Imaging Pearls ❯ Syndromes in CT ❯ Von Hippel Lindau Syndrome
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- “Patients with VHL are susceptible to developing a variety of benign and malignant tumors involving multiple organ systems. The most prevalent clinical manifestation of VHL is hemangioblastoma (occurring in the brain, spinal cord, or retina), observed in approximately 40-80% of individuals. Clinical manifestations correlate with the tumor’s location and size, presenting symptoms like headache, paresthesia, and dizziness; laboratory tests may reveal erythrocytosis . Moreover, VHL may affect the pancreas, adrenal glands, kidneys, and reproductive organs, leading to the development of pNENs, pancreatic cysts, pancreatic cystadenomas, clear cell renal cell carcinomas, renal cysts, pheochromocytomas, or paragangliomas. ”
Genetic syndromes associated with pancreatic neurendocrine neoplasms and imaging diagnostic strategies
Jiawei Liu et al.
Abdominal Radiology https://doi.org/10.1007/s00261-024-04764-0
- “Von Hippel–Lindau (VHL) disease is a rare autosomal dominantly inherited familial syndrome with an incidence of 2–3 cases per 100,000 population . Approximately 65–75% of patients with VHL as a component of multi-visceral tumors have some form of pancreatic lesions (cystic and solid tumors) .The incidence of pancreatic lesions among the VHL population varies considerably among different kindred. An incidence rate of 37% in Hawaiian VHL kindred was reported compared with 0% in Newfoundland VHL kindred. The pancreatic lesions can be benign or malignant, can produce symptoms due to the mass effect or hormonal activity, can present as recurrent multifocal lesions, or be associated with lesions involving several organs simultaneously. Thus, it is of paramount importance to understand the management of various pancreatic manifestations of VHL.”
Pancreatic manifestations in von Hippel–Lindau disease: A case report
Subhashini Ayloo, Michele Molinari
International Journal of Surgery Case Reports 21 (2016) 70–72 - “Patients with VHL disease are found to have retinal angiomas, renal cell carcinomas, pheochromocytomas, CNS hemangioblastomas, tumors of the inner ear and epididymis, cystic lesions of the ovaries, and cystic and endocrine tumors of the pancreas. The clinical diagnostic criteria, as proposed in 1964 by Melmon and Rosen for VHL disease, are as follows: (i) greater than one CNS hemangioblastoma; (ii) CNS hemangioblastoma in combination with visceral manifestation of VHL disease; and (iii) any manifestation and a known family history of VHL disease.”
Pancreatic manifestations in von Hippel–Lindau disease: A case report
Subhashini Ayloo, Michele Molinari
International Journal of Surgery Case Reports 21 (2016) 70–72 - “Pancreatic neuroendocrine tumors (pNETs) are found in 5–17% of VHL disease patients [8]. Often of islet cell tumor origin and often found in women (66%) at a median age of 38 years, 17–25% of pNETs have metastasized at the time of diagnosis. On the other hand, most cystic manifestations of VHL disease are benign, but differentiation of these lesions from premalignant cystic lesions, such as intraductal papillary mucinous neoplasms or mucinous cystadenomas is mandatory. Because renal cell carcinoma is one of the components of VHL disease, metastatic lesions to the pancreas should also be considered in the differential diagnosis.”
Pancreatic manifestations in von Hippel–Lindau disease: A case report
Subhashini Ayloo, Michele Molinari
International Journal of Surgery Case Reports 21 (2016) 70–72 - Pancreatic Lesions in VHL
- IPMN
- Serous cystadenoma
- PNET
- Metastatic RCC to pancreas
- “In VHL, CNS HBs most commonly occur in the cerebellum (44%–72%), followed by the spinal cord and brainstem The mean age of onset is 33 years (range, 9–78 years). Patients with cerebellar HB may develop gait ataxia, dysmetria, headaches, diplopia, vertigo, and emesis .It should be noted that in many patients, the symptoms may be caused by the cyst or syrinx associated with the tumor rather than the tumor itself.”
Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Com- prehensive State-of-the-Art Review
Ganeshan D et al.
RadioGraphics 2018 (in press) - Spinal HBs manifest in 13%–50% of cases of VHL. The mean age of onset is 33 years (range, 11–66 years). Although any part of the spinal canal can be affected, spinal HBs are more common in the thoracic and cervical cord. Radiculopathy and myelopathy-associated symptoms predominate in spinal HB, including hyperesthesia, weakness, gait ataxia, hyperreflexia, pain, incontinence, and rarely quadriplegic.
Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Com- prehensive State-of-the-Art Review
Ganeshan D et al.
RadioGraphics 2018 (in press) - “The differential diagnosis includes metastasis, ependymoma, meningioma, arteriovenous malformation, or arteriovenous fistula. Surgical resection and γ-knife radiation therapy may be offered as treatment options in the management of these tumors.”
Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Com- prehensive State-of-the-Art Review
Ganeshan D et al.
RadioGraphics 2018 (in press) - “Von Hippel–Lindau syndrome (VHL) is a hereditary tumor syndrome, arising owing to germline mutations in the VHL tumor sup- pressor gene, located on the short arm of chromosome 3.VHL is an autosomal dominant disorder, with a prevalence of around one in 36 000 and one in 50 000 live births. Around 80% of patients with VHL inherit the disorder from an affected parent, while it may arise de novo in 20%.The mean age of initial tumor diagnosis in VHL is 26 years (range, 1–70 years).”
Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Com- prehensive State-of-the-Art Review
Ganeshan D et al.
RadioGraphics 2018 (in press) - VHL is a highly penetrant disease, with more than 90% of patients developing symptoms by 65 years of age. Patients may develop multiple benign and malignant tumors involving various organ systems, including retinal hemangioblastomas (HBs), central nervous system (CNS) HBs, endolymphatic sac tumors, pancreatic neuroendocrine tumors (NETs), pancreatic cystadeno- mas, pancreatic cysts, clear cell renal cell carcinomas (RCCs), renal cysts, pheochromocytomas, paragangliomas, and epididymal and broad ligament cystadenomas.”
Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Com- prehensive State-of-the-Art Review
Ganeshan D et al.
RadioGraphics 2018 (in press)
- “Von Hippel–Lindau syndrome (VHL) is a hereditary tumor syndrome, arising owing to germline mutations in the VHL tumor suppressor gene, located on the short arm of chromosome 3. VHL is an autosomal dominant disorder, with a prevalence of around one in 36 000 and one in 50 000 live births. Around 80% of patients with VHL inherit the disorder from an affected parent, while it may arise de novo in 20%.The mean age of initial tumor diagnosis in VHL is 26 years (range, 1–70 years).” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- “VHL is a highly penetrant disease, with more than 90% of patients developing symptoms by 65 years of age. Patients may develop multiple benign and malignant tumors involving various organ systems, including retinal hemangioblastomas (HBs), central nervous system (CNS) HBs, endolymphatic sac tumors, pancreatic neuroendocrine tumors (NETs), pancreatic cystadenomas, pancreatic cysts, clear cell renal cell carcinomas (RCCs), renal cysts, pheochromocytomas, paragangliomas, and epididymal and broad ligament cystadenomas.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- “Patients may develop multiple benign and malignant tumors involving various organ systems, including retinal HBs, CNS HBs, endolymphatic sac tumors, pancreatic NETs, pancreatic cystadenomas, pancreatic cysts, clear cell RCCs, renal cysts, pheochromocytomas, paragangliomas, and epididymal and broad ligament cystadenomas.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- “Missense mutations (27%–52%) are the most common type of germline mutations reported in VHL. However, a wide spectrum of germline mutations have been described, including frame- shift mutations, nonsense mutations, large or microdeletions, gene rearrangements, in-frame deletions or insertions, and splice site mutations. Somatic inactivation of the wild-type allele may arise owing to allelic loss, hypermethylation, or point mutations.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- “VHL is associated with multiple tumors affecting various organs. A VHL diagnosis can be made clinically when the characteristic clinical history and findings have manifested. The clinical diagnosis of VHL can be made in the following circumstances: (a) in a patient with a family history of VHL and at least one of the characteristic VHL-related tumors (eg, retinal HBs, CNS HBs, clear cell RCCs, pancreatic NETs, and endolymphatic sac tumors); (b) in the presence of two or more retinal or CNS HBs; or (c) in the presence of one retinal or CNS HB, plus at least one of the characteristic VHL-related visceral tumors, excluding renal and epididymal cysts.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- Table 1: VHL Manifestations
• Retina
• Retinal HBs
• CNS
• Cerebellar and spinal HBs
• Head and Neck
• Endolymphatic sac tumors
• Pancreas
• Pancreatic cysts
• Serous cystadenomas
• Pancreatic NETs
• Kidney
• Renal cysts
• Clear cell RCCs
• Adrenal gland
• Pheochromocytoma - “Multicentric renal cysts and clear cell RCCs may manifest in more than two-thirds of VHL cases. Even grossly normal renal parenchyma may demonstrate hundreds of microscopic renal cysts and tumors. The cystic lesions may be a combination of simple benign cysts, complex atypical cysts with epithelial hyperplasia/cytologic atypia, or cystic RCCs.The number and size of the cysts in VHL have not been shown to be associated with malignant potential. Patients may be asymptomatic despite the manifestation of a large number of cysts.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- “VHL is characterized by the development of a clear cell RCC histologic subtype. The prevalence of RCC in VHL varies from 25% to 45%, with the frequency increasing with age. VHL-related RCCs tend to develop at a much younger age compared with that of sporadic RCCs. The mean age of onset for VHL-related RCCs is 39 years (range, 13–70 years), and clear cell RCCs are frequently bilateral.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- “It should be noted that bilateral clear cell RCCs on their own are not diagnostic of VHL, as other hereditary renal tumor syndromes and rarely even sporadic tumors may manifest as bilateral multifocal tumors. However, the presence of bilateral or multifocal clear cell RCCs or tumors in patients younger than 50 years of age is an indication for VHL genetic screening.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- “Patients with VHL can develop pancreatic cysts, serous cystadenomas, and pancreatic NETs. Pancreatic cysts are com- mon in VHL and may be seen in 42% of cases (range, 7%–72%). These are typically multiple and usually asymptomatic. Interestingly, pancreatic cysts may be the only manifestation in about 12% of patients at the time of initial VHL diagnosis.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- “Serous cystadenomas occur in 11% of patients (range, 9%–17%) At histopathologic analysis, serous cystadenomas demonstrate well- demarcated multilocular clusters of small cysts, separated by thin fibrous septa. These cystic lesions are lined by cuboidal cells, without mucin or papillary structures. Both pancreatic cysts and serous cystadenomas tend to be asymptomatic, but larger lesions may cause nonspecific abdominal pain, and extensive cystic lesions replacing most of the pancreas may result in pancreatic insufficiency and diabetes mellitus.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- “Pancreatic NETs develop in 15% of patients with VHL (range, 9%–17%) . The mean age of onset is 35 years, but NETs have been reported in patients as young as 13 years of age. About 53% of VHL-associated pancreatic NETs are multiple. Although any part of the pancreas may be involved, they are more common in the head and uncinate process of the pancreas. Pancreatic NETs associated with VHL manifest at a much younger age compared with that of sporadic NETs, and they are more commonly multifocal.The vast majority of these pancreatic NETs are nonfunctional tumors.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- “Considering that less than 20% of pancreatic NETs associated with VHL are malignant, a conservative approach with a “watch-and-wait” strategy is an important part of the management of these tumors. Studies have shown that about 40% of NETs in VHL may be stable or even decrease in size. Surgical resection may be appropriate for pancreatic NETs in VHL when the tumor size is greater than 3 cm (or >2 cm for lesions in the head of the pancreas), the tumor doubling time is less than 500 days, there is a mutation in exon 3, or there is suspicion of regional nodal metastases.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- “Adrenal pheochromocytomas may develop in 25%–30% of VHL cases The mean age of onset is 27 years (range, 5–58 years). VHL- associated pheochromocytomas manifest more commonly in boys , and 20%–50% may be bilateral.The risk of developing a second tumor increases with age, with studies reporting a 50% risk of a second tumor at 30 years after the initial diagnosis; 1%–5% of these tumors are malignant.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- “Extra-adrenal pheochromocytomas/paragangliomas may be seen in 15% of VHL cases at various sites along the sympathetic chain in the abdomen, thorax, or head and neck. Patients may be asymptomatic or experience classic symptoms such as paroxysmal or refractory hypertension, palpitations, headaches, sweating, and hypertensive crises. A diagnosis of a pheochromocytoma is usually confirmed on the basis of biochemical abnormalities, including elevated plasma metanephrine and 24-hour urinary catecholamine levels.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
- “VHL is a familial cancer syndrome caused by a mutation in the VHL tumor suppressor gene, mapped on human chromosome 3p25. Patients with VHL are at risk for developing numerous benign and malignant tumors that affect multiple organs. While some of the VHL-related manifestations such as renal and pancreatic cysts are frequently asymptomatic, other manifestations such as retinal and CNS HBs, RCCs, pheochromocytomas, and pancreatic NETs may be associated with significant morbidity and mortality. Early detection plays a key role in the optimal management of this condition.” Tumors in von Hippel–Lindau Syndrome: From Head to Toe—Comprehensive State-of-the-Art Review Ganeshan D et al. RadioGraphics 2018 (in press)
