Von Hippel–Lindau syndrome with multiple neuroendocrine neoplasms as the initial manifestation - a case report of an elusive presentation

doi:10.21203/rs.3.rs-2739711/v1

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Case Report

Von Hippel–Lindau syndrome with multiple neuroendocrine neoplasms as the initial manifestation - a case report of an elusive presentation

https://doi.org/10.21203/rs.3.rs-2739711/v1

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Background Von Hippel–Lindau (VHL) syndrome is a rare genetic tumor characterized by the recurrent development of multiple benign or malignant tumors involving multiple organs throughout a patient’s life. It is easy to precisely diagnose when the patient has characteristic central nervous system hemangioblastomas (CNS-H) as the main manifestation.VHL disease can be classified into type 1,2A,2B, and 2C based on the type of gene mutation and tumor occurrence.

Case presentation This paper presents a case of a 29-year-old female patient who presented with multiple retroperitoneal tumors as the primary manifestation of her condition. Following surgical intervention, pathological examination confirmed the presence of multiple paraganglioma-pheochromocytoma (PCC/PGL) and pancreatic neuroendocrine tumors. Subsequent brain magnetic resonance imaging (MRI) revealed the presence of a small, highly vascularized nodule in the cerebellum, which was strongly indicative of a hemangioblastoma based on imaging characteristics. The VHL germline mutation was confirmed through molecular testing, and the final diagnosis was multiple neuroendocrine neoplasms in VHL type 2B.

ConclusionThe patient had VHL syndrome with multiple neuroendocrine tumors as the initial manifestation, which can be easily overlooked during clinical and pathological diagnosis.Therefore, young patients with multiple tumors should essentially be thoroughly examined to determine the relationship between the diseases. Furthermore, pathologists need to be knowledgeable about tumors that arise from different gene mutations and consider the patient’s family history. This strategy will enable early diagnosis, timely treatment, and effective prevention of this disease.

VHL

pheochromocytoma

paraganglioma

neuroendocrine tumors

Von Hippel–Lindau (VHL) disease is a rare familial genetic tumor syndrome that involves multiple organs and results in the development of multiple tumors. The most specific pathological change associated with VHL disease is hemangioblastoma in the central nervous system (CNS), but patients with VHL disease can also develop other tumors such as pheochromocytoma (PCC), endolymphatic sac tumors, pancreatic neuroendocrine tumors, renal cell carcinoma (RCC), etc [1]. Other rare tumors, such as multiple lung adenocarcinoma, have also been reported [2]. This genetic tumor syndrome has a prevalence rate of approximately one in 36,000–50,000 people in the population, with a median onset age of 26 years [1]. This article presents a rare case of a patient with VHL disease with multiple neuroendocrine tumors as the primary manifestation. Additionally, a comprehensive review of the literature is provided to enhance the understanding of the clinicopathological characteristics of this disease.

A 29-year-old female patient was admitted to the hospital for dizziness and palpitation in 1 month without any apparent cause. The patient did not report any medical history of hypertension, diabetes, or coronary heart disease and had no history of prior surgical procedures or injuries. Her father had died of an “intracranial tumor” over 20 years ago, while her eldest sister had died of “adrenal disease” and “high blood pressure” during pregnancy over 10 years ago. The details of their conditions are unknown. Laboratory examination revealed free methylnorepinephrine levels of 2,894.9 pg/mL. The abdominal enhanced computed tomography (CT) showed bilateral adrenal glands (Fig. 1A) with retroperitoneal vena cava anterior nodules (Fig. 1B) and multiple nodules near the uncinate process of the pancreas with lumpy heterogeneous and obviously enhanced lesions (Fig. 1C). Based on these findings, the preliminary clinical diagnosis was multiple PCC. The multiple tumors were successfully laparoscopically resected after thorough preoperative preparation. The patient underwent postoperative magnetic resonance imaging (MRI) of the head, which revealed a small abnormally enhancing nodule in the right cerebellar hemisphere with a diameter of 3.6 mm (Fig. 2).

Postoperative pathological examination of the left adrenal gland and tumor showed two pieces of soft grayish-yellow and gray-brown tissue with clear boundaries. The larger and smaller tissue pieces measured 60 mm × 50 mm × 40 mm and 50 mm × 30 mm × 25 mm, respectively (Fig. 3A). The tumor tissue from the right adrenal gland area was also a grayish-yellow, gray-brown with clear boundaries, and measured 35 mm × 20 mm × 13 mm, and with a cut surface similar to that of the previous samples. The tumor of the retroperitoneal vena cava anterior is a piece of grayish yellow and grayish brown tissue with a size of 18mm × 16mm × 13mm, a clear boundary, same section as before. The tumor tissue next to the uncinate process of the pancreas was gray-brown, measuring 40 mm × 30 mm × 23 mm with an unclear boundary and a hard grayish-white or gray-brown cut surface. The morphological appearance of the bilateral adrenal tumors and the retroperitoneal vena cava anterior tumor under the microscope was consistent with immunohistochemical analysis(Fig. 3 B-H) . The tumors cells were arranged in spherical tufts, surrounded by rich thin-walled capillaries. Furthermore, the immunohistochemical analysis revealed tumor cells that were positive for chromogranin A (CgA) and synaptophysin (Syn) but negative for cytokeratin (CK). Supporting cells were S-100 positive.

The tumor next to the uncinate process of the pancreas showed cells arranged in spherical tufts surrounded by thin-walled capillaries. The cells exhibited a mild tumor cell morphology and rare mitotic figures (approximately 3 mitoses /2mm²), and the surrounding tissue showed collagenization and calcification(Fig.4A). The immunohistochemical analysis results showed positive staining for CK(Fig.4B), CgA(Fig.4C), and Syn, while the Ki67 labeling index was approximately 5%(Fig.4D). The pathomorphological diagnosis revealed that the patient had PCC in both adrenal glands, paraganglioma (PGL) in the retroperitoneal vena cava anterior, and the tumor located next to the uncinate process of the pancreas was a neuroendocrine tumor G2.

The genetic test results of the blood samples revealed the presence of a heterozygous missense mutation, c.499C>T:p.R167W, in the VHL gene. This mutation replaces C at the 499th base of the cDNA with a T, resulting in the substitution of the amino acid residue arginine with tryptophan at the 167th codon.

The final diagnosis of the pathology indicates the presence of multiple neuroendocrine neoplasms in Von Hippel-Lindau Syndrome Type 2B.

The current consensus suggests that over 40% of PCC/PGL cases have a genetic predisposition [3, 4]. The patient in this case study was 29 years old and received a postoperative pathological diagnosis of multiple PCC/PGL. A review of the patient’s family history revealed that her father had an intracranial tumor, and her sister had a history of hypertension and adrenal gland disease. Although the precise diagnoses of her relatives were unclear, these findings suggest a potential genetic predisposition to the disease. Currently, over 12 susceptibility genes have been identified, and most familial tumors are caused by pathogenic variants of the succinate dehydrogenase (SDH) subunit genes or in VHL [4]. The SDHX gene, which encodes SDH, is responsible for up to 30% of hereditary PCC/PGL mutations and is most frequently associated with these mutations. SDH is a membrane-bound mitochondrial complex with essential functions in two metabolic pathways, the citric acid cycle (TCA) and oxidative phosphorylation. The disruption and inactivation of this complex can result in cellular respiratory dysfunction, which can trigger the development of tumors [5]. In addition to PCC/PGL, tumors associated with SDHX mutations include renal cell carcinoma, gastrointestinal stromal tumors, etc. Moreover, the VHL gene accounts for a mutation rate of 4%–7% in hereditary PCC/PGL and is a tumor suppressor gene that encodes the VHL protein[4]. The hypoxia-inducible factor 1 subunit alpha (HIFA) protein plays a critical role in the hydroxylation process [6]. VHL gene mutation results in HIFA accumulation that leads to abnormal cytokine release and promotes angiogenesis, which may significantly contribute to the high vascularity of VHL gene-related tumors. Additionally, HIFA is a nuclear protein with a transcriptional activity that regulates nearly 100 target genes, exerting a critical influence on cell proliferation and differentiation [7]. Various tumors are associated with VHL, the most notable being CNS-hemangioblastoma (CNS-H). Moreover, the rates of RCC and pancreatic neuroendocrine tumors (PNETs) are as high as 70% and 56%, respectively [4]. Two other common genetic mutations found in PCC/PGL are rearranged during transfection (RET) and neurofibromatosis type 1 (NF1), which account for 6% and 3% of the genetic mutation rates in PCC/PGL, respectively [4]. RET is involved in numerous different physiological and developmental functions. Alterations in RET mutations influence disease in a variety of organ systems, from Hirschsprung’s disease and multiple endocrine neoplasia 2 (MEN2) to papillary thyroid carcinoma (PTC) and non-small cell lung cancer (NSCLC) [8]. The NF1 gene encodes neurofibromin, which is one of the primary negative regulatory factors of the Ras protein. Neurofibromin 1 (NF1) mutations cause an autosomal dominant genetic susceptibility syndrome known as neurofibromatosis type 1 [9].

The patient was diagnosed with multiple PCC/PGL with pancreatic neuroendocrine tumors. However, no space-occupying lesions were identified in other organs, and we wondered whether the patient exhibited mutations in the above-mentioned genes. Reviewing the patient’s family history, given his father’s death from an intracranial tumor, we recommended that the patient undergo an intracranial MRI after surgery. Sure enough, a tiny nodule rich in blood vessels was found in the patient’s cerebellum, and the imaging features highly suggested that it was hemangioblastoma. Compared with the tumor prone to occur after the above gene mutations, it is highly suggested that the patient is familial VHL disease. After gene testing, it is confirmed that there is a VHL germline mutation.

Over 300 different types of mutations have been identified in the VHL gene, mostly consisting of missense/nonsense mutations and large deletions [10]. VHL disease can be classified into type 1 and 2 based on the type of gene mutation and tumor occurrence. Type 1 disease is likely caused by mutations leading to severe disruption of protein activity, including deletions, nonsense mutations, and other microdeletions/insertions. This subtype is associated with a high risk of CNS-H and RCC but a low risk of PCC/PGL [11-12]. Type 2 VHL disease is commonly caused by missense mutations and can be further classified into three subtypes: 2A, 2B, and 2C. The mutation sites of type 2A and 2B are located at codons 169 and 167, respectively. Patients with these two subtypes often have PCC/PGL and CNS-H. The biggest difference is that type 2B is also associated with a high risk of RCC. Rare kindreds with only pheochromocytomas were found to have specific missense mutations at VHL codons 238 and 259 and other rare point mutations and were classified as VHL type 2C [12-13]. After comparing the gene mutation sites and clinical manifestations of different subtypes of VHL, the disease, in this case, was determined to be consistent with VHL type 2B. Because this subtype is associated with a high risk of RCC, the follow-up observation of the patient should include highly vigilant monitoring for the occurrence of renal tumors.

In conclusion, VHL disease is a rare genetic syndrome with various clinical manifestations. Most reported cases have been diagnosed with CNS-H as the primary manifestation. This paper presents a case of VHL syndrome where the patient exhibited multiple neuroendocrine tumors as the initial manifestation, which could be easily overlooked during clinical and pathological diagnosis. Thus, where a patient presents with multiple tumors and an early age of onset, it is essential to thoroughly investigate the relationship between the diseases. Furthermore, it is important to be knowledgeable about tumors that arise from different gene mutations and to consider the patient’s family history. This strategy will enable early diagnosis, timely treatment, and effective prevention of this disease.

Acknowledgments: We would like to thank Editage (www.editage.cn) for English language editing.

Authors’ contributions: Ying Chen and Deyu Guo conceived and designed the case report. Ning Zhou, Hao Tang, and Xin He made the pathological diagnosis of the patient. Wenfeng Xu and Zhongjiao Chen contributed to figure collection, and Fanrong Wang rechecked it. Yuanliang Su provided imaging data.All authors contributed to the writing of the paper and approved the final version for publication.

Conflicts of interest: None

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Consent to participate and statement of ethics: For this study, photos, and writing of our manuscript, the patient or the patient’s parents have given their written informed consent. This study was approved by the ethics committee of Guiqian International General Hospital.

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No competing interests reported.

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Von Hippel–Lindau syndrome with multiple neuroendocrine neoplasms as the initial manifestation - a case report of an elusive presentation

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