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.
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 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 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.