The N0 Neck
Etai Funk, M.D.
December 1, 2005

George Crile was considered the father of the neck dissection and described the en bloc resection with radical neck dissection in 1906 in his landmark article in JAMA.  This radical neck dissection was further popularized by prominent head and neck surgeons such as Hayes Martin and John Conley in the 1950s and E. Bocca’s article in 1967.  He began popularizing conservation techniques in neck dissection sparing structures such as the IJ-XI and the SCM.  Modified radical neck dissection was further popularized by Robert Byers here at the MD Anderson in the late 70s and 80s.  In 1991, under the leadership of Tom Robbins, The American Academy of Head And Neck Surgery Oncology developed a standardized classification of neck dissection in 1991.  This was further updated in 2002 when they included sub levels for neck dissections: level IA, submental nodes; IB, submandibular nodes; IIA and IIB, together compromising the upper jugular nodes; and VA, spinal accessory nodes; and VB, transverse cervical and supra clavicular nodes. In addition, their terminology changed and they say that we should refer to these dissections as selected neck dissection, and the numbers as opposed to those previously mentioned suporaomohyoid lateral and anterior dissections. 

The N0 neck is a controversial topic and for good reason.  The presence of regional metastases to the lymph nodes at initial presentation is one of the single most important factors in outcome in terms of recurrence and survival of patients with upper aerodigestive tract squamous cell carcinoma.  That is what I would like to concentrate on today: the upper aerodigestive tract.  The questions we have to pose to ourselves are: Is there a need for elective treatment of N0 neck? Which patients with N0 necks require intervention?  What type of elective intervention is best? Is this intervention beneficial?
 
In order to diagnose the N0 neck, we must understand how to diagnose the N positive neck.  Physical exam gives us for a positive sensitivity of 74% and a specificity of 81%, whereas CT is 83% for both.  The combination of physical exam and CT scan demonstrates a sensitivity of 91%.  The radiographic criteria for suspicious nodes were described by Friedman and Moreau as size greater than 1-1.5cm.  However, most (85%) of level I metastases are actually less than 1 cm, as described by Byers, and an estimated 50% of cervical metastases are actually less than 5mm, as described by Don in 1995.  Other radiographic criteria for suspicious nodes include spherical shape, necrosis, soft tissue invasion, and multiple nodes per level.  Other methods of diagnosing the N-positive neck include ultrasound-guided FNA or PET scan, which we will further discuss later. 

In order to understand which levels of the neck we need to address, we need to understand the patterns of cervical lymph nodes metastasis from each primary.  These were studied in these three major studies.  First, Dr. Lindberg in 1972 looked at 2044 patients.  Over 1100 of these were N-positive, and studying these primaries and where they metastasized to, he was able to infer where the patterns of cervical lymph node metastasis occur.  Byers and Shah looked at N0 necks after elective neck dissection and were able to infer where these metastases occurred after elective neck dissection.  The most important point is that most of their studies demonstrated the same levels of patterns of cervical lymph node metastasis.  There was one difference between Shah  Byers for the hypopharynx, and we will discuss that later.  Shah describes the risk factors for the occult metastasis to be anatomic location, size, T-stage, depth of invasion, and endophytic growth pattern.  In Lindberg’s study, he found that the incidence of metastasis actually increased with a more advanced T-stage in the oral cavity, the tonsillar pillar, and the soft palate. However, this relationship was not seen in primary lesions of the tonsillar fossa, the base of tongue, the hypopharynx or the supraglottics.

So what are the treatment options for the N0 neck?

Proponents for close observation state that more than 50% of patients without occult metastases with an N0 neck will end up receiving treatment and this treatment increases morbidity and cost depending on the type of intervention used.  Opponents, such as Anderson, state that if the patient has an N0 neck and is closely observed, they will not necessarily progress in an orderly fashion to an N1 and then to an N2 neck.  Seventy-seven percent of these N0 patients after close observation will develop disease greater than N1 or extracapsular spread, which carries a poor prognosis with it.  McGirt demonstrated that the salvage rate for regional recurrence after close observation with therapeutic neck dissection is 50-59%.  These studies looked at survival with elective neck dissection versus therapeutic neck dissection after close observation.  These are retrospective studies and we cannot completely infer from them that survival is improved with elective neck dissection.  We would need prospective studies.  In one prospective study, of which there are very few, Vanderbrouck looked at 75 patients with T1 and T2 oral cavity squamous cell carcinoma.  His only statistical difference was that he demonstrated that there was a 25% extracapsular spread in therapeutic neck dissection after close observation of the N0 neck versus 13% in elective neck dissection.  He did not demonstrate any statistical difference in survival between elective neck dissection and therapeutic neck dissection.  For close observation, close follow-up is essential and the patient must be compliant.  Given idiosyncrasies of character and social background, we must sometimes reconsider close observation and pursue elective neck dissection, as described by Gallo, who also states that patients with a short, fat or muscular neck may benefit from an elective neck dissection.  Prospective randomized trials must be performed comparing close observation with elective neck treatment in order to get further results.

What are our indications for elective neck treatment in the N0 neck? Weiss in 1994 performed a decision analysis and he showed that the treatment of the N0 neck should be pursued if the probability of occult metastases is greater than 20% and in some “10-15” and some “25”.  Twenty percent seems to be the number that is used predominantly in the literature.  There are numerous treatment decisions.  One is which type of treatment do we pursue.  The others are extent of treatment, in terms of which levels of the neck should be treated, whether bilateral neck dissections should be pursued and the role of adjuvant treatment. The answers are based on the primary site, the stage of the primary, and pathologic findings.  In general, elective neck irradiation is a useful form of treatment when radiation is the treatment for the primary.  Mendenhall in 1980 demonstrated that ENI reduces the failure rate in the N0 neck from 18% to 1.9% compared to observation when the primary is controlled.  Regional recurrence rates between dissection for the N0 neck and for irradiation for the N0 neck are approximately the same.

Therefore, we must consider other factors when deciding whether to pursue dissection with or without irradiation.  We have morbidity associated with XRT: xerostomia, fibrosis, and contracture.  We also lack the ability to pathologically stage the neck if we do pursue radiation and we lose the ability to use XRT a second time if the patient  develops a recurrence after dissection.  The morbidity of radiation may also confound our physical exam later to monitor for recurrences.  Therefore, when we pursue the elective neck dissection, prognostic information will be gained, regional control may be obtained, pathologic staging is possible and early detection of regional metastasis may be obtained.  Based on this pathologic staging, we can pursue adjuvant treatment with radiation or chemotherapy.  Extracapsular spread may be found, which has been shown to be present in 6-35% of occult nodal metastases, in addition to the multiplicity of nodes that may be found in levels of the neck, which is an indication for adjuvant treatment.  Both of these carry a poor prognosis.

What  types of neck dissections are available?

When deciding which type of dissection is to be performed, we have multiple decisions.  We have the selective neck dissection versus the modified radical neck dissection. Regional recurrences for pathologically N0 necks are similar between both types of dissections, selective and the modified radical, about 5%.  There was a Brazilian study with a prospective randomized trial looking at supraglottic and transglottic lesions.  This demonstrated left neck failure in 3.3% of patients with selective neck dissections versus 5.6% with modified radical, with survival about the same.  This study was criticized as being poorly randomized, and not differentiating between local and regional recurrences.  For regional recurrence for patients who have pathologically positive neck nodes, these differ throughout multiple studies: 3-9% for the modified radical neck dissection vs. 16-21% for the selective neck dissection.  It is difficult to compare these recurrence rates since each study had different primaries and different T stages for these primaries.  However, out of field recurrences have been recorded in sporadic cases (Spiro, 1996) and “skip lesions” have been documented (Byers).

Pitman in 1997 demonstrated that regional recurrences after selective neck dissection do not occur outside the lymph node basin of the primary, which may be included in the modified radical neck dissection.  Therefore the recurrence occurs in the area where we perform the selective neck dissection.  Clayman gave a good review of this literature in 1998 highlighting more prospective trials are needed to determine whether or not selective neck dissection versus the modified radical is the best in terms of pathologically positive nodes.  However, we are leaning towards more conservative approach in the management of the N0 neck. 

Level IIB is another issue of contention.  Dissecting level IIB comes with a risk of injuring the X1.  Therefore, studies have investigated the necessity of actually performing dissection at this level.  Corlette in 2005 performed elective neck dissections and therapeutic neck dissections in cancers throughout the entire aerodigestive tract.  He found that 4.5% of nodes were positive at level IIB.  Of this 4.5%, 20% were actually from the tonsil, which was the largest amount aside from the parotid and skin.  For therapeutic neck dissections after close observation, these invasions occurred in the neck.  There were 36% positive nodes in level IIB and the tonsil accounted for 60%.  Therefore, his recommendations for dissection level IIB are only for therapeutic neck dissections for oropharyngeal squamous cell carcinoma at the base of tongue or tonsil and obviously for elective and therapeutic for the parotid and the skin.

I would like to go through the primary signs and talk about the N0 neck in each one of these primary sites.  For the oral cavity, which probably has the most literature, 40-50% of N0 necks followed clinically will develop regional metastases.  Based on Shah’s and Byers’s study, they noticed occult metastasis after elective neck dissection in 34% and 45% respectively, and most of these metastases were in level I through III.  The majority of this literature is on the oral tongue and, as you can see from these three studies, performing elective neck dissections with resection of the primary actually improves survival rates.  Recurrence rates were 49% of the primary along with 72% with elective neck dissection.  In Yuen’s study, it was 86% versus 55% and Lydiatt’s study found 55% versus 33% with regional control demonstrated at 91% versus 50%.  Soprano and Weber looked at the predictors of occult neck metastasis in the N0 neck based in the oral tongue and one of the bigger outcomes was the thickness/depth of invasion of the tongue.  Many people use the number >4mm and perform an elective neck dissection.  Other predictors of occult neck metastases include cell differentiation, T2 disease, and perineural invasion. 

McGirt looked at the floor of the mouth in 129 patient, comparing floor of mouth resection with and without elective neck dissection, and he demonstrated a 100% survival with elective neck dissection versus 85% with just resection of primary.  Dr. Eicher looked at the lower gingiva and found 15% late occult metastases.  She found  the risk factors for occult neck metastases with lower gingiva squamous cell carcinoma included radiographic signs of mandibular invasion and advanced T stage in addition to decreased tumor differentiation.

Lip squamous cell carcinoma, there seems to be an increased incidence of regional metastases when the oral commissure is involved.  It was recommended for T1 and T2 disease to resect the primary only, and for T3 to T4 disease or poorly differentiated disease, to perform elective neck dissection.  Hard palate and buccal squamous cell carcinoma have a low risk for occult metastases with low T stage, and again, the Byers study that looked at level IV for the oral cavity, demonstrated a 15% rate of skipped metastases.  However, Medina contradicted this and stated that the Byers study actually looks at primaries of all T stages with and without clinically positive lymph node metastases and he stated that it is more likely that this rate at level IV for skip metastases is less than 5%.

In summary, for the oral cavity it is essential to perform elective neck dissection or elective neck radiation for levels T2 through T4.  For level T1, the recommendation is to  resect the primary and observe the neck except for patients with oral tongue lesion, taking into account those previous risk factors that we stated.  Bilateral elective neck dissection and radiation is recommended for the tip of the oral tongue or lesions crossing the midline. 

Occult metastases in the oropharynx were demonstrated in 31% of patients from Shah’s study and 39% in Byers’s study.  The majority of these occur in levels II through IV.  Shah recommends elective neck treatment for levels II through IV with primaries in this region and bilateral treatment of the neck should be considered in base of tongue lesion.  Dr. Lim demonstrated a 16% rate of occult contralateral metastasis in tonsil squamous cell carcinoma and 21% when ipsilateral metastases were clinically present.  One also has to consider treating the retropharyngeal nerves in oropharyngeal cancer and these are typically treated with radiation.  There is about a 44% rate of occult metastases to the retropharyngeal nodes. 

Shah looked at the advanced lesions of the glottis and supraglottis and demonstrated 37% of occult metastases whereas Byers separated these and saw 26% in the supraglottic and 15.7% for the glottis.  The majority of these were also found in levels II through IV. One also must look at level VI, where Byers demonstrated 10% for supraglottic lesions and 18% for glottic lesions.  So T1 and T2 lesions of the glottis have a low incidence of occult metastasis, but one must consider elective neck dissection for these when they are recurrent, as the rate of occult metastasis increases to 20%.  Olsen in 1997 demonstrated that T1 and T2 lesions of the glottis with positive Delphian node may indicate lateral neck metastases in 40% of patients, requiring elective neck dissection.  For more advanced glottic lesions, T3 through T4, Johnson recommended elective neck dissections II through IV and level VI with hemithyroidectomy.  The rate of salvage laryngectomy after XRT failure has an incidence of 17-22% occult metastasis with glottic cancer, and he recommended elective neck dissection.

For the supraglottic, there is a much higher rate of occult metastasis, 21-41%, compared to the glottis.  Lutz in 1990 looked at 202 patients.  He demonstrated that after resecting a primary, there was a 23% rate of local-regional recurrence.  Eighty-seven percent of those were regional, and 75% were in the contralateral neck.  Therefore, for supraglottic lesions it is essential to treat the contralateral neck in addition to the primary and ipsilateral.

Hicks in 1999 demonstrated a 44% incidence of bilateral regional metastases in the N0 neck.  He performed primary surgery and primary surgery with postoperative XRT of both necks and demonstrated the difference in survival between these.  For primary surgery alone there was 64% survival.  With the radiation there was 82% survival.  The recurrence rates were 29% versus 15% with radiation.  Gallo in 2000 looked at patients with clinically positive ipsilateral nodes and demonstrated that there was pathologically positive contralateral nodes in close to 40% of patients on elective neck dissection and pathologically positive nodes after observation with therapeutic neck dissection in about 40% of the patients as well.  In terms of the subglottis, it is a fairly rare place for the primary to occur, and there is about a 10% rate of occult metastasis.  It is recommended to perform bilateral paratracheal neck dissection and Weber, in 1991, demonstrated that paratracheal dissection will actually decrease peristomal recurrence and the presence of paratracheal nodes may actually lead to poorer prognosis.

For the larynx, it is recommended to perform what we previously stated is lateral neck dissection versus selective neck dissections II, III and IV in addition to VI for advanced glottic lesions and for supraglottic lesions, in addition to treating the contralateral neck for the supraglottic lesions and level VI for subglottic lesions.  The rate of occult metastasis for the hypopharynx was actually 17% per Shah, but 56% per Byers.  In a later study by Pitman she demonstrated a metastasis rate of approximately 36%.  There is increased risk for bilateral involvement with hypopharyngeal squamous cell carcinoma if it emanates from the medial piriform sinus, the midline hypopharyngeal wall or the postcricoid regions.  The bilateral selective neck dissections II through IV are recommended for hypopharyngeal primaries and one must consider dissecting level VI as well.  Radiation is recommended for piriform sinus carcinoma as there is a higher rate of failure in this area and, in addition, just as in oropharyngeal primaries, we must treat the retropharyngeal nodes with hypopharyngeal primaries.

In the nasopharynx, the incidence of the N0 neck is actually quite low as most patients present with clinically N-positive necks with nasopharyngeal carcinoma.  For the sinuses, elective neck dissection or radiation is recommended for tumor extension to the soft palate or the nasopharynx.

The role of PET scan has become interesting lately and Myers and Wax in 1998, looking at only 11 patients, demonstrated 78% rate of sensitivity and 100% specificity.  Others have looked at the PET scan and the N0 neck and demonstrated anywhere from 50-100% rate of sensitivity.  The limitation of the PET scan is with nodes less than 5mm and nodes in close proximity to primary I and II.  Others have recommended that if the PET scan is positive, one must consider pursuing elective neck dissection or radiation, and if negative, one must consider a sentinel node biopsy.  Intraoperative staging has also been investigated.  Rassekh looked at intraoperative inspection and palpation of the neck and demonstrated this is no more effective in preoperative clinical staging.  He also looked at frozen section biopsies of these nodes and deciding whether or not to pursue elective neck dissection based on the frozen section.  He demonstrated sensitivity of 90.5% with specificity of 100%.  However, in the later study by Wein, the sensitivity was only noted to be 42% and he stated that performing frozen sections does not provide significant advantage in staging and proceeding with neck dissection.  With regards to the frozen section, it is fairly institution- and pathologist-dependent and can be extremely time consuming and expensive. Further studies are needed to assess this modality.

Ultrasound-guided FNA has been a modality that has gained popularity in Europe, specifically in the Netherlands.  Van den Brekel and Snow looked at T1 and T2 squamous cell carcinomas in the oral cavity in 92 patients.  Patients who had negative FNAs of the nodes were followed under close observation and they developed recurrence rates of approximately 21%.  Van den Brekel stated that one can FNA nodes  smaller than 3mm.  However, an experienced radiologist is needed on staff and he also states, in a later study, that sensitivity is not improved by using ultrasound guided FNA for the sentinel node biopsy.  Snow demonstrated in another study a specificity of 75-77%. 

The initial metastatic colony is limited to the first draining lymph node of the primary tumor, which is the basis behind the sentinel node biopsy.  One can prevent the patient’s exposure to neck dissection and radiation treatment and decrease costs.  This may be shown to have a 95% sensitivity for head and neck melanoma.  However, there are substantial problems in using this for a squamous cell carcinoma of the aerodigestive tract:  proximity to the primary tumor, the difficulty with intramucosal injection as it extrudes frequently into the saliva, and inaccessibility of certain areas and certain primaries in the head and neck.  When Pitman did animal studies demonstrating transit of technetium and dye to the sentinel node, it took about 5 minutes and lasted for approximately 24 hours.  She also states that injecting is difficult.

Two major studies recently performed were by Werner and Dunne and by Ross.  Werner and Dunne’s study looked at 90 patients with N0 necks and compared the results of sentinel node biopsies with elective neck dissections.  After elective neck dissection, 23 of these 90 patients had an occult metastasis and 20 of these 23 (87%) were actually detected before the elective neck dissection by sentinel node biopsy.

Ross performed multicenter studies in six institutions in Europe looking at 227 sentinel node biopsy procedures in 134 patients.  The sentinel node was actually identified in 93% of the patients and in 42 of these 125 that were upstaged, they were found to have pathologically positive nodes and the sentinel node was removed and there was no selective neck dissection performed.  The follow-up was 12-24 months with a 94% sensitivity. There were only three regional recurrences at two years.  Ross states that the sentinel lymph node biopsy allows for immunohistochemistry, which may be able to reveal micrometastases.  However, further prospective studies are needed to validate this type of study versus performing the elective neck dissection or radiation.

When is adjuvant treatment necessary after treating the N0 neck?  It is necessary in all T4 lesions, in patients who have greater than two to three positive nodes, and in patients who have extracapsular spread, which carries a poor prognosis.  Byers showed that the recurrence rate for patients who have extracapsular spread after dissection and after irradiation is 9-15% versus 5% in patients who do not have extracapsular spread.  Other indications are perineural invasion, intravascular spread positive margins and multiple levels of lymph node involvement.

Further investigation is being performed to investigate the risk of occult mets using molecular markers, looking at cytokeratin, p53 mutations, the ploidy of the DNA, matrix metalloproteinase, and chromosomal abnormalities.

In summary, understanding the patterns of regional spread, the incidence of occult metastasis and the realization of factors such as extracapsular spread and multiple positive lymph nodes will negatively impact patient outcome are essential to the approach of N0 neck.  The surgical management of the N0 neck appears to be trending towards a more conservative approach.  Newer concepts such as sentinel node biopsy, ultrasound guided FNA and use of molecular markers must be further investigated before being accepted into standard practice prices.  These investigations must include prospective trials which could provide unequivocal evidence that demonstrates that elective treatment of the N0 neck actually improves survival. 

Case Presentation:

RLF is a 52 year-old white male who presented with a painful, enlarging, right oral tongue lesion that he had for a few months.  He also complained of right otalgia and odynophagia.  He was otherwise healthy with no surgical history.  He had smoked one pack per day for 30 years and denied alcohol or drug abuse.
 
His physical exam demonstrated a 2.5cm x 1.5cm right lateral oral tongue mass extending to the right posterior floor of mouth encroaching on the alveolar ridge.  He had good tongue mobility.  He was thought to have some lymphadenopathy at level II.

CT scan demonstrated a 2.6cm x 1.5cm x 1.4cm ill-defined mass around the right lateral tongue and FOM.  There was no erosion of bone present.  There were no pathologic nodes seen.
Clinic biopsies confirmed moderately differentiated SCCA. He was staged T2N0M0 SCCA of oral tongue.

He was taken to the operating room on 10/24/05 for direct laryngoscopy, esophagoscopy, right partial glossectomy, excision of right posterior FOM, tracheotomy, and selective neck dissection I-III.

Pathology demonstrated invasive SCCA, poorly differentiated, with positive inferior and medial margins, and perineural invasion.  There were 20 benign lymph nodes identified with no pathologic evidence of regional metastases.

He underwent full mouth extraction of teeth at a later date and XRT will begin soon.

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