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The New Face of Head and Neck Cancer: The HPV Epidemic: Page 2 of 3

The New Face of Head and Neck Cancer: The HPV Epidemic: Page 2 of 3

Figure 1. Human papillomavirus (HPV) is a sexually transmitted virus a...
Figure 2. Imaging Studies of HPV-Positive OPSCC
Figure 3. Risk Stratification for Oropharyngeal Squamous Cell Carcinom...
Table 1. Comparison of HPV-Negative and HPV-Positive Head and Neck Cancers
Table 2. Notable Ongoing Deintensification Trials in HPV-OPSCC
Table 3. Summary: Management and Treatment Options in HPV-OPSCC

Clinical and Pathologic Presentation of HPV-OPSCC

Up to 90% of patients with HPV-OPSCC present with an asymptomatic neck mass.[20] Some may have no evidence of a primary tumor on direct transoral examination because the tumors are typically small (early T stage) and often concealed within abundant surrounding tonsillar tissue. The neck nodes are frequently cystic, leading to nondiagnostic aspirates (Figure 2).

There are opportunities for delay in diagnosis at several levels:

(1) Lack of suspicion due to negative smoking history.

(2) Absence of symptoms and signs in early disease.

(3) Inadequate oropharyngeal examination due to lack of training or proper equipment.

(4) Microscopic disease below the imaging threshold for detection.

(5) Inadequacy of aspirates collected and processed from cystic nodes.

(6) Random and nonsystematic oropharyngeal biopsies during surgery without the benefit of detailed imaging.

Diagnostic imaging is critical. Computed tomography (CT) and/or magnetic resonance imaging (MRI) are necessary preliminary studies. In the setting of an unknown primary, a positron emission tomography (PET)/CT scan may be helpful in localizing the primary cancer and should be performed before any surgical intervention.

Ultrasound guidance may increase the diagnostic yield of fine-needle aspirates taken from abnormal neck nodes, especially if cystic.[21] Specimens should be processed for HPV markers. The feasibility of HPV detection in fine-needle aspirates from cervical lymph nodes has been confirmed using both p16 immunohistochemistry (IHC) and in situ hybridization (ISH) platforms.[22,23]

Excisional biopsy of cervical lymph nodes should be avoided if possible, particularly if performed prior to PET/CT, because inflammation from excision surgery can distort PET/CT results.[24]

If the fine-needle aspirate collected from a cervical node tests positive for HPV, this should raise concern for an oropharyngeal primary tumor. Careful review of imaging should focus on any oropharyngeal soft-tissue fullness or asymmetry. In the setting of an unknown primary tumor, a palatine and/or lingual tonsillectomy for primary site detection is preferred over random biopsies.

HPV-OPSCCs display poorly differentiated, nonkeratinizing, basaloid histology with permeation by lymphocytes.[25] These tumors demonstrate diffuse nuclear and cytoplasmic staining for p16.

HPV Testing

A reliable surrogate marker for HPV infection in patients with OPSCC is p16 IHC, given its high sensitivity (p16 IHC is falsely negative in only 4% of cases).[26] Strong nuclear and cytoplasmic expression is highly predictive of HPV-OPSCC. In cases with intermediate levels of p16 expression, ISH or reverse transcription-polymerase chain reaction (RT-PCR) should be performed.[26] PCR-based assays cannot differentiate integrated DNA from episomal viral DNA (passenger virus), which significantly lowers the specificity of the test. DNA ISH can detect integrated viral DNA, which increases its specificity in the clinical setting, although its sensitivity is lower than that of PCR.[27] The ISH test is easily performed in the surgical pathology laboratory. Lewis et al found that 98.5% of nonkeratinizing OPSCCs were positive for HPV by ISH, compared with only 13.6% of keratinizing OPSCCs.[26]

The development of RNA ISH probes to E6/E7 microRNA permits direct visualization of viral transcripts in routinely processed tissues and has created the opportunity for accurate HPV detection in the clinical care setting.[28] RNA ISH may soon become a favored test for HPV confirmation of p16-positive tumor samples, especially since p16 may also be overexpressed through non–virally mediated mechanisms. This overexpression may lead to a false-positive result (p16-positive, HPV-negative) that could result in nonoptimal patient counseling and management decisions. It is expected that RNA ISH to E6/E7 will become the favored method for HPV-OPSCC testing in the future.

Cancer Care Ontario has recommended the following testing procedures in patients with HNSCC[29]:

(1) Tumors of all adult OPSCC patients should be routinely tested for HPV.

(2) Metastatic cervical nodal tissue of patients with an unknown head and neck primary tumor should be routinely tested for HPV.

(3) HPV status in OPSCC should initially be determined using p16 IHC, because of the high sensitivity of this test.

Impact of HPV on Prognosis

Multiple studies have confirmed the favorable impact of HPV positivity in patients with OPSCC.[30-33] Of interest, a favorable prognosis is seen even in recurrent or metastatic HPV-OPSCC, which necessitates intensive intervention in this setting as well.

Ang et al published the largest retrospective analysis of the impact of HPV on outcomes in OPSCC within the Radiation Therapy Oncology Group (RTOG) 0129 study, which employed cisplatin with either standard or accelerated fractionation radiation.[34] HPV testing was performed using ISH. The 3-year rates of overall survival (OS) were 82.4% (95% confidence interval [CI], 77.2–87.6) in the HPV-positive OPSCC subgroup and 57.1% (95% CI, 48.1–66.1) in the HPV-negative OPSCC subgroup, while the 3-year rates of progression-free survival were 73.7% (95% CI, 67.7–79.8) and 43.4% (95% CI, 34.4–52.4), respectively. Patients with HPV-OPSCC had a 58% lower risk of death (hazard ratio [HR], 0.42 [95% CI, 0.27–0.66]; P < .001) and a 51% lower risk of progression (HR, 0.49 [95% CI, 0.33–0.74]; P < .001). Patients were further divided into risk-of-death categories (low, moderate, and high) based on their HPV status, tumor burden, and tobacco use (Figure 3). Three-year survival was 93%, 70.8%, and 46.2% in the low-, moderate-, and high-risk groups, respectively. Tobacco use had a negative impact on prognosis, independent of HPV status. This study, while retrospective, clearly confirmed a better prognosis for HPV-positive patients with OPSCC.

In a retrospective analysis of the TAX 324 trial, HPV testing was performed using E6/E7 PCR methods. This study examined triple-agent vs double-agent induction chemotherapy. Eighty-two percent of HPV-positive patients were alive at 5 years compared with 35% of HPV-negative patients (P < .0001).[35] The improved survival was attributed to significantly better locoregional control in the patients with HPV-OPSCC but was also due to fewer disease-unrelated deaths in this predominantly younger and healthier subgroup of OPSCC patients.

The Eastern Cooperative Oncology Group (ECOG) 2399 trial was a phase II prospective study of patients with stage III and IV, M0, oropharynx and larynx cancer that examined paclitaxel/carboplatin induction chemotherapy followed by concurrent chemotherapy with paclitaxel and standard fractionation radiation therapy.[30] Tumors were tested for HPV by p16 IHC. Patients with HPV-positive OPSCC had a 61% lower risk of death (HR, 0.39 [95% CI, 0.15–1.05]; P = .06) and a 62% lower risk of progression (HR, 0.38 [95% CI, 0.12–1.15]; P = .09) than patients with HPV-negative OPSCC, after adjustments for age, tumor stage, and ECOG performance status.

In a prospective analysis, Rischin et al reported results of a randomized phase III study of radiation therapy with cisplatin, with or without tirapazamine, in 206 patients with OPSCC.[31] Two-year OS was significantly better in patients with p16-positive vs p16-negative tumors (91% vs 74%; HR, 0.36; P = .004).

Surgical series likewise support the favorable impact of p16 positivity in OPSCC. Rich et al reported on 84 patients with stage III or IV oropharyngeal cancers treated with transoral laser microsurgery (TLM) ± adjuvant therapy.[32] Patients with p16-positive tumors had significantly higher 5-year OS and disease-specific survival (DSS) rates than those with p16-negative tumors: 90% (95% CI, 79–96) vs 25% (95% CI, 1–66) (P < .0001), and 94% (95% CI, 82–98) vs 50% (95% CI, 1–91) (P = .0078), respectively.

Collectively, these multiple studies performed retrospectively and prospectively have confirmed the superior prognosis of HPV-positive vs HPV-negative OPSCC. The excellent prognosis in HPV-positive patients may have considerable treatment implications in the future.


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