopsies/Surgeries.
Fine needle aspiration specimen of right level II lymph node showing nests of nonkeratinizing carcinoma (20X magnification); B - p63 immunohistochemistry on the right level II lymph node FNA showing strong, diffuse nuclear staining; C - Biopsy specimen from right tonsillar tumor showing nonkeratinizing squamous cell carcinoma (20X magnification); D – Left neck dissection specimen showing metastatic nonkeratinizing squamous cell carcinoma in a lymph node (4X magnification).
Seven years later, he presented with left-sided neck swelling. A CT scan of the neck showed a 2.4 x 3.3 cm left level II lymph node along with a cluster of prominent but not pathologically enlarged lymph nodes slightly inferiorly. A fine needle aspiration of the level II node was performed and revealed metastatic squamous cell carcinoma. Again, PCR showed the tumor to be positive for HPV 16. A PET/CT scan confirmed hypermetabolic left cervical adenopathy along with focal asymmetric uptake within the left lingual tonsil (see Figure 3). Direct laryngoscopy was performed and multiple biopsies of the left lingual tonsil and left tongue base were negative for malignancy. His case was reviewed by a multidisciplinary tumor board where he was felt to have the new metachronous disease of unknown primary, TXN2BM0 (the decision to consider this an SPT and not a nodal failure was made based upon the long time interval and contralateral location).
Figure 2. Primary Tumor PET/CT Images.
PET/CT scan from 2008 showing uptake within the right level II lymph node and right tonsillar fossa.
Figure 3. Second Primary Tumor PET/CT Images.
PET/CT scan from 2014 showing hypermetabolic left cervical adenopathy along with focal asymmetric uptake within the left lingual tonsil.
Left neck dissection was recommended with pathology revealing the involvement of 16 of 40 levels II, III, and IV lymph nodes with squamous cell carcinoma and evidence of extracapsular nodal extension (see Figure 1, Panel D). Based upon negative biopsies of the oropharynx, radiation with sensitizing chemotherapy was recommended and he was treated with ipsilateral IMRT to the left hemi-neck only (6000 cGy) with weekly Carboplatin AUC 2 and Paclitaxel 40 mg/m2. No oropharyngeal radiation was given due to concerns of overlap with the prior treatment field and added toxicity. He tolerated treatment well and experienced Grade 2 dermatitis and mild fatigue as his primary side effects.
Figure 4. Fusion of Primary and Secondary Treatment Plans. Treatment planning fusion with summative isodose lines overlaying
the treatment CT scan.
This case illustrates the treatment of a patient who developed an HPV-positive SPT following treatment with ipsilateral IMRT for an HPV-positive primary SCC of the oropharynx. Current guidelines for the treatment of oropharyngeal SCC suggest that ipsilateral radiation to the primary site and regional nodes are sufficient for patients with <1 cm invasion into the soft palate or base of tongue, a lateralized tumor more than 1 cm from the midline, and N2a or lesser nodal involvement. Consequently, this patient was treated appropriately given his original stage III disease, and the occurrence of an SPT does not indicate a treatment failure but, rather, illustrates the very real trade-off between minimizing toxicity through ipsilateral treatment and accepting unaddressed risk for contralateral tumor development.
Importantly, such a trade-off has only become possible with the development of advanced radiation technologies which allow for ipsilateral field design. Fortunately, in this case, the highly conformal dose distributions and steep dose gradients allowed for by IMRT facilitated the creation of initial and secondary treatment plans with minimal overlap (see Figure 4). This benefit of IMRT has particular utility in head and neck radiotherapy because organs at risk can reach their radiation tolerance during the first course, and radiation of head and neck cancers within previously irradiated territory has been shown to carry increased risk of acute and late toxicities[12-15]. As the proportion of HPV-positive HNSCCs is expected to continue rising in the coming decades, it will be important for clinicians to remember the potential for development of SPTs in this population and design treatment fields with the goal of providing excellent ipsilateral coverage without compromising any contralateral treatment which might become necessary in the future. Importantly, this forward-thinking approach is even more important in the ipsilateral treatment of patients with HPV-negative disease given their increased likelihood of SPT development.
In addition to illustrating the importance of intelligent field design in the treatment of patients with HPV-positive HNSCC, this case also highlights the need for greater understanding of the etiology, pathogenesis, clinical behavior, and prognosis of SPTs in HPV-positive patients. Indeed, current publications regarding this phenomenon are limited to small series or case reports and few conclusions can reliably be drawn [9-10, 16- 17]. From these published data, overall rates of SPT development in HPV-positive patients are estimated to be 2-3% which is much lower than the overall rate of 11.5% for HNSCC as a whole. Although rates of death from SPTs have not been shown to differ according to HPV-status, such a difference in incidence among HPV-positive patients is highly significant as SPTs are the leading cause of mortality in all patients with HNSCC overall[2,18]. Further understanding of the time frame for SPT development in HPV-positive patients is also important as the largest published case series showed an average interval of five years (range of two to nine) for SPT development. Such a range aligns well with our reported seven-year interval and suggests that HPV status could potentially be important in the design of protocols for follow-up after treatment for HNSCC.
The location of SPT development in HPV-positive patients also requires further study, although previous studies suggest that they are most likely to occur in the lymphoepithelial tissues of the head and neck (e.g. Waldeyer’s ring)[17, 19-20]. This distribution is interesting in light of our patient’s persistent FDG-avidity of the left base of the tongue. Although multiple biopsies showed only inflammatory changes, the possibility of the SPT site of origination being in lingual tonsillar tissue certainly raises clinical suspicion and provides the impetus for continued attention on follow-up.
Importantly, such a location would be consistent with either of the proposed models for SPT development in patients with HPV-positive primary tumors. The first of these models proposes that multiple inoculation events might be responsible for SPT development and has been evidenced by the discovery of identical HPV variants among sexual partners with oropharyngeal SCC [16, 21]. These inoculations could occur at multiple sites during a single exposure or during multiple events either from external exposures or autoinoculation. The second of these models proposes that a single exposure could result in SPT development via intraepithelial clonal migration and has been evidenced by identification of cervical tumors/dysplasias with metachronous vulvar tumors with the same viral integration sites[16, 22]. To date, no data has been published to clearly demonstrate the superiority of either of these models in accurately explaining the pathogenesis of SPT development in this unique subgroup of HNSCC patients. Interestingly, however, both mechanisms differ significantly from the classic model for SPT development in HPV-negative HNSCC patients in which “field cancerization” occurs due to carcinogen exposure (primarily cigarette smoke) that creates an area of premalignant tissue primed for further genetic alterations and subsequent tumor development .
Importantly, the possibility of this case representing a late nodal failure rather than a true SPT cannot be completely ruled out. However, the elapsed time of seven years between primary and secondary sites of disease is significantly longer than previous cutoffs used by other groups as a criterion for SPT classification (three and five years)[23-24]. In addition, the contralateral location easily surpasses previous cutoffs for the distance between second and primary sites used by other groups as well (1.5 and 2 cm)[24-25]. Given these features, our multidisciplinary tumor board felt confident that this case did represent a true SPT and elected to treat the case accordingly. Indeed, the remaining possibility of this case representing a late nodal failure rather than a true SPT is a reminder of the known uncertainty and difficulty in applying the third of Warren and Gates’ criteria for defining SPTs, namely exclusion of the possibility of a second tumor being a metastasis from the primary .
Moving forward, the previously well-regarded phenomenon of SPTs in patients with HPV-negative HNSCC will have to be considered more commonly in patients with HPV-positive HNSCC. Consequently, it will be important for clinicians to leverage the advantages of advanced radiation technologies such as IMRT to create treatment plans that will allow for minimal overlap if a contralateral treatment ever becomes necessary. Indeed, designing treatment fields while keeping in mind the possibility of a future contralateral treatment should be considered by all providers caring for patients with HNSCC regardless of HPV status. In addition, the increasing recognition of HPV-positive oropharyngeal SCC as a unique clinical entity should be considered in the design of future trials and in the management and follow-up of patients in current oncologic practice.
Conflicts of Interest