New HPV guideline for head, neck cancers

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Karen Titus

February 2018—Like a pair of one-size-fits-all jeans, testing all head and neck carcinomas for human papillomavirus may have seemed like a good idea at one time. In many cases, in fact, HPV testing is just what treating clinicians and patients need. On the other hand, not every head and neck case requires it. Now, a newly published CAP guideline should help physicians figure out the right fit in multiple settings.

“There’s a lot of testing going on,” not all of it warranted, says William Faquin, MD, PhD, a coauthor and committee co-chair of the guideline (Lewis JS Jr., et al. Arch Pathol Lab Med. Epub ahead of print Dec. 18, 2017. doi:10.5858/arpa.2017-0286-CP).

The new guideline calls for HPV testing by p16 immuno-histochemistry on all newly diagnosed oropharyngeal squamous cell carcinomas. “We hope this will lead to more consistency in testing practices for these patients,” says Dr. James Lewis (right).

“A significant amount of it seems to be driven by clinicians pushing for it,” adds guideline co-chair and lead author James Lewis Jr., MD. “There’s a lot of data. It’s confusing and complicated.” And pathologists don’t necessarily know how, or if, clinicians will use test results. “That’s where the pathologists start feeling pinched. It’s hard to say ‘no.’”

The guideline should help pathologists put their collective foot down as needed, say its authors, by giving clear guidance on the different scenarios for HPV testing.

Equally useful, they say, is that the guideline coincides with the eighth edition of the American Joint Committee on Cancer’s staging system, which took effect in January. The new edition stages patients specifically based on p16 or HPV-specific testing (depending on what approach institutions use). “It lines up perfectly,” Dr. Lewis says of the overlapping documents.

This, in turn, reinforces the need for laboratories to do appropriate testing, since the two groups (HPV positive and HPV negative) have different implications for patients and their management, says Dr. Faquin, professor of pathology, Harvard Medical School, director of head and neck pathology at the Massachusetts Eye and Ear hospital, Boston, and staff pathologist at Massachusetts General Hospital.

The timing of the guideline is fortuitous for another reason, says Dr. Faquin. In the past five or so years information about the role of high-risk HPV in head and neck cancers has grown tremendously. The literature on which the recommendations are based is robust—no small thing for this complicated and evolving field.

Like Orion’s Belt (to continue the vague sartorial analogy), the guideline contains three prominent points to help orient physicians, according to Dr. Lewis.

The first is statement No. 1 (there are 14 in total), which calls for routinely testing newly diagnosed oropharyngeal (tonsil and base of tongue) squamous cell carcinomas, of all histologic subtypes, from the primary tumor or from cervical nodal metastases using p16 immunohistochemistry, which is a prognostic marker and surrogate marker of high-risk HPV.

Second, the authors essentially state there’s no indication for routine testing for HPV or p16 in any other tumor type or at any other primary site in the head or neck. “We see testing being done for nonoropharyngeal sites from various institutions around the U.S.,” says Dr. Lewis, professor of pathology, Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center. This new guideline, he adds, “should give pathologists the strength to say no when asked for the test when it’s not indicated,” thereby cutting down on wasteful and potentially misleading testing.

Finally, Dr. Lewis says, the guideline offers much-needed direction on handling cases involving neck lymph nodes, where the risk of false-positives is higher. “The guideline will be very helpful, particularly with cancer of unknown primary, where you’ve got a squamous cell carcinoma in neck lymph nodes and it isn’t clear where it arose”—a fairly common scenario, he adds.

That first recommendation is critical, agrees Dr. Faquin. It’s a departure from what pathologists have traditionally done, which was to group all oral cavity and oropharyngeal carcinomas together. The guideline distinguishes between carcinomas from the oropharynx and those of the oral cavity.

Dr. Faquin also echoes Dr. Lewis in drawing attention to statement No. 5: Pathologists should routinely perform high-risk HPV testing on all patients with metastatic squamous cell carcinoma of unknown primary in a cervical upper- or mid-jugular chain lymph node (essentially levels II and III). Roughly 80 percent of patients with OPSCC develop metastases to their cervical lymph nodes. “If it’s positive for HPV, that helps the treating clinician to know this metastatic cancer is very likely coming from the oropharynx,” says Dr. Faquin.

There was plenty of discussion about metastases of unknown primary to a level II or III lymph node, Dr. Faquin recalls. “What do you do when it’s keratinizing?” he asks.

Nonkeratinizing SCC can be tested with p16. Standard nonkeratinizing morphology with positive p16 can be interpreted as HPV-positive SCC because both are very strong surrogate markers for transcriptionally active high-risk HPV. However, cases with keratinizing morphology and positive p16 are somewhat different. Is p16 testing sufficient, or is a confirmatory HPV-specific test needed? Eventually, the group decided a p16-positive test in that scenario should be followed with an HPV-specific test.

One way to think about that, Dr. Faquin explains, is to consider a subset of p16-positive skin SCC. “You can imagine a scenario where you have a metastatic, keratinizing skin squamous cell carcinoma to a cervical lymph node,” positive for p16 but HPV negative. That drives home another key point: “You shouldn’t interpret p16 immunohistochemistry positivity by itself as a marker of high-risk HPV outside of these specific recommendations in the guideline,” says Dr. Faquin. Positive results don’t carry the same meaning for tumors in other areas of the head and neck. “That’s something a lot of pathologists may not appreciate.”

It’s also important for physicians to know that, depending on the specifics of the case, p16 often can be used as a surrogate marker for high-risk HPV infection. “And then we also make a statement that additional HPV-specific testing can be done at the discretion of the pathologist or clinician,” Dr. Faquin says.

The guideline is far from simple, but it offers clarity in an area where, until now, confusion had been piloting the plane. Head and neck anatomy, with its wide range of tissues, is complex; likewise, a variety of cancers can arise not only in the oropharynx but in other areas of the head and neck, many of them HPV positive. This complexity creates a testing dilemma, Dr. Faquin says. “You want to perform a test where the result is going to mean something.”

Hence the exhaustive literature search that underpins the guideline. One intent was to identify situations in which testing could lead to a different prognosis. “But it’s even more than that,” Dr. Faquin says. “We found that it’s really only the [OPSCC] where being positive for high-risk HPV implies an improved prognosis.” These patients might be eligible for clinical trials involving deescalation. “In the past these patients have been treated the same way that patients with conventional squamous cell carcinomas were treated—very aggressively, which has a lot of associated morbidity.”