miércoles, 6 de marzo de 2019

Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®) 2/3 —Health Professional Version - National Cancer Institute

Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Pancreatic manifestations
VHL patients may develop multiple serous cystadenomas, pancreatic NETs, and simple pancreatic cysts.[1] VHL patients do not have an increased risk of pancreatic adenocarcinoma. Serous cystadenomas are benign tumors and warrant no intervention. Simple pancreatic cysts can be numerous and rarely cause symptomatic biliary duct obstruction. Endocrine function is nearly always maintained; occasionally, however, patients with extensive cystic disease requiring pancreatic surgery may ultimately require pancreatic exocrine supplementation.
Pancreatic NETs are usually nonfunctional but can metastasize (to lymph nodes and the liver). The risk of pancreatic NET metastasis was analyzed in a large cohort of patients, in which the mean age at diagnosis of a pancreatic NET was 38 years (range, 16–68 y).[90] The risk of metastasis was lower in patients with small primary lesions (≤3 cm), in patients without an exon 3 pathogenic variant, and in patients whose tumor had a slow doubling time (>500 days). Nonfunctional pancreatic NETs can be followed by imaging surveillance with intervention when tumors reach 3 cm. Lesions in the head of the pancreas can be considered for surgery at a smaller size to limit operative complexity.
Endolymphatic sac tumors (ELSTs)
ELSTs are adenomatous tumors arising from the endolymphatic duct or sac within the posterior part of the petrous bone.[91] ELSTs are rare in the sporadic setting, but are apparent on imaging in 11% to 16% of patients with VHL. Although these tumors do not metastasize, they are locally invasive, eroding through the petrous bone and the inner ear structures.[91,92] Approximately 30% of VHL patients with ELSTs have bilateral lesions.[91,93]
ELSTs are an important cause of morbidity in VHL patients. ELSTs evident on imaging are associated with a variety of symptoms, including hearing loss (95% of patients), tinnitus (92%), vestibular symptoms (such as vertigo or disequilibrium) (62%), aural fullness (29%), and facial paresis (8%).[91,92] In approximately half of patients, symptoms (particularly hearing loss) can occur suddenly, probably as a result of acute intralabyrinthine hemorrhage.[92] Hearing loss or vestibular dysfunction in VHL patients can also present in the absence of radiologically evident ELSTs (approximately 60% of all symptomatic patients) and is believed to be a consequence of microscopic ELSTs.[91]
Hearing loss related to ELSTs is typically irreversible; serial imaging to enable early detection of ELSTs in asymptomatic patients and resection of radiologically evident lesions are important components in the management of VHL patients.[94,95] Surgical resection by retrolabyrinthine posterior petrosectomy is usually curative and can prevent onset or worsening of hearing loss and improve vestibular symptoms.[92,94]
Broad/round ligament papillary cystadenomas
Tumors of the broad ligament can occur in females with VHL and are known as papillary cystadenomas. These tumors are extremely rare, and fewer than 20 have been reported in the literature.[96] Papillary cystadenomas are histologically identical to epididymal cystadenomas commonly observed in males with VHL.[97] One important difference is that papillary cystadenomas are almost exclusively observed in patients with VHL, whereas epididymal cystadenomas in men can occur sporadically.[98] These tumors are frequently cystic, and although they become large, they generally have a fairly indolent behavior.
Epididymal cystadenomas
Fluid-filled epididymal cysts, or spermatoceles, are very common in adult men. In VHL, the epididymis can contain more complex cystic neoplasms known as papillary cystadenomas, which are rare in the general population. More than one-third of all cases of epididymal cystadenomas reported in the literature and most cases of bilateral cystadenomas have been reported in patients with VHL.[99] These well-circumscribed lesions have variable amounts of cystic and papillary components that are lined with epithelial cuboidal or columnar clear cells.[100] Among symptomatic patients, the most common presentation of epididymal cystadenoma is a painless, slow-growing scrotal swelling. The differential diagnoses of epididymal tumors include adenomatoid tumor (which is the most common tumor in this site), metastatic ccRCC, and papillary mesothelioma.[101]
In a small series, histological analysis did not reveal features typically associated with malignancy, such as mitotic figures, nuclear pleomorphism, and necrosis. Lesions were strongly positive for CK7 and negative for RCC. Carbonic anhydrase IX (CAIX) was positive in all tumors. PAX8 was positive in most cases. These features were reminiscent of clear cell papillary RCC, a relatively benign form of RCC without known metastatic potential.[97]

Management

Risk assessment for VHL

The primary risk factor for VHL (or any of the hereditary forms of renal cancer under consideration) is the presence of a family member affected with the disease. Risk assessment should also consider gender and age for some specific VHL-related neoplasms. For example, pheochromocytomas may have onset in early childhood,[1] as early as age 8 years.[102] Gender-specific VHL clinical findings include epididymal cystadenoma in males (10%–26%), which are virtually pathognomonic for VHL, especially when bilateral, and are rare in the general male population. Epididymal cysts are also common in VHL, but they are reported in 23% of the general male population, making them a poor diagnostic discriminator.[1] Females have histologically similar lesions to cystadenomas that occur in the broad ligament.[1]
Each offspring of an individual with VHL has a 50% chance of inheriting the VHL variant allele from their affected parent. Diagnosis of VHL is frequently based on clinical criteria. If there is family history of VHL, then a patient with one or more specific VHL-type tumors (e.g., hemangioblastoma of the CNS or retina, pheochromocytoma, or ccRCC) may be diagnosed with VHL.
Genetic testing
At-risk family members should be informed that genetic testing for VHL is available. A family member with a clinical diagnosis of VHL or who is showing signs and symptoms of VHL is initially offered genetic testing. Germline pathogenic variants in VHL are detected in more than 99% of families affected by VHL. Sequence analysis of all three exons detect point variants in the VHL gene (~72% of all pathogenic variants).[103] Deletions are detected mainly by using next-generation sequencing (NGS), with confirmation using targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification. Array comparative genomic hybridization is also being used to identify genomic imbalances. Anecdotal evidence exists for the utility of NGS in cases of suspected mosaicism with a negative VHL genetic test.[104]
Genetic counseling is first provided, including discussion of the medical, economic, and psychosocial implications for the patient and their bloodline relatives. After counseling, the patient may choose to voluntarily undergo testing, after providing informed consent. Additional counseling is given at the time results are reported to the patient. When a VHLpathogenic variant is identified in a family member, their biologic relatives who then test negative for the same pathogenic variant are not carriers of the trait (i.e., they are true negatives) and are not predisposed to developing any VHL manifestations. Equally important, the children of true-negative family members are not as risk of VHL either. Clinical testing throughout their lifetime is therefore unnecessary.[3]
Genetic diagnosis
A germline pathogenic variant in the VHL gene is considered a genetic diagnosis. It is expected to carry a predisposition to clinical VHL and confers a 50% risk among offspring to inherit the VHL pathogenic variant. Approximately 400 unique pathogenic variants in the VHL gene have been associated with clinical VHL, and their presence verifies the disease-causing capability of the variant. The diagnostic genetic evaluation in a previously untested family generally begins with a clinically diagnosed individual. If a VHL pathogenic variant is identified, that specific pathogenic variant becomes the DNA marker for which other biological relatives may be tested. In cases where there is a clear VHL clinical diagnosis without a VHL pathogenic variant by usual testing of peripheral blood lymphocytes and without a history of VHL in the biological parents or in the parents’ kindreds, then either a de novo pathogenic variant or mosaicism may be the cause. The latter may be detected by performing genetic testing on other bodily tissues, such as skin fibroblasts or exfoliated buccal cells.
Clinical diagnosis
Diagnosis of VHL is frequently based on clinical criteria (refer to Table 4). If there is family history of VHL, then a previously unevaluated family member may be diagnosed clinically if they present with one or more specific VHL-related tumors (e.g., CNS or retinal hemangioblastoma, pheochromocytoma, ccRCC, or endolymphatic sac tumor). If there is no family history of VHL, then a clinical diagnosis requires that the patient have two or more CNS hemangioblastomas or one CNS hemangioblastoma and a visceral tumor or endolymphatic sac tumor. Refer to Table 4 for more diagnostic details.[2-4]
Since 1998, when a cohort of 93 VHL families in whom all germline pathogenic variants were identified was reported, diagnoses have included a combined approach of clinical and genetic testing within families. The diagnostic strategy differs among individual family members. Table 4 summarizes a combined approach of genetic testing and clinical diagnosis.
Table 4. Diagnostic Approaches to von Hippel-Lindau Disease (VHL) in Individuals With and Without a Family History
Family History of VHLGenetic TestingClinical DiagnosisRequirements for Clinical Diagnosis
CNS = central nervous system; ccRCC = clear cell renal cell cancer.
Adapted and updated from Glenn et al. [4] and Pithukpakorn and Glenn.[3]
With a family history of VHLTest DNA for the same VHL gene pathogenic variant as previously identified in affected biologic relative(s)When VHL gene pathogenic variant is unknown for a biologic relativeOne or more of the following is required for a clinical diagnosis:
- Epididymal or broad ligament cystadenomas
- CNS hemangioblastoma
- ccRCC, multifocal
- Pheochromocytoma
- Retinal hemangioblastomas
- Pancreatic neuroendocrine tumor
- Pancreatic cysts and/or cystadenomas
- Endolymphatic sac tumor
Without a family history of VHLMay be negative if the VHL pathogenic variant occurred postzygotically (e.g., VHLmosaicism)When VHLpathogenic variant is unknown or germline negative, but there are clinical signs compatible for VHLEither or both of the following are required for a clinical diagnosis:
- CNS hemangioblastoma
- Retinal hemangioblastomas
If only one of the above is present, then also one of the following:
- ccRCC
- Pheochromocytoma
- Pancreatic cysts and/or cystadenomas
- Endolymphatic sac tumor
- Epididymal or broad ligament cystadenomas

Surveillance

Surveillance guidelines that have been suggested for various manifestations of VHL are summarized in Table 5. In general, these recommendations are based on expert opinion and consensus; most are not evidence-based. These modalities may be used for the initial clinical diagnostic testing and also for periodic surveillance of at-risk individuals for early detection of developing neoplasm. Periodic presymptomatic screening is advised for at-risk individuals. At-risk individuals are those testing positive for a VHL pathogenic variant and those individuals who choose not to be tested for a VHL pathogenic variant but have biologic relatives affected by VHL. The risk of inheriting the VHL predisposition in such persons may be as high as 50%.
Table 5. Practice Guidelines for Surveillance of von Hippel-Lindau Disease (VHL)
Examination/TestCondition Screened ForStarting Age/Frequencya
CNS = central nervous system; CT = computed tomography; IACs = internal auditory canals; MRI = magnetic resonance imaging.
aFrequencies of exams or tests may be increased at organ sites of VHL lesions being monitored.
bBrain MRIs may be used to examine areas of the IACs for signs of endolymphatic sac tumors (ELSTs). If signs or symptoms of ELSTs are present, examine IACs by CT and MRI.
Adapted from VHL Alliance.[105]
OphthalmoscopyRetinal hemangioblastomaAnnually from age 1 y
Plasma or 24-hour urinary catecholamines and metanephrinesPheochromocytomaFrom age 5 y; annually and as clinically indicated when blood pressure is elevated
Enhanced MRI of brain/spinebCNS and peripheral hemangioblastomaFrom age 16 y; every 2 y and if symptoms appear
MRI of abdomen with and without contrastRenal, pancreatic, and adrenal neoplasms and cystsFrom age 16 y; annually alternating with ultrasound
Ultrasound of abdomenRenal, pancreatic, and adrenal neoplasms and cystsFrom age 16 y; annually alternating with MRI
Audiology; MRI and CT of IACs; neurologyEndolymphatic sac tumorAudiology from age 5 y; every 2–3 y or annually if hearing loss, tinnitus, or vertigo. Imaging as needed at any age for hearing loss, tinnitus, vertigo. Annual neurological assessment from age 5 y
Level of evidence: 5

Treatment

Treatment of renal tumors
Surgical interventions
The management of VHL has changed significantly as clinicians have learned how to balance the risk of cancer dissemination while minimizing renal morbidity. Some of the initial surgical series focused on performing a bilateral radical nephrectomy for renal tumors followed by a renal transplantation.[106,107] Nephron-sparing surgery (NSS) for VHL was introduced in the 1980s after several groups demonstrated a low risk of cancer dissemination with a less-radical surgical approach.[108,109] In 1995, a large multi-institutional series demonstrated how NSS could produce excellent cancer-specific survival in patients with RCC.[110] Because of multiple reports of excellent outcomes, NSS is now considered the surgical standard of care when technically feasible. Over time, the technique of NSS in this population has been refined to minimize damage to the adjacent normal parenchyma. Instead of taking a wide margin traditionally described for NSS, enucleation was developed to allow the tumor and pseudocapsule to be shelled off the surrounding adjacent normal parenchyma.[111]
Patients with VHL can have dozens of renal tumors; therefore, resection of all evidence of disease may not be feasible. To minimize the morbidity of multiple surgical procedures, loss of kidney function, and the risk of distant progression, a method to balance over- and under-treatment was sought. The National Cancer Institute (NCI) evaluated a specific size threshold to trigger surgical intervention. An evaluation of 52 patients treated when the largest solid lesion reached 3 cm demonstrated no evidence of distant metastases or need for renal replacement therapy at a median follow-up of 60 months.[68] Later retrospective series reinforced that this was an important threshold because 0 of 108 patients with tumors managed at 3 cm or smaller had evidence of distant spread.[112] For patients with tumors larger than 3 cm, a total of 27.3% (20 of 73) developed distant recurrence.[112] This threshold is now widely used to trigger surgical intervention for VHL-associated ccRCC. When surgery is performed on a patient with VHL, resection of as many renal tumors as is clinically feasible may delay the need for further surgical interventions.[113] The use of intraoperative ultrasound is helpful to identify and then remove smaller lesions.[114]
Many patients with VHL develop new RCCs on an ongoing basis and may require further intervention. Adhesions and perinephric scarring make subsequent surgical procedures more challenging. While a radical nephrectomy could be considered, NSS remains the preferred approach, when feasible. While there may be a higher incidence of complications, repeat and salvage NSS can enable patients to maintain excellent renal function outcomes and provide promising oncologic outcomes at intermediate follow-up.[115,116] These surgeries may be best handled at a specialized center with significant experience with the management of hereditary forms of kidney cancer.[117]
Level of evidence: 3di
Ablative techniques
Radiofrequency ablation (RFA) and cryoablation (CA)
Thermal ablative techniques utilize either extreme heating or cooling of a mass in an effort to destroy the tumor. CA and RFA were introduced into the management of small renal masses in the late 1990s.[118,119] For sporadic renal masses, both thermal ablative techniques have a recurrence-free survival rate of nearly 90%, leading the American Urologic Association to consider this as a recommendation in high-risk patients with a small renal mass (≤4 cm).[120] For patients with VHL, the clinical applications of ablative techniques are still not clearly defined, and surgery remains the most-studied intervention. Ablative techniques were first introduced into the management of VHL-associated RCC in a phase II trial investigating the effects of ablation at the time of lesion resection. In this study, 11 tumors were treated, and an intra-operative ultrasound showed complete elimination of blood flow to the tumors; on final pathology, there was evidence of treatment effect on all tumors.[121] Since that time, some centers have utilized thermal ablative techniques for primary and salvage management in patients with VHL with good success.[122] Other centers have found that techniques such as RFA have a higher failure rate and should be reserved for patients with marginal renal function.[123] Despite limited long-term data, these techniques have been increasingly utilized in the treatment of RCC in patients with VHL. A single-institution study evaluated treatment trends in RCC in 113 patients with VHL. Between 2004 and 2009, 43% of cases were managed with RFA at this center.[124]
Thermal ablation may play an increasing role in the salvage therapy setting for individuals with a high risk of morbidity from surgery. CA as salvage therapy was evaluated in a series of 14 patients to avoid the morbidity of repeat NSS. There was minimal change in renal function; at a median follow-up of 37 months, there was suspicion for lesion recurrence in only 4 of 33 tumors (12.1%).[125] However, it must be cautioned that surgery after thermal ablation is a very challenging endeavor, with a significantly higher rate of postoperative complications due to adhesions and scarring, especially along the tract of the ablative probes.[126-128] In younger individuals who may need further surgical management in their lifetimes, clinicians must consider how a thermal ablation could impact future RCC management.[117,129]
The clinical applications of ablative techniques in VHL are not clearly defined, and surgery remains the most-studied intervention. The available clinical evidence suggests that ablative approaches be reserved for small (≤3 cm) solid-enhancing renal masses in older patients with high operative risk, especially in patients facing salvage renal surgery because of a higher complication rate. Young age, tumor size larger than 4 cm, hilar tumors, and cystic lesions can be regarded as relative contraindications.[130,131]
Level of evidence: 3di
Chemotherapy
Much of the preclinical data that form the basis for current systemic treatment strategies stem from the study of VHL alteration. All the large randomized phase III trials investigating aldesleukin, vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, mTOR inhibitors, and checkpoint inhibitors are based on data from the treatment of sporadic clear cell kidney cancer. Despite limited studies investigating these agents in the VHL population with metastatic kidney cancer, they are believed to be efficacious and are available as treatment options. Systemic therapy to limit the development or progression of VHL manifestations has been of interest to many groups.
A 2011 study prospectively evaluated the safety and efficacy of sunitinib in patients.[132] Fifteen patients were given 50 mg of sunitinib daily for 28 days, followed by 14 days off for up to four cycles, with a primary endpoint of toxicity. Grade 3 toxicity included fatigue in five patients (33%); dose reductions were made in ten patients (75%). A significant response was observed in RCC but not in hemangioblastoma. Eighteen RCCs and 21 hemangioblastoma lesions were evaluable. Of these, six RCCs (33%) had partial responses, versus none of the hemangioblastomas (P = .014). Archival VHL-related tumor specimens were evaluated to determine expression of relevant sunitinib targets. The expression of pFRS2 in hemangioblastoma tissue was observed to be higher than in RCC, thus raising the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with hemangioblastoma.[132] A retrospective study of 14 VHL patients with RCC, 10 of whom had metastatic disease, demonstrated significant response in metastatic and primary RCC lesions. Eleven patients had cerebellar hemangioblastomas, and eight had spinal hemangioblastomas. No response was seen in patients with hemangioblastomas.[133]
A study of intravitreally administered pegaptanib, an anti-VEGF therapy, was evaluated in five patients with VHL-associated retinal hemangioblastomas.[134] Only two patients were able to complete the intended therapy, and no responses were seen in the primary tumors. Two patients had decreased retinal thickening and reduced hard exudates. Although the agent is approved by the U.S. Food and Drug Administration for macular degeneration, it is not approved for the treatment of VHL retinal lesions.
Level of evidence: 2
Treatment of pheochromocytomas
Surveillance of pheochromocytomas
Pheochromocytomas can be a source of significant morbidity in patients with VHL due to the cardiovascular effects of excess catecholamines. In individuals that undergo surgery or childbirth without proper medical management, the results can be catastrophic due to massive surges in catecholamine release. Because tumors can also undergo malignant transformation, it is imperative that surveillance and early intervention are performed in this patient population. Available surveillance guidelines are shown in Table 5. Assessment of catecholamines/metanephrines and cross-sectional abdominal imaging are key to early detection.
Biochemical testing
Biochemical testing remains critical to the evaluation of individuals with VHL as levels can often be elevated in the absence of anatomic imaging findings. Assessment begins in childhood with some guidelines recommending initiation at age 5 years (see Table 5). Clinicians have the option of performing plasma testing, urinary testing, or both. Because the levels of catecholamines can greatly vary due to diet and medications, measurement of their metabolites, metanephrines, is suggested due to higher performance metrics. A fourfold, or greater, elevation of metanephrines is suggestive of the presence of a pheochromocytoma or paraganglioma.[135] Individuals with VHL pheochromocytomas often have isolated normetanephrines while other endocrine syndromes have a different functional profile.[88] Refer to the Clinical Diagnosis of Paraganglioma (PGL) and Pheochromocytoma (PHEO) section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information regarding diet methods of testing.
Imaging of pheochromocytomas
Cross-sectional imaging is initiated early in the second decade of life to evaluate the kidneys, adrenal glands, and pancreas. Both magnetic resonance imaging (MRI) and computed tomography (CT) scans have excellent performance characteristics for the detection of pheochromocytomas with a sensitivity of greater than 90%.[136] When there is clinical suspicion on the basis of biochemical studies and there are no lesions visible, additional imaging studies may be of clinical utility. While most tumors arising from chromaffin tissue in VHL are pheochromocytomas, paragangliomas can also occur in the chest, abdomen, pelvis, and head and neck.[88] Dedicated cross-sectional imaging can be performed in those areas in addition to a whole-body functional imaging. Refer to the Clinical Diagnosis of PGL and PHEO section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for a detailed discussion of nuclear medicine imaging modalities for both sporadic and various hereditary pheochromocytomas. In patients with VHL, functional imaging studies such as scintigraphy (nuclear medicine) or positron emission tomography (PET) scans are useful in the localization of pheochromocytomas when there is high suspicion and CT or MRI fails to detect a tumor. Imaging performance can vary on the basis of tumor location and by the genetic background. Iodine I 123 (123I)-metaiodobenzylguanidine scintigraphy coupled with CT imaging provides anatomic and functional information with good sensitivity (80%–90%) and specificity (95%–100%).[137] Other modalities such as fluorine F 18 (18F)-fluorodopa and 18F-fludeoxyglucose PET/CT are also very useful for tumor localization.[138]
Surgery
Surgical resection is the mainstay of management of pheochromocytoma in individuals with VHL. Prior to surgical resection, all patients should have a detailed endocrine evaluation and perioperative blockade. Often, medications need to be initiated and carefully titrated preoperatively to prevent potentially life-threatening cardiovascular complications. Refer to the Preoperative management section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information.
Pheochromocytomas in patients with VHL may have different management than in individuals with sporadic tumors or other hereditary cancer syndromes. The incidence of bilaterality and multifocality is nearly 50% and historically many patients underwent bilateral adrenalectomy and required lifelong steroid replacement.[139] The morbidity of adrenal replacement and development of Cushing syndrome raised the interest in pursuing cortical-sparing partial adrenalectomy in this population. Even after extensive adrenal mobilization and tumor resection, the adrenal gland has extensive collateral arterial supply and venous drainage that can permit organ survival.[140] Leaving at least 15% to 30% of the residual gland volume is necessary to allow sufficient hormone production.[141] With modern techniques, the majority of glands can maintain functional cortisol production. In a solitary gland, a series demonstrated that 1 of 13 (8%) patients required lifelong steroid replacement.[142]
Leaving residual cancer behind is a concern with a partial adrenalectomy in patients with a malignant pheochromocytoma; however, in the VHL population, the malignancy rate is extremely low (<5%).[143] The local recurrence rate with partial adrenalectomy appears low (0%–33%). Therefore, when feasible and safe from an oncologic perspective, most guidelines advocate for partial adrenalectomy for the management of pheochromocytoma in VHL patients.
With total adrenalectomy, the adrenal vein is generally divided early to limit catecholamine release with gland mobilization. In a partial adrenalectomy, this can lead to venous congestion and gland compromise.[144] In a patient with an effective preoperative catecholamine block, it may be possible to only clamp the adrenal vein during the resection and unclamp it after tumor excision. The optimal amount of adjacent normal parenchyma to remove is unclear. The initial surgical approach to partial adrenalectomy described surgery for patients with tumors in the tail/head of the adrenal with amputation of that region, while tumors in the body of the adrenal had a thin rim of normal parenchyma included with the specimen. As further data have clarified the risk of malignancy and local recurrence in patients with VHL, an enucleative resection of the tumor pseudocapsule has been described that is similar to the renal tumor approach. This may maximally preserve cortical tissue and limit vascular compromise to the residual gland.[139] Concerns over a higher rate of local recurrence may limit this approach.
Both open resection and laparoscopic approaches are safe, but if feasible, laparoscopic removal is preferred.[145,146] Means of exposure and approach are based on the anatomic location of the tumor. Direct access to the adrenal and para-aortic region can be achieved with the posterior approach. It is direct, safe, and efficient.[147] Adequate exposure of the complete tumor is important for complete removal. Robotic assistance can be utilized in select cases because it offers a three-dimensional, magnified view of the anatomy.[148] With multiple abdominal procedures, a minimally invasive approach may often not be feasible because of adhesions. Open resection is commonly recommended for patients with large tumors because of the increased risk of complications owing to the surgical technical difficulty within the confined space of laparoscopy. (Refer to the Surgerysection in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for a discussion of the surgical approaches to pheochromocytoma.)
Treatment of retinal hemangioblastomas
Treatment of retinal hemangioblastomas includes laser treatment, photodynamic therapy, and vitrectomy. Efforts have also been made to use either local or systemic therapy.
Laser photocoagulation is extensively used for retinal hemangioblastomas in patients with VHL disease. A retrospective review of 304 treated retinal hemangioblastomas in 100 eyes showed that laser photocoagulation had a control rate greater than 90%, and was most effective in smaller lesions measuring up to 1 disk diameter.[149]
Twenty-one patients with severe retinal detachment achieved varying degrees of visual preservation when treated with pars plana vitrectomy with posterior hyaloid detachment, epiretinal membrane dissection, and silicone oil or gas injection with retinectomy or photocoagulation/cryotherapy to remove the retinal hemangioblastoma.[150] Pars plana vitrectomy in advanced VHL eye disease was shown to improve or preserve visual function in a second group of 23 patients, but postoperative progression of ocular VHL disease was possibly accelerated in cases where a retinotomy was performed.[151]
Photodynamic therapy reduced macular edema in a case series of two patients with bilateral retinal hemangioblastoma involvement, but with minimal, if any, benefit in visual acuity.[152] In a second series of five patients, including four with VHL disease, photodynamic therapy was performed on six eyes, resulting in tumor regression or stabilization and the improvement of subretinal fluid and lipid exudation in all cases. However, stabilization or improvement of visual acuity was observed in only 50% of the cases.[153]
Case reports of intravitreal treatment with bevacizumab resulted in stabilization for over 2 years in one case report,[154] and improvement in vision in one of five treated eyes in a second case report.[155] Intravitreal ranibizumab did not provide consistent benefit in a case series of five patients.[156] Treatment with systemic bevacizumab provided marginal, if any, benefit in individual case reports.[157,158] Treatment with sunitinib resulted in possible visual stabilization in three patients, but with significant concomitant toxicity.[159]
A case study of proton therapy of eight eyes in eight patients demonstrated resolution of macular edema in seven of eight patients, and preservation of vision in all treated eyes after a median of 84 months of follow-up.[160]
Treatment of CNS hemangioblastomas
Surgical resection of cerebellar or spinal hemangioblastomas has been the standard treatment approach. While it is generally accepted that surgical resection of tumors be performed prior to the onset of neurologic symptoms,[161] when to intervene on asymptomatic individuals varies by center and may be influenced by patient factors and tumor factors including edema, location, hydrocephalus, and growth rate. Spinal lesions are often approached posteriorly and require a laminectomy. Because patients often require multiple operations during their lifetime, removal of support can lead to progressive spinal instability requiring stabilization/fusion.[162] For cerebellar lesions, the approach depends on the lateral orientation of the tumor, but many can be approached through a midline suboccipital incision. Preoperative embolization can be performed to reduce bleeding, but this approach is dependent on surgeon preference.[163]
Because patients may have multiple tumors and require several surgical procedures, external beam radiation therapy has emerged as an alternative when surgical resection is not feasible. Stereotactic radiosurgery has become a commonly utilized approach to hemangioblastoma treatment.[164] Retrospective series have demonstrated that treatment was associated with a size reduction in more than 50% of treated lesions, with a low rate of complications.[164] A prospective study at the NCI evaluated local control of treated lesions. As tumors can have a saltatory growth pattern, long-term series may be necessary to assess the effectiveness of this modality. In this series, 33% of treated subcentimeter, asymptomatic tumors progressed during follow-up. Because of concerns of long-term local control, the authors concluded that treatment with stereotactic radiosurgery should be reserved for the treatment of tumors not amenable to surgical resection.[165] Systemic therapy for CNS hemangioblastomas with pazopanib has been used in select cases with success when surgical options were not feasible.[166,167] Use of another tyrosine kinase inhibitor, sunitinib, was shown to be ineffective for treating cerebellar or spinal hemangioblastomas in a phase II trial of 15 patients with VHL.[132] Further research is required to continue to reduce the morbidity of these benign but often problematic tumors.
Treatment of ELSTs
There are limited data on the management of ELSTs, consisting largely of case series detailing surgical management of sporadic and VHL-associated tumors. The largest series details the outcomes in 31 patients treated with surveillance and surgical resection.[168] In this retrospective analysis, complete surgical resection with preservation of hearing and vestibular function was feasible in most patients; when complete resection was achieved, the risk of recurrence was low. Because audiovestibular compromise is not dependent on tumor size and can occur with small tumors, early intervention is generally preferred. Early intervention may also minimize the risk of spread to surrounding structures and increase the probability of complete resection. Preoperative embolization was used effectively in this series in select cases to minimize the risk of perioperative morbidity and hemorrhage.

VHL in pregnancy

Two studies have examined the effect of pregnancy on hemangioblastoma progression in patients with VHL.[169,170] One study retrospectively examined the records of 29 patients with VHL from the Netherlands who became pregnant 48 times (49 newborns) between 1966 and 2010 (40% became pregnant before 1990); imaging records were available for 31% of the pregnancies. Researchers reported that 17% of all pregnancies had VHL-related complications, including three patients who had craniospinal hemangioblastoma that significantly (P = .049) changed in progression score before and after pregnancy.[169] This study's findings are in contrast with a small, prospective investigation.[170] Until a large-scale, international, prospective investigation is conducted, all investigations suggest using a conservative approach that includes medical surveillance during pregnancy.

Prognosis

Morbidity and mortality in VHL vary and are influenced by the individual and the family’s VHL phenotype (e.g., Type 1, 2A, 2B, or 2C). (Refer to the VHL familial phenotypes section of this summary for more information.)
In the past, metastatic RCC has caused about one-third of deaths in patients with VHL, and in some reports, it was the leading cause of death.[102,171-173] With increased surveillance of pathogenic variant–positive individuals, the RCC mortality rate is thought to have diminished significantly because of adherence to RCC treatment recommendations including the 3 cm rule. A Danish study compared the life expectancy of individuals with VHL disease with that of their unaffected siblings, and demonstrated a median survival of 67 years in men and 60 years in women with VHL disease. The study reported an increased hazard ratio for death of 2.25 (95% confidence interval [CI], 1.02–4.95; P = .045) in men and 8.09 (95% CI, 4.88–13.40; P < .001) in women.[174] The risk of VHL-related death decreased with younger age. Genotype did not have an effect on survival probability. The main cause of VHL disease–related death was due to complications arising from hemangioblastomas. Patients with truncating pathogenic variants benefitted more from surveillance than individuals with missense variants.
Hemangioblastomas of the CNS, although histologically benign, are a major cause of morbidity and arise anywhere along the craniospinal axis, including the brainstem.[2] Pancreatic NETs, formerly called pancreatic islet cell tumors, in some cases, may grow rapidly and metastasize to liver and bone.[171,175] Hearing and vision may also be decreased or lost as a result of VHL tumors. Periodic screening allows early detection and may prevent advanced disease.

Future Directions

Currently, the renal manifestations of VHL are generally managed surgically or with thermal ablation. There is a clear unmet need for better management strategies and development of targeted systemic therapy. These will include defining the molecular biology and genetics of kidney cancer development, which may result in the development of effective prevention or early intervention therapies. In addition, the evolving understanding of the molecular biology of established kidney cancers may provide opportunities to phenotypically normalize the cancer by modulating residual VHL function, identifying new targets, or discovering synthetic lethal strategies that can effectively eradicate RCC.
References
  1. Choyke PL, Glenn GM, Walther MM, et al.: von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology 194 (3): 629-42, 1995. [PUBMED Abstract]
  2. Lonser RR, Glenn GM, Walther M, et al.: von Hippel-Lindau disease. Lancet 361 (9374): 2059-67, 2003. [PUBMED Abstract]
  3. Pithukpakorn M, Glenn G: von Hippel-Lindau syndrome. Community Oncology 1 (4): 232-43, 2004.
  4. Glenn GM, Daniel LN, Choyke P, et al.: Von Hippel-Lindau (VHL) disease: distinct phenotypes suggest more than one mutant allele at the VHL locus. Hum Genet 87 (2): 207-10, 1991. [PUBMED Abstract]
  5. Latif F, Tory K, Gnarra J, et al.: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260 (5112): 1317-20, 1993. [PUBMED Abstract]
  6. Knudson AG Jr, Strong LC: Mutation and cancer: neuroblastoma and pheochromocytoma. Am J Hum Genet 24 (5): 514-32, 1972. [PUBMED Abstract]
  7. Knudson AG Jr: Genetics of human cancer. Annu Rev Genet 20: 231-51, 1986. [PUBMED Abstract]
  8. Maher ER, Iselius L, Yates JR, et al.: Von Hippel-Lindau disease: a genetic study. J Med Genet 28 (7): 443-7, 1991. [PUBMED Abstract]
  9. Binderup ML, Galanakis M, Budtz-Jørgensen E, et al.: Prevalence, birth incidence, and penetrance of von Hippel-Lindau disease (vHL) in Denmark. Eur J Hum Genet 25 (3): 301-307, 2017. [PUBMED Abstract]
  10. Evans DG, Howard E, Giblin C, et al.: Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A 152A (2): 327-32, 2010. [PUBMED Abstract]
  11. Neumann HP, Wiestler OD: Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. Lancet 337 (8749): 1052-4, 1991. [PUBMED Abstract]
  12. Poulsen ML, Budtz-Jørgensen E, Bisgaard ML: Surveillance in von Hippel-Lindau disease (vHL). Clin Genet 77 (1): 49-59, 2010. [PUBMED Abstract]
  13. Zbar B, Kishida T, Chen F, et al.: Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 8 (4): 348-57, 1996. [PUBMED Abstract]
  14. Chen F, Slife L, Kishida T, et al.: Genotype-phenotype correlation in von Hippel-Lindau disease: identification of a mutation associated with VHL type 2A. J Med Genet 33 (8): 716-7, 1996. [PUBMED Abstract]
  15. Mettu P, Agrón E, Samtani S, et al.: Genotype-phenotype correlation in ocular von Hippel-Lindau (VHL) disease: the effect of missense mutation position on ocular VHL phenotype. Invest Ophthalmol Vis Sci 51 (9): 4464-70, 2010. [PUBMED Abstract]
  16. Wong WT, Agrón E, Coleman HR, et al.: Genotype-phenotype correlation in von Hippel-Lindau disease with retinal angiomatosis. Arch Ophthalmol 125 (2): 239-45, 2007. [PUBMED Abstract]
  17. Sgambati MT, Stolle C, Choyke PL, et al.: Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. Am J Hum Genet 66 (1): 84-91, 2000. [PUBMED Abstract]
  18. Austin KD, Hall JG: Nontraditional inheritance. Pediatr Clin North Am 39 (2): 335-48, 1992. [PUBMED Abstract]
  19. Ang SO, Chen H, Hirota K, et al.: Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 32 (4): 614-21, 2002. [PUBMED Abstract]
  20. Pastore YD, Jelinek J, Ang S, et al.: Mutations in the VHL gene in sporadic apparently congenital polycythemia. Blood 101 (4): 1591-5, 2003. [PUBMED Abstract]
  21. Cario H, Schwarz K, Jorch N, et al.: Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and VHL-haplotype analysis in patients with presumable congenital erythrocytosis. Haematologica 90 (1): 19-24, 2005. [PUBMED Abstract]
  22. Popova T, Hebert L, Jacquemin V, et al.: Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet 92 (6): 974-80, 2013. [PUBMED Abstract]
  23. Farley MN, Schmidt LS, Mester JL, et al.: A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma. Mol Cancer Res 11 (9): 1061-71, 2013. [PUBMED Abstract]
  24. Cancer Genome Atlas Research Network: Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499 (7456): 43-9, 2013. [PUBMED Abstract]
  25. Benusiglio PR, Couvé S, Gilbert-Dussardier B, et al.: A germline mutation in PBRM1 predisposes to renal cell carcinoma. J Med Genet 52 (6): 426-30, 2015. [PUBMED Abstract]
  26. Iliopoulos O, Ohh M, Kaelin WG Jr: pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Proc Natl Acad Sci U S A 95 (20): 11661-6, 1998. [PUBMED Abstract]
  27. Pause A, Lee S, Lonergan KM, et al.: The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc Natl Acad Sci U S A 95 (3): 993-8, 1998. [PUBMED Abstract]
  28. Kurban G, Hudon V, Duplan E, et al.: Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. Cancer Res 66 (3): 1313-9, 2006. [PUBMED Abstract]
  29. Thoma CR, Toso A, Gutbrodt KL, et al.: VHL loss causes spindle misorientation and chromosome instability. Nat Cell Biol 11 (8): 994-1001, 2009. [PUBMED Abstract]
  30. Maxwell PH, Wiesener MS, Chang GW, et al.: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399 (6733): 271-5, 1999. [PUBMED Abstract]
  31. Ivan M, Kondo K, Yang H, et al.: HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292 (5516): 464-8, 2001. [PUBMED Abstract]
  32. Jaakkola P, Mole DR, Tian YM, et al.: Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292 (5516): 468-72, 2001. [PUBMED Abstract]
  33. Keith B, Johnson RS, Simon MC: HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12 (1): 9-22, 2012. [PUBMED Abstract]
  34. Gordan JD, Bertout JA, Hu CJ, et al.: HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11 (4): 335-47, 2007. [PUBMED Abstract]
  35. Koh MY, Lemos R Jr, Liu X, et al.: The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res 71 (11): 4015-27, 2011. [PUBMED Abstract]
  36. Koh MY, Darnay BG, Powis G: Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1alpha, leading to its oxygen-independent degradation. Mol Cell Biol 28 (23): 7081-95, 2008. [PUBMED Abstract]
  37. Monzon FA, Alvarez K, Peterson L, et al.: Chromosome 14q loss defines a molecular subtype of clear-cell renal cell carcinoma associated with poor prognosis. Mod Pathol 24 (11): 1470-9, 2011. [PUBMED Abstract]
  38. Kondo K, Klco J, Nakamura E, et al.: Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 1 (3): 237-46, 2002. [PUBMED Abstract]
  39. Kondo K, Kim WY, Lechpammer M, et al.: Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 1 (3): E83, 2003. [PUBMED Abstract]
  40. Zimmer M, Doucette D, Siddiqui N, et al.: Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL-/- tumors. Mol Cancer Res 2 (2): 89-95, 2004. [PUBMED Abstract]
  41. Zimmer M, Ebert BL, Neil C, et al.: Small-molecule inhibitors of HIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing. Mol Cell 32 (6): 838-48, 2008. [PUBMED Abstract]
  42. Metelo AM, Noonan HR, Li X, et al.: Pharmacological HIF2α inhibition improves VHL disease-associated phenotypes in zebrafish model. J Clin Invest 125 (5): 1987-97, 2015. [PUBMED Abstract]
  43. Scheuermann TH, Li Q, Ma HW, et al.: Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat Chem Biol 9 (4): 271-6, 2013. [PUBMED Abstract]
  44. Pan J, Snell W: The primary cilium: keeper of the key to cell division. Cell 129 (7): 1255-7, 2007. [PUBMED Abstract]
  45. Simons M, Walz G: Polycystic kidney disease: cell division without a c(l)ue? Kidney Int 70 (5): 854-64, 2006. [PUBMED Abstract]
  46. Thoma CR, Frew IJ, Hoerner CR, et al.: pVHL and GSK3beta are components of a primary cilium-maintenance signalling network. Nat Cell Biol 9 (5): 588-95, 2007. [PUBMED Abstract]
  47. Hergovich A, Lisztwan J, Barry R, et al.: Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nat Cell Biol 5 (1): 64-70, 2003. [PUBMED Abstract]
  48. Hergovich A, Lisztwan J, Thoma CR, et al.: Priming-dependent phosphorylation and regulation of the tumor suppressor pVHL by glycogen synthase kinase 3. Mol Cell Biol 26 (15): 5784-96, 2006. [PUBMED Abstract]
  49. Roe JS, Kim HR, Hwang IY, et al.: von Hippel-Lindau protein promotes Skp2 destabilization on DNA damage. Oncogene 30 (28): 3127-38, 2011. [PUBMED Abstract]
  50. Kim J, Jonasch E, Alexander A, et al.: Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma. Clin Cancer Res 15 (1): 81-90, 2009. [PUBMED Abstract]
  51. Roe JS, Youn HD: The positive regulation of p53 by the tumor suppressor VHL. Cell Cycle 5 (18): 2054-6, 2006. [PUBMED Abstract]
  52. Roe JS, Kim H, Lee SM, et al.: p53 stabilization and transactivation by a von Hippel-Lindau protein. Mol Cell 22 (3): 395-405, 2006. [PUBMED Abstract]
  53. Ohh M, Yauch RL, Lonergan KM, et al.: The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell 1 (7): 959-68, 1998. [PUBMED Abstract]
  54. Lolkema MP, Gervais ML, Snijckers CM, et al.: Tumor suppression by the von Hippel-Lindau protein requires phosphorylation of the acidic domain. J Biol Chem 280 (23): 22205-11, 2005. [PUBMED Abstract]
  55. Hall DP, Cost NG, Hegde S, et al.: TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma. Cancer Cell 26 (5): 738-53, 2014. [PUBMED Abstract]
  56. Mikhaylova O, Stratton Y, Hall D, et al.: VHL-regulated MiR-204 suppresses tumor growth through inhibition of LC3B-mediated autophagy in renal clear cell carcinoma. Cancer Cell 21 (4): 532-46, 2012. [PUBMED Abstract]
  57. Haase VH, Glickman JN, Socolovsky M, et al.: Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc Natl Acad Sci U S A 98 (4): 1583-8, 2001. [PUBMED Abstract]
  58. Frew IJ, Thoma CR, Georgiev S, et al.: pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. EMBO J 27 (12): 1747-57, 2008. [PUBMED Abstract]
  59. Hickey MM, Lam JC, Bezman NA, et al.: von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis. J Clin Invest 117 (12): 3879-89, 2007. [PUBMED Abstract]
  60. Varela I, Tarpey P, Raine K, et al.: Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469 (7331): 539-42, 2011. [PUBMED Abstract]
  61. Dalgliesh GL, Furge K, Greenman C, et al.: Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463 (7279): 360-3, 2010. [PUBMED Abstract]
  62. Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, et al.: BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 44 (7): 751-9, 2012. [PUBMED Abstract]
  63. Binderup ML, Budtz-Jørgensen E, Bisgaard ML: Risk of new tumors in von Hippel-Lindau patients depends on age and genotype. Genet Med 18 (1): 89-97, 2016. [PUBMED Abstract]
  64. Brauch H, Kishida T, Glavac D, et al.: Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect. Hum Genet 95 (5): 551-6, 1995. [PUBMED Abstract]
  65. Hoffman MA, Ohh M, Yang H, et al.: von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet 10 (10): 1019-27, 2001. [PUBMED Abstract]
  66. Choyke PL, Glenn GM, Walther MM, et al.: The natural history of renal lesions in von Hippel-Lindau disease: a serial CT study in 28 patients. AJR Am J Roentgenol 159 (6): 1229-34, 1992. [PUBMED Abstract]
  67. Poston CD, Jaffe GS, Lubensky IA, et al.: Characterization of the renal pathology of a familial form of renal cell carcinoma associated with von Hippel-Lindau disease: clinical and molecular genetic implications. J Urol 153 (1): 22-6, 1995. [PUBMED Abstract]
  68. Walther MM, Choyke PL, Glenn G, et al.: Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery. J Urol 161 (5): 1475-9, 1999. [PUBMED Abstract]
  69. Walther MM, Lubensky IA, Venzon D, et al.: Prevalence of microscopic lesions in grossly normal renal parenchyma from patients with von Hippel-Lindau disease, sporadic renal cell carcinoma and no renal disease: clinical implications. J Urol 154 (6): 2010-4; discussion 2014-5, 1995. [PUBMED Abstract]
  70. Libutti SK, Choyke PL, Bartlett DL, et al.: Pancreatic neuroendocrine tumors associated with von Hippel Lindau disease: diagnostic and management recommendations. Surgery 124 (6): 1153-9, 1998. [PUBMED Abstract]
  71. Weisbrod AB, Kitano M, Thomas F, et al.: Assessment of tumor growth in pancreatic neuroendocrine tumors in von Hippel Lindau syndrome. J Am Coll Surg 218 (2): 163-9, 2014. [PUBMED Abstract]
  72. Chew EY: Ocular manifestations of von Hippel-Lindau disease: clinical and genetic investigations. Trans Am Ophthalmol Soc 103: 495-511, 2005. [PUBMED Abstract]
  73. Dollfus H, Massin P, Taupin P, et al.: Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study. Invest Ophthalmol Vis Sci 43 (9): 3067-74, 2002. [PUBMED Abstract]
  74. Wong WT, Agrón E, Coleman HR, et al.: Clinical characterization of retinal capillary hemangioblastomas in a large population of patients with von Hippel-Lindau disease. Ophthalmology 115 (1): 181-8, 2008. [PUBMED Abstract]
  75. Kreusel KM, Bechrakis NE, Krause L, et al.: Retinal angiomatosis in von Hippel-Lindau disease: a longitudinal ophthalmologic study. Ophthalmology 113 (8): 1418-24, 2006. [PUBMED Abstract]
  76. Schmidt D, Neumann HP: Retinal vascular hamartoma in von Hippel-Lindau disease. Arch Ophthalmol 113 (9): 1163-7, 1995. [PUBMED Abstract]
  77. Wittström E, Nordling M, Andréasson S: Genotype-phenotype correlations, and retinal function and structure in von Hippel-Lindau disease. Ophthalmic Genet 35 (2): 91-106, 2014. [PUBMED Abstract]
  78. Toy BC, Agrón E, Nigam D, et al.: Longitudinal analysis of retinal hemangioblastomatosis and visual function in ocular von Hippel-Lindau disease. Ophthalmology 119 (12): 2622-30, 2012. [PUBMED Abstract]
  79. Huntoon K, Wu T, Elder JB, et al.: Biological and clinical impact of hemangioblastoma-associated peritumoral cysts in von Hippel-Lindau disease. J Neurosurg 124 (4): 971-6, 2016. [PUBMED Abstract]
  80. Kanno H, Kuratsu J, Nishikawa R, et al.: Clinical features of patients bearing central nervous system hemangioblastoma in von Hippel-Lindau disease. Acta Neurochir (Wien) 155 (1): 1-7, 2013. [PUBMED Abstract]
  81. Lonser RR, Butman JA, Huntoon K, et al.: Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease. J Neurosurg 120 (5): 1055-62, 2014. [PUBMED Abstract]
  82. Walther MM, Reiter R, Keiser HR, et al.: Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. J Urol 162 (3 Pt 1): 659-64, 1999. [PUBMED Abstract]
  83. Aufforth RD, Ramakant P, Sadowski SM, et al.: Pheochromocytoma Screening Initiation and Frequency in von Hippel-Lindau Syndrome. J Clin Endocrinol Metab 100 (12): 4498-504, 2015. [PUBMED Abstract]
  84. Welander J, Söderkvist P, Gimm O: Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocr Relat Cancer 18 (6): R253-76, 2011. [PUBMED Abstract]
  85. Eisenhofer G, Walther MM, Huynh TT, et al.: Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab 86 (5): 1999-2008, 2001. [PUBMED Abstract]
  86. Friedrich CA: Genotype-phenotype correlation in von Hippel-Lindau syndrome. Hum Mol Genet 10 (7): 763-7, 2001. [PUBMED Abstract]
  87. Eisenhofer G, Vocke CD, Elkahloun A, et al.: Genetic screening for von Hippel-Lindau gene mutations in non-syndromic pheochromocytoma: low prevalence and false-positives or misdiagnosis indicate a need for caution. Horm Metab Res 44 (5): 343-8, 2012. [PUBMED Abstract]
  88. Shuch B, Ricketts CJ, Metwalli AR, et al.: The genetic basis of pheochromocytoma and paraganglioma: implications for management. Urology 83 (6): 1225-32, 2014. [PUBMED Abstract]
  89. Eisenhofer G, Timmers HJ, Lenders JW, et al.: Age at diagnosis of pheochromocytoma differs according to catecholamine phenotype and tumor location. J Clin Endocrinol Metab 96 (2): 375-84, 2011. [PUBMED Abstract]
  90. Blansfield JA, Choyke L, Morita SY, et al.: Clinical, genetic and radiographic analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs). Surgery 142 (6): 814-8; discussion 818.e1-2, 2007. [PUBMED Abstract]
  91. Manski TJ, Heffner DK, Glenn GM, et al.: Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. JAMA 277 (18): 1461-6, 1997. [PUBMED Abstract]
  92. Choo D, Shotland L, Mastroianni M, et al.: Endolymphatic sac tumors in von Hippel-Lindau disease. J Neurosurg 100 (3): 480-7, 2004. [PUBMED Abstract]
  93. Megerian CA, Haynes DS, Poe DS, et al.: Hearing preservation surgery for small endolymphatic sac tumors in patients with von Hippel-Lindau syndrome. Otol Neurotol 23 (3): 378-87, 2002. [PUBMED Abstract]
  94. Kim HJ, Butman JA, Brewer C, et al.: Tumors of the endolymphatic sac in patients with von Hippel-Lindau disease: implications for their natural history, diagnosis, and treatment. J Neurosurg 102 (3): 503-12, 2005. [PUBMED Abstract]
  95. Lonser RR, Kim HJ, Butman JA, et al.: Tumors of the endolymphatic sac in von Hippel-Lindau disease. N Engl J Med 350 (24): 2481-6, 2004. [PUBMED Abstract]
  96. Nogales FF, Goyenaga P, Preda O, et al.: An analysis of five clear cell papillary cystadenomas of mesosalpinx and broad ligament: four associated with von Hippel-Lindau disease and one aggressive sporadic type. Histopathology 60 (5): 748-57, 2012. [PUBMED Abstract]
  97. Cox R, Vang R, Epstein JI: Papillary cystadenoma of the epididymis and broad ligament: morphologic and immunohistochemical overlap with clear cell papillary renal cell carcinoma. Am J Surg Pathol 38 (5): 713-8, 2014. [PUBMED Abstract]
  98. Brady A, Nayar A, Cross P, et al.: A detailed immunohistochemical analysis of 2 cases of papillary cystadenoma of the broad ligament: an extremely rare neoplasm characteristic of patients with von hippel-lindau disease. Int J Gynecol Pathol 31 (2): 133-40, 2012. [PUBMED Abstract]
  99. Odrzywolski KJ, Mukhopadhyay S: Papillary cystadenoma of the epididymis. Arch Pathol Lab Med 134 (4): 630-3, 2010. [PUBMED Abstract]
  100. Uppuluri S, Bhatt S, Tang P, et al.: Clear cell papillary cystadenoma with sonographic and histopathologic correlation. J Ultrasound Med 25 (11): 1451-3, 2006. [PUBMED Abstract]
  101. Vijayvargiya M, Jain D, Mathur SR, et al.: Papillary cystadenoma of the epididymis associated with von Hippel-Lindau disease diagnosed on fine needle aspiration cytology. Cytopathology 25 (4): 279-81, 2014. [PUBMED Abstract]
  102. Maher ER, Yates JR, Harries R, et al.: Clinical features and natural history of von Hippel-Lindau disease. Q J Med 77 (283): 1151-63, 1990. [PUBMED Abstract]
  103. Stolle C, Glenn G, Zbar B, et al.: Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 12 (6): 417-23, 1998. [PUBMED Abstract]
  104. Coppin L, Grutzmacher C, Crépin M, et al.: VHL mosaicism can be detected by clinical next-generation sequencing and is not restricted to patients with a mild phenotype. Eur J Hum Genet 22 (9): 1149-52, 2014. [PUBMED Abstract]
  105. VHL Alliance: Suggested Surveillance. Boston, MA: VHL Alliance, 2016. Available online. Last accessed December 14, 2018.
  106. Goldfarb DA, Neumann HP, Penn I, et al.: Results of renal transplantation in patients with renal cell carcinoma and von Hippel-Lindau disease. Transplantation 64 (12): 1726-9, 1997. [PUBMED Abstract]
  107. Fetner CD, Barilla DE, Scott T, et al.: Bilateral renal cell carcinoma in von Hippel-Lindau syndrome: treatment with staged bilateral nephrectomy and hemodialysis. J Urol 117 (4): 534-6, 1977. [PUBMED Abstract]
  108. Pearson JC, Weiss J, Tanagho EA: A plea for conservation of kidney in renal adenocarcinoma associated with von Hippel-Lindau disease. J Urol 124 (6): 910-2, 1980. [PUBMED Abstract]
  109. Loughlin KR, Gittes RF: Urological management of patients with von Hippel-Lindau's disease. J Urol 136 (4): 789-91, 1986. [PUBMED Abstract]
  110. Steinbach F, Novick AC, Zincke H, et al.: Treatment of renal cell carcinoma in von Hippel-Lindau disease: a multicenter study. J Urol 153 (6): 1812-6, 1995. [PUBMED Abstract]
  111. Walther MM, Thompson N, Linehan W: Enucleation procedures in patients with multiple hereditary renal tumors. World J Urol 13 (4): 248-50, 1995. [PUBMED Abstract]
  112. Duffey BG, Choyke PL, Glenn G, et al.: The relationship between renal tumor size and metastases in patients with von Hippel-Lindau disease. J Urol 172 (1): 63-5, 2004. [PUBMED Abstract]
  113. Fadahunsi AT, Sanford T, Linehan WM, et al.: Feasibility and outcomes of partial nephrectomy for resection of at least 20 tumors in a single renal unit. J Urol 185 (1): 49-53, 2011. [PUBMED Abstract]
  114. Choyke PL, Pavlovich CP, Daryanani KD, et al.: Intraoperative ultrasound during renal parenchymal sparing surgery for hereditary renal cancers: a 10-year experience. J Urol 165 (2): 397-400, 2001. [PUBMED Abstract]
  115. Bratslavsky G, Liu JJ, Johnson AD, et al.: Salvage partial nephrectomy for hereditary renal cancer: feasibility and outcomes. J Urol 179 (1): 67-70, 2008. [PUBMED Abstract]
  116. Johnson A, Sudarshan S, Liu J, et al.: Feasibility and outcomes of repeat partial nephrectomy. J Urol 180 (1): 89-93; discussion 93, 2008. [PUBMED Abstract]
  117. Shuch B, Linehan WM, Bratslavsky G: Repeat partial nephrectomy: surgical, functional and oncological outcomes. Curr Opin Urol 21 (5): 368-75, 2011. [PUBMED Abstract]
  118. Gill IS, Novick AC, Soble JJ, et al.: Laparoscopic renal cryoablation: initial clinical series. Urology 52 (4): 543-51, 1998. [PUBMED Abstract]
  119. McGovern FJ, Wood BJ, Goldberg SN, et al.: Radio frequency ablation of renal cell carcinoma via image guided needle electrodes. J Urol 161 (2): 599-600, 1999. [PUBMED Abstract]
  120. Campbell SC, Novick AC, Belldegrun A, et al.: Guideline for management of the clinical T1 renal mass. J Urol 182 (4): 1271-9, 2009. [PUBMED Abstract]
  121. Walther MC, Shawker TH, Libutti SK, et al.: A phase 2 study of radio frequency interstitial tissue ablation of localized renal tumors. J Urol 163 (5): 1424-7, 2000. [PUBMED Abstract]
  122. Shingleton WB, Sewell PE Jr: Percutaneous renal cryoablation of renal tumors in patients with von Hippel-Lindau disease. J Urol 167 (3): 1268-70, 2002. [PUBMED Abstract]
  123. Park BK, Kim CK: Percutaneous radio frequency ablation of renal tumors in patients with von Hippel-Lindau disease: preliminary results. J Urol 183 (5): 1703-7, 2010. [PUBMED Abstract]
  124. Joly D, Méjean A, Corréas JM, et al.: Progress in nephron sparing therapy for renal cell carcinoma and von Hippel-Lindau disease. J Urol 185 (6): 2056-60, 2011. [PUBMED Abstract]
  125. Yang B, Autorino R, Remer EM, et al.: Probe ablation as salvage therapy for renal tumors in von Hippel-Lindau patients: the Cleveland Clinic experience with 3 years follow-up. Urol Oncol 31 (5): 686-92, 2013. [PUBMED Abstract]
  126. Nguyen CT, Lane BR, Kaouk JH, et al.: Surgical salvage of renal cell carcinoma recurrence after thermal ablative therapy. J Urol 180 (1): 104-9; discussion 109, 2008. [PUBMED Abstract]
  127. Karam JA, Wood CG, Compton ZR, et al.: Salvage surgery after energy ablation for renal masses. BJU Int 115 (1): 74-80, 2015. [PUBMED Abstract]
  128. Kowalczyk KJ, Hooper HB, Linehan WM, et al.: Partial nephrectomy after previous radio frequency ablation: the National Cancer Institute experience. J Urol 182 (5): 2158-63, 2009. [PUBMED Abstract]
  129. Shuch B, Singer EA, Bratslavsky G: The surgical approach to multifocal renal cancers: hereditary syndromes, ipsilateral multifocality, and bilateral tumors. Urol Clin North Am 39 (2): 133-48, v, 2012. [PUBMED Abstract]
  130. Dominguez-Escrig JL, Sahadevan K, Johnson P: Cryoablation for small renal masses. Adv Urol : 479495, 2008. [PUBMED Abstract]
  131. Aron M, Gill IS: Minimally invasive nephron-sparing surgery (MINSS) for renal tumours. Part II: probe ablative therapy. Eur Urol 51 (2): 348-57, 2007. [PUBMED Abstract]
  132. Jonasch E, McCutcheon IE, Waguespack SG, et al.: Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease. Ann Oncol 22 (12): 2661-6, 2011. [PUBMED Abstract]
  133. Roma A, Maruzzo M, Basso U, et al.: First-Line sunitinib in patients with renal cell carcinoma (RCC) in von Hippel-Lindau (VHL) disease: clinical outcome and patterns of radiological response. Fam Cancer 14 (2): 309-16, 2015. [PUBMED Abstract]
  134. Dahr SS, Cusick M, Rodriguez-Coleman H, et al.: Intravitreal anti-vascular endothelial growth factor therapy with pegaptanib for advanced von Hippel-Lindau disease of the retina. Retina 27 (2): 150-8, 2007. [PUBMED Abstract]
  135. Neary NM, King KS, Pacak K: Drugs and pheochromocytoma--don't be fooled by every elevated metanephrine. N Engl J Med 364 (23): 2268-70, 2011. [PUBMED Abstract]
  136. Čtvrtlík F, Koranda P, Schovánek J, et al.: Current diagnostic imaging of pheochromocytomas and implications for therapeutic strategy. Exp Ther Med 15 (4): 3151-3160, 2018. [PUBMED Abstract]
  137. Ilias I, Pacak K: Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 89 (2): 479-91, 2004. [PUBMED Abstract]
  138. Ilias I, Meristoudis G: Functional Imaging of Paragangliomas with an Emphasis on Von Hippel-Lindau-Associated Disease: A Mini Review. J Kidney Cancer VHL 4 (3): 30-36, 2017. [PUBMED Abstract]
  139. Benhammou JN, Boris RS, Pacak K, et al.: Functional and oncologic outcomes of partial adrenalectomy for pheochromocytoma in patients with von Hippel-Lindau syndrome after at least 5 years of followup. J Urol 184 (5): 1855-9, 2010. [PUBMED Abstract]
  140. Baghai M, Thompson GB, Young WF Jr, et al.: Pheochromocytomas and paragangliomas in von Hippel-Lindau disease: a role for laparoscopic and cortical-sparing surgery. Arch Surg 137 (6): 682-8; discussion 688-9, 2002. [PUBMED Abstract]
  141. Brauckhoff M, Gimm O, Thanh PN, et al.: Critical size of residual adrenal tissue and recovery from impaired early postoperative adrenocortical function after subtotal bilateral adrenalectomy. Surgery 134 (6): 1020-7; discussion 1027-8, 2003. [PUBMED Abstract]
  142. Walther MM, Keiser HR, Choyke PL, et al.: Management of hereditary pheochromocytoma in von Hippel-Lindau kindreds with partial adrenalectomy. J Urol 161 (2): 395-8, 1999. [PUBMED Abstract]
  143. Fallon SC, Feig D, Lopez ME, et al.: The utility of cortical-sparing adrenalectomy in pheochromocytomas associated with genetic syndromes. J Pediatr Surg 48 (6): 1422-5, 2013. [PUBMED Abstract]
  144. Roukounakis N, Dimas S, Kafetzis I, et al.: Is preservation of the adrenal vein mandatory in laparoscopic adrenal-sparing surgery? JSLS 11 (2): 215-8, 2007 Apr-Jun. [PUBMED Abstract]
  145. Timmers HJ, Gimenez-Roqueplo AP, Mannelli M, et al.: Clinical aspects of SDHx-related pheochromocytoma and paraganglioma. Endocr Relat Cancer 16 (2): 391-400, 2009. [PUBMED Abstract]
  146. Vargas HI, Kavoussi LR, Bartlett DL, et al.: Laparoscopic adrenalectomy: a new standard of care. Urology 49 (5): 673-8, 1997. [PUBMED Abstract]
  147. Perrier ND, Kennamer DL, Bao R, et al.: Posterior retroperitoneoscopic adrenalectomy: preferred technique for removal of benign tumors and isolated metastases. Ann Surg 248 (4): 666-74, 2008. [PUBMED Abstract]
  148. Dickson PV, Jimenez C, Chisholm GB, et al.: Posterior retroperitoneoscopic adrenalectomy: a contemporary American experience. J Am Coll Surg 212 (4): 659-65; discussion 665-7, 2011. [PUBMED Abstract]
  149. Krivosic V, Kamami-Levy C, Jacob J, et al.: Laser photocoagulation for peripheral retinal capillary hemangioblastoma in von Hippel-Lindau disease. Ophthalmol Retina 1 (1): 59-67, 2017. Also available online. Last accessed December 14, 2018.
  150. Gaudric A, Krivosic V, Duguid G, et al.: Vitreoretinal surgery for severe retinal capillary hemangiomas in von hippel-lindau disease. Ophthalmology 118 (1): 142-9, 2011. [PUBMED Abstract]
  151. Krzystolik K, Stopa M, Kuprjanowicz L, et al.: PARS PLANA VITRECTOMY IN ADVANCED CASES OF VON HIPPEL-LINDAU EYE DISEASE. Retina 36 (2): 325-34, 2016. [PUBMED Abstract]
  152. Papastefanou VP, Pilli S, Stinghe A, et al.: Photodynamic therapy for retinal capillary hemangioma. Eye (Lond) 27 (3): 438-42, 2013. [PUBMED Abstract]
  153. Sachdeva R, Dadgostar H, Kaiser PK, et al.: Verteporfin photodynamic therapy of six eyes with retinal capillary haemangioma. Acta Ophthalmol 88 (8): e334-40, 2010. [PUBMED Abstract]
  154. Ach T, Thiemeyer D, Hoeh AE, et al.: Intravitreal bevacizumab for retinal capillary haemangioma: longterm results. Acta Ophthalmol 88 (4): e137-8, 2010. [PUBMED Abstract]
  155. Slim E, Antoun J, Kourie HR, et al.: Intravitreal bevacizumab for retinal capillary hemangioblastoma: A case series and literature review. Can J Ophthalmol 49 (5): 450-7, 2014. [PUBMED Abstract]
  156. Wong WT, Liang KJ, Hammel K, et al.: Intravitreal ranibizumab therapy for retinal capillary hemangioblastoma related to von Hippel-Lindau disease. Ophthalmology 115 (11): 1957-64, 2008. [PUBMED Abstract]
  157. von Buelow M, Pape S, Hoerauf H: Systemic bevacizumab treatment of a juxtapapillary retinal haemangioma. Acta Ophthalmol Scand 85 (1): 114-6, 2007. [PUBMED Abstract]
  158. Wackernagel W, Lackner EM, Pilz S, et al.: von Hippel-Lindau disease: treatment of retinal haemangioblastomas by targeted therapy with systemic bevacizumab. Acta Ophthalmol 88 (7): e271-2, 2010. [PUBMED Abstract]
  159. Knickelbein JE, Jacobs-El N, Wong WT, et al.: Systemic Sunitinib Malate Treatment for Advanced Juxtapapillary Retinal Hemangioblastomas Associated with von Hippel-Lindau Disease. Ophthalmol Retina 1 (3): 181-187, 2017 May-Jun. [PUBMED Abstract]
  160. Seibel I, Cordini D, Hager A, et al.: Long-term results after proton beam therapy for retinal papillary capillary hemangioma. Am J Ophthalmol 158 (2): 381-6, 2014. [PUBMED Abstract]
  161. Harati A, Satopää J, Mahler L, et al.: Early microsurgical treatment for spinal hemangioblastomas improves outcome in patients with von Hippel-Lindau disease. Surg Neurol Int 3: 6, 2012. [PUBMED Abstract]
  162. Asthagiri AR, Mehta GU, Butman JA, et al.: Long-term stability after multilevel cervical laminectomy for spinal cord tumor resection in von Hippel-Lindau disease. J Neurosurg Spine 14 (4): 444-52, 2011. [PUBMED Abstract]
  163. Das JM, Kesavapisharady K, Sadasivam S, et al.: Microsurgical Treatment of Sporadic and von Hippel-Lindau Disease Associated Spinal Hemangioblastomas: A Single-Institution Experience. Asian Spine J 11 (4): 548-555, 2017. [PUBMED Abstract]
  164. Kano H, Shuto T, Iwai Y, et al.: Stereotactic radiosurgery for intracranial hemangioblastomas: a retrospective international outcome study. J Neurosurg 122 (6): 1469-78, 2015. [PUBMED Abstract]
  165. Asthagiri AR, Mehta GU, Zach L, et al.: Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease. Neuro Oncol 12 (1): 80-6, 2010. [PUBMED Abstract]
  166. Kim BY, Jonasch E, McCutcheon IE: Pazopanib therapy for cerebellar hemangioblastomas in von Hippel-Lindau disease: case report. Target Oncol 7 (2): 145-9, 2012. [PUBMED Abstract]
  167. Taylor DG, Ilyas A, Mehta GU, et al.: Variable response of CNS hemangioblastomas to Pazopanib in a single patient with von Hippel-Lindau disease: Case report. J Clin Neurosci 50: 154-156, 2018. [PUBMED Abstract]
  168. Kim HJ, Hagan M, Butman JA, et al.: Surgical resection of endolymphatic sac tumors in von Hippel-Lindau disease: findings, results, and indications. Laryngoscope 123 (2): 477-83, 2013. [PUBMED Abstract]
  169. Frantzen C, Kruizinga RC, van Asselt SJ, et al.: Pregnancy-related hemangioblastoma progression and complications in von Hippel-Lindau disease. Neurology 79 (8): 793-6, 2012. [PUBMED Abstract]
  170. Ye DY, Bakhtian KD, Asthagiri AR, et al.: Effect of pregnancy on hemangioblastoma development and progression in von Hippel-Lindau disease. J Neurosurg 117 (5): 818-24, 2012. [PUBMED Abstract]
  171. Lamiell JM, Salazar FG, Hsia YE: von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore) 68 (1): 1-29, 1989. [PUBMED Abstract]
  172. Horton WA, Wong V, Eldridge R: Von Hippel-Lindau disease: clinical and pathological manifestations in nine families with 50 affected members. Arch Intern Med 136 (7): 769-77, 1976. [PUBMED Abstract]
  173. Neumann HP: Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. Vasa 16 (3): 220-6, 1987. [PUBMED Abstract]
  174. Binderup ML, Jensen AM, Budtz-Jørgensen E, et al.: Survival and causes of death in patients with von Hippel-Lindau disease. J Med Genet 54 (1): 11-18, 2017. [PUBMED Abstract]
  175. Karsdorp N, Elderson A, Wittebol-Post D, et al.: Von Hippel-Lindau disease: new strategies in early detection and treatment. Am J Med 97 (2): 158-68, 1994. [PUBMED Abstract]

Hereditary Leiomyomatosis and Renal Cell Cancer

Introduction

Hereditary leiomyomatosis and renal cell cancer (HLRCC) (OMIM) is characterized by the presence of one or more of the following: cutaneous leiomyomas (or leiomyomata), uterine leiomyomas (fibroids) in females, and renal cell cancer (RCC). Germline pathogenic variants in the fumarate hydratase (FH) gene are responsible for the susceptibility to HLRCC. FH encodes fumarate hydratase, the enzyme that catalyzes the conversion of fumarate to malate in the tricarboxylic acid cycle (Krebs cycle).

Nomenclature

Historically, the predisposition to the development of cutaneous leiomyomas was referred to as multiple cutaneous leiomyomatosis. In 1973, two kindreds were described in which multiple members over three generations exhibited cutaneous leiomyomas and uterine leiomyomas and/or leiomyosarcomas inherited in an autosomal dominant pattern.[1] That report also described a woman aged 20 years with uterine leiomyosarcoma and metastatic RCC. Subsequently, the association of cutaneous and uterine leiomyomas became known as Reed syndrome. However, the clear association of cutaneous leiomyomas and RCC was not described until 2001, when a study reported two Finnish families in whom cutaneous and uterine leiomyomas and papillary type 2 RCC co-segregated [2] and the name hereditary leiomyomatosis and renal cell cancer (HLRCC) was introduced.
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