HPV a game changer in head, neck tumors

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Karen Titus

December 2013—Not that any cancer is ever “easy,” but until relatively recently, the culprit in head and neck squamous cell carcinomas was clear. The vast majority were caused by “smoking, smoking, and smoking,” says William Westra, MD, professor of pathology, oncology, and otolaryngology/head and neck surgery, and associate director, surgical pathology, The Johns Hopkins Medical Institutions. Call this HNSCC’s antediluvian era.
In the last decade or so, however, physicians have seen a surge in the HPV-related form of head and neck cancers. The impact on patients, pathologists, and clinicians has been compelling, to say the least. And the new era is only in its genesis.

Dr. William Faquin, left, and Dr. James Rocco will begin work with others on an evidence-based guideline for high-risk HPV testing in head and neck squamous cell carcinomas. Says Dr. Rocco, “We’re rapidly approaching a time where HPV status is going to dictate what happens.”

As with so many other cancers—breast, lung, colon—molecular insights now mean HNSCCs no longer fall into one conveniently labeled bin. Instead, they’re distinguished by whether they’re mediated by the human papillomavirus, which, among other things, has sparked no shortage of interesting conversations among physicians. One pathologist recalled the clinician who expressed surprise at learning of a patient’s papilloma in the oral cavity, since the patient was “a good Christian woman.” Another said that at many conferences, physicians shift into the role of patient, asking thinly veiled questions about their own lives: “You don’t have to pay attention very long to figure out that the risk factor for this is something everyone in the room has done.”

Tempting though it is to focus on sex, there are plenty of other, equally intriguing issues to draw pathologists’ attention. What do laboratories need to know about HPV-related head and neck squamous cell carcinomas?

One of the first things to understand is that these tumors are clinically distinct from smoking-related cancers, says Dr. Westra, who is also director of The Head and Neck Pathology Consultation Service at Johns Hopkins. They’re associated with much-improved clinical outcomes, which has helped transform the pathologist’s role. “It’s my job not just to diagnose the presence of the cancer, but also to make this distinction. That’s now a big part of what I do as a diagnostic head and neck surgical pathologist,” he says.
For years, head and neck tumors primarily affected older individuals with a history of smoking and drinking. The tumors were aggressive, and they didn’t respond well to traditional chemoradiation therapy. The good news is they’ve also been decreasing, due in part, perhaps, to a decrease in smoking incidence.

HPV-related head and neck squamous cell carcinomas, on the other hand, have been increasing fairly dramatically over the last few decades, says William Faquin, MD, PhD, director, head and neck pathology, Department of Pathology, Massachusetts General Hospital. Epidemiologically, they’re different. They’re more common in men, primarily middle-aged or older, who neither drink nor smoke. “And they usually have a history of sexual activity that would expose them to oral infection by HPV.”

“Head and neck” might be a slight misnomer. The majority occur in the oropharynx, or tonsils and base of the tongue. It’s a fact worth noting, since physicians don’t always appreciate the difference.
When clinicians ask Margaret Brandwein-Gensler, MD, to perform HPV testing for head and neck cancers, her response is a pointed, “Why do you want to know?” Too often, the request is made for specimens from the oral cavity in general, rather than the oropharynx specifically, says Dr. Brandwein-Gensler, section head, surgical pathology, Division of Anatomic Pathology, Department of Pathology, The University of Alabama at Birmingham. “Oral cavity and oropharynx—they sound alike, right?” she says with a laugh. “But there’s a big difference in how we treat those two sites.”

Dr. Westra, too, sees increased interest in HPV testing among his clinical colleagues. That’s not entirely good. As more physicians tune into the importance of HPV status in head and neck cancers, Dr. Westra says, many are ordering HPV testing on all such cancers, regardless of anatomic subsite. Because HPV-related HNSCCs are restricted in distribution to the oropharynx, there’s no role for HPV testing outside that site, he says, such as the oral tongue or lip.

Interestingly, says Dr. Faquin, the tonsils are a specialized structure related to the immune system and antigen presentation. They’re covered by squamous epithelium, which has specialized crypts where the squamous epithelium dips down underneath the surface epithelium. Deep within these crypts the squamous epithelium transitions into more of a lymphoepithelial-lined mucosa. “There’s an intimate association between the crypt-lining epithelium and the surrounding lymphocytes,” says Dr. Faquin. It’s here that HPV causes infection and the development of HPV-related squamous cell carcinomas.

This is no mere biology lesson, he hastens to add. “For all clinicians, it’s important to understand that the HPV-related squamous cell carcinomas are developing in these deep crypts. If there’s a clinical exam done by an ENT doctor, for example, they will often not see any abnormality, because these cancers can be very small.” Like Achilles lounging in his tent, they’re hidden from view.

Some physicians play the curiosity card when they ask for HPV testing, Dr. Brandwein-Gensler says. “They have this idea of, ‘W-e-l-l, I just want that information. Maybe I can do something with it. Maybe I can use it in a study.’” In such cases, HPV status is less of a testing issue than one of clinician education. “People are well-meaning,” she says diplomatically. “They’re hearing HPV is a big deal, and they’re interested.” But they need to understand that HPV testing in clinical settings needs to be driven by laser-like focus, rather than good-hearted expansiveness.

Adds Dr. Westra: “Even among my clinical colleagues here at Hopkins, still a very fundamental question is, ‘When should I perform HPV testing?’ And how?”

As Dr. Brandwein-Gensler suggests, “Why?” is another question worth posing.

One reason is that HPV status—high-risk HPV specifically—is perhaps the most powerful prognostic indicator for patients with head and neck cancer. Of three major retrospective analyses, in which researchers looked at HPV-positive versus -negative tumors in patients who received the same treatment, patients who were positive did about three times better in terms of overall survival: 80 to 85 percent versus approximately 35 to 38 percent. “To the outside world, these tumors would look the same,” says James Rocco, MD, PhD, the Daniel Miller Chair of Otology and Laryngology, Harvard Medical School, and director, head and neck research, MGH.

While there are many types of high-risk HPVs, some 95 percent or more are type 16. Any lab that tests for HPV-related HNSCC will need an assay that can pick up that type, “but you also want to be open to detecting other high-risk types,” says Dr. Faquin. Low-risk types, most commonly 6 and 11, can cause laryngeal papillomatosis. While this can be a morbid disease and is frequently seen in pediatric ENT pathology, low-risk HPVs do not lead to cancer.

HPV testing can also help localize the primary site of tumor origin for patients who present with metastatic disease. One unusual aspect of these tumors, says Dr. Westra, is that they often arise in the tonsils and are sometimes so small that they elude clinical and radiographic detection. “It’s not uncommon for the patient to present with an enlarged cervical lymph node,” Dr. Faquin says. When an FNA is performed on these lymph nodes, the diagnosis is a metastatic, nonkeratinizing SCC. “If you can tell the clinician that this metastatic squamous cell carcinoma in the patient’s cervical lymph node is HPV related—and specifically high-risk HPV-related—they know with a fair degree of certainty that the cancer is coming from the oropharynx.”
This, in turn, can affect treatment, Dr. Faquin says. If the site of origin is identified as the oropharynx, then radiotherapy can be directed more specifically to that spot, rather than irradiating a patient in a wider range of the head and neck structures.

“At the same time,” he continues, “because HPV status is so important now, both in terms of prognosis and, in the very near future, actually directing specific therapy, we have been advocating for routine testing of all cancers arising in the oropharynx.”

Indeed, says Dr. Rocco, “We’re rapidly approaching a time where HPV status is going to dictate what happens,” including possible deintensification of therapy.

Some suggest that HPV-positive and HPV-negative tumors also differ in their rates of distant relapses. Dr. Rocco calls it “an anecdotal feeling” among many who treat people with head and neck cancers that the metastases from HPV-related disease seem to behave slightly differently than those from HPV-negative tumors. For a traditional patient with head and neck cancer, the risk of distant metastases is under five percent, says Dr. Rocco. When they do occur, it’s usually after a bilateral, bulky neck adenopathy; they almost always go to the lung.

In HPV-related tumors, published data indicate the rate of distant metastases is similar—about three percent. “What’s different is you don’t necessarily need to have this big, bulky disease or advanced disease for it to happen,” Dr. Rocco says. It also seems to occur in different locations. In his own practice, Dr. Rocco sees maybe one to three cases of distant mets annually. “I don’t think I’ve ever seen distant mets go to the cervical spine in my old practice—pre-HPV—but I’ve seen that happen with HPV,” he says. “I’ve seen brain mets, and liver mets, and spine mets, which I’ve never seen before.”

“But remember: The numbers are small,” he says. And about 80 percent of the patients he cares for who have head and neck cancers have HPV-related tumors; at his institution overall, about 90 percent of patients with oropharyngeal cancers have HPV-related tumors. The numbers, in short, are skewed—clinicians aren’t seeing an equal number of non-HPV-related HNSCC. “So that could be fooling us as doctors into drawing conclusions that aren’t there.”