J Ped Surg Case Reports 11 (2016) 22e24
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Multifocal appendiceal ganglioneuroma as the presenting symptom in a patient with PTEN hamartoma syndrome Katherine W. Gonzalez a, Jeffrey J. Dehmer a, Katherine M. Chastain b, Lei Shao c, Richard J. Hendrickson a, * a b c
Department of Surgery, Children’s Mercy Hospital, Kansas City, MO, USA Department of Hematology & Oncology, Children’s Mercy Hospital, Kansas City, MO, USA Department of Pathology, Children’s Mercy Hospital, Kansas City, MO, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 May 2016 Received in revised form 19 May 2016 Accepted 20 May 2016
Pediatric ganglioneuroma, although benign, is typically treated by surgical resection. However, it is often asymptomatic and an incidental finding. We present an incidental multifocal ganglioneuroma diagnosed within the appendix and the subsequent treatment for this lesion. This intraoperative discovery led to the diagnosis of PTEN (phosphatase and tensin homolog) hamartoma syndrome which had otherwise gone undiagnosed. Ó 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Key words: Ganglioneuroma Appendix Pediatric PTEN
Ganglioneuroma is a benign, well differentiated neoplasm within the spectrum of neuroblastic tumors. These tumors arise from neural crest cells and are characterized by mature ganglion cells. The clinical presentation is varied and imaging is often useful in characterizing the neoplasm [1]. Here we describe a case of incidental multifocal ganglioneuroma discovered following laparoscopic appendectomy and the subsequent postoperative oncologic evaluation leading to the eventual diagnosis of PTEN hamartoma tumor syndrome (PHTS). 1. Case report Patient is a 13-year old female with a history of sickle cell trait, asthma and Chiari malformation who presented with a 5 day history of abdominal pain. The pain was initially diffuse and then localized to the lower quadrants of the abdomen. The patient reported nausea, vomiting and constipation. On physical exam, the patient was non-tachycardic and afebrile. She had tenderness at McBurney’s point and a positive Roving’s sign. White blood cell * Corresponding author. Department of Surgery, Children’s Mercy Hospital, 2401 Gillham Road, Kansas City, MO 64108, USA. Tel.: þ1 816 234 3575; fax: þ1 816 983 6885. E-mail address:
[email protected] (R.J. Hendrickson).
count was elevated at 15.2 103/mL and anemia with a hemoglobin of 8.4 gm/dL. Abdominal ultrasound revealed a dilated, noncompressible appendix measuring 10 mm in diameter. The bowel wall appearance was normal. She was taken to the operating room for laparoscopic appendectomy for presumed appendicitis. An inflamed appendix was visualized in the right lower quadrant (Fig. 1). The appendix was mobilized and divided using an endoGIA stapler. The mesoappendix was similarly divided and the specimen removed. She was discharged uneventfully on postoperative day one. Final pathology revealed multifocal ganglioneuroma with microscopic nodular areas greater than 1.0 cm apart within the appendix. The largest lesion was located near the tip, polypoid in appearance, and measured 1.0 0.4 0.4 cm. The lesion was confined to the mucosa. Microscopic inspection displayed ganglion cells with surrounding spindle and inflammatory cells. There were no mitotic figures and the mucosal layer was intact (Fig. 2). Synaptophysin stains were positive in the ganglion and spindle cells. Due to the multifocal nature, further oncologic evaluation was recommended to rule out ganglioneuromatosis and other associated diseases. On further history and exam, the patient was noted to have macrocephaly, upper lid lipoma, a large lipoma of the sternocleidomastoid, a breast nodule, and skin findings consistent with
2213-5766/Ó 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.epsc.2016.05.009
K.W. Gonzalez et al. / J Ped Surg Case Reports 11 (2016) 22e24
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Further workup was initiated given the cancer predisposition syndrome. Urine catecholamines, serum metanephrines, and chromogranin A were within normal limits. Positron emission tomography (PET), metaiodobenzylguanidine scan (MIBG), and computed tomography of the neck, chest, abdomen and pelvis were performed. There was persistent expected inflammation in the postoperative region on PET scan, but this was not felt to represent residual ganglioneuroma, and MIBG and CT scans were negative. Thyroid ultrasound was normal. Urine catecholamines were done every 3 months for 1-year, followed by every 6 months for 2 year. Thyroid US and dermatology exams have been done yearly. Breast nodules are followed every 6 months with US. There has been no recurrence and no new symptoms corresponding to the patient’s PHTS, and the patient is now 18 months from surgical resection. Fig. 1. Intraoperative evaluation.
2. Discussion trichilemmomas. Her family history was significant for a variety of cancers including breast, uterine, and pancreatic, as well as possible thyroid issues. Thus the patient was referred for genetic testing and found to be heterozygous for a pathogenic variant in the PTEN gene, consistent with a diagnosis of PTEN hamartoma tumor syndrome. Due to the history of a Chiari malformation, a genome-wide microarray was also performed that showed no other clinically significant variants.
Fig. 2. Histologic examination of the mucosal ganglioneuroma; A) Displacement of dilated crypts (2 magnification) B) Many ganglion cells (40 magnification).
Peripheral neuroblastic tumors arise from neural crest cells, the origin of the sympathetic nervous system. As they become increasingly well differentiated, neuroblasts develop into neurons with surrounding stromal component. Neuroblastoma and ganglioneuroblastoma are stroma poor in contrast to the stroma rich ganglioneuroma [2]. Ganglioneuromas may be isolated or occur in conjunction with neurofibromatosis type 1, Cowden syndrome or PTEN hamartoma tumor syndrome, and multiple endocrine neoplasia type 2B [3,4]. Those that arise spontaneously are typically located in the mediastinum, retroperitoneum, colon and mesentery [5]. Ganglioneuroma has a good prognosis compared to its counterparts. However, even with biopsy it can be difficult to characterize these neuroblastic tumors. Traditionally, the treatment recommendation for ganglioneuroma is surgical excision. A large French review suggested appendectomy alone was a sufficient intervention for incidentally identified ganglioneuroma within the appendix (rather than hemicolectomy) [6]. However two retrospective reviews have challenged the necessity of any operative intervention. In one series of 24 ganglioneuroma patients, four were left with residual disease but had no recurrence after an average of 84 months. There were also 6 patients with postoperative complications including bowel obstruction, urinary retention, scoliosis, and Horner’s syndrome [7]. A separate series of 24 ganglioneuroma patients found 30% had postoperative complications; again Horner’s and intestinal obstruction were included. There were more complications for thoracic versus abdominal resection. There was no evidence of tumor progression and no mortality at follow up, average 33.5 months [8]. If surgical excision of a suspected ganglioneuroma is pursued, consideration must be given to intraoperative catecholamine release as there can be tumoral hypersecretion. One recent case report highlighted unexpected hypertension during excision requiring intravenous stabilization. It is unclear who requires preoperative alpha blockade at this time and further studies are needed [9], however if patients have symptoms suggestive of tumoral hypersecretion (episodic headaches, hypertension, sweating, and tachycardia) then further workup is crucial prior to operative procedures. PTEN hamartoma syndrome has variable manifestations arising from mutations in the PTEN gene, a tumor suppressor gene on chromosome 10. Patients typically have multiple hamartomas in more than one organ and an elevated malignancy risk [3]. In patients with incidentally diagnosed ganglioneuroma as part of the PTEN syndrome, colonoscopy should be performed as surveillance beginning at age 35 due to the increased risk for colorectal cancer [3]. Some authors propose additional surveillance of the thyroid, uterus and breast due to the association with these syndromes [10]. Because of our patient’s family history, she continues with yearly thyroid ultrasounds, and every 6 month breast ultrasounds.
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3. Conclusion Current recommendations for the treatment of appendiceal ganglioneuromas include surgical excision. However, consideration must be given for postoperative complications particularly in pediatric patients. PET scan may be useful to help assess the burden of disease peri-operatively. Thorough family history and clinical exam are imperative to ruling out cancer predisposition syndromes that may present with intestinal ganglioneuromas. Financial disclosure This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest There are no conflicts of interest. References [1] Alessi S, Grignani M, Carone L. Ganglioneuroblastoma: case report and review of the literature. J Ultrasound 2011 Jun;14(2):84e8.
[2] Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Hematol Oncol Clin North Am 2010 Feb;24(1):65e86. [3] Stanich PP, Pilarski R, Rock J, Frankel WL, El-Dika S, Meyer MM. Colonic manifestations of PTEN hamartoma tumor syndrome: case series and systematic review. World J Gastroenterol 2014 Feb;20(7):1833e8. [4] Herranz Bachillar MT, Barrio Andrés J, Pons F, Alcaide Suárez N, Ruiz-Zorilla R, Sancho Del Val L, et al. Diffuse intestinal ganglioneuromatosis an uncommon manifestation of Cowden syndrome. World J Gastrointest Oncol 2013 Feb;5(2):34e7. [5] Lockhart ME, Smith JK, Canon CL, Morgan DE, Heslin MJ. Appendiceal ganglioneuromas and pheochromocytoma in neurofibromatosis type 1. Am J Roentgenol 2000 Jul;175(1):132e4. [6] de Lambert G, Lardy H, Martelli H, Orbach D, Gauthier F, Guérin F. Surgical management of neuroendocine tumors of the appendix in children and adolescents: a retrospective French multicenter study of 114 cases. Pediatr Blood Cancer 2016 Apr;63(4):598e603. [7] Sánchez-Galán A, Barrena S, Vilanova-Sánchez A, Martín SH, Lopez-Fernandez S, García P, et al. Ganglioneuroma: to operate or not to operate. Eur J Pediatr Surg 2014 Feb;24(1):25e30. [8] Retrosi G, Bishay M, Kiely EM, Sebire NJ, Anderson J, Elliott M, et al. Morbidity after ganglioneuroma excision: is surgery necessary? Eur J Pediatr Surg 2011 Jan;21(1):33e7. [9] Gupta C, Abid N, Bailie K, Terris M, Dick A, McCarthy A. The need for preoperative a-adrenergic blockage for ganglioneuroma excision. Paediatr Anaesth 2014 Mar;24(3):347e9. [10] Fiori E, Pozzessere C, Lamazza A, Leone G, Borrini F, Schillaci A, et al. Endoscopic treatment of ganglioneuroma of the colon associated with a lipoma: a case report. J Med Case Rep 2012 Sep;6:304.
