Natural Course of an Untreated Metastatic Perirectal Lymph Node After the Endoscopic Resection of a Rectal Neuroendocrine Tumor

Abstract

Lymph node metastasis is rare in small (i.e., <10 mm) rectal neuroendocrine tumors (NETs). In addition to tumor size, pathological features such as the mitotic or Ki-67 proliferation index are associated with lymph node metastasis in rectal NETs. We recently treated a patient who underwent endoscopic treatment of a small, grade 1 rectal NET that recurred in the form of perirectal lymph node metastasis 7 years later. A 7-mm-sized perirectal lymph node was noted at the time of the initial endoscopic treatment. The same lymph node was found to be slightly enlarged on follow-up and finally confirmed as a metastatic NET. Therefore, the perirectal lymph node metastasis might have been present at the time of the initial diagnosis. However, the growth rate of the lymph node was extremely low, and it took 7 years to increase in size from 7 to 10 mm. NETs with low Ki-67 proliferation index and without mitotic activity may grow extremely slowly even if they are metastatic.

Full text

CASE REPORT
(i.e., <10 mm) rectal NETs is 2−9.7%.6,7 In addition to tumor
size, lymphovascular invasion, muscularis propria invasion,
and the mitotic and Ki-67 proliferation indices are also asso-
ciated with lymph node metastasis in rectal NETs, and rectal
NETs without lymph node metastasis or its risk factors are
potential candidates for endoscopic resection.7-10 Therefore,
preoperative assessment of any metastatic lesions is neces-
sary to determine the therapeutic options for small rectal
NETs. However, it is often difficult to distinguish between
benign and metastatic nodes in the case of very small lymph
nodes, even in patients with more advanced malignancies
such as advanced rectal adenocarcinoma.
Here, we describe an endoscopically treated patient who
had a small, grade 1 rectal NET and a tiny perirectal lymph
node metastasis that was initially regarded as benign at pre-
sentation, but was confirmed as a metastatic lymph node 7
years later.
INTRODUCTION
Neuroendocrine tumors (NETs) are heterogeneous, and
arise from the diffuse neuroendocrine system; they are pri-
marily found in the gastrointestinal and respiratory systems.
Rectal NETs arise from L−cells, and they are showing an in-
creasing incidence worldwide.1-3 Recent increases in the use
of screening colonoscopy may have contributed to the rise
in the incidence of rectal NETs and may help detect early-
stage tumors.4,5 The risk of lymph node metastasis in small
© Copyright 2015. Korean Association for the Study of Intestinal Diseases. All rights reserved.
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ISSN 1598-9100(Print) • ISSN 2288-1956(Online)
http://dx.doi.org/10.5217/ir.2015.13.2.175
Intest Res 2015;13(2):175-179
Natural Course of an Untreated Metastatic Perirectal
Lymph Node After the Endoscopic Resection of a Rectal
Neuroendocrine Tumor
Sang Hyung Kim1, Dong-Hoon Yang2, Jung Su Lee1, Soyoung Park1, Ho-Su Lee2, Hyojeong Lee2,
Sang Hyoung Park2, Kyung-Jo Kim2, Byong Duk Ye2, Jeong-Sik Byeon2, Seung-Jae Myung2,
Suk-Kyun Yang2, Jin-Ho Kim2, Chan Wook Kim3, Jihun Kim4
Departments of Internal Medicine1, Gastroenterology2, Colon and Rectal Surgery3, and Pathology4, Asan Medical Center, University of Ulsan
College of Medicine, Seoul, Korea
Lymph node metastasis is rare in small (i.e., <10 mm) rectal neuroendocrine tumors (NETs). In addition to tumor size, patho-
logical features such as the mitotic or Ki-67 proliferation index are associated with lymph node metastasis in rectal NETs. We
recently treated a patient who underwent endoscopic treatment of a small, grade 1 rectal NET that recurred in the form of
perirectal lymph node metastasis 7 years later. A 7-mm-sized perirectal lymph node was noted at the time of the initial endo-
scopic treatment. The same lymph node was found to be slightly enlarged on follow-up and finally confirmed as a metastatic
NET. Therefore, the perirectal lymph node metastasis might have been present at the time of the initial diagnosis. However,
the growth rate of the lymph node was extremely low, and it took 7 years to increase in size from 7 to 10 mm. NETs with low
Ki-67 proliferation index and without mitotic activity may grow extremely slowly even if they are metastatic. (Intest Res
2015;13:175-179)
Key Words: Rectum; Neuroendocrine tumor; Lymph node; Metastasis
Received July 18, 2014. Revised August 20, 2014.
Accepted September 1, 2014.
Correspondence to Dong-Hoon Yang, Department of Gastroenterology,
Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro
43-gil, Songpa-gu, Seoul 138-736, Korea. Tel: +82-2-3010-5809, Fax: +82-
2-3010-6517, E-mail: dhyang@amc.seoul.kr.
Financial support: None. Conflict of interest: None.

Sang Hyung Kim, et al. • Natural Course of a Metastatic Lymph Node in Rectal NET
176 www.irjournal.org
CASE REPORT
A 51-year-old male patient was referred to Asan Medical
Center on August 10, 2005 for a rectal NET that was found
incidentally on screening colonoscopy. The patient had
undergone hemorrhoidectomy in his twenties, but other-
wise had no significant past medical history. He was a non-
smoker and non-drinker. His height and weight were 164
cm and 59.3 kg, respectively. His initial vital signs included a
blood pressure of 116/74 mmHg, pulse of 84 beats/minute,
respiratory rate of 20 breaths/minute, and body temperature
of 36.6oC.
Physical examination revealed no abnormalities. Labora-
tory data and the results of urinalysis and stool examination
were all within normal limits. Chest and abdominal radi-
ography were also unremarkable. Colonoscopy revealed a
5-mm-sized subepithelial tumor in the rectum, 5 cm above
the anal verge; histological analysis of a forceps biopsy speci-
men revealed a rectal NET that was positive for both synap-
tophysin and chromogranin. Abdominopelvic CT showed
no definite rectal lesions, but did reveal a 7-mm-sized peri-
rectal lymph node. Considering the small size of the lymph
node and the rare incidence of small metastatic rectal NETs,
the malignant potential of the perirectal lymph node was
regarded as very low. We discussed the CT findings with the
patient, and finally decided to first remove the primary rectal
NET endoscopically, with more invasive surgery to be con-
sidered if histological analysis revealed any other unfavor-
able findings, such as lymphovascular invasion, ≥2 mitoses
per 50 high-power fields, and/or Ki-67 index >2%.
Fig. 2. Histopathological findings of the rectal neuroendocrine tumor. (A) The endoscopically resected specimen mostly consisted of a relatively well-
demarcated tumor. The tumor involved the mucosa and submucosa, and it measured 8 mm across the greatest dimension. The deep resection margin
characterized the tumor (H&E, ×10). (B) The tumor cells formed nests or cords in the sclerotic stroma and demonstrated histological patterns typical of
a neuroendocrine tumor. The tumor cell nuclei are round or ovoid and demonstrate fine salt-and-pepper chromatin (H&E, ×200).
A B
Fig. 1. Endoscopic findings. (A) A 5-mm-sized subepithelial tumor in the rectum. (B and C) Endoscopic mucosal resection was performed.
A B C

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Endoscopic mucosal resection was performed (Fig. 1).
The tumor measured 8×5×5 mm, and the vertical resection
margin was positive. The tumor involved the mucosa and
submucosa without angioinvasion. The Ki-67 index was
0.8%. Hence, the lesion was diagnosed as a well-differenti-
ated grade 1 NET (Fig. 2). Given the favorable histological
Fig. 4. Histological findings of the perirectal lymph node. (A) The meta-
static node was located in the pericolic adipose tissue, but there was no
recognizable lymph node structure. The node demonstrated a stellate
shape (H&E, ×10). (B) Lymphovascular invasion was noted in the pe-
ripheral part of the metastatic node (H&E, ×100). (C) Some parts of the
tumor demonstrated neural and perineural invasion (H&E, ×100).
A
C
B
Fig. 3. Abdominopelvic CT findings. (A) The initial CT imaging showed perirectal lymph node. (B) Seven years later, the perirectal lymph node had
slightly enlarged from 7 to 10 mm.
A B

Sang Hyung Kim, et al. • Natural Course of a Metastatic Lymph Node in Rectal NET
178 www.irjournal.org
results of the resected specimen, we considered metastasis
to the perirectal lymph nodes to be extremely unlikely; thus,
we elected to follow-up the patient using endoscopy (annual
sigmoidoscopy for the first 3 years, then colonoscopy every 3
years) and annual abdominopelvic CT.
For up to 7 years after endoscopic resection, the size of the
perirectal lymph node remained unchanged on CT, and no
intraluminal recurrence was identified on serial endoscopic
follow-up examinations. However, 7 years after the resection,
the lymph node was found to have enlarged slightly, from
7 to 10 mm (Fig. 3), although colonoscopy revealed no evi-
dence of recurrence in the rectum. Transrectal ultrasound-
guided biopsy was performed on the perirectal lymph node,
and histological analysis revealed a well-differentiated NET.
Preoperative MRI showed two perirectal lymph nodes sus-
picious for metastasis. Laparoscopic low anterior resection
and lymph node dissection were also performed. The surgi-
cal specimen contained two metastatic lymph nodes, mea-
suring 10×8×8 mm and 6×5×5 mm, respectively. Although
lymphovascular and perineural invasion were present, the
resection margins were clear. The specimen was positive for
synaptophysin, but negative for chromogranin. The Ki-67 la-
beling index was ≤2%, but no mitosis was noted. Finally, the
surgical specimen was diagnosed as a metastatic, well-dif-
ferentiated, grade 1 NET (Fig. 4). The patient was discharged
without complications and was scheduled to continue to
receive follow-up examinations on a regular basis.
DISCUSSION
Using studies that correlate NET prognosis, the Ki-67
proliferation index, and the mitotic count, the NET classifi-
cations of the World Health Organization (WHO) were up-
dated in 2010.11 Although the natural course of rectal NETs
is not fully understood, recent studies suggest that the WHO
classification system correlates well with the metastatic
potential and prognosis of rectal NETs.9,12 Moreover, recent
Korean studies suggest that the endoscopic treatment of
small (i.e., <10 mm) rectal NETs without evidence of regional
or distant metastasis can achieve highly favorable long-term
outcomes.13,14 Another recent Korean study suggested that
the risk of recurrence is markedly increased in rectal NET
patients with metastatic lymph nodes, even after radical
surgery (hazard ratio, 12.8; 90% CI, 4−41 on univariate analy-
sis), although this study did not investigate the histological
grade of NETs.15 Therefore, before deciding on therapy for a
small rectal NET, the presence of metastatic lesions should
be investigated by using various imaging modalities, such as
CT, MRI, or endoscopic ultrasonography. However, all these
imaging modalities have demonstrated limited diagnostic
accuracy for assessing perirectal metastatic lymph nodes.16
Although indium-111 pentetreotide scintigraphy remains
the gold standard for the diagnosis and localization of most
NETs, its utility in colorectal NETs has not been validated
owing to the sparse data available, and it may be more dif-
ficult to detect lesions of these types because of the greater
background activity in the colon and rectum.17 Fludeoxy-
glucose (FDG) used in PET accumulates only in high-grade
NETs,18 and therefore, FDG-PET has not been considered for
imaging in low-grade NETs. Endoscopic ultrasound-guided
fine needle aspiration (EUS-FNA) for perirectal lesions could
be another option to confirm perirectal lymph node metas-
tasis, but it was not a well-established diagnostic procedure
for perirectal lesions less than 10 mm in size in 2005, when
the patient described in the current report was treated.19 In
our case, a small NET was noted in the distal rectum and a
7-mm-sized perirectal lymph node was also identified. As
mentioned above, it was highly difficult to assess the histo-
logical nature of the lymph node without performing surgery
at that time. Meanwhile, radical surgery for distal rectal le-
sions carries the potential risks of bladder or bowel dysfunc-
tion and stoma formation.20 Therefore, after discussion with
the patient, we decided to first perform endoscopic resection
of the rectal NET. After removal of that lesion, we discussed
the favorable histology of the resected specimen, as well as
the question of the unresected small perirectal lymph node
with uncertain histology, and the patient finally elected a
course of follow-up without invasive surgery.
Because the size of the initially noted lymph node re-
mained unchanged for up to 7 years of follow-up examina-
tions, our initial belief was that this lymph node was benign.
However, 7 years and 1 month after the initial local excision,
the lymph node was found to have slightly enlarged, and it
was finally diagnosed as a metastatic, grade 1 NET. If the ini-
tial perirectal lymph node was a metastasis from the rectal
NET, this case suggests that metastatic lesions from grade
1 rectal NET might demonstrate an extremely slow growth
rate. Therefore, any patients with small, grade−1, rectal NETs
that are locally excised should receive long-term follow-up
examinations when lesions are suspected to be metastatic
but are too small for the performance of EUS-FNA for his-
tological confirmation. Highly aggressive approaches such
as surgical lymph node dissection can also be considered.
However, considering the operation-related complications,
the extremely slow growth rate, and the very low incidence
of lymph node metastasis from small rectal NETs, surgical

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excision might be substituted by EUS-FNA or by regular fol-
low-up with imaging modalities if EUS-FNA is impossible or
does not help in the diagnosis. However, little is known about
the adequate follow-up interval in these kinds of situations.
On the other hand, if the locally excised primary lesions
demonstrate grade 2 histology and any lesions suspected of
metastasis are present, either EUS-FNA or surgical excision
should be considered to rule out the possibility of metastasis.
FDG-PET may also be useful for the staging of grade 2 or 3
NETs compared with grade 1 NETs.18
Generalization of the information presented in this ex-
tremely rare case should be avoided. Nonetheless, to the best
of our knowledge, the natural course of untreated perirectal
lymph node metastasis from a grade 1 rectal NET has never
been previously described. Thus, this case discussed here
can help clinicians understand the nature of metastatic le-
sions from small, grade 1 rectal NETs.
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