Discussion
Age, histological grade, myometrial invasion (MI), lymph-vascular space
invasion (LVSI), tumor size (TS) have been proved to have value on
prediction of lymph node metastasis (LNM) which might help physicians to
make better clinical decisions 12-15. How can we
achieve the goal of maximum resection of lesions and cause minimum
injury if it is not accessible to use SLN. We believe the pathologic
grade should be the most reliable and accessible factor. That’s the
reason grade 3 was chosen as the indicator to evaluate the possibility
of LNM in this study.
Inconsistent standard were published by different institutions: Mayo and
FIGO(The International Federation of Gynecology and Obstetrics)
guidelines tend to categorize TS > 2cm as high-risk, while
for NCCN (The National Comprehensive Cancer Network) and ESMO (Europe’s
leading medical oncology society) guidelines, TS was not considered as a
high-risk factor5,16,17. In fact, it is uneasy to
determinate the size of tumor due to its irregular shape of lesion, and
the latest NCCN guideline had deleted this factor16.
It is true that deep myometrial invasion increased the risk of lymph
nodes metastasis based on suggestions of almost every international or
national guideline and our data (not shown in this study). However, it
is not easy to accurately evaluate the deep myometrial invasion before
operation. Although the NCCN guidelines recommend the use of pelvic
enhanced MRI to determine the depth of myometrial invasion (myoinvasion
>50% is considered as a risk factor)16,
the accuracy of MRI is about 68% for T2-weithgted
imaging18.
For age, it was considered older age was associated with higher chance
of LNM, while the age cut-off was still inconsistent. According to the
latest NCCN guidelines, “age >= 60” was considered as an
age cut-off 16, while in our data
>=70-year-old seemed to have significant impact on LNM.
For LVSI, never to be ignored in EC carcinogenesis, which has been
emphasized again recently. LVSI is a potential predictor for EC
recurrence14,19 and associated with a significant
higher rate of paraaortic LNM with OR at five 20. A
retrospective study showed no overall survival difference between
adjuvant external beam radiation therapy versus vaginal brachytherapy in
LVSI-positive patients, while it was associated with increased risk of
death (hazard ratio of 1.94) 21. Unfortunately, it is
quite difficult to get before operation.
Finally, we selected G3 as our first concern in making decisions before
operations of EC patients. We found that EEC G3 patients without any
extra risk factor (LVSI, AI or CSI) had an LNM rate of 16.4%, which is
remarkably lower than other risk factors, for which LND might not be
needed. On the contrary, EEC G3 patients with one or more extra risk
factors mentioned above had higher chances of lymph node metastasis,
which could be explained by synergetic effects in between these risk
factors. Grade 3 EEC patients with only one risk factor presented with
an LNM rate ranged at 14.5% to 50% while if with two extra risk
factors, LNM rate increased to 60% and 75%. Although grade 3 EEC
patients with positive LVSI, AI and CSI, was found to have lower LMN
incidence at 33.3%, also known as 1 out of 3. We assume it was due to
the limited sample size.
The categorization of three tiers of LVSI was mentioned by pathologists
to evaluate its potential risk19. Although our study
failed to categorize LVSI into three tiers, our findings are consistent
with these opinions. LVSI were independent risk factors of both grade 3
and grade 1&2 subgroups, increased the LNM rates more than 3 folds and
8 folds, respectively. Therefore, we recommend EEC G3 patients with LVSI
should undertake lymph node evaluation, EEC G3 patients with no other
risk factor could be evaluated only with imaging, while EEC G3 patients
with positive LVSI in their final pathological diagnosis, should be
evaluated by both imaging and comprehensive staging surgery if not done
previously, which is consistent with the latest NCCN
guidelines16.
Two randomized trials indicated that systematic pelvic LND had no
survival benefit compared with no LND in early EC patients8,9. Our data showed no survival difference between
grade 3 and grade 1&2 patients, which indicated that “grade” might
not influence patients’ prognosis although grade 3 patients had higher
rate of LNM than grade 1&2 patients. This could be due to the small
sample size of grade 3 patients. Similarly, patients with pelvic and
para-aortic lymph node dissection done had similar OS and PFS than
patients with only pelvic lymph node dissection done in grade 3
population at early stage, suggesting a less traumatic treatment could
be considered in these patients.
In addition, we found that MELF and MI only increased the LNM rate of
grade 1&2 population, while CSI increased the LNM risk of grade 3
patients. This might indicate different metastasis pathways in EC
patients with different grades, for which further investigations should
be carried out.
In this study, our strength stood on the follow-up duration of almost
ten years. In addition, the independent high-risk factors were robust
with adjustments. We also provided clinically friendly data by
stratifying these risk factors, providing certain evidence for clinical
practice especially in areas with poor medical resource. However, this
study still had some limitations. Since this is a retrospective
analysis, selection bias may have influenced the treatments given to
these grade 3 patients. Only 381 (30.9%) patients were found to have
complete follow-up data due to technical reasons. Larger sample size and
prospective clinical trial design with novel molecular classification
warrant more consideration.