Boris Hristov and Giuseppe Sanguineti
H&N cancers of an unknown primary represent what % of H&N cancers?
~3%–5% of all H&N cancers are of an unknown primary.
What is the most commonly presumed general site of origin for H&N cancers of an unknown primary?
The oropharynx (OPX) is the presumed site of origin for most cases (less common are the nasopharynx [NPX], hypopharynx [HPX], and larynx).
What subsites constitute the OPX?
Soft palate, tonsils, tonsillar pillars, base of tongue (BOT), and pharyngeal walls
What are the 2 most common originating sites/primary locations if the cancer is presumed to be of oropharyngeal origin?
Tonsils and BOT. Up to 80% of presumed oropharyngeal tumors are thought to originate from these 2 sites.
Approximately what % of pts with tonsillar primaries harbor Dz in both tonsils?
~5%–10% of pts with tonsillar primaries harbor Dz in both tonsils.
A primary can be identified in what % of H&N cancers of unknown primary?
A primary site of origin can ultimately be identified in ~40% of pts.
What is the most common presentation for H&N cancers of an unknown primary?
Painless upper neck LAD (IB–III) is the most common presentation.
What is the T staging if no primary H&N site is found after workup?
T0 (not TX) is the assigned T stage if no primary is found.
On what are the overall stage groupings based if the primary is not known?
LN involvement determines the stage groupings:
1. Stage III: N1
2. Stage IVA: N2
3. Stage IVB: N3
4. Stage IVC: M1
What % of pts with an unknown primary present with bilat LAD (N2c)?
~10% of pts present with bilat neck Dz.
What does the workup include for pts with an unknown H&N primary?
Unknown H&N primary workup: H&P, CT/MRI, FNA of involved node, panendoscopy + directed Bx, and bilat tonsillectomy (+/− PET, bronchoscopy, esophagoscopy)
If FNA is negative in H&N pts with an unknown primary, what other kind of nodal Bx can be attempted?
If FNA is negative, a core Bx can be attempted next. Avoid incisional/excisional Bx, as this would result in “neck violation.”
What does cystic appear-ance of the involved LNs suggest in pts with H&N cancers?
Cystic appearance on imaging suggests HPV positivity/etiology.
What is the significance of nodal location in terms of likely primary sites?
If upper neck nodes are involved, they are more likely to be due to a H&N primary (e.g., if level I LNs, oral cavity [OC]; if upper level V, NPX primary). If lower neck or supraclavicular nodes are involved, they are more likely to be due to a chest or abdominal primary.
What is the significance of histology in terms of likely primary sites?
1. Squamous cell: more likely to be a H&N primary
2. Adenocarcinoma: more likely to be a chest or abdominal primary
What sites are traditionally biopsied for level II nodal involvement?
The BOT, NPX, pyriform sinus, and tonsils are typically biopsied with level II LN involvement.
When is a PET scan indicated for pts with an unknown H&N primary?
Per NCCN guidelines, PET is indicated only if other workup is unrevealing. It can be useful in excluding a larynx/HPX primary.
Why is it problematic to obtain the PET scan after endoscopy and Bx in pts with an unknown H&N primary?
Post-Bx inflammation may lead to false+ results. This is why some advocate that if used, PET scans should be done initially.
When is triple endoscopy indicated in pts with neck Dz and an unknown primary?
Triple endoscopy is generally reserved for pts with level IV–V LAD (more likely to be lung/abdominal primary). Also, PET/CT C/A/P should be considered in such cases.
Site-directed Bx will reveal the primary in roughly what % of unknown primary cases?
Site-directed Bx will reveal the H&N primary in ~50% of cases.
Unilat tonsillectomy will reveal the primary in approximately what % of cases?
Unilat tonsillectomy will reveal the primary in ~25% of cases.
PET/CT will reveal the primary in approximately what % of unknown H&N primary cases?
PET/CT will reveal the primary in ~20%–25% of cases.
What does the data show in regard to bilat tonsillectomy for pts with an unknown H&N primary?
Data from the Johns Hopkins Hospital (McQuone S et al., Laryngoscope 1998) showed improved diagnostic yields with bilat tonsillectomy. Additionally, it may render follow-up with PET/CT easier.
When should tonsillectomy be performed in pts being worked up for an unknown primary?
Tonsillectomy is generally performed at the time of direct laryngoscopy.
What are the approximate predictive values of PET for pts with an unknown primary?
The PPV is ~90% and the NPV is ~75% for pts with an unknown primary.
What % of pts with an unknown H&N primary have metastatic Dz on PET/CT?
~10% have metastatic Dz on PET/CT—yet another reason to consider upfront PET.
What is the general Tx paradigm for H&N cancers if a primary is found vs. if there is an unknown primary?
H&N cancer Tx paradigm:
1. If primary found: treat according to the primary location
2. If no primary found: surgery +/− RT, RT alone, or RT +/− neck dissection
Which unknown primary pts can be treated with neck dissection alone?
Generally, N1 ( <3 cm) pts. B/c of this and b/c it allows for better staging, some advocate upfront neck dissection at the time of direct laryngoscopy. (Coster JR et al., IJROBP 1992)
For which H&N pts is upfront neck dissection a reasonable approach?
Upfront neck dissection is reasonable if better staging is desired (e.g., if the path is unclear), if the neck has been “violated” (i.e., after incisional Bx), and with a small, unilat, single +node (N1).
What % of pts with N1 Dz fail at the primary site after neck dissection alone?
~25% of N1 pts ultimately fail at the primary site after neck dissection alone. However, this can vary from 10%–50%.
What is the approximate overall neck failure rate after neck dissection alone?
The overall neck failure rate is ~15% after neck dissection alone. (Coster JR et al., IJROBP 1992)
What is the approximate neck failure rate after neck dissection if there is evidence of ECE?
The approximate neck failure rate after neck dissection alone is ~60% with ECE. (Coster JR et al., IJROBP 1992)
What are the indications for PORT in pts with an unknown H&N primary?
≥N2 Dz, ECE/+margin, or neck violation (e.g., after open/excisional Bx)
What do the standard RT fields include in pts with an unknown H&N primary?
The fields generally include both necks and the mucosal sites at risk (NPX, OPX, HPX, larynx). Some advocate omission of the HPX/larynx from the RT fields.
What are the historical 5-yr LC and OS rates after definitive RT for pts with an unknown H&N primary?
1. University of Florida data (Erkal HS et al., IJROBP 2001): LC 78% and OS 47%
2. Danish data (Grau C et al., Radiother Oncol 2000): OS 37%
What factors have been traditionally associated with inferior OS after definitive RT for H&N tumors of an unknown primary?
More advanced N stage, ECE, and lower RT doses have been associated with inferior outcomes. (Erkal HS et al., IJROBP 2001)
What standard RT fields have been traditionally used for H&N tumors of an unknown primary?
Opposed lats matched with an ant low neck/supraclavicular field (with post neck electron fields after 40–44 Gy)
What are the typical borders of the lat fields used for H&N tumors of an unknown primary?
1. Anterior: behind OC/hard palate
2. Superior: to base of skull to include NPX
3. Posterior: below tragus to post edge of spinous processes
4. Inferior: sup edge of thyroid cartilage; if level III or IV, inf edge of cricoid to cover larynx (Fig. 35.1)
What RT doses are generally employed?
70 Gy to gross Dz, 60 Gy to intermediate-risk areas, and 50 Gy to low-risk areas (all in 2 Gy/fx)
What evidence supports the omission of the larynx/HPX from the standard RT fields?
University of Florida data (Baker CA et al., Am J Clin Oncol 2005): larynx-sparing RT is just as effective with less toxicity.
What is the evidence in favor of bilat neck irradiation for H&N tumors of an unknown primary?
Loyola data (Reddy SP et al., IJROBP 1997): contralat nodal failure is higher (44%) in pts receiving unilat nodal RT (vs. 14% for bilat nodal RT). Also, there is a higher primary emergence rate with unilat RT (44% vs. 8%).
What is the role of IMRT in H&N cancer of an unknown primary?
Recent studies (Klem ML et al., IJROBP 2008) have shown feasibility of IMRT, and it is widely utilized.
What are a few of the advantages of IMRT for H&N tumors of an unknown primary?
Greater parotid sparing, can consider concurrent chemo (Klem ML et al., IJROBP 2008), can use simultaneous integrated boost dosing (e.g., 212 × 33 = 6,996 cGy, 180 × 33 = 5,940 cGy, and 170 × 33 = 5,610 cGy)
When is neck dissection entertained after definitive RT for H&N tumors of an unknown primary?
Post-RT neck dissection is considered with persistence of Dz (e.g., on PET or clinically). Some still consider it standard for all pts with ≥N2 Dz.
Within what time frame after RT should neck dissection be performed if decided upon upfront (i.e., regardless of response to RT)?
Neck dissection should occur ~3–4 mos (and no later than 6 mos) after RT.
What are common acute side effects from RT to the H&N region?
Mucositis, hoarseness, and malnutrition (weight loss)
What are common long-term complications from RT to the H&N region?
Xerostomia, dysphagia, neck scarring and edema (especially if combined with neck dissection), hypothyroidism, and laryngeal dysfunction (aspiration, hoarseness, etc.)
After what dose must the practitioner come “off-cord” when irradiating the post necks with standard fields?
The practitioner must come off-cord after a dose of 40–44 Gy (in 2 Gy/fx). Use matching electron fields or IMRT if greater post neck doses are desired.
After RT, when should PET be performed to assess for nodal response?
PET should be performed no sooner than ~2–3 mos after RT. (TROG analysis: Corry J et al., Curr Oncol Rep 2008)
FIGURE 35.1 Standard fields for H&N cancer of an unknown primary site.
A:Standard fields if level III or IV LNs are involved. B:Standard fields if no level III or IV LN involvement to spare the larynx.