Tackling unknown primary cancers of the head and neck at Penn ENT

For more than a decade, researchers at Penn Otorhinolaryngology-Head and Neck Surgery have been exploring the nuances of transoral robotic surgery (TORS) for human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV+ OSCC). The latest in the division’s ongoing series of reports explores TORS in the management of cancers of unknown primary (CUP) origin in HPV+ oropharyngeal cancers.

This study is the largest to date describing detection rates, oncologic outcomes, and pathology-based adjuvant therapy de-escalation using a TORS-assisted approach to HPV-driven oropharyngeal CUP. Study lead author Karthik Rajasekaran, MD, FACS, has contributed to more than 40 journal reports on the treatment of HPV-associated head and neck cancers since 2019.

In the United States, around 70 percent of OSCCs have an association with HPV infection. Now the largest subset of head and neck cancers, HPV+ OSCC is notable for its rapid increase in incidence since the 1990s, and the distinctions that can be made between it and HPV-negative oropharyngeal cancers in terms of demographics, etiology, treatment, and prognosis.

HPV as a factor in oropharyngeal cancers has brought about a redefinition of the “typical” patient profile for these malignancies. Formerly, the typical, HPV-negative patient with oropharyngeal cancer was a male in late middle age with a history of alcohol and tobacco abuse.

By contrast, patients with HPV-associated oropharyngeal cancers are younger and less likely to abuse alcohol and tobacco. They also have better treatment outcomes and survival rates. All of these tendencies contributed to the de-escalation of therapy in HPV+ head and neck cancers with the goal of reducing the treatment intensity, minimizing side effects, and maintaining high cure rates.

OSCC cancers of unknown primary: Quandary and quarry

The majority of patients with OSCC present with a painless neck mass. This neck mass represents a metastatic lymph node (or nodes). The primary usually is from a subsite of Waldeyer’s ring (palatine or lingual tonsils).

However, in 2 to 9 percent of cases, the source is not obvious on physical examination. Detection rates have improved nominally with CT and MRI imaging, as well as with standard surgical endoscopy combined with PET. Nevertheless, even with these advances, up to 50 percent of primary lesions remain undetected.

To address this deficit, researchers and surgeons at Penn Ear, Nose, and Throat (ENT) brought their experience in transoral robotic surgery to bear on the issue. They introduced robotic head and neck surgery in 2005 and achieved the first FDA indication for transoral robotic surgery (TORS) in 2009.

In the intervening years, researchers with the department have explored TORS in many aspects of HPV-associated head and neck cancer, including cancers of unknown primary. For individuals with HPV+ CUP, TORS-assisted endoscopy offers the advantage of high-definition visualization and the possibility of staged procedures guided by pathologic analysis, both of which augment the detection of CUP.

Outcomes of HPV+ Oropharyngeal CUP Following Transoral Robotic Surgery at Penn Otorhinolaryngology - Head and Neck Cancer

In their recent report, Penn ENT researchers set out to describe a benchmark for oncologic outcomes in the institution's TORS-assisted approach to HPV-associated oropharyngeal CUP.

Key takeaways

• The study included all patients with HPV-mediated CUP who had TORS-assisted endoscopy at Penn Medicine in the years 2010 to 2021.
• CUP was defined as an individual presenting with a biopsy-proven HPV+ squamous cell carcinoma in a cervical lymph node, with uncertainty regarding the location of the primary cancer. The primary malignancy had eluded detection in all patients despite a comprehensive preoperative workup and advanced imaging.
• An algorithm utilizing TORS-assisted endoscopy and a step-wise approach to the subsite using TORS was used to identify and manage patients with CUP OSCC.
• A primary tumor was identified in 88 percent of patients.
• Among the 12 percent of patients in whom a primary tumor was not found, the primary may have been smaller than 2 mm and/or was adequately controlled (presumably immunologically) within the tumor microenvironment. These patients were still considered cured and did not receive radiation to the primary site.
• Two-thirds of patients avoided chemoradiation.
• The five-year overall survival was 96 percent, while the recurrence-free survival rate was 94 percent at two years and 92 percent at 5 years.
• In terms of treatment-related swallowing morbidity, none of the patients had esophageal strictures or the need for a permanent gastrostomy tube.

Conclusions

The TORS-assisted approach demonstrates a high rate of identification for previously occult mucosal malignancies, and thus the potential to avoid or de-escalate guideline-based adjuvant therapy, especially chemotherapy, in patients with favorable pathologic features. Moreover, the TORS-assisted approach does not compromise the achievement of excellent oncologic outcomes and superlative functional results.

Referrals

Physicians interested in referring to the TORS HPV+ OSCC investigators at Penn Otorhinolaryngology-Head and Neck Surgery may contact Karthik Rajasekaran, MD, FACS, by calling 732-261-9409, or by emailing him directly at: Karthik.Rajasekaran@pennmedicine.upenn.edu.