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\begin{document}

\title{Incorporation of a Sentinel Lymph Node Mapping Algorithm in Patients
with Clinical Stage I Endometrial Cancer}



\author[1]{Sarah Wener}%
\author[1]{Therese Gadomski}%
\author[2]{Tung Ming Leung}%
\author[1]{Elena Pereira}%
\author[1]{Jeaninne Villella}%
\affil[1]{Lenox Hill Hospital}%
\affil[2]{Northwell Health Feinstein Institutes for Medical Research}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objective: Sentinel lymph node biopsy (SLNB) has emerged as an
alternative to complete lymph node dissection (PPALND) in the management
of endometrial cancers. The referenced data is published from
high-volume specialized institutions and PPALND is still performed by
many at smaller, non-specialized centers. Our aim is to demonstrate that
SLNB is feasible, reproducible, and sensitive without affecting
cancer-specific outcomes when implemented at a non-specialized center.
Setting: Patients with clinical stage I endometrial cancer were reviewed
from 2016 through 2020. Population: A total of 92 patients were
included: 69 stage IA, 12 stage IB, 3 stage II and 8 stage III.
Endometrioid (73\%), followed by UPSC (15.0\%), MMMT (5.0\%) and CC
(4\%). Methods: Endometrioid, uterine papillary serous (UPSC), malignant
mixed mesodermal tumor (MMMT), and clear cell (CC) histologies were
included. Complete PPALND was performed for patients with MMMT, UPSC or
CC. Sentinel lymph nodes (SLN) were evaluated using ultra-staging
protocols. The medical record was queried for evidence of recurrence.
Results: A total of 92 patients were included: 69 stage IA, 12 stage IB,
3 stage II and 8 stage III (2 IIIA, 2 IIIC1, 4 IIIC2). At least one SLN
was detected in 95.4\% of cases. The bilateral SLN detection was 74.3\%
and improved from 2017-2019: 70\%-80\%. Non-SLN were positive in 3
patients, all with high-risk histology. There have been no recurrences
to date. Conclusions: Our results are comparable to the rates reported
in literature and demonstrate that when applied at non-specialized
centers this approach is safe and reproducible. Funding: None%
\end{abstract}%



\sloppy


\emph{Incorporation of a Sentinel Lymph Node Mapping Algorithm in
Patients with Clinical Stage I Endometrial Cancer}

Sarah Werner M.D\textsuperscript{1}, Therese Gadomski
M.D\textsuperscript{1}, TungMing Leung\textsuperscript{2}, Jeaninne
Villella D.O\textsuperscript{1}, Elena Pereira M.D\textsuperscript{1}

Lenox Hill Hospital, Northwell Health Department of OB/GYN. New York, NY

Northwell Health, New Hyde Park, NY

\emph{Corresponding Author}

Sarah Werner

Lenox Hill Hospital

100 E. 77\textsuperscript{th} St

New York, NY 10075

212-434-6128

SLN Manuscript

Abstract:

\emph{Objective:} Sentinel lymph node biopsy (SLNB) has emerged as an
alternative to complete lymph node dissection (PPALND) in the management
of endometrial cancers. The referenced data is published from
high-volume specialized institutions and PPALND is still performed by
many at smaller, non-specialized centers. Our aim is to demonstrate that
SLNB is feasible, reproducible, and sensitive without affecting
cancer-specific outcomes when implemented at a non-specialized center.

\emph{Setting:} Patients with clinical stage I endometrial cancer were
reviewed from 2016 through 2020.

\emph{Population:} A total of 92 patients were included: 69 stage IA, 12
stage IB, 3 stage II and 8 stage III. Endometrioid (73\%), followed by
UPSC (15.0\%), MMMT (5.0\%) and CC (4\%).

\emph{Methods:} Endometrioid, uterine papillary serous (UPSC), malignant
mixed mesodermal tumor (MMMT), and clear cell (CC) histologies were
included. Complete PPALND was performed for patients with MMMT, UPSC or
CC. Sentinel lymph nodes (SLN) were evaluated using ultra-staging
protocols. The medical record was queried for evidence of recurrence.

\emph{Results:} A total of 92 patients were included: 69 stage IA, 12
stage IB, 3 stage II and 8 stage III (2 IIIA, 2 IIIC1, 4 IIIC2). At
least one SLN was detected in 95.4\% of cases. The bilateral SLN
detection was 74.3\% and improved from 2017-2019: 70\%-80\%. Non-SLN
were positive in 3 patients, all with high-risk histology. There have
been no recurrences to date.

\emph{Conclusions:} Our results are comparable to the rates reported in
literature and demonstrate that when applied at non-specialized centers
this approach is safe and reproducible.

\emph{Funding:} None

\textbf{Introduction:}

Endometrial cancer is the most common gynecological malignancy in the
United States, with~65,620 new cases estimated and 12,000 deaths
predicted in the year 2020~{[}1{]}.~Most women present with early stage
disease, and surgical resection of the primary tumor along with a
comprehensive lymph node dissection has traditionally been the mainstay
of treatment. Historically, complete pelvic and paraaortic
lymphadenectomy has been performed as part of surgical staging and to
guide subsequent adjuvant therapies for women diagnosed with uterine
cancer. Complete pelvic lymphadenectomy is not without surgical
morbidity, and is associated with 20-47\% risk of lymphedema in patients
with endometrial cancer, as well as prolonged operative time, and
increased risk of neurologic or vascular injuries {[}2{]}. Sentinel
lymph node mapping has emerged as an alternate approach to comprehensive
staging that allows surgeons to identify lymph node metastasis while
reducing the surgical morbidity associated with a full pelvic and
paraaortic lymphadenectomy {[}2{]}.

Sentinel lymph node~(SLN)~mapping was initially described in breast
cancer and cutaneous melanoma~{[}3{]} and has more recently been
incorporated into the staging of vulvar, cervix and endometrial cancers.
Initial studies in endometrial cancers reported the use of blue dyes and
radioactive colloid technetium-99, while more recent protocols have
utilized indocyanine green, as near-infrared camera capabilities become
more widely available. The majority of referenced studies were performed
at cancer specialty centers with many surgeons in non-specialty centers
continuing to perform comprehensive lymph node dissections. A survey
performed by The Society of Gynecologic Oncology (SGO) several years ago
reported that only 28.6\% of respondents were routinely performing SLN
mapping for endometrial cancers {[}4{]}. When performing SLN mapping,
technique and expertise are critical and a learning curve of
approximately 30 cases has previously been described {[}2{]}. The
objective of this study is to~demonstrate that~SLNB~is feasible,
reproducible, and sensitive without affecting cancer-specific outcomes
when implemented at a non-specialized center.

\textbf{Methods}

After institutional board review approval, all patients with clinical
stage I endometrial cancer who underwent either robot-assisted or
laparoscopic total hysterectomy from our institution were
retrospectively selected from 2016-2020. Clinical stage I endometrial
cancer was determined by preoperative physical exam and imaging. The
decisions to perform surgery robotically verses laparoscopically was
based on surgeon preference. Patients with endometrioid, uterine
papillary serous (UPSC), malignant mixed mesodermal tumor (MMMT), and
clear cell (CC) histologic subtypes were included.

Indocyanine green was reconstituted per the manufacturer's directions
and injected into the cervix bilaterally at 3 and 9 o'clock both
superficially (submucosally) and deep (1 cm into the stroma). Sentinel
nodes were identified using near-infrared technology. Patients with
suboptimal lymph node mapping or nodes suspicious for metastasis during
surgical evaluation underwent a side specific pelvic lymph node
dissection (LND). Paraaortic LND was performed at the discretion of the
surgeon. In addition to SLNB, complete pelvic and paraaortic lymph node
dissection (PPALND) was performed for patients with the following
high-risk histologic subtypes: UPSC, CC and MMMT. SLNs were then
evaluated by gynecologic pathologists using ultra-staging protocols
including serial sectioning and cytokeratin staining. The medical record
was queried for clinical or radiographic evidence of recurrence; median
follow up was 22 months for this cohort.

The primary objective was to evaluate the accuracy and sensitivity of
SLN mapping at our university affiliated community-based institution. In
addition, rates of SLN detection were evaluated over 3 years to chart
potential improvements over time as correlating to surgeon experience.
Descriptive statistics, such as frequency distribution, mean, median,
interquartile range, minimum and maximum were calculated for relevant
variables. To compare successful mapping rates at our institution to
those in the literature a one sample test of proportion was performed.
Chi square and Fisher's Exact test were performed to determine whether
successful mapping rates among patients was related to patient specific
factors such as BMI as well as pathologic factors such as the presence
of uterine leiomyoma, adenomyosis, lymphovascular space invasion and
tumor depth of invasion (\textless{}50\% vs. \emph{\textgreater{}}
50\%).

\textbf{Results}

92 patients with endometrial cancer underwent total hysterectomy,
bilateral salpingoophorectomy and lymphatic mapping between September
2016 and February 2020. The surgeries were all performed at our
institution by two Gynecologic Oncology surgeons. Demographic and
clinicopathologic characteristics of the study population are summarized
in Table 1. The median age of the patients was 62 years old (range
28-83), and the median BMI was 30.85 kg/m\textsuperscript{2} (range
19.9-53.4). Surgical approach was at the discretion of the provider. 70
out of the 92 cases evaluated were performed with robotic assistance
(76\%), while 22 cases were completed laparoscopically (24\%).

The distribution of histologic types was as follows: endometrioid
(73\%), followed by UPSC (15.0\%), MMMT (5.0\%) and CC (4\%). Stage I
disease was confirmed in the majority of patients; 69 stage IA (71\%),
12 stage IB (14\%). A total of 8 patients were found to have stage III
disease, of which 6 were stage III based on node positivity: 2 IIIA, 2
IIIC1, 4 IIIC2. Of the stage III patients, 2 patients had endometrioid
histology and 6 had UPSC.

One unilateral sentinel lymph node was detected in 88 (95.4\%) patients.
The overall rate of bilateral SLND was 75.3\%. Overtime bilateral SLN
detection rate improved from 70.5\% (2017) to 80\% (2020) (Figure 1).
Twenty patients underwent PPALND (16 for high-grade histology, 3 for
failed mapping, and 1 secondary to a clinically suspicion lymph node).
Per the algorithm, intraoperative evaluation of the uterine specimen was
performed for 12 patients with failed SLN mapping and findings were
consistent with low-risk for lymph node metastasis and therefore PPALND
was not performed.

SLN mapping rates were analyzed among five subgroups based on additional
patient specific and pathologic factors: depth of invasion (DOI),
presence of lymphovascular space invasion (LVSI), uterine leiomyoma,
uterine adenomyosis, and BMI. None of these factors were significantly
associated with rate of successful bilateral SLN mapping (DOI p = 0.1;
LVSI p = 0.22; uterine leiomyoma p = 1.0; adenomyosis p = 0.29; BMI p =
0.91.).

Three patients were found to have positive nodes other than the
surgically identified SLN. All three had serous histology. Two of the
patients underwent planned PPALND for known high-risk histology. The
third patient had a suspicious enlarged lymph node on preoperative
imaging, which was found to be positive for disease at time of surgery.
Of note, the pre-operative diagnosis for this patient was endometrioid
adenocarcinoma and the UPSC component was diagnosed on final pathology.

In a comparison to the selected meta-analysis {[}5{]}, both bilateral
(75.3\% vs. 61\%; p = 0.0001) and unilateral (95.4\% vs. 78\%; p =
0.0111) SLN mapping rates were significantly higher in our cohort.

\textbf{Discussion}

\textbf{Main Findings}

Our results support that sentinel lymph node biopsy is feasible,
reproducible, and sensitive without affecting cancer-specific outcomes
when implemented at a non-specialized center for Type I endometrial
cancer. SLN mapping alone accurately identified at least one lymph node
in 95.4\% of patients with endometrial cancer at our institution and our
overall bilateral SLN mapping rate reached 80\% by the end of our study
period.

\textbf{Strengths}

These figures are on par, if not better than those reported in the
literature. Two meta-analysis performed by Smith et al. and Kang et al.
on endometrial cancer SLN mapping reported a unilateral pooled average
detection rate of 78-81\% with a bilateral detection rate of 61\% {[}2,
5{]}. Although single institution data is difficult to compare to a
meta-analysis, this finding supports that our results are comparable to
those at other institutions.

Guidelines extrapolated from studies of breast cancer, melanoma and
vulvar cancer suggest that surgeons need to complete 30 cases in order
to achieve competency for the reliable detection of SLN in endometrial
cancer staging procedures {[}6{]}. Following recommendations from the
American Society of Clinical Oncology (ASCO) on acceptable proficiency
for breast cancer SLN mapping, the metastatic detection rate should be
greater than 80-90\% and the false negative rate should be less than
5\%. {[}7{]}. In our cohort, the rates of successful SLN mapping
improved over the course of our study period. This reflects increased
provider detection rates over time with improvement of surgical skill.
With regards to false negative rates, our data performed well with
disease detected in only three non-SLN. All three patients had serous
components to their tumors, and received adjuvant treatment with
chemotherapy and radiation. To date, there have been no disease
recurrences in this cohort over a median follow up of 22 months.

\textbf{Interpretation}

Prior to introducing SLNB as an alternative to full pelvic and
paraaortic lymphadenectomy, it was important to first demonstrate that
lymphadenectomy does not provide an independent therapeutic benefit. The
CONSORT and ASTEC trials, are often considered together and were
fundamental in demonstrating that complete lymphadenectomy is not
associated with an overall survival benefit in women with endometrial
cancer {[}8, 9{]}. Despite this evidence, many practicing gynecologic
oncologists continue to perform full lymph node dissections at time of
surgical staging for endometrial cancer. In 2015, only 28.6\% of
gynecologic oncologists participating in a survey conducted by the
society of gynecologic oncology performed SLN mapping for their
endometrial cancer patients, thus continuing to reflect a wide range of
provider--specific practices {[}4{]}. More recent studies generated by
large cancer specialty centers report overall recurrence rates as low as
1.4-9.4\% in SLN cohorts with stage I endometrial cancer {[}10, 11{]}.
In one such study, one-year disease free recurrence rates among patients
who underwent SLN mapping were similar to those who underwent complete
lymphadenectomy, with a 9.4\% recurrence rate in the SLN group and a
14\% recurrence in the complete LND cohort. Additionally, SLN cohorts
were found to have improved pelvic side wall recurrence free survival
compared to patients undergoing complete pelvic lymph node dissection
{[}12{]}. Our data further demonstrate that cancer-specific outcomes are
not affected by the omission a full lymph node dissection, with no
recurrences in our cohort. Taken together, this data supports the
growing consensus that SLN mapping can be implemented as an appropriate
balance between nodal assessment and the morbidities associated with
complete pelvic and paraaortic lymphadenectomy, while increasing the
detection rate of clinically significant metastatic disease.

\textbf{Limitations}

Our study has several limitations. Since the clinical impact of SLN
mapping for high-risk endometrial histologies, such as UPSC, CC and MMMT
are not as robustly studied, it is difficult to assess the significance
of the three documented false negative SLN in patients with UPSC
histology in our cohort. It has previously been shown that elimination
of lymphadenectomy in cases of high-risk histology may be associated
with more risk of treatment failure {[}10{]}. Given the relatively small
sample size, the data in our study is insufficient to comment on safety
or feasibility of SLNB in high-risk endometrial histologic subtypes and
our practice is to perform a complete lymphadenectomy after SLN mapping
for these cases. Additionally, although we did not discover associations
between SLN mapping rates and BMI, presence of leiomyoma, adenomyosis
and depth of invasion, it is possible that associations would be seen in
a larger cohort. Overall, the power of this study is limited by the
sample size of patients and the retrospective nature of our study
design. There were no recurrences in our patients, but long-term follow
up will provide additional information with regards to disease
recurrence.

\textbf{Conclusion}

Our data demonstrates that high SLN detection rates can be achieved by
gynecologic oncologists treating women with endometrial cancer at
non-specialty surgical institutions. Optimization of provider technique
and expertise is critical in order to meet defined standards of SLN
detection accuracy. Once individual surgeons demonstrate proficiency in
SLN mapping and detection, based on our data, it would seem reasonable
to recommend SLN mapping and biopsy as standard of care for the
treatment and management of uterine endometrial cancer across all
institutions.

Declarations:

The authors have no financial, personal, political, intellectual or
religious interests to disclose.

Contribution to authorship:

Sarah Werner is the main investigator- including planning and compiling
data and writing abstract and manuscript. Therese Gadomski provided
assistance with project planning, data collection and manuscript
editing. Drs. Pereira and Villella are the primary investigators for
this project and are involved in conception, planning and manuscript
editing. Tung Ming Leung contributed with data analysis.

Ethics: IRB approval for this retrospective analysis did not include
approval from ethics committee.

Funding: Authors have no external funding to disclose for the completion
of this project.

References

\begin{enumerate}
\tightlist
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\item
  NCCN, Guidelines Version 1.2014, Endometrial Carcinoma, 2014 (Accessed
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  Society of Gynecologic Oncology. (2015) \emph{Clinical Practice
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\end{enumerate}

\emph{Figure Legend:}

Table 1: Demographic Characteristics

Figure 1: Bilateral SLN detection rates by year\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

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Table 1: Demographic Characteristics\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 1: Bilateral SLN detection rates by year

\selectlanguage{english}
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