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Tirelli et al. J Cancer Metastasis Treat 2023;9:20 https://dx.doi.org/10.20517/2394-4722.2022.98 Page 5 of 11

the size of nodes in this area. In 76% of cases, only one node would have been left; in 19%, 2 nodes and in
5%, 3 nodes. The average number of PFN described by our group was 1.6 (range 0-5), that is, lower than the
2.1 (range 0 - 8) reported by Lim et al. One of the most important findings of the study is that, owing to the
AFV anatomical variables relative to the submandibular gland, Rouvière’s classical distinction between
pre/retrovascular and pre/retroglandular is often not applicable [2,13,16] . Because of this, Tirelli and Marcuzzo
proposed the name “perimarginal nodes” to refer to that group of nodes at risk of being left unharvested
during ND and located in close proximity to the marginal mandibular nerve .
[13]

Perimarginal nodes in oral cancer
In 2019, Tirelli et al. assessed the incidence of PMN metastasis from oral cavity SCC. Thirty-nine patients
[8]
affected by oral cancer were included and PMN metastases were found in 8 patients (20.5%) . Extranodal
extension, a well-known predictor of poor prognosis, was present in 2 of 8 cases (25%) in which the PMN
were involved [8,25] . Five of 39 (12.8%) patients had only PMN metastases, consistent with the findings of
[20]
Agarwal et al., who identified isolated PFN metastases in 19 /231 patients (8.2%) . No patient or primary
tumor characteristics were found to correlate with a higher risk of PMN metastases. The same trend was
later confirmed in a larger study by the same group (17.5%) . In this later study, a significant correlation
[7]
was found between PMN involvement and the upper zone of the oral cavity (P < 0.001). Even though no
statistical correlation was found between primary tumor or patient characteristics and PMN metastases, in
both of these studies by Tirelli, a trend of increasing incidence of metastasis in high-grade primary tumors
[8,9]
was appreciated . This finding is in agreement with the findings of Agarwal et al. who reported a
significantly higher rate of PFN metastases in patients with T3 and T4 stage oral cavity SCC .
[20]
These findings seem to indicate that the only characteristics of the primary tumor that correlate with an
increased incidence of PMN metastases are a high grade (mild correlation) and the site of origin of the
tumor. It has indeed been shown - although the finding has yet to be confirmed by larger patient series -
that tumors originating from the upper oral cavity are more likely to metastasize to the PMN compared
with tumors of the lower oral cavity [8,9,16] . This apparently unexpected finding may be accounted for by the
lymphatic drainage routes of the oral cavity. While the lower parts of the mouth (tongue, floor of mouth,
etc.) are drained by the jugulodigastric nodes, the upper parts are drained by lymph vessels emptying into
the lymphatic network surrounding the facial vein and thus crossing the PMN. Previous studies on PFN
had reported a higher incidence of metastases to the submandibular region. DiNardo in 1998 found 16/41
[14]
(39%) cases of PFN metastases, but a proportion of his patients had clinical lymph node metastases . This
finding is consistent with the later study of Lim et al., in which the incidence of metastases in clinically
positive necks was 6/17, or 35% . The same author found a significantly lower incidence of PFN metastases
[2]
from oral cavity cancer when the neck was clinically negative (6.1%) . Both findings of Lim are similar to
[16]
the results reported by Malik, who analyzed 137 patients with oral SCC who underwent a level IB ND.
Metastases at level IB were found in 7/85 (8.2%) of patients with a clinically negative neck, and in 24/60
(40%) patients with a clinically positive neck . Therefore, PMN involvement in clinically negative necks is
[26]
not an uncommon finding [13,16,26] . [Table 1]

Perimarginal nodes in oropharyngeal cancer
The incidence of metastases to submandibular nodes from oropharyngeal SCC is known to be very low, and
indeed, the guidelines on elective ND in oropharyngeal cancers do not consider level IB dissection to be
mandatory . In detail, three articles in the literature have analyzed the incidence of oropharyngeal cancer
[27]
metastases to the PMN. In the retrospective study of Lim et al., the majority of patients included (49/66,
74%) had an oropharyngeal tumor, and metastases to the PFN were found in 4/49 (8%) . This finding is in
[2]
contrast with the report of Riffat et al. who retrospectively analyzed recurrences within the PFN region from
2004 to 2009 in patients with oropharyngeal SCC who underwent ND without systematic removal of the