503

CASE REPORTAn incidentally discovered paraganglioma that caused sinus
arrest after resection
Takayuki Sano1, Takeshi Inoue1, Naoko Irie1, Tatsuo Ichikawa1, Akira Iai1, Kiyoshi Osa1, Satoshi Ono1, Kozo Asanuma1,Shiori Kaneko1, Tadao Kuribara1, Itaru Shigeyoshi1, Kouta Matsubara1, Kanako Suzuki1, Hideki Ishizu2,and Keishin Sunagawa2
Department of Surgery and 2Department of Pathology, Saitama Cooperative Hospital, Saitama, Japan1

Abstract : Paragangliomas are neural-crest-derived nonepithelial neuroendocrine tumors distributed along theparasympathetic and sympathetic nerves. To our knowledge, no studies were reported regarding sinus arrest
on day 4 after paraganglioma resection. A 66-year-old female patient with a history of pulmonary vein isolation
visited our department for sigmoid colon cancer treatment. Enhanced computed tomography revealed an enhanced small nodule-like lymph node near the root of the inferior mesenteric artery. The patient underwent laparoscopic colectomy with regional lymph node dissection. Postoperatively, paroxysmal atrial fibrillation attacks
developed, and the patient resumed oral medication. Additionally, sinus arrest after tachycardia developed.
Changing the oral medication could maintain her circulatory dynamics. Pathological examination revealed thatdifferentiated tubular adenocarcinoma infiltrated the submucosa. Immunohistochemically, the excised nodule
as a lymph node was considered a functional paraganglioma. Our case indicates that paraganglioma resection
and oral medication resumption may contribute to sinus arrest. When arrhythmias affecting the circulation
occur perioperatively, the presence of a catecholamine-producing tumor should be considered in addition to
cardiac disease. J. Med. Invest. 70 : 503-507, August, 2023
Keywords : Paraganglioma, sinus arrest, colon cancer

INTRODUCTION
Paragangliomas are neural-crest-derived nonepithelial neuroendocrine tumors distributed along the parasympathetic andsympathetic nerves. Head-and-neck paragangliomas have beenrecognized as nonchromaffin, nonfunctional, parasympathetic
tumors. By contrast, thoracoabdominal paragangliomas andpheochromocytomas are chromaffin, functional, sympathetic
tumors (1). To the best of our knowledge, no studies have beenreported regarding sinus arrest on day 4 after paraganglioma
resection. Here we present an incidentally discovered paraganglioma that developed sinus arrest after resection.

consisted of differentiated tubular adenocarcinoma. Enhanced
computed tomography revealed an enhanced nodule-like regional lymph node near the root of the inferior mesenteric artery,5 × 6 mm in diameter (Fig. 2) ; however, the primary lesion
remained unclear. There were no findings suggesting distantmetastasis. According to the Tumor, Node, Metastasis Staging
classification of the Union for International Cancer Control,
the preoperative evaluation of this colon carcinoma was cT1cN1acM0, cStage Ⅲ-A.
On admission, she had a regular pulse of 56 beats / min anda blood pressure of 96 / 63 mmHg. Electrocardiogram was normal. The patient underwent laparoscopic colectomy with an

CASE PRESENTATION
A 66-year-old female patient visited our department for surgical colon cancer treatment. She was aware of the symptoms ofparoxysmal headaches, sweating, and pallor. She had a historyof paroxysmal atrial fibrillation (PAF) in addition to hypertension and underwent pulmonary vein isolation when she was
65 years old. She was treated with oral amlodipine, bisoprolol,
olmesartan, apixaban, and bepridil after pulmonary vein isolation. The blood tests were within the normal range except forthe brain natriuretic peptide levels, which had increased to 110
pg / ml. Colonoscopy revealed a 10-mm large semipedunculated
tumor in the sigmoid colon (Fig.1). Subsequent pathologicalexamination of the biopsy specimens revealed that the tumor
Received for publication December 21, 2022 ; accepted March 12,2023.
Address correspondence and reprint requests to Takayuki Sano,MD, Department of Surgery, Saitama Cooperative Hospital, 1317
Kizoro, Kawaguchi-shi, Saitama, Japan and Fax : +81-48-296-7182.
E-mail : mz2ue4@bma.biglobe.ne.jp

Figure 1. Colonoscopy findings. A 10-mm large semipedunculated
tumor in the sigmoid colon.

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T. Sano, et al. Paraganglioma that caused sinus arrest

all-regional lymph node dissection. Intraoperatively, the lesion-like regional lymph node near the root of the inferior mesenteric artery appeared to be a metastatic lymph node with animpression of solidity (Fig. 3). During intraoperative lymph nodedissection, a spike in blood pressure of approximately 20 mmHg
was noted (Fig. 4). She had a PAF attack on postoperative day
1, she was given oral pilsicainide, and her electrocardiogram
became sinus rhythm. However, PAF attacks repeatedly developed ; thus, she began to take bisoprolol, bepridil, and apixaban.
Moreover, sinus arrest with presyncope repeatedly occurred
approximately 5 seconds after tachycardia on postoperative day
4 (Fig. 5). A pacemaker implantation was proposed ; however,the patient refused. Bepridil was discontinued, and amiodarone
was initiated. Afterward, sinus arrest did not occur. Circulatory
dynamics were maintained with medication, and she was discharged 15 days postoperatively.

The postoperative colon cancer evaluation was pT1pN0cM0,pStage Ⅰ. The resected specimen was a differentiated tubular
adenocarcinoma that infiltrated 2000 μm into the submucosa(Fig.6). Microscopically, large cells grew like a zellballen in thenodule submitted as a lymph node near the root of the inferior
mesenteric artery among the excised tissues as lymph nodesof the sigmoid mesocolon. Immunohistochemically, the nodule
was positive for chromogranin A. S100 showed a developed
sustentacular cell network (Fig. 7). Ki-67 staining indicatedFigure 2. Enhanced computed tomography findings. An axial image(a), a colonal image (b). Enhanced nodule-like regional lymph nodenear the root of the inferior mesenteric artery (arrow).

Figure 3. Intraoperative findings. The tumor of paraganglioma
resembles a metastatic lymph node with an impression of solidity(arrow).

Figure 4. Anesthesia record. Consistent with the timing of lymph node dissection, spike-like bloodpressure elevation is noted (arrow).

The Journal of Medical Investigation Vol. 70 August 2023
that the proliferating cells were almost undetectable. Regarding
catecholamine synthesis enzymes, tyrosine hydroxylase, dopa
decarboxylase, and dopamine beta-hydroxylase were expressed.
In contrast, phenylethanolamine N-methyltransferase, whichconverts norepinephrine to epinephrine, was not expressed (Fig.

5058). Since it was not suspected to be a paraganglioma, preoperative blood catecholamine levels were not tested ; however, thelevels were found to be normal postoperatively. Her symptoms ofheadache, sweating, and pallor improved postoperatively.

Figure 5. Electrocardiogram findings. Sinus arrest after tachycardia.

Figure 6. Histopathological findings of resected colon cancer. Macroscopic view (arrow) (a),a lower magnification image of the tumor after hematoxylin–eosin staining (b).

Figure 7. Histopathological findings of resected paraganglioma. A lower magnification imageof the nodule after hematoxylin–eosin staining (×12.5) (a), a higher magnification image (×400)(b). Immunohistochemical staining is positive for chromogranin A (×400) (c). S100 shows adeveloped sustentacular cell network (×400) (d).

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T. Sano, et al. Paraganglioma that caused sinus arrest

Figure 8. Functional immunohistochemistry of resected paraganglioma (×200).

The tumor shows positive for tyrosine hydroxylase (a), dopa decarboxylase (b), and dopamine
beta-hydroxylase (c), and negative for phenylethanolamine N-methyltransferase (d).

DISCUSSION
This case revealed two important clinical suggestions. Sinus
arrest can be developed after paraganglioma resection andsurgery with lymph node dissection may lead to the diagnosis ofparaganglioma.
First, sinus arrest can be developed on day 4 after paraganglioma resection. Several cases reported that patients withpheochromocytoma developed bradycardia, including sinus
arrest during the perioperative period (2, 3, 4). There was also
a report regarding circulatory failure during the resection ofparaganglioma (5). In our case, we managed circulation failure
although we did not reach the diagnosis of paraganglioma. Before the pathology diagnosis was made, sinus arrest developedon postoperative day 4, and there were no reports regarding
such a timing of sinus arrest after paraganglioma resection. In
our case, tyrosine hydroxylase, dopa decarboxylase, and dopamine beta-hydroxylase were expressed. Kimura reported that
dopamine beta-hydroxylase is constantly and strongly expressedin pheochromocytoma and paraganglioma regardless of thepresence or absence of catecholamine secretion (6). Kimura etal. reported that tyrosine hydroxylase is a rate-limiting enzyme
for catecholamine biosynthesis and that deficiency of tyrosinehydroxylase is an important feature of extra-adrenal nonfunctioning pheochromocytomas (7). Furthermore, the spike-likeincrease in blood pressure during lymph node dissection, i.e.,during near-tumor manipulation, suggests that catecholamine
secretion from the tumor might occur temporarily. The patientoriginally had paroxysmal headaches, sweating, and pallorand she noticed improvement in these symptoms after surgery.
Based on these reports and the facts, it is possible that our case
had a functional paraganglioma producing dopamine or norepinephrine ; however, epinephrine was not produced.
On the contrary, sinus arrest was reported as a complicationof pulmonary vein isolation (8). However, the only time sinus
arrest occurred after the patient underwent pulmonary vein

isolation was during the postoperative hospitalization for coloncancer, and no sinus arrest occurred for 2 years thereafter. The
patient was preoperatively controlled for PAF with antiarrhythmic agents and beta blockers. Catecholamine secretion could decrease with tumor resection, and the positive chronotropic effectcould subsequently decrease. Additionally, the patient resumed
oral administration, such as antiarrhythmic. Therefore, tumor
resection and oral medication resumption could contribute tosinus arrest. Moreover, bepridil is a multi-channel blocker witha better defibrillation effect than other antiarrhythmic drugs. Itexerts a strong defibrillation effect, especially for K channels, because it exerts a blocking effect on IKur, which is the cardiac ultrarapid activating outward potassium current specific to humanatrial myocytes. Bepridil has a stronger inhibitory effect on IKur
than amiodarone ; thus, taking amiodarone instead of bepridil
improves bradycardia and sinus arrest (9, 10, 11).
Second, surgery with lymph node dissection may lead to thediagnosis and treatment of paraganglioma. Since the 2017 World
Health Organization classification, pheochromocytomas andparagangliomas were considered as malignant neoplasms withvariable metastatic potential similar to epithelial neuroendocrine neoplasms (12). Surgery is the sole cure for pheochromocytomas and paragangliomas ; however, limited biochemical
and tumor control of the metastatic disease can be achieved
with treatments, such as 131I-metaiodobenzylguanidine treatment, chemotherapy, and radiation (13). In our case, endoscopic
findings suggested that the tumor depth reached the submucosa. The frequency of lymph node metastasis is only 10% in
pedunculated submucosal invasive colorectal carcinomas withinvasion depth ≧ 2000 μm to < 2500 μm (14). However, computed
tomography showed a lymph node-like structure with a strong
contrast effect near the root of the inferior mesenteric artery.
An all-regional lymph node dissection is the standard surgicaloption for Stage Ⅲ colon carcinoma according to the JapaneseSociety for Cancer of the Colon and Rectum Guidelines for theTreatment of Colorectal Cancer ; thus, an all-regional lymph

The Journal of Medical Investigation Vol. 70 August 2023
node dissection was performed. Consequently, surgery withlymph node dissection enabled the diagnosis and treatment ofparaganglioma in this case.
In conclusion, we reported a rare case of paraganglioma withcolon cancer that caused sinus arrest on day 4 after surgicalresection. Our case suggests that paraganglioma resection andthe resumption of antiarrhythmic drug may contribute to sinus
arrest. When arrhythmias affecting the circulation occur postoperatively, the presence of a catecholamine-producing tumor
should be considered in addition to cardiac disease.

CONFLICTS OF INTEREST
The authors have no conflicts of interest to disclose and received no financial support for this report.

ACKNOWLEDGEMENTS
We would like to thank Enago (www.enago.jp) for the English
language editing.
And we would like to thank Hironobu Sasano, Yuto Yamazaki(Department of Anatomic Pathology, Tohoku University Schoolof Medicine) for conducting the pathological examination.

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