Early Screening and Identification of an Asymptomatic Pheochromocytoma in a Child with Von Hippel-Lindau: A Case Report

Von Hippel-Lindau (VHL) is a rare autosomal dominant genetic condition which results from a pathologic variant or deletion in the VHL gene [1]. The annual birth incidence of VHL internationally ranges from roughly 1 in 36,000–91,000 live births [2]. Patients diagnosed with VHL have increased risk of tumor development over the course of their lives, including tumors in the central nervous system, retina, and abdomen. Tumor types associated with VHL syndrome include hemangioblastomas, endolymphatic sac tumors, renal cysts, renal cell carcinoma, pheochromocytomas (PCCs), pancreatic cysts, pancreatic neuroendocrine tumors, and genitourinary cystadenomas [3]. PCCs affect 10–30% of patients with the diagnosis of VHL [4, 5]. Patients found to have a VHL syndrome due to a pathologic missense variant are at higher risk for a PCC [6, 7]. These tumors are important to identify and address as they result in increased sympathetic activity including life-threatening hypertension [8].

A number of groups have established guidelines for tumor surveillance in VHL. These guidelines all include screening recommendations for PCC; however, they are not consistent in their age of onset, Table 1. The literature is limited on patients with VHL under the age of 5 being diagnosed with PCC. There are reports of three children with VHL, between the ages of 2 and 4 years old, diagnosed with PCC due to acute onset of PCC-related symptoms [7, 9, 10]. There are currently no reports in the literature of asymptomatic patients under the age of 5. Here we present a case of a 4-year-old asymptomatic female with VHL who had a PCC identified on screening laboratories that was able to undergo adrenal sparing surgery due to its small size. The CARE Checklist has been completed by the authors for this case report, attached as online supplemental material (for all online suppl. material, see https://doi.org/10.1159/000541527).

A 4-year-old female presented to the pediatric Cancer Predisposition Clinic for evaluation due a maternal history of VHL. Mother was initially diagnosed with a PCC in her mid 30s, presenting with classic symptoms of tachycardia, diaphoresis, and hypertension. She underwent resection and was appropriately counseled to have germline genetic testing completed. Her testing was positive for a pathologic missense variant in VHL c.524A>G (p.Tyr175Cys). Subsequently, many family members including our patient all underwent testing for this pathologic variant. Our patient, along with maternal grandmother, two maternal aunts, and one sibling, tested positive for the pathologic variant (Fig. 1). After VHL tumor surveillance was initiated in the mother and other family members, additional tumors were identified including a PCC in maternal aunt and papillary thyroid cancer and spinal hemangioblastomas in the patient’s mother.

Following the pediatric ACCR guidelines [5], the patient underwent plasma metanephrine screening at her initial visit. This screening laboratory was abnormal and confirmed with a 24-h urine metanephrine collection, which demonstrated elevated normetanephrine and metanephrine levels, detailed in Table 2. Based on these results, a Ga-68 DOTATATE PET was obtained that revealed a T2 hyperintense mass in the anterior right suprarenal region measuring ∼1.5 cm. Our institution did not have 18F-DOPA PET easily available at this time, which is sometimes used in this clinical scenario given its high detection rates for PCC [13]. However, the Ga-68 DOTATATE PET provided the diagnostic information needed to proceed with treatment planning in our case. Her laboratory results and imaging were reviewed by a multidisciplinary tumor board team including pediatric oncology, pediatric cancer predisposition specialists, general surgery, and radiology, the tumor board recommendation was to proceed with surgical resection with cortical-sparing adrenal tumor resection.

Throughout this work up, the patient remained asymptomatic, normocardic, and normotensive. She underwent preoperative alpha blockade with doxazosin over the course of 4 weeks. She then underwent laparoscopic cortical-sparing adrenal tumor resection utilizing indocyanine green (ICG) for tumor localization and sparing. In this case, 5 mg of ICG was administered intravenously after presumptive intraoperative visualization of the right adrenal gland and mass. The normal cortical adrenal parenchyma fluoresced with the 1.9 cm pheochromocytoma demonstrating hypofluorescence. Intraoperative ultrasound is another tool that can be used for partial adrenalectomy; however, the diameter of the ports used in this case (3 mm) was unable to accommodate the use of the ultrasound probe, so ICG was utilized alone with success to minimize need for intraoperative instrument exchange. In addition, the ICG facilitated identification of the tumor margin, allowing laparoscopic complete resection with preservation of sufficient normal adrenal parenchyma and the main adrenal vasculature. After resection of the pheochromocytoma, additional ICG administration confirmed perfusion of the residual adrenal gland with bright ICG fluorescence. The patient remained hemodynamically stable throughout the operation. Postoperatively, she was observed overnight and discharged the following day. Final pathology was classic pheochromocytoma with negative margins. Metanephrine levels normalized at the time of the patient’s 3-month follow-up visit and have remained normal at her 1-year post-surgery follow-up.

Pheochromocytomas can be one of the early tumors to develop in pediatric patients with VHL. Genotype-phenotype correlations are being identified in the VHL population, which are beginning to define more specific risks to patients based on their underlying pathologic variant [6]. There is a clearly identified increased risk of PCC reported in patients with missense variants in VHL [7]. Currently, while the genotype-phenotype correlations continued to be identified, it is recommended that all patients undergo the same screening [5]. However, there remains some discrepancy and variability across guidelines, particularly in regard to when to start screening for pheochromocytomas.

Early identification of tumors that impacts treatment and outcomes is the primary driver for the screening recommendations in cancer predisposition syndromes. Monitoring with laboratories is a relatively easy way to screen for these tumors. Elevated normetanephrine levelsare a well-established biomarker to indicate the presence of pheochromocytomas in patients with VHL, as was seen in our patient [14]. When PCCs are identified at a small size they are more amendable to partial adrenalectomy, which is important in both young patients and patients with predisposition for future adrenal tumor development [15]. A systematic review found that a majority of patients (88%) were steroid independent following laparoscopic partial adrenalectomy [16]. Patients with PCCs are known to have a higher risk for cardiovascular events when diagnosis is delayed [17]. To reduce pre- and postsurgical complications and increase the likelihood of adrenal preserving resection, early identification of PCCs is ideal.

Laparoscopic adrenalectomy has become the standard of care for resection of adrenal lesions [18, 19]. The addition of ICG illumination has been recently shown to be safe, feasible, and beneficial in localization of various tumors throughout the body. ICG is a sterile, anionic, water-soluble dye developed in 1955. When given intravenously, ICG dye nearly completely binds plasma proteins, serving as a contemporaneous intravascular contrast (30–75 second lag), and is eliminated by hepatic uptake and biliary excretion [20]. The contrast between the hyperfluorescent, well-vascularized adrenal tissue and surrounding hypofluorescent tissue allows for easier gland localization. While the technique for ophthalmology, neurosurgery, thoracic surgery, colorectal and hepatobiliary surgery has been well characterized, there are limited data for adrenalectomy and especially for pediatric pheochromocytoma – the technique and experience are limited to case reports. In the adult literature, pheochromocytomas have been described in conflicting reports as either isofluorescent to adrenal tissue or hypofluorescent [19, 21]. The most recent and largest (n = 46) characterization of fluorescence patterns describes approximately 50% of pheochromocytomas as exhibiting fluorescence but does not describe inclusion of any pediatric patients [22]. This technique was used successfully in our patient and aided in successful laparoscopic cortical-sparing adrenal tumor resection.

This case provides support for early implementation of screening for pheochromocytomas in children with VHL under the age of 5. As genotype-phenotype correlations become more established, there may be higher risk groups identified that more fully warrant earlier screening (e.g., those with missense VHL variants) but until that data mature, this early screening should be considered for all pediatric patients with a VHL diagnosis.

Ethical approval is not required for this study in accordance with local guidelines. Written informed consent was obtained from the guardian of the patient for publication of this case report and any accompanying images.

The authors have no conflicts of interest to disclose.

There was no funding support for this research report.

Kristine Schmeling, DO, and Jennifer Schuh, MD: writing – original draft; Dave Lal, MD, and Kerri Becktell, MD: conceptualization and writing – review and editing.

All data generated during this study are included in this article. Further inquires can be directed to the corresponding author.