Episode 158: Head and Neck Cancer Series, Pt. 1 - Introduction
This week, we kick off our Head and Neck Cancer series. Using the case of a man with a painless neck mass, we build a framework for the whole series: why head and neck cancer is really two distinct diseases, the biology behind HPV-associated oropharyngeal cancer, how to work up a neck mass and hunt for an unknown primary, the cervical lymph node levels, and AJCC 8th edition staging — including the single most counterintuitive point in the field, that "Stage IV" does not mean metastatic in HPV-positive disease. Treatment of locoregional disease is coming up in Part 2!
This episode is sponsored by Primum! To learn more, sign up for your free account, and to ask questions to Primum experts, click here!
Meet the patient:
A 61-year-old man presents to his primary care doctor with a lump on the right side of his neck that he noticed about six weeks ago while shaving. It's painless and he feels otherwise well. He has a 15 pack-year smoking history but quit a decade ago, drinks socially, and has no fevers, night sweats, or weight loss. On exam there's a firm, 2.5 cm mobile node in the right neck just below the angle of the jaw. He's given a course of antibiotics for presumed reactive adenopathy, but the node is still there at his four-week recheck.
How common is head and neck cancer, and why is it really two different diseases these days?
"Head and neck cancer" is an umbrella term for cancers of the oral cavity, oropharynx, larynx, hypopharynx, nasopharynx, and sinonasal tract (see figure below - *** HIGH YIELD***).
More than 90% are squamous cell carcinomas arising from the mucosal lining.
Worldwide it is the seventh most common cancer, and it has historically been a disease of older men, with a male predominance that persists today.
The key framing for the whole series: today we essentially have two biologically distinct diseases that happen to live in the same anatomic neighborhood.
Carcinogen-driven cancer (tobacco and alcohol): older patients, can arise anywhere in the tract, carries field cancerization and second-primary risk, worse prognosis stage-for-stage.
HPV-associated oropharyngeal cancer: driven by high-risk HPV, classically in the tonsil and base of tongue; patients are often younger, frequently never- or light-smokers, with a dramatically better prognosis.
As smoking rates fell, tobacco-related disease declined, while HPV-associated oropharyngeal cancer rose so sharply that it now accounts for the majority of oropharyngeal cancers in the U.S., and oropharyngeal cancer has overtaken cervical cancer as the most common HPV-associated malignancy in the U.S.
Head and neck anatomy. Image from https://nhcancerclinics.com/cancer-types/head-and-neck-cancer/.
The tobacco–alcohol connection — is it just additive, or something more?
It is synergistic, not just additive. Heavy tobacco and heavy alcohol together multiply risk well beyond the sum of either alone — on the order of a 30-fold-plus increase in the heaviest users. Alcohol acts partly as a solvent enhancing mucosal penetration of tobacco carcinogens, and its metabolite acetaldehyde is itself a carcinogen.
This is the origin of field cancerization, a concept introduced by Slaughter and colleagues in 1953. The entire aerodigestive mucosa is bathed in the same carcinogens, so the whole field is primed. That's why these patients develop second primary tumors at a rate of a few percent per year, and why we image the chest and keep a low threshold for synchronous lung and esophageal cancers.
Betel nut / areca chewing is a major risk factor for oral cavity cancer in South and Southeast Asia.
The nasopharynx, which is its own entity: EBV (Epstein-Barr virus) is the key driver, with a striking geographic and ethnic distribution (Southern China, Southeast Asia). EBV in the nasopharynx is the analog of HPV in the oropharynx — a virus defining a distinct entity, and EBV DNA can be followed in the blood as a biomarker.
What is high-risk HPV actually doing to these cells, and how did we figure out it causes cancer?
The causal story is one of the great translational arcs in oncology. Through the 1990s and early 2000s, Maura Gillison and colleagues at Johns Hopkins assembled the evidence that a subset of oropharyngeal cancers were caused by HPV. This was highlighted in their landmark 2000 paper in JNCI (Gillison et al.) showing HPV as a distinct etiologic agent with a different risk-factor profile and better survival.
The high-risk genotypes to know are HPV-16, 18, 33, and 35, with HPV-16 responsible for the vast majority of HPV-associated oropharyngeal disease.
Mechanistically it comes down to two viral oncoproteins:
E6 promotes degradation of p53, knocking out the cell's main "guardian of the genome" and its apoptosis brake.
E7 binds and inactivates the retinoblastoma (Rb) protein, releasing E2F and driving the cell through the cycle.
The clinically useful trick: when Rb is knocked out by E7, the cell loses Rb-mediated feedback suppression of p16, so p16 piles up. That is why p16 overexpression by immunohistochemistry works as an inexpensive surrogate marker for transcriptionally active high-risk HPV in the oropharynx.
Testing options: p16 IHC (cheap, fast, the workhorse) and HPV in situ hybridization or HPV RNA/DNA testing (more specific). For oropharyngeal primaries, p16 IHC is required.
Does p16 mean the same thing everywhere in the head and neck? ***HIGH YIELD CONCEPT***
No!
p16 positivity is only prognostically and biologically meaningful in the oropharynx. A p16-positive larynx or oral cavity cancer does not carry the same favorable biology, and routine HPV/p16 testing outside the oropharynx is not recommended.
When you see "p16+" on a path report, always anchor it to the primary site before letting it change your prognosis or staging.
What’s the workup for a patient with a new mass in the head and neck cancer region?
The single most important early step: get ENT involved for direct visualization. A flexible fiberoptic exam of the entire upper aerodigestive tract is non-negotiable — many primaries (tonsil, base of tongue) are invisible externally.
For the neck node itself, FNA is the right first biopsy.
For cystic-appearing nodes, image-guided (ultrasound or CT) needle biopsy improves yield over palpation-guided FNA.
What we do not want to do reflexively is an open excisional biopsy of a neck node in someone who might have a mucosal squamous primary. Get the FNA and find the primary first.
Imaging:
CT neck with contrast to characterize the primary and nodes, plus CT chest for distant disease and synchronous lung primaries.
A PET/CT is frequently obtained since it’s more sensitive for nodal and distant disease, and especially useful for radiation planning and for hunting an unknown primary.
Easy-to-forget supportive care that matters enormously before radiation: a dental evaluation (to reduce osteoradionecrosis risk), a baseline swallow evaluation, audiometry if we plan to usecisplatin, and smoking cessation counseling (continued smoking during treatment worsens outcomes).
Our patient’s FNA returns p16-positive squamous cell carcinoma, but the scope shows no obvious primary. How do we find it, and why does it matter so much?
This is the squamous cell carcinoma of unknown primary scenario, and a p16-positive cervical node is a huge clue — it points strongly to an oropharyngeal primary (tonsil or base of tongue), even when the scope looks clean.
When the primary isn't obvious on PET, the next step is an exam under anesthesia (EUA) with directed biopsies, often including tongue-base biopsies and ipsilateral (or bilateral) tonsillectomy, because the primary frequently hides in the tonsillar crypts
Why obsess over this? Because primary site dictates staging, treatment, and prognosis. A p16+ oropharyngeal primary is handled completely differently from, say, a laryngeal primary — and finding it lets the radiation oncologist treat a targeted field rather than the entire mucosa.
Can you orient us to the cervical lymph node levels — the geography of the neck?
The neck is divided into levels (the Robbins/AHNS classification):
Level I — submental and submandibular (floor of mouth, oral cavity, lip).
Level II — upper jugular, around the jugulodigastric node below the angle of the mandible. The classic landing spot for oropharyngeal primaries — and exactly where our patient's node is.
Level III — mid-jugular.
Level IV — lower jugular (worry about hypopharynx, larynx, and infraclavicular spread).
Level V — posterior triangle (nasopharynx, thyroid).
Level VI — central compartment (thyroid, subglottic larynx, cervical esophagus).
TL;DR: (in general) Level 1 is higher up, Level 6 is further down
Pattern recognition: a high level II p16+ node screams oropharynx; a level IV / supraclavicular node should prompt thoughts of infraclavicular sources and more advanced disease; an isolated posterior triangle node should raise nasopharynx.
Head and neck lymph node distribution. Image from: https://www.cancer.gov/types/head-and-neck/hp/adult/oropharyngeal-treatment-pdq
What are the principles of T and N staging? How does HPV status affect this?
Staging is AJCC 8th edition, which includes a separate staging system for p16-positive oropharyngeal cancer, because the old system badly overstaged a disease that does very well.
T staging - here’s what to pay attention for that is going to upstage your patient:
Oral cavity incorporates depth of invasion: deeper invasion upstages you even at the same surface size.
Oropharynx advanced T means invasion of nearby structures (larynx, extrinsic tongue muscle, pterygoids, hard palate, mandible).
Larynx: invasion through the thyroid cartilage (T4a) generally pushes toward total laryngectomy rather than larynx preservation, whereas vocal cord fixation defines T3.
N staging — for carcinogen-driven (p16-negative) cancers and oral cavity:
N1: single ipsilateral node ≤ 3 cm, ENE-negative.
N2: single ipsilateral node > 3 but ≤ 6 cm, or multiple ipsilateral, or bilateral/contralateral nodes (none > 6 cm), ENE-negative (N2a/b/c).
N3: node > 6 cm (N3a), or clinically overt extranodal extension (N3b).
The other big 8th edition change for non-HPV disease: extranodal extension (ENE) is now incorporated into N staging, because it is one of the most powerful adverse prognostic features we have.
The HPV/p16-positive oropharynx system is deliberately different:
No ENE in the staging. ENE isn't the same prognostic driver in HPV+ disease.
Nodal staging is driven by size, laterality, and for pathologic staging the number of involved nodes (pN1 ≤ 4 nodes, pN2 > 4 nodes).
Stage groupings are compressed so that even fairly bulky nodal disease lands at stage I or II.
Important points in head and neck cancer:
For p16-positive oropharyngeal cancer, "Stage IV" does NOT mean metastatic, and it does NOT mean incurable. In the older (7th edition) system, these patients were routinely labeled stage IV with bilateral or bulky nodes — yet the majority were cured with definitive therapy.
In the HPV+ system, Stage IV is reserved for distant metastatic (M1) disease unlike essentially every other head and neck site, where stage IV can still be locoregional and very curable.
Practical translation: counsel HPV+ oropharynx patients on the biology and the TNM, not the scary Roman numeral. Many "stage IV" patients in the old framework had cure rates north of 80%.
Our patient’s outcomes:
EUA with bilateral tonsillectomy and tongue-base biopsies revealed a p16-positive squamous cell carcinoma of the right tonsil, and PET/CT confirmed the right level II node without distant disease.
So he has p16-positive oropharyngeal squamous cell carcinoma — a small primary with a single sub-3 cm ipsilateral node, consistent with favorable, early-stage disease in the HPV+ system, and a patient we expect to cure.
That sets up next episode's question: with disease this favorable, how much treatment does he actually need, and can we de-escalate without giving up cures?
Quick recap / board pearls
Head and neck cancer is two diseases: carcinogen-driven (tobacco/alcohol, worse prognosis, field cancerization, second primaries) and HPV-associated oropharyngeal (better prognosis, younger patients).
HPV mechanism: E6 → p53 degradation, E7 → Rb inactivation → p16 overexpression; p16 IHC is the surrogate marker, but only meaningful in the oropharynx.
EBV is to nasopharynx what HPV is to oropharynx.
Workup: ENT scope + FNA of the node (image-guided if cystic), CT neck/chest, PET/CT, dental eval, swallow study, smoking cessation. Find the primary — it changes everything.
Staging is AJCC 8th edition with a separate, more favorable system for p16+ oropharynx — no ENE, node number matters, and Stage IV ≠ metastatic in HPV+ disease.
Next episode: definitive and adjuvant management of locoregional disease — surgery versus chemoradiation by subsite, the cisplatin dosing wars, the adjuvant ENE/positive-margin story, induction chemo, and the new neoadjuvant/adjuvant immunotherapy data.
References:
https://pubmed.ncbi.nlm.nih.gov/10793107/ — Gillison ML, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92(9):709–720.
https://pubmed.ncbi.nlm.nih.gov/13094644/ — Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953;6(5):963–968.
Regimen reference (for the series):HemOnc.org – Head and Neck Cancer ·HemOnc.org – Oropharyngeal cancer, HPV-positive
This episode is sponsored by Primum! To learn more, sign up for your free account, and to ask questions to Primum experts, click here!
The crew behind the magic:
Show outline: Vivek Patel
Production and hosts: Vivek Patel, Dan Hausrath, Ronak Mistry
Editing: Resonate Recordings
Shownotes: Ronak Mistry
Graphics, social media management: Ronak Mistry
