Neuroendocrine tumor chromogranin A response following synthetic somatostatin analog (lanreotide): Early observations from an isolated duodenal neoplasm

Abstract

Neuroendocrine tumors (NETs) of duodenal origin are an unusual subset among all NETs, comprising only about 3% of this neoplasm class. In general, NETs are characterized by overexpression of somatostatin receptors and carry an excellent prognosis with early diagnosis and intervention. Chromogranin A (CgA), a protein originating in secretory vesicles of neurons and endocrine cells, has gained wide usage in NET diagnosis and surveillance. Lanreotide is a synthetic octapeptide somatostatin analog with potent anti-proliferative action which has been approved by the FDA (U.S.) and EMA (E.U.) for NET treatment. It is known for its inhibitory effects on growth hormone, serotonin, CgA, and other markers. Here we describe a 56yr-old female with functional NET of duodenal origin, where serum CgA was successfully reduced from 3636 to <100 ng/mL after multidose lanreotide within five months. Of note, no metastatic spread was identified on positron emission tomography/computed tomography with 64Cu-labeled somatostatin analog tracer. Surgical resection of distal antrum, pylorus, and proximal duodenum was completed without complication. Histology revealed well-differentiated tumor cells with characteristic neuroendocrine features and clear surgical margins; low proliferation index (2%) was noted on Ki-67 staining. While select laboratory and imaging modalities are available for diagnosis and monitoring of duodenal NET, this is the first reported therapeutic use of lanreotide in this NET setting. The observed serum chromogranin A attenuation, even before surgery, supports its effectiveness in management of primary nonmetastatic duodenal NET.

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Neuroendocrinol Lett 2023; 44(4):265–269
CASE REPORT
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Neuroendocrine tumor chromogranin A response
following synthetic somatostatin analog
(lanreotide): Early observations from an isolated
duodenal neoplasm
E. Scott S1,2, Samuel H. W2,3, Seang Lin T4,5, Daniel M. I6
1 Center for Advanced Genetics/FertiGen, Regenerative Biology Group; San Clemente, California
92673 USA.
2 Department of Obstetrics & Gynecology, Palomar Medical Center; Escondido, California 92029 USA
3 Gen 5 Fertility Center; San Diego, California 92121 USA.
4 OriginElle Fertility Clinic; Montréal, Quebec Canada.
5 Department of Obstetrics & Gynecology, McGill University Health Centre; Montréal, Quebec
Canada.
6 Tennessee Cancer Specialists; Knoxville, Tennessee 37923 USA.
Correspondence to: E. Scott Sills, MD PhD
Regenerative Biology Group P.O. Box 73910, San Clemente, California 92673 USA
: +1 949-899-5686, -: ess@prp.md
Submitted: 2023-03-23 Accepted: 2023-04-20 Published online: 2023-04-20
Key words: neuroendocrine tumor; duodenum; chromogranin A; lanreotide; surgery
Neuroendocrinol Lett 2023; 44(3):265–269 PMID: 37466065 NEL440423C03 © 2023 Neuroendocrinology Letters • www.nel.edu
Abstract
Neuroendocrine tumors (NETs) of duodenal origin are an unusual subset among
all NETs, comprising only about 3% of this neoplasm class. In general, NETs are
characterized by overexpression of somatostatin receptors and carry an excellent
prognosis with early diagnosis and intervention. Chromogranin A (CgA), a protein
originating in secretory vesicles of neurons and endocrine cells, has gained wide
usage in NET diagnosis and surveillance. Lanreotide is a synthetic octapeptide
somatostatin analog with potent anti-proliferative action which has been approved
by the FDA (U.S.) and EMA (E.U.) for NET treatment. It is known for its inhibitory
effects on growth hormone, serotonin, CgA, and other markers. Here we describe
a 56yr-old female with functional NET of duodenal origin, where serum CgA
was successfully reduced from 3636 to <100 ng/mL after multidose lanreotide
within five months. Of note, no metastatic spread was identified on positron emis-
sion tomography/computed tomography with 64Cu-labeled somatostatin analog
tracer. Surgical resection of distal antrum, pylorus, and proximal duodenum was
completed without complication. Histology revealed well-differentiated tumor
cells with characteristic neuroendocrine features and clear surgical margins; low
proliferation index (2%) was noted on Ki-67 staining. While select laboratory
and imaging modalities are available for diagnosis and monitoring ofduodenal
NET, this is the first reported therapeutic use of lanreotide in this NET setting.
The observed serum chromogranin A attenuation, even before surgery, supports
its effectiveness in management of primary nonmetastatic duodenal NET after
resection.

266
Copyright © 2023 Neuroendocrinology Letters ISSN 0172–780X • www.nel.edu
Sills et al: Chromogranin A after lanreotide in NET
INTRODUCTION
Neuroendocrine tumors (NETs) are malignancies
ofendocrine origin with an incidence perhaps as low as
2:100,000 (Armentano et al. 2022). These lesions derive
from neuroendocrine cells which may potentially arise
anywhere in the body; detection is difficult due to long
periods of quiescence. NET cells overexpress surface
somatostatin receptors (SSTRs) which are therapeutic
targets for synthetic somatostatin analogs (e.g., octreotide
& lanreotide). NET diagnosis can be assisted by avariety
of positron emission tomography/CT radiopharmaceuti-
cals, including 64Cu-dotatate (Zobel et al. 2021).
CLINICAL PRESENTATION
A 56yr old non-smoking Caucasian female in good
general health presented for abdominal discomfort and
chronic reflux. Evaluation included upper endoscopy
for direct visualization to the descending duodenum.
Esophageal and stomach survey was unremarkable
although a small polypoid structure was noted at the
duodenal bulb mucosa (Figure 1). Snare cautery was
used to remove the lesion retrieved via Roth Net®
(Steris Healthcare, Dublin IRL). Histology showed
clear deep margins of the sampled tissue with no
necrosis and low mitotic activity at <2 mitoses/2 mm2
field. Immunohistochemical staining was positive for
synaptophysin with a Ki-67 proliferation index of 2%
(Figure 2). These findings were consistent with well-
differentiated neuroendocrine tumor (NET), Grade 1,
with imaging studies and laboratory tests scheduled
torefine the treatment approach.
While electrolytes and CBC were essentially
normal, serum Chromogranin A (CgA) was mark-
edly elevated at 3636 ng/mL (normal <311 ng/mL);
serotonin was undetectable (<10 ng/mL). CBC showed
neutrophil/lymphocyte ratio at 2.38 (normal <3) and
for platelet/lymphocyte this was 12.88 (normal <150)
(Armentano et al. 2022). The aberrant CgA value
supported prompt chemotherapy with 120 mg lanreo-
tide (Depot Somatuline®, Ipsen PharmaBiotech; Signes,
FR) and three doses were administered before surgery.
Contemporaneous CgA measurements confirmed an
adequate tissue response (see Figure 3).
Positron emission tomography/CT images obtained
from mid-skull through proximal femur after i.v.
administration of 3.87mCi of 64Cu-dotatate (Detectnet®,
Curium US LLC; Maryland Heights, MO) revealed
physiologic distribution of radiotracer, with no patho-
logic foci or scatter to suggest metastatic disease (Figure
4). Next, exploratory laparotomy, resection of distal
antrum, pylorus and first portion of the duodenum
was performed after private insurance approval four
months later. Multiple fluoroscopy images confirmed
patency and integrity of the gastrointestinal tract
during the procedure, and the postoperative recovery
was unremarkable.
Microscopic exam of surgical specimens agreed with
earlier biopsy findings, showing four local nests of well-
differentiated neuroendocrine tumor cells involving
lamina propria and submucosa at the gastroduodenal
junction. Mitotic activity was <1 per hpf, without
necrosis. Paraffin immunohistochemistry confirmed
cytokeratin AE1/AE3+, synaptophysin+ staining with
Ki-67 proliferation index of 2%. One additional lanreo-
tide dose was given post-operatively, then discontinued
due to satisfactory normalization of serum CgA.
DISCUSSION
Primary duodenal NET has a favorable overall prog-
nosis, and recent published experience in this subgroup
shares some features with our case. For example, a61yr
Fig. 1. Pre-resection view of duodenal neuroendocrine
tumor polyp (arrow). Bar = 1mm.

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Sills et al: Chromogranin A after lanreotide in NET
old female in Japan was found to have a 15mm nodule
at the descending duodenum confirmed as NET after
endoscopic biopsy. Serum testing was normal and
the lesion was classified as nonfunctional; the patient
underwent subtotal stomach-preserving pancreatico-
duodenectomy with good results (Aoyama et al. 2022).
In China, NET was reported in a 55yr-old female
with a palpable non-tender upper abdominal mass.
Ultrasound-guided abdominal biopsy obtained tissue
for histologic analysis where cells positive for chro-
mogranin A, synaptophysin, and cytokeratin were
identified; partial duodenal resection followed without
complication (Wang et al. 2021).
Certainly uncommon now, NET was once encoun-
tered even less often—A fivefold increase for this
diagnosis was noted between 1973 and 2004 (Yao et al.
2008). The upward trend is likely attributed tobetter
detection from endoscopy, as well as improved imaging
and laboratory techniques. Some 60% of NETs have
either a pancreatic or gastrointestinal primary source
(i.e., appendix, colon, intestine, rectum, stomach),
collectively termed gastroenteropancreatic NETs
(Khatri et al. 2023). Approximately 30% of NETs are
functionally secretory, producing bioactive peptides
and neuroamines which can cause fatigue, abdominal
discomfort, muscle weakness, or dermal flushing/
Fig. 2. For this duodenal NET, 2%
proliferation index was noted on
paraffin immunohistochemistry Ki-67
nuclear staining (red circles). Multiple
nested organoid proliferations of
well-differentiated cells with typical
neuroendocrine features were noted
at the gastroduodenal junction on
standard histology.
Scale = 100μ (original magnification
400x)
Fig. 3. Diagnosis (dx) by
endoscopic biopsy
(A) and subsequent
resection (B) for duodenal
neuroendocrine tumor
is shown with CgA
measurements (blue),
responsive to preoperative
synthetic somatostatin
analog (SSA) lanreotide
(red arrows). Only one
SSA dose was given
postoperatively (green
arrow) as CgA normalized.

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Sills et al: Chromogranin A after lanreotide in NET
cutaneous vasodilation (Paulson et al. 2022). Among
all NETs, those of duodenal origin comprise only 1-3%
with clinical manifestations similar to other digestive
tract tumors, resulting in nonspecific and variable
clinical symptoms (Gaiani et al. 2019). Most NETs
develop sporadically, with no recognized causes or
identifiable risk factors.
Chromogranin A (CgA) testing offers a noninvasive
approach for detection and management of NET, as
several neuroendocrine cell types express it. However,
misleading results are possible among patients with
chronic non-NET conditions or with certain medica-
tions (e.g., omeprazole, losartan, aspirin, paracetamol,
and others) so a careful history is needed to inter-
pret CgA values accurately (Al-Risi et al. 2017). In
metastatic NET, CgA levels are typically far higher
than for local NET (Qiao et al. 2014) yet the order-
of-magnitude elevation above reference range (with
no metastatic spread) observed in this case highlights
the variability of this parameter. Ki-67 is considered
a proxy marker for mitosis/proliferative index, as it
a nuclear protein expressed throughout the active
cell cycle except in G0 (i.e., absent in resting cells).
Another widely used marker in NET assessment is
synaptophysin, a synaptic vesicle glycoprotein present
in neuroendocrine cells and in virtually all brain and
spinal cord neurons.
Highly specific radiotracers have encouraged
atrend away from conventional scintigraphy to posi-
tron emission tomography/CT. The drive to enhance
cell target specificity includes the development
of 64copper-labeled [1,4,7,10-tetraazacyclododecane-
N,N´,N´´,N´´´-tetraacetic acid]-D-Phe1, Tyr3-octreotate
radiotracer (64Cu-dotatate), which preferentially seeks
the G-protein-coupled receptor somatostatin receptor
subtype-2 (Zobel et al. 2021). 64Cu has a low maximal
positron energy (0.653 MeV) resulting in a shorter
mean positron range compared to 68Ga. Moreover,
64Cu has a longer t1/2 than gadolinium-based radio-
tracers (12.7h vs. 68min) which favors the copper
reagent by prolonging its use time (Loft et al. 2021).
While 64Cu-dotatate has been broadly used to diagnose
somatostatin receptor-positive NET (Delpassand et al.
2020), this is among the first to describe its application
specifically for duodenal NET.
Because native somatostatin has a circulatory half-
life of ≤3min, its therapeutic use to inhibit dysfunc-
tional neuroendocrine output has been overtaken by
long-acting synthetic analogs (Simonenko et al. 2006).
Lanreotide is in this category, with approval for use in
refractory acromegaly, gastroenteropancreatic NET,
and adult carcinoid syndrome (Kehoe, 2021). Here the
sharp CgA decreases measured in response to lanreo-
tide, even before surgery, illustrate its efficacy for
duodenal NET. While lanreotide has been used for other
neuroendocrine tumors, this is the first known descrip-
tion of its successful application in isolated, primary
duodenal NET. Periodic monitoring is planned, and it is
anticipated that our case will provide another successful
nonrecurrence.
ACKNOWLEDGEMENTS
The authors are grateful to Norma M. Edwards, MD
and Guy E. Nichols, MD PhD (Knoxville, TN) for their
expert contributions to surgery and histology, and
toM.R.T. Pitt (Jonesboro, AR) for assistance in patient
coordination.
AUTHOR CONTRIBUTIONS
ESS and SHW organized manuscript drafts; ESS, SHW,
SLT and DMI reviewed the literature and developed
revisions; all authors read and approved the final
manuscript.
COMPETING INTERESTS
None/Not applicable.
FUNDING
This project received no external funding.
Fig. 4. Representative positron emission tomography/CT image
obtained before surgery with i.v. 64Cu-dotatate (dose=3.87
mCi), showing radiotracer uptake near the duodenal bulb. No
evidence of distant metastatic disease, no ascites, pulmonary
nodularity or adnexal mass were apparent on CT.

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Sills et al: Chromogranin A after lanreotide in NET
INSTITUTIONAL REVIEW BOARD
STATEMENT
Not applicable.
INFORMED CONSENT STATEMENT
Written consent for publication was obtained from the
patient.
DATA AVAILABILITY STATEMENT
Redacted reports and images available upon written
request.
REFERENCES
1 Al-Risi ES, Al-Essry FS, Mula-Abed WS (2017). Chromogranin A as
a biochemical marker for neuroendocrine tumors: A single center
experience at Royal Hospital, Oman. Oman Med J. 32(5): 365–70.
doi: http://dx.doi.org/10.5001/omj.2017.71
2 Armentano DPD, Monteiro MR, Aguiar PN Jr, Tsukamoto JS, Pio
RB, Arakelian R, et al. (2022). Laboratory variables as predictors of
progression in gastroenteropancreatic neuroendocrine tumors
in different lines of antineoplastic treatments. Einstein (Sao
Paulo). 20: eAO6985. doi: http://dx.doi.org/10.31744/einstein_
journal/2022AO6985
3 Aoyama N, Wada M, Taniguchi Y, Inokuma T, Nakanishi Y, Fukuda
A, et al. (2022). A case of neuroendocrine neoplasm of the minor
duodenal papilla. Clin J Gastroenterol. Dec 21. doi: http://dx.doi.
org/10.1007/s12328-022-01739-w
4 Delpassand ES, Ranganathan D, Wagh N, Shafie A, Gaber A, Abbasi
A, et al. (2020). 64Cu-Dotatate PET/CT for imaging patients with
known or suspected somatostatin receptor-positive neuroen-
docrine tumors: Results of the first U.S. prospective, reader-
masked clinical trial. J Nucl Med. 61(6): 890–6. doi: http://dx.doi.
org/10.2967/jnumed.119.236091
5 Gaiani F, de'Angelis N, Minelli R, Kayali S, Carra MC, de'Angelis
GL (2019). Pediatric gastroenteropancreatic neuroendocrine
tumor: A case report and review of the literature. Medicine
(Baltimore). 98(37): e17154. doi: http://dx.doi.org/10.1097/
MD.0000000000017154
6 Kehoe TE (2021). NDA approval notification [letter to InvaGen
Pharmaceuticals]. U.S. FDA Reference ID: 4906945; Silver Spring
MD, 17 December: 1–5. doi: https://www.accessdata.fda.gov/
drugsatfda_docs/appletter/2021/215395Orig1s000ltr.pdf
7 Khatri W, Spiro E, Henderson A, Rowe SP, Solnes LB (2023). Gastro-
enteropancreatic tumors: FDG positron emission tomography/
computed tomography. PET Clin. S1556-8598(22)00094-3. doi:
http://dx.doi.org/10.1016/j.cpet.2022.11.007
8 Loft M, Carlsen EA, Johnbeck CB, Johannesen HH, Binderup T,
Pfeifer A, et al. (2021). 64Cu-DOTATATE PET in patients with neu-
roendocrine neoplasms: Prospective, head-to-head comparison
ofimaging at 1 hour and 3 hours after injection. J Nucl Med. 62(1):
73–80. doi: http://dx.doi.org/10.2967/jnumed.120.244509
9 Paulson S, Ray D, Aranha S, Scales A, Wang Y, Liu E (2022). Lan-
reotide depot to treat gastroenteropancreatic neuroendocrine
tumors in a U.S. community oncology setting: A prospective,
observational study. Oncol Ther. 10(2): 463–79. doi: http://dx.doi.
org/10.1007/s40487-022-00208-1
10 Qiao XW, Qiu L, Chen YJ, Meng CT, Sun Z, Bai CM, et al. (2014).
Chromogranin A is a reliable serum diagnostic biomarker for
pancreatic neuroendocrine tumors but not for insulinomas. BMC
Endocr Disord. 14: 64. doi: http://dx.doi.org/10.1186/1472-6823-
14-64
11 Simonenko VB, Dulin PA, Makanin MA (2006). Somatostatin ana-
logues in treatment of gastrointestinal and pancreatic neuroen-
docrine tumors. Klin Med (Mosk). 84(4): 4–8. doi: https://pubmed.
ncbi.nlm.nih.gov/16755846/
12 Wang X, Wu Y, Cao X, Zhang X, Cheng Y, Kong L (2021). Duo-
denal neuroendocrine tumor: A rare case report. Medicine
(Baltimore). 100(6): e24635. doi: http://dx.doi.org/10.1097/
MD.0000000000024635
13 Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al.
(2008). One hundred years after "carcinoid": Epidemiology of and
prognostic factors for neuroendocrine tumors in 35,825 cases in
the United States. J Clin Oncol. 26(18): 3063–72. doi: http://dx.doi.
org/10.1200/JCO.2007.15.4377
14 Zobel EH, Ripa RS, von Scholten BJ, Curovic VR, Diaz LJ, Hansen
TW, et al. (2021). Effect of liraglutide on vascular inflammation
evaluated by [64Cu]DOTATATE. Diagnostics (Basel). 11(8):1431.
doi: http://dx.doi.org/10.3390/diagnostics11081431