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Clinical, genetic and radiographic analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by pancreatic neuroendocrine tumors (PNETs)
Abstract
von Hippel-Lindau (vHL) disease is an autosomal dominant syndrome associated with neoplasms in multiple organs, which includes the pancreas. Here, we report the greatest single center experience in patients with vHL pancreatic endocrine neoplasm (PNETs).
Between December 1998 and November 2006, 633 patients with vHL were evaluated and those with PNETs were enrolled on a prospective protocol.
Overall, 108 vHL patients had PNETs (17%). Nine patients had metastatic disease (8.3%) from their PNET. Patients with lesions greater than 3 cm (n = 25) were more likely to develop metastases than patients with lesions less than 3 cm (n = 83) (P < .005). Thirty-nine patients underwent resection. Germline sequencing showed that 78% of patients with metastases (7/9) had exon 3 mutations compared with 46% of patients without metastases (32/98; P < .01). Tumor doubling time was calculated for the largest PNET. The group with metastases had an average tumor doubling time of 337 days (range, 180-463 days) compared with 2630 days (range, 103-9614 days) for those without metastases (P < .0001).
By implementing a system of selective operative resection based on defined criteria, vHL patients with PNETs can be managed safely. For patients with small primary lesions (<3 cm), without a mutation of exon 3 and slow tumor doubling time (>500 days), a nonoperative approach may be appropriate for these nonfunctional neoplasms.
... The majority of panNENs in VHL are well differentiated (grade 1 or 2), small (<2 cm) and present a slow growth when compared with sporadic tumours. As a result of its clinical indolence, many of these lesions are diagnosed incidentally during routine VHL surveillance for renal lesions [62]. However, in 8-50% of VHL patients, panNENs are metastatic and LMs occur in 9-37% [63]. ...
... NF-1 is due to mutations in the NF-1 gene on chromosome 17q11.2, which encodes the protein neurofibromin, which affects cell growth, through Ras protein activation and mammalian target of rapamycin (mTOR) cascade regulation [46,62]. This condition is characterized by the development of several tumours, including neurofibroma, pheochromocytoma, and GI stromal tumour (Table 1) [46,62]. ...
... which encodes the protein neurofibromin, which affects cell growth, through Ras protein activation and mammalian target of rapamycin (mTOR) cascade regulation [46,62]. This condition is characterized by the development of several tumours, including neurofibroma, pheochromocytoma, and GI stromal tumour (Table 1) [46,62]. CNS abnormalities are frequent with learning disorders (30-60%), attention deficit hyperactivity disorder, and epilepsy [46,62]. ...
Pancreatic neuroendocrine neoplasms (panNENs) have been historically regarded as rare, but their incidence has raised more than 6-fold over the last 3 decades, mostly owing to improvement in the detection of small asymptomatic tumours with imaging. Early detection and proper classification and staging are essential for the prognosis and management of panNENs. Histological evaluation is mandatory in all patients for the diagnosis of panNEN. Regarding localization and staging, multiphasic contrast-enhanced computer tomography is considered the imaging study of choice. Nevertheless, several other diagnostic modalities might present complementary information that can help in diagnosis and staging optimization: magnetic resonance imaging, somatostatin receptor imaging using positron emission tomography in combination with computed tomography (PET/CT), PET/CT with fluorodeoxyglucose (<sup>18</sup>F-FDG), and endoscopic ultrasound. Approximately 10% of panNENs are due to an inherited syndrome, which includes multiple endocrine neoplasia type 1, von Hippel-Lindau disease, neurofibromatosis type 1 (NF-1), tuberous sclerosis complex, and Mahvash disease. In this review, the Portuguese Pancreatic Club summarizes the classification, diagnosis, and staging of panNENs, with a focus on imaging studies. It also summarizes the characteristics and particularities of panNENs associated with inherited syndromes.
... Primary pNETs larger than 3.0 cm in size were present in six patients. Two patients died as a result of complications brought on by metastases (18). On the other hand, the primary tumor size was greater than 3.0 cm in 19 patients who did not have metastatic disease. ...
... Data from additional international cohorts show that pNET frequencies varied from 14 to 33%. The median age at which pNET first appeared was between 33 and 38 years, with a range of 12-68 years (18)(19)(20). pNETs found in the body and tail of the pancreas are treated with a distal pancreatectomy. Only pancreatic tumors could also be considered. ...
... Resection criteria included a 3-cm tumor, a pathogenic variant in exon 3, and a tumor that had doubled in size in less than 500 days. Depending on the site, nucleation, Whipple, or distal pancreatectomy is advised because these characteristics raise the risk of metastasis (8,18,23,24). The only reports on pNETs in VHL patients are case reports and radiological series. ...
Multiorgan tumors are a hallmark of the autosomal dominant genetic disorder known as Von Hippel-Lindau syndrome (VHL), which is typically the result of inherited aberrations of the VHL tumor suppressor gene. The most frequent cancer is retinoblastoma, which can also occur in the brain and spinal cord, renal clear cell carcinoma (RCCC), paraganglioma, and neuroendocrine tumors. There may also be lymphangiomas, epididymal cysts, and pancreatic cysts or pancreatic neuroendocrine tumors (pNETs). The most frequent causes of death are metastasis from RCCC and neurological complications from retinoblastoma or central nervous system (CNS). Pancreatic cysts are present in 35–70% of VHL patients. Simple cysts, serous cysts, or pNETs are possible presentations, and the likelihood of malignant degeneration or metastasis is no greater than 8%. Although VHL has been associated with pNETs, their pathological characteristics are unknown. Furthermore, it is unknown whether variations in the VHL gene cause the development of pNETs. Hence, this retrospective study was undertaken with the main aim to examine whether pNETs are connected to VHL from a surgical perspective.
... In VHL, PNEN prevalence ranges between 1 and 17% in the various cohorts [4,6,[8][9][10][11] with age at diagnosis significantly younger in VHL-related PNEN (vPNEN) compared with sporadic PNEN (sPNEN) [12,13]. vPNENs are more frequently multifocal and very rarely functional [13][14][15]. ...
... vPNENs usually follow a more benign course with lower grade, G1\G2 in most cases [16], are less prone to metastasize than sporadic disease, and the patients are at a lower mortality risk than those harboring sPNENs [13,17]. In the European-American-Asian-VHL-PNEN-registry [18], comprising 273 patients with vPNEN, metastatic disease was found in 20% of cases, while a much lower risk was reported in other cohorts, ranging between 4.5 and 8.3% of cases [10,16]. Risk factors for metastatic disease in vPNEN include lesion diameter greater than 3 cm, a short lesion volume doubling time (<500 days), and presence of a missense VHL gene pathogenic variant or a pathogenic variant located in exon 3 [10,16,18,19]. ...
... In the European-American-Asian-VHL-PNEN-registry [18], comprising 273 patients with vPNEN, metastatic disease was found in 20% of cases, while a much lower risk was reported in other cohorts, ranging between 4.5 and 8.3% of cases [10,16]. Risk factors for metastatic disease in vPNEN include lesion diameter greater than 3 cm, a short lesion volume doubling time (<500 days), and presence of a missense VHL gene pathogenic variant or a pathogenic variant located in exon 3 [10,16,18,19]. ...
Von Hippel–Lindau (VHL) is a rare autosomal dominant hereditary cancer predisposition syndrome. Patients with VHL have a high risk for developing retinal and central nervous system hemangioblastoma, pheochromocytoma, renal cell carcinoma, and pancreatic neuroendocrine neoplasms (PNEN). About a fifth of patients with VHL will develop PNEN, and only a tenth of them will develop metastatic or unresectable (advanced) PNEN requiring medical intervention. In this review, we performed a literature search for studies, written in English, on the medical interventions for VHL-related localized and advanced PNENs and their clinical outcomes. We detail the various medical interventions for this rare group of patients, including their mode of action and potential efficacy and toxicity. Finally, based on the current literature, we delineate a possible management algorithm for patients with VHL and advanced PNEN. We can conclude that data on the efficacy of various vascular endothelial growth factor (VEGF) receptor inhibitors, and on the efficacy of belzutifan, a novel hypoxia-inducible factor 2 inhibitor, for the management of advanced PNEN in VHL, are scarce. Hence, deduction from the management of sporadic PNEN is required, and is implemented in the proposed management algorithm provided within this review.
... PanNENs diagnosis occurs in 10%e20% of patients, with a slight female predominance [58,59]. Patients with VHL syndrome typically develop multiple, non-functioning Pan-NENs [60], which are more frequently located in the pancreatic head or uncinate process. VHL-related PanNENs usually display a lower malignant potential compared to sporadic neoplasms, with a consequently reduced rate of high-grade and metastatic lesions (9%e12%) [60]. ...
... Patients with VHL syndrome typically develop multiple, non-functioning Pan-NENs [60], which are more frequently located in the pancreatic head or uncinate process. VHL-related PanNENs usually display a lower malignant potential compared to sporadic neoplasms, with a consequently reduced rate of high-grade and metastatic lesions (9%e12%) [60]. Symptoms ...
... Surgical resection should be considered for patients with VHL-related PanNENs at high risk of developing metastatic disease. Tumor size more than 3 cm predicts disease aggressiveness and represents the major risk-stratifying parameter in these patients [60,73]. Therefore, surgical resection is currently recommended for all the patients with VHL-related PanNENs more than 3 cm [56,59]. ...
Objective
The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance, treatment and follow-up of the different primary tumors developed by patients diagnosed with VHL syndrome.
Methods
A non-systematic narrative review of original articles, meta-analyses, and randomized trials was conducted, including articles in the pre-clinical setting to support relevant findings.
Results
Von Hippel-Lindau (VHL) disease is the most common rare hereditary disorder associated with clear cell renal cell carcinoma. Affected individuals inherit a germline mutation in one VHL allele, and any somatic event that disrupt the other allele can trigger mutations, chromosomal rearrangements, or epigenetic regulations leading to oncogenesis. From a clinical perspective, patients continuously develop multiple primary tumors.
Conclusions
Because VHL is considered a rare disease, very limited evidence is available for diagnosis, surveillance, active treatment with local or systemic therapy and follow-up.
... 5 In another study, which included 633 patients, the prevalence of panNENs amounted to 17%. 6 In general, panNENs are divided into functional and non-functional tumors. Functional panNENs cause a hormonal hypersecretion syndrome. ...
... 31 These three studies reported on a small number of patients, which limits their value in comparison to studies investigating the correlation between biomarkers and panNENs in larger populations that did not report conclusive evidence. 6,22 Future directions Surveillance for panNENs and other manifestations in VHL patients is an intensive and lifelong necessity. Fundamental to the screening programs in the current era are the imaging modalities such as, MRI and computed tomography (CT). ...
... 6DiscussionThis article is the first to present an overview of previous research in VHL patients reporting on biomarkers in relation to panNENs. At this time the role of biomarkers seems limited with no evident association between VHL-related panNENs and biomarkers in larger study populations.6,22 However, the number of studies is few and therefore conclusions must be drawn with care. ...
Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by the development of multi-organ neoplasms. Among the manifestations of VHL are pancreatic neuroendocrine neoplasms (panNENs). In order to detect these lesions in a timely manner, patients are enrolled in a surveillance program, in accordance with the several existing VHL guidelines. However, these guidelines remain unclear about the role of biomarkers in diagnosing panNENs, despite the benefits a biomarker may offer regarding early detection of new lesions, thereby possibly limiting radiation exposure, and improving quality of life. The aim is to determine which biomarkers might be available in VHL patients and to assess what their clinical relevance in diagnosing panNENs in VHL patients is.
We searched the databases of Pubmed/Medline, Embase and Web of Science to identify relevant articles. Seven studies assessing the diagnostic or prognostic value of biomarkers were included. The results from these studies were conflicting. Since no evident association between VHL-related panNENs and biomarkers was established in studies with larger study populations, currently biomarkers do not play a significant role in early detection or follow-up for panNENs in VHL patients. The absence of evidence underscores the need for specific research to address this unmet need.
... The latter is often the main factor affecting prognosis, with kidney cancer being the most common cause of death. For these patients, there is an association between VHL and (i) PNETs with an incidence ranging from 5 to 18% and (ii) (Pheo) that occur in up to 20% of the patients (11)(12)(13)(14)(15).The objective of this retrospective study is to analyze abdominal manifestations of VHL from a surgical point of view. ...
... A central pancreatectomy is used to treat small, low grade tumors (31,32). Blansfield et al. (13) identified three main factors that can determine the risk of metastasis: tumor size, exon 3 mutation, and mean doubling time. There is an apparent 12% association between neuroendocrine tumors of the pancreas and pheochromocytomas in patients with VHL disease (33). ...
... The resection criteria are given by a major tumor of 3 cm or a pathogenic variant in exon 3 and tumor with a growth rate doubling in fewer than 500 days. Because these characteristics increase the risk of metastasis, enucleation, Whipple, or distal pancreatectomy is indicated depending on the site (13,34,35). In recent years new medical therapies targeting the VHL/ HIF axis have been investigated, with some of them being used in clinical trials. ...
Von Hippel-Lindau syndrome (VHL) is an autosomal dominant disease caused by a genetic aberration of the tumor suppressor gene VHL and characterized by multi-organ tumors. The most common neoplasm is retinal or cerebral hemangioblastoma, although spinal hemangio-blastomas, Renal Clear Cell Carcinoma (RCCC), pheochromocytomas (Pheo), paragangliomas, Pancreatic Neuroendocrine Tumors (PNETs), cystadenomas of the epididymis, and tumors of the lymphatic sac can also be found. Neurological complications from retinal or CNS hemangio-blastoma and metastases of RCCC are the most common causes of death. There is a strong association between pheochromocytoma and VHL syndrome, and pheochromocytoma is often a classic manifestation of the syndrome. RCCCs are often incidental and identified during other tests. Between 35 and 70% of patients with VHL have pancreatic cysts. These can manifest as simple cysts, serous cystoadenomas, or PNETs with a risk of malignant degeneration or metastasis of no more than 8%. The objective of this retrospective study is to analyze abdominal manifestations of VHL from a surgical point of view.
... 1,2 VHL is caused by pathogenic variants in the VHL tumor suppressor gene 3 located at chromosome 3p25, and it manifests with hemangioblastoma of the central nervous system and retina, adrenal pheochromocytoma, renal cell carcinoma (RCC), pancreatic neuroendocrine tumors and cysts, and other neoplasms/cysts of the ear, broad ligament, testicles, and more. 4 The penetrance of pancreatic neuroendocrine tumors (PNETs) among patients with VHL ranges between 8% and 17% [5][6][7][8] and may have a female predominance. [5][6][7][8][9] Other pancreatic abnormalities, including cysts, cystadenomas, and mixed tumors, 6 may also develop in patients with VHL, and this should be considered a possible diagnostic pitfall. ...
... 4 The penetrance of pancreatic neuroendocrine tumors (PNETs) among patients with VHL ranges between 8% and 17% [5][6][7][8] and may have a female predominance. [5][6][7][8][9] Other pancreatic abnormalities, including cysts, cystadenomas, and mixed tumors, 6 may also develop in patients with VHL, and this should be considered a possible diagnostic pitfall. ...
... 10 Compared with sporadic PNENs, VHL-related PNENs are much less often high-grade 11,12 or metastatic. 8 The rarity of high-grade VHL-related PNENs has led the committee to use VHL-related PNET throughout this article. ...
Von Hippel–Lindau disease (VHL) is a multineoplasm inherited disease manifesting with hemangioblastoma of the central nervous system and retina, adrenal pheochromocytoma, renal cell carcinoma, pancreatic neuroendocrine tumors and cysts, and neoplasms/cysts of the ear, broad ligament, and testicles. During 2018‐2020, the VHL Alliance gathered several committees of experts in the various clinical manifestations of VHL to review the literature, gather the available evidence on VHL, and develop recommendations for patient management. The current report details the results of the discussion of a group of experts in the pancreatic manifestations of VHL along with their proposed recommendations for the clinical surveillance and management of patients with VHL. The recommendations subcommittee performed a comprehensive systematic review of the literature and conducted panel discussions to reach the current recommendations. The level of evidence was defined according to the Shekelle variation of the Grading of Recommendations, Assessment, Development, and Evaluation grading system. The National Comprehensive Cancer Network Categories of Evidence and Consensus defined the committee members' interpretation of the evidence and degree of consensus. The recommendations encompass the main aspects of VHL‐related pancreatic manifestations and their clinical management. They are presented in a clinical orientation, including general planning of screening and surveillance for pancreatic neuroendocrine tumors, utility of biochemical biomarkers, the optimal choice for imaging modality, indirect risk stratification, indications for tissue sampling of VHL‐related pancreatic neuroendocrine tumors, and interventions. These recommendations are designed to serve as the reference for all aspects of the screening, surveillance, and management of VHL‐related pancreatic manifestations.
... The von Hippel-Lindau syndrome, as discussed in the section on renal tumors, is an autosomal dominant disorder that predisposes individuals to a range of malignant and benign tumors, including renal cell carcinoma (clear cell subtype), pheochromocytoma, CNS hemangioblastomas, and retinal angiomas. Up to 12% of patients with vHL syndrome may develop pancreatic neuroendocrine tumors (PNETs), although most pancreatic lesions associated with the vHL syndrome are cysts or serous cystadenomas [90]. In the case series of Blansfield et al., 8.3% had metastatic disease from their PNETs, and lesions larger than 3 cm were more likely to develop metastases (p < 0.005) [90]. ...
... Up to 12% of patients with vHL syndrome may develop pancreatic neuroendocrine tumors (PNETs), although most pancreatic lesions associated with the vHL syndrome are cysts or serous cystadenomas [90]. In the case series of Blansfield et al., 8.3% had metastatic disease from their PNETs, and lesions larger than 3 cm were more likely to develop metastases (p < 0.005) [90]. ...
Hereditary cancer syndromes account for nearly 10% of cancers even though they are often underdiagnosed. Finding a pathogenic gene variant could have dramatic implications in terms of pharmacologic treatments, tailored preventive programs, and familiar cascade testing. However, diagnosing a hereditary cancer syndrome could be challenging because of a lack of validated testing criteria or because of their suboptimal performance. In addition, many clinicians are not sufficiently well trained to identify and select patients that could benefit from a genetic test. Herein, we searched the available literature to comprehensively review and categorize hereditary cancer syndromes affecting adults with the aim of helping clinicians in their daily clinical practice through a visual tool.
... VHL disease is the second most common autosomal dominant hereditary syndrome, which also manifests in PanNET tumors in more than 20% of the cases. Distant metastases are exhibited in 10-20% of these cases (Blansfield et al., 2007;Yamasaki et al., 2006). VHL associated PanNETs are exclusively non-functional, with 80% of the cases harboring germline alteration in the Von Hippel-Lindau (VHL) gene (Blansfield et al., 2007;Hammel et al., 2000). ...
... Distant metastases are exhibited in 10-20% of these cases (Blansfield et al., 2007;Yamasaki et al., 2006). VHL associated PanNETs are exclusively non-functional, with 80% of the cases harboring germline alteration in the Von Hippel-Lindau (VHL) gene (Blansfield et al., 2007;Hammel et al., 2000). ...
Neuroendokrine Neoplasmen der Bauchspeicheldrüse (PanNEN) sind eine seltene und vielfältige Form von Krebs. PanNENs umfassen hochgradige PanNECs und NETG3 PanNETs, sowie die öfter diagnostizierten NETG1 und NETG2 PanNETs. Hochgradige PanNENs weisen eine schlechte Prognose auf, und sind histologisch schwierig zu diagnostizieren. In dieser Studie wird eine auf Methylierung basierende Klassifizierung vorgestellt, die PanNETs von PanNECs unterscheidet und die zugrunde liegende Komplexität in Bezug auf molekularen Merkmalen und den Ursprungszellen der PanNENs aufzeigt. Zuerst wurden PanNENs auf Grundlage ihrer Methylierungsprofile gruppiert, wodurch sich die PanNETs und PanNECs in zwei Gruppen A und B aufteilten. Während Tumore der Gruppe B häufig Veränderungen in KRAS, TP53 und SMAD4 aufweisen, umfasst das Mutationsspektrum von Gruppe A Veränderungen in klassischen PanNEN-Genen wie MEN1, DAXX, ATRX und VHL. Darüber hinaus ist Gruppe A durch chromosomale Aberrationen geprägt, während Gruppe B eine signifikante fokale Deletion des RB1-Lokus aufweist. Anhand von Methylierungsprofilen von alpha-, beta-, duktalen und azinären Pankreaszellen sowie von Expressionsmustern normaler Zelltyp Markergene innerhalb der Tumore folgt, dass die PanNETs alpha-, beta- und intermediär-ähnliche Tumore endokrinen Ursprungs sind, während die PanNECs azinäre Tumore vermutlich exokrinen Ursprungs sind. Ausprägung des Azinuszellenprofils und Expression des SOX9-Proteins in Gruppe B sind vergleichbar mit denen des duktalen Adenokarzinoms der Pankreas (PDAC), einer Tumorentität mit nachgewiesen exokrinen Zellursprung. Insgesamt ergeben die neuen Erkenntnisse dieser Arbeit ein umfassendes Profil, das PanNET- und PanNEC-Tumore genetisch und epigenetisch eindeutig charakterisiert. Weiterhin liefert diese Arbeit starke Beweise für die aufkommende, aber unbewiesene Theorie des exokrinen Ursprungs von PanNECs und somit einen neuen Ansatz für die Behandlung dieser seltenen, aber oft tödlichen Krankheit.
... VHL is an autosomal dominant hereditary disease characterized by multiple and recurrent neoplastic lesions in a variety of organs. In addition to PNETs, which are estimated to affect 10-17% of patients with VHL, CNS hemangioblastomas, retinal hemangioblastomas, endolymphatic sac tumors, pheochromocytomas, renal cell carcinomas, and pancreatic cysts have been described in VHL patients [2][3][4]. ...
... For these reasons, practitioners should be cautious when deciding whether surgery is suitable for VHL-associated PNETs [5,6]. Blansfield, Ganeshan, and others proposed the following criteria as surgical indications for PNETs in VHL patients: (1) tumor size > 3 cm (or > 2 cm for lesions in the head of the pancreas), (2) tumor Clinical Journal of Gastroenterology doubling time < 500 days, (3) mutation in exon 3, and (4) suspicion of regional nodal metastases [4,7]. After fully explaining our rationale to the patient, we decided to perform pancreaticoduodenectomy because of the tumor's diameter and doubling rate. ...
Von Hippel-Lindau disease (VHL) is frequently associated with pancreatic neuroendocrine tumors (PNETs). Here, we report a case of tumor-to-tumor metastasis in a VHL patient in whom colon cancer metastasized to the interior of a PNET. A 65-year-old man had undergone bilateral adrenalectomy for pheochromocytomas in both adrenal glands in his 50 s. Genetic screening was performed considering his family history of pheochromocytoma, and he was diagnosed with VHL. PNET was detected, for which the patient was regularly monitored by follow-up imaging. One year ago, the patient underwent right hemicolectomy to remove a tumor in the ascending colon (pT3N0M0, pStage IIA). He was admitted to our department for detailed examination because the pancreatic tumor had grown, and thus, pancreaticoduodenectomy was performed. Diagnostic imaging and histological findings indicated tumor-to-tumor metastasis, in which the patient’s previous colon cancer had metastasized to and proliferated within the PNET. Colon cancer metastasizing to a PNET is extraordinarily rare and has never been reported in the literature. Thus, practitioners should be vigilant for tumor-to-tumor metastasis when performing imaging surveillance of PNETs.
... Tumor size is the strongest risk factor of aggressiveness. In a prospective study enrolling 108 patients with VHL-related panNENs, tumors with size >3 cm were more likely to develop metastasis (24 versus 3.6%, p < 0.005) [121]. In a recent retrospective report including 17 VHL-related panNENs, seven patients with tumor size <3 cm were treated conservatively, with all but one displaying stable disease at a 2 year median follow-up [122]. ...
... The current trend is to propose a conservative treatment for NF-panNENs with size <3 cm in the body/tail of the pancreas, this cut-off being decreased to 2 cm in the pancreatic head when suitable for enucleation [118,123]. Tumors with increasing size during follow-up, associated with a germline mutation in exon 3 and suspicion of LNM (if 90% of the primary tumor seems resectable), are discussed surgical indications [118,121,123,124]. As shown in a retrospective study including 11 patients with small VHL-associated panNENs, tumors with size <1.5 cm do not progress when left in place [125] and therefore should not be removed when identified intra-operatively [118]. ...
Pancreatic neuroendocrine neoplasms (panNENs) are a heterogeneous group of tumors derived from cells with neuroendocrine differentiation. They are considered malignant by default. However, their outcomes are variable depending on their presentation in the onset of hereditary syndromes, hormonal secretion, grading, and extension. Therefore, although surgical treatment has long been suggested as the only treatment of pancreatic neuroendocrine neoplasms, its modalities are an evolving landscape. For selected patients (small, localized, non-functional panNENs), a “wait and see” strategy is suggested, as it is in the setting of multiple neuroendocrine neoplasia type 1, but the accurate size cut-off remains to be established. Parenchyma-sparring pancreatectomy, aiming to limit pancreatic insufficiency, are also emerging procedures, which place beyond the treatment of insulinomas and small non-functional panNENs (in association with lymph node picking) remains to be clarified. Furthermore, giving the fact that the liver is generally the only metastatic site, surgery keeps a place of choice alongside medical therapies in the treatment of metastatic disease, but its modalities and extensions are still a matter of debate. This narrative review aims to describe the current recommended surgical management for pancreatic NENs and controversies in light of the actual recommendations and recent literature.
... The management strategy for pNETs is determined by prognostic factors including tumor size (surgical resection is typically recommended for pNETs ≥3 cm in the body and tail and ≥2 cm in the head of the pancreas) and tumor growth kinetics/doubling time (4,10,14,17,18). Active surveillance is generally recommended for smaller tumors with no malignant characteristics (4,10). ...
Purpose
Primary analysis of the ongoing, single-arm, phase 2 LITESPARK-004 study (NCT03401788) showed clinically meaningful antitumor activity in von Hippel–Lindau (VHL) disease–associated renal cell carcinoma (RCC) and other neoplasms with belzutifan treatment. We describe results of belzutifan treatment for VHL disease–associated pancreatic lesions [pancreatic neuroendocrine tumors (pNET) and serous cystadenomas].
Patients and Methods
Adults with VHL diagnosis based on germline VHL alteration, ≥1 measurable RCC tumor, no renal tumor >3 cm or other VHL neoplasm requiring immediate surgery, Eastern Cooperative Oncology Group performance status of 0 or 1, and no prior systemic anticancer treatment received belzutifan 120 mg once daily. End points included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and linear growth rate (LGR) in all pancreatic lesions and pNETs per RECIST version 1.1 by independent review committee, and safety.
Results
All 61 enrolled patients (100%) had ≥1 pancreatic lesion and 22 (36%) had ≥1 pNET measurable at baseline. Median follow-up was 37.8 months (range, 36.1–46.1). ORR was 84% [51/61; 17 complete responses (CR)] in pancreatic lesions and 91% (20/22; 7 CRs) in pNETs. Median DOR and median PFS were not reached in pancreatic lesions or pNETs. After starting treatment, median LGR for pNETs was –4.2 mm per year (range, –7.9 to –0.8). Eleven patients (18%) had ≥1 grade 3 treatment-related adverse event (AE). No grade 4 or 5 treatment-related AEs occurred.
Conclusions
Belzutifan continued to show robust activity and manageable safety in VHL disease–associated pNETs.
... Several genetic disorders predispose to the development of PNETs, and surgical management of PNET may be specific to these conditions. In these conditions, expectant management rather than aggressive surgical resection of small PNETs is established practice [107,108]. Von Hippel-Lindau (VHL) is an autosomal dominant inherited disease associated with increased risk of several tumors, including PNETs in up to 17% of all VHL patients. PNETs are less likely to be high grade in VHL patients. ...
Simple Summary
This review, as part of a series of reviews on neuroendocrine tumors, focuses on the particular management strategies for pancreatic neuroendocrine tumors. While far less common than pancreatic ductal adenocarcinoma, neuroendocrine tumors of the pancreas are increasingly recognized in the setting of high-quality cross-sectional imaging. These tumors demonstrate a range of behavior from the nonfunctional to hormone-secreting functional tumors, and from relatively indolent neoplasms to those with more aggressive behavior. Management principles unique to these tumors are addressed, including the role of surgery for both oncologic as well as palliative goals, indications for surgery versus observation in small nonfunctional tumors, and management of metastatic disease.
Abstract
Pancreatic neuroendocrine tumors (PNETs) are relatively uncommon malignancies, characterized as either functional or nonfunctional secondary to their secretion of biologically active hormones. A wide range of clinical behavior can be seen, with the primary prognostic indicator being tumor grade as defined by the Ki67 proliferation index and mitotic index. Surgery is the primary treatment modality for PNETs. While functional PNETs should undergo resection for symptom control as well as potential curative intent, nonfunctional PNETs are increasingly managed nonoperatively. There is increasing data to suggest small, nonfunctional PNETs (less than 2 cm) are appropriate follow with nonoperative active surveillance. Evidence supports surgical management of metastatic disease if possible, and occasionally even surgical management of the primary tumor in the setting of widespread metastases. In this review, we highlight the evolving surgical management of local and metastatic PNETs.
... Nevertheless, the presence of metastatic PNET is associated with increased mortality, with tumor size above 3 cm and a pathogenic variant in exon 3 of the VHL gene associated with an increased chance of metastatic disease [14][15][16][17][18]. The prevalence of VHL-related PNET (vPNET) is, on average, 5%, reaching up to 17% in specific cohorts [4,5,[19][20][21][22]. Compared with sporadic PNET (sPNET), vPNET is diagnosed at a relatively young age, is often non-functional, multifocal, is usually grade 1 or 2, and typically carries a more benign course compared with sPNET [17,[23][24][25][26]. Based on the distinct clinical course of vPNET compared to sPNET, supported by retrospective data on differences in mortality risk [13], specific management recommendations for vPNET were developed by Laks et al. in 2022 [27], which differ from the guidelines for sPNET management in various parameters [28,29]. ...
Simple Summary
Von Hippel–Lindau is a rare endocrine (and other organ) multi-neoplasia syndrome. A clinical diagnosis may be defined using different diagnostic criteria. However, the validity of these criteria has not been evaluated thus far. Here, we assess the patient population defined by the main sets of diagnostic criteria and demonstrate the different diagnostic accuracy of each diagnostic criterion based on patients’ characteristics and genetic analysis.
Abstract
Von Hippel–Lindau (VHL) disease diagnosis is based on two criteria sets: International criteria (IC, two hemangioblastomas, one hemangioblastoma plus one visceral lesion, or VHL family history/pathogenic variant plus hemangioblastoma/visceral lesion); or Danish criteria (DC, two clinical manifestations, or VHL family history/pathogenic variant plus hemangioblastoma/visceral lesion). We aimed to compare the characteristics of patients with VHL-related pancreatic neuroendocrine tumor (vPNET) meeting either the clinical Danish criteria only (DOC) or IC to those with sporadic PNET (sPNET). The cohort included 33 patients with VHL (20 vPNETs) and 65 with sPNET. In terms of genetic testing and family history of VHL, 90.0% of the patients with vPNET in the IC group had a germline VHL pathogenic variant, and 70.0% had a family history of VHL vs. 20% and 10% in the DOC group, respectively (p < 0.05 for both). Patients with vPNET were younger at diagnosis compared with sPNET (51.6 ± 4.1 vs. 62.8 ± 1.5 years, p < 0.05). Patients in the IC group were younger at diagnosis with VHL, vPNET, pheochromocytoma, or paraganglioma (PPGL) and renal-cell carcinoma (RCC) than those in the DOC group (p < 0.05 for all comparisons). The most prevalent presenting manifestations were hemangioblastoma (42.8%) and PPGL (33.3%) vs. RCC (58.3%) and PNET (41.7%) in the IC vs. DOC groups. In conclusion, patients with vPNET meeting DOC criteria show greater similarity to sPNET. We suggest performing genetic testing, rather than solely using clinical criteria, for establishing the diagnosis of VHL.
... Other studies endorsed these findings in the following years 8,12,16,22,23 . Nowadays, surgeons must consider three factors for indicating operative treatment in these patients 7,8,12,16,22,23 : (1) mutation in the exon 3, (2) tumors with 30 mm or larger, and (3) fast growth pattern (double size in 1 year or less). ...
BACKGROUND
The von Hippel-Lindau disease is a highly penetrant autosomal dominant syndrome characterized by tumor predisposition in different organs.
AIM
This study aimed to describe a case of a pancreatoduodenectomy for a 30-year-old male patient with von Hippel-Lindau disease.
METHODS
We present a case study and the literature review aiming at the state-of-the-art management of a patient with pheochromocytoma, capillary hemangioblastoma in the peripheral retina, and two neuroendocrine tumors in the pancreas.
RESULTS
A larger pancreatic lesion was located in the uncinate process, measuring 31 mm. The smaller lesion was located in the proximal pancreas and was detected only on the positron emission tomography-computed tomography scan with DOTATOC-68Ga. Genetic investigation revealed a mutation in the locus NM_000551.3 c.482G>A (p.Arg161Gln) of the Von Hippel-Lindau Human Suppressor gene. The uncinate process tumor was larger than 30 mm and the patient had a mutation on exon 3; therefore, we indicated a pancreatoduodenectomy involving the proximal pancreas to resect both tumors en bloc. During the postoperative period, the patient presented a peripancreatic fluid collection, which was treated as a grade B pancreatic fistula with clinical resolution of the complication. On postoperative day 21, he was discharged home.
CONCLUSION
The management of patients with von Hippel-Lindau disease and pancreatic neuroendocrine tumors is complex and must be centered on tertiary institutions with a large volume of pancreatic surgery. Although the current literature assists in decision-making in most situations, each step of the treatment requires analysis and discussion between different medical specialties, including surgeons, clinicians, radiologists, and anesthesiologists.
HEADINGS:
Pancreaticoduodenectomy; von Hippel-Lindau Disease; Neuroendocrine Tumors
... Interestingly, missense mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic pNETs [74]. Additional risk factors for malignant VHL-associated pNETs include tumor size greater than 3 cm, short tumor diameter doubling time (less than 500 days), and other genetic factors [75][76][77][78]. ...
PurposeNeuroendocrine neoplasms can occur as part of inherited disorders, usually in the form of well-differentiated, slow-growing tumors (NET). The main predisposing syndromes include: multiple endocrine neoplasias type 1 (MEN1), associated with a large spectrum of gastroenteropancreatic and thoracic NETs, and type 4 (MEN4), associated with a wide tumour spectrum similar to that of MEN1; von Hippel-Lindau syndrome (VHL), tuberous sclerosis (TSC), and neurofibromatosis 1 (NF-1), associated with pancreatic NETs. In the present review, we propose a reappraisal of the genetic basis and clinical features of gastroenteropancreatic and thoracic NETs in the setting of inherited syndromes with a special focus on molecularly targeted therapies for these lesions.
Methods
Literature search was systematically performed through online databases, including MEDLINE (via PubMed), and Scopus using multiple keywords’ combinations up to June 2022.ResultsSomatostatin analogues (SSAs) remain the mainstay of systemic treatment for NETs, and radiolabelled SSAs can be used for peptide-receptor radionuclide therapy for somatostatin receptor (SSTR)-positive NETs. Apart of these SSTR-targeted therapies, other targeted agents have been approved for NETs: the mTOR inhibitor everolimus for lung, gastroenteropatic and unknown origin NET, and sunitinib, an antiangiogenic tyrosine kinase inhibitor, for pancreatic NET. Novel targeted therapies with other antiangiogenic agents and immunotherapies have been also under evaluation.
Conclusions
Major advances in the understanding of genetic and epigenetic mechanisms of NET development in the context of inherited endocrine disorders have led to the recognition of molecular targetable alterations, providing a rationale for the implementation of treatments and development of novel targeted therapies.
... VHL is another tumor syndrome that phenotypically includes pNETs along with pheochromocytoma, renal cell carcinoma and hemangioblastoma and results from mutation in the VHL gene on chromosome 3p25 (26). It is thought that mutated VHL facilitates degradation of hypoxia inducible factor 1, which induces production of growth factors, angiogenesis and tumor growth (34). TSC arises from mutations in the TSC1 gene on chromosome 9q34 or TSC2 gene on chromosome 16p13.3 ...
Gastroenteropancreatic neuroendocrine neoplasms are a rare, diverse group of neuroendocrine tumors that form in the pancreatic and gastrointestinal tract, and often present with side effects due to hormone hypersecretion. The pathogenesis of these tumors is known to be linked to several genetic disorders, but sporadic tumors occur due to dysregulation of additional genes that regulate proliferation and metastasis, but also the epigenome. Epigenetic regulation in these tumors includes DNA methylation, chromatin remodeling and regulation by noncoding RNAs. Several large studies demonstrate the identification of epigenetic signatures that may serve as biomarkers, and others identify innovative, epigenetics-based targets that utilize both pharmacological and theranostic approaches towards the development of new treatment approaches.
... They modified the recommendation given by Libutti et al. (Fig. 1). 62 Surgical resection includes enucleation for small tumors located away from the pancreatic duct, pylorus-preserving pancreaticoduodenectomy (Whipple's procedure) for tumor located at the head of pancreas, and partial or total pancreatectomy with replacement for multiple pancreatic lesions. In patients with hepatic metastasis, local therapies including ablative therapy or chemoembolization have been associated with long-term control of the tumor. ...
... If surgery is indicated, a procedure that preserves as much pancreatic function as possible is recommended. In a setting of VHL disease, surgery is considered for tumors that are C 2 cm and have a doubling time \ 500 days [72]. ...
Neuroendocrine neoplasms (NENs) are rare neoplasms that occur in various organs and present with diverse clinical manifestations. Pathological classification is important in the diagnosis of NENs. Treatment strategies must be selected according to the status of differentiation and malignancy by accurately determining whether the neoplasm is functioning or nonfunctioning, degree of disease progression, and presence of metastasis. The newly revised Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) comprises 5 chapters—diagnosis, pathology, surgical treatment, medical and multidisciplinary treatment, and multiple endocrine neoplasia type 1 (MEN1)/von Hippel–Lindau (VHL) disease—and includes 51 clinical questions and 19 columns. These guidelines aim to provide direction and practical clinical content for the management of GEP-NEN preferentially based on clinically useful reports. These revised guidelines also refer to the new concept of “neuroendocrine tumor” (NET) grade 3, which is based on the 2017 and 2019 WHO criteria; this includes health insurance coverage of somatostatin receptor scintigraphy for NEN, everolimus for lung and gastrointestinal NET, and lanreotide for GEP-NET. The guidelines also newly refer to the diagnosis, treatment, and surveillance of NEN associated with VHL disease and MEN1. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the first edition was published.
... Although the most frequent pancreatic lesions include pancreatic cysts, which are found in 75% of vHL patients, one-fifth of the vHL patients will present pNETs, arising earlier than in non-syndromic patients, mostly in the fourth decade of life [112,113]. ...
The presence of pancreatic cancer during childhood is extremely rare, and physicians may be tempted to overlook this diagnosis based on age criteria. However, there are primary malignant pancreatic tumors encountered in pediatric patients, such as pancreatoblastoma, and tumors considered benign in general but may present a malignant potential, such as the solid pseudo-papillary tumor, insulinoma, gastrinoma, and vasoactive intestinal peptide secreting tumor. Their early diagnosis and management are of paramount importance since the survival rates tend to differ for various types of these conditions. Many pediatric cancers may present pancreatic metastases, such as renal cell carcinoma, which may evolve with pancreatic metastatic disease even after two or more decades. Several childhood diseases may create a predisposition for the development of pancreatic cancer during adulthood; hence, there is a need for extensive screening strategies and complex programs to facilitate the transition from pediatric to adult healthcare. Nevertheless, genetic studies highlight the fact the specific gene mutations and family aggregations may be correlated with a special predisposition towards pancreatic cancer. This review aims to report the main pancreatic cancers diagnosed during childhood, the most important childhood diseases predisposing to the development of pancreatic malignancies, and the gene mutations associates with pancreatic malignant tumors.
... MSNN with associated VHL associated syndrome requires further consideration as VHL syndrome-associated MSNN presents at a younger age, has diffuse-type PCSN, has a larger PanNET size, and has other associated tumors (such as renal clear cell carcinoma, cerebellar/retina hemangioblastoma, liver angioma, adrenal pheochromocytoma, and paravertebral paraganglioma) [8]. Moreover, VHL syndrome associated with PanNET has a higher potential for malignancy [18]. Thus, MSNN patients should be meticulously evaluated for the presence of other lesions and VHL syndrome. ...
Mixed serous-neuroendocrine neoplasm constitutes pancreatic serous cystic neoplasms and pancreatic neuroendocrine tumor, two tumor components with different underlying pathologies. The differentiation of these tumors is important as the management and prognosis depend on the pancreatic neuroendocrine tumor component. We report a case of mixed serous-neuroendocrine neoplasm in a 47-year-old female who presented with epigastric pain abdomen for two years. Imaging studies, tumor markers, thorough systemic evaluation, surgical resection, histopathological examination, and timely follow-up constituted our management approach. A 4 cm × 4 cm mass in the distal pancreas with multiple cysts in the pancreatic parenchyma containing serous fluid on distal pancreatectomy and splenectomy was found. The histopathological examination revealed combined benign serous cystadenoma and neuroendocrine tumor. She did not have any recurrence or metastasis by four years of follow-up.
Von Hippel-Lindau disease (VHL) is a multiple organ neoplastic syndrome with autosomal dominant transmission, complete penetrance, and variable expression caused by mutations in the VHL gene. Although VHL disease is hereditary in many cases, new mutations cause up to 20 % of the incidence. Mutations in VHL may cause the development of cysts and tumors in many organs, including brain and spinal cord hemangioblastoma, renal cell carcinoma (RCC), retinal heman-gioblastoma (RH), pheochromocytoma, epididymal and broad ligament cystadenomas, endo-lymphatic sac tumor, pancreatic neuroendocrine tumors, and renal and pancreatic cysts. VHL is a syndrome associated with functional inactivation of the Von Hippel–Lindau protein (pVHL). pVHL is a tumor suppressor mainly known for its role as a regulator of hypoxia-inducible factor (HIF) activity. The prevalence of VHL disease is between 1 in 39 000 and 1 in 91 000 individuals in different regional populations. Here, we review the etiology, epidemiology, pathophysiology, genetics, clinical manifestations, diagnosis, and current treatments, as well as the molecular aspects of this disease. We also discuss the animal models used to study this disease, VHL biomarkers, and current VHL clinical trials for VHL according to NIH.
Background
Von Hippel-Lindau disease (VHL) is a rare autosomal dominant hereditary cancer-predisposition syndrome caused by germline pathogenic variants (PV) in VHL gene. It is associated with a high penetrance of benign and malignant vascular tumors in multiples organs, including pancreatic neuroendocrine tumors (PanNETs), whose long-term natural history is ill-known.
Methods
Patients with both documented germline PV in VHL gene and PanNETs included in the French PREDIR database between 1995 and 2022 were included. Primary endpoint was the proportion of patients with PanNET-related metastases and secondary endpoint was overall survival (OS). Genotype/phenotype correlations were studied.
Results
We included 121 patients with 259 PanNETs. Median age at diagnosis was 38 years. Median follow-up was 89.5 months. PanNET surgical resection was performed in 51 patients. Overall, 29 patients (24%) had metastases (5 synchronous, 10 metachronous), with a higher risk in case of larger PanNET size (p=0.0089; best threshold 28 mm) and grade 2 PanNET (p=0.048), and a pejorative prognostic impact (p=0.043). Patients with PV in VHL exon 1 had larger PanNETs (p=0.018), more often metastatic disease (48% vs 11.5%; p < 0.001) and a trend toward shorter OS (p=0.16).
Conclusion
The risk of metastases associated to VHL-related PanNETs remains low (24%) but increases with tumor size >28 mm, higher grade and in case of PV located VHL exon 1. These data might help improving the management of these patients, who should be referred to an expert center.
Von Hippel–Lindau (VHL) disease, an autosomal dominant genetic disorder caused by a germline mutation, is associated with non-functional and slow-growing pancreatic neuroendocrine tumor (PNET) and kidney cancer. We describe the case of a 46 year-old man with a 35 mm mass in the pancreatic head causing stricture of the bile duct and main pancreatic duct, a 55 mm mass in the pancreatic tail causing obstruction of the splenic vein (SV), and multiple masses of > 36 mm on both kidneys. We performed a two-stage resection. First, a total pancreatectomy with superior mesenteric vein (SMV) resection and reconstruction and retroperitoneoscopic right partial nephrectomy (NP) for five lesions was performed, followed by retroperitoneoscopic left partial NP of the five lesions 6 months later. Postoperative histopathological examination revealed NET G2 in the pancreatic head with SMV invasion and somatostatin receptor type 2A (SSTR2A) positivity, NET G2 in the pancreatic tail showed SV invasion and negative SSTR2A, and multiple clear cell renal cell carcinomas (RCC) were also noted. Multiple liver recurrences occurred 22 months after primary surgery. The patient remains alive 41 months after primary surgery. Kidney cancer generally determines VHL prognosis; however, we experienced dual-advanced PNETs with a more defined prognosis than multiple RCC associated with VHL.
Background
Von-Hipple Lindau syndrome is an uncommon autosomal dominant disorder. 17 years ago we diagnosed a young woman with VHL syndrome validated by Sanger sequencing, her family members were genetically tested as well, and 187 healthy people were randomly selected for VHL genetic testing as controls. We analyze the clinical and genetic characteristics of VHL syndrome in a Chinese lineage and with 17-year follow-up.
Case presentation
A woman was finally diagnosed with VHL syndrome due to the detection of a missense mutation c.353T > C in exon 2 of the short arm of chromosome 3, which resulted in a leucine substitution at amino acid 118 of the encoded protein by a proline, which may be thought the main cause of the disease. The same mutation was observed in two other family members, their clinical symptoms are not entirely identical. However, this mutation was not found in other family members or 187 healthy controls. She clinically presented with central nervous system hemangioblastomas, clear renal cell carcinoma, and pancreatic neuroendocrine neoplasms, despite the multi-organ involvement and several relapses during the disease, the patients survive well for she was treated with aggressive surgery early in the course of the plaguing symptoms, whereas patients who are not aggressively treated have a poorer prognosis.
Conclusion
The clinical presentation of VHL syndrome is atypical, and early identification and treatment of VHL syndrome is possible by genetic testing techniques. Multiple relapses occurred during the course of the disease, but early diagnosis and aggressive treatment allowed the patients to survive well.
Patients with VHL disease develop tumors affecting various organ systems and anatomical locations starting at an early age. Effective management of this disease involves detecting and intervening on these tumors at appropriate timepoints before the development of symptoms or progression to metastatic disease. Screening and surveillance guidelines based on our understanding of the natural history of VHL disease have been developed to guide management of these complex tumors. The goal is to reduce tumor-related morbidity and mortality while preserving organ functions. This chapter summarizes the screening and surveillance guidelines put forth by various international societies as well as the general management strategies for various VHL lesions. In short, patients with VHL should enter screening and surveillance programs—ideally at institutions with multidisciplinary clinics specializing in VHL disease management—at early age and should undergo annual or biennial follow-up to track their disease progression and determine the appropriate time for intervention if needed.
von Hippel-Lindau (VHL) disease is a hereditary autosomal dominant syndrome characterized by the development of several different neoplasms. Although central nervous system hemangioblastomas and renal cell carcinomas are the most significant source of morbidity and mortality associated with VHL disease, approximately two-thirds of patients with VHL will have pancreatic lesions identified throughout their lifetime. Cystic pancreatic lesions are benign; however solid lesions most commonly represent pancreatic neuroendocrine tumors (PanNETs), which have the ability to metastasize. VHL-associated PanNETs are almost uniformly nonfunctional with variable metastatic potential. Surgical treatment depends on the size of the lesion, tumor genotype, the location within the pancreas as well as patient-related factors. This chapter will outline the treatment options for patients with VHL disease and PanNETs.
von Hippel-Lindau disease (VHL) is an autosomal dominant disease with a penetrance of nearly 100% by age 70 years. The prevalence is about one in 39,000 to 85,000 people. VHL is characterized by the development of benign and malignant tumors, including hemangioblastomas of the retina and central nervous system, clear cell renal cell carcinomas and cysts, pheochromocytomas and paragangliomas, pancreatic neuroendocrine tumors and cysts, endolymphatic sac tumors, and epididymal and broad ligament cysts. Herein, we describe the diagnostic criteria, VHL classification, and the disease’s epidemiological spectrum.
Von Hippel-Lindau syndrome (VHL) is an inherited autosomal dominant condition characterized by tumors of the kidney, central nervous system, and adrenal glands among others. Within VHL, tumors in the pancreas may occur, and pancreas lesions are seen in VHL types 1 and 2A (Nordstrom-O'Brien et al., Hum Mutat 31(5):521–37, 2010). Pancreatic neuroendocrine tumors (PNETs) are found in 8–17% of patients while pancreatic cystic neoplasms, either cysts or serous cystadenoma, occur in anywhere from 17% to 56% (Lonser et al., Lancet 361(9374):2059–67, 2003). Both tend to occur in patients in their mid to late 30s. Distinguishing between tumor type informs plans for follow-up, expected outcomes, as well as future management. Because they occur within the setting of a genetic mutation and because recurrence or multiple tumors are expected, recommendations for treatment deviate from what would be expected in a solitary tumor. While pancreas tumors are not the primary cause of mortality in VHL, they do require surveillance and, in some cases, surgical management.
Cancer metabolism research area evolved greatly, however, is still unknown the impact of systemic metabolism control and diet on cancer. It makes sense that systemic regulators of metabolism can act directly on cancer cells and activate signalling, prompting metabolic remodelling needed to sustain cancer cell survival, tumour growth and disease progression. In the present review, we describe the main glucagon functions in the control of glycaemia and of metabolic pathways overall. Furthermore, an integrative view on how glucagon and related signalling pathways can contribute for pancreatic neuroendocrine tumours (pNETs) and hepatocellular carcinomas (HCC) progression, since pancreas and liver are the major organs exposed to higher levels of glucagon, pancreas as a producer and liver as a scavenger. The main objective is to bring to discussion some glucagon-dependent mechanisms by presenting an integrative view on microenvironmental and systemic aspects in pNETs and HCC biology.
The simultaneous or metachronous occurrence of pancreatic neuroendocrine tumor (panNET) and renal cell carcinoma (RCC) may represent a rare coincidence or a manifestation of von Hippel-Lindau disease (VHL). These two malignancies share both radiological and cytopathological features, making the differential diagnosis very challenging. In this review, we collected all cases of concurrent diagnosis of localized panNET and RCC, with or without VHL, as reported in the literature to date. We aimed to provide an insight into the differential diagnosis between panNET and RCC pancreatic metastasis with a focus on the optimal therapeutic algorithm depending on the diagnosis. We performed literature research in PubMed library databases for articles about coexisting panNET and RCC published from 2001 to 2018. We selected nine articles with a total of 13 patients, including one treated at our institution. Patients' median age was 49 years and eight out of 13 patients were women. VHL was diagnosed in nine cases. Most patients underwent radical nephrectomy for RCC (9/13) and a clear cell renal carcinoma variant was identified in six cases. The diagnosis of panNET was synchronous with RCC detection in nine cases and metachronous in four cases. The diameter of the pancreatic lesion was >2 cm in six cases. In two cases the panNET was misdiagnosed as metastatic RCC by radiological tests. Somatostatin receptor scanning was performed only in our patient (Octreoscan) showing intense uptake in the pancreatic mass. Endoscopic ultrasound fine needle aspiration of the pancreatic lesion was performed in four patients: in two cases the panNET was confused with metastatic RCC by cytological analysis. Most patients underwent pancreatic surgery (10/13) without histological confirmation. Clear cell panNET was recognized in six cases, while mixed neuroendocrine non-neuroendocrine neoplasm was diagnosed in one patient. Immunohistochemistry (IHC) staining showed positivity to typical neuroendocrine markers (chromogranin A and synaptophysin) in all reported tested cases (8/8). Three patients underwent systemic treatment: two patients received sunitinib and one patient interleukin-2 (IL-2). Other neoplasms were observed in seven patients, of whom six were affected by VHL syndrome. When neoplastic lesions are recognized in both the kidney and pancreas, panNET and RCC pancreatic metastasis are often misdiagnosed due to similar radiological and cytopathological features. An accurate differential diagnosis is crucial and IHC plays a central role in distinguishing the two entities. The therapeutic algorithm may change depending on the diagnosis: while pancreatic RCC metastases benefit from resection, in panNETs and VHL the indication for surgery must be carefully evaluated.
Рост заболеваемости нейроэндокринными опухолями увеличивает интерес к изучению генетического ландшафта новообразований. В большей степени нейроэндокринные опухоли (НЭО) исследованы в контексте наследственных генетических синдромов, включая гены, такие как MEN1 , VHL , TSC1 / TSC2 , NF1 и CDKN1B . Взаимосвязь между наследственными (генеративными) мутациями в генах системы репараций ДНК и нейроэндокринными опухолями на сегодня практически не изучена.
В условиях ГАУЗ «Республиканский клинический онкологический диспансер Министерства здравоохранения Республики Татарстан имени профессора М. З. Сигала» был изучен молекулярный профиль пациентов с диагнозом «нейроэндокринная опухоль» в зависимости от наследственного анамнеза. В проведенном исследовании у каждого четвертого пациента обнаруживались патогенные мутации. У 33 % пациентов при наличии наследственного анамнеза выявлены патогенные, либо условно-патогенные мутации
Gastro-entero-pancreatic (GEP-NET) and thoracic neuroendocrine tumours (NETs) are one of the most heritable groups of neoplasms in the body, being multiple endocrine neoplasia syndrome type 1 (MEN1), the genetic syndrome most frequently associated with this type of tumours. Moreover, Von Hippel Lindau syndrome, tuberous sclerosis, type 4 multiple neoplasia syndrome, and type 1 neurofibromatosis are associated with an increased risk of developing GEP-NETs. Another important aspect in GEP-NETs and thoracic NETs is the knowledge of the molecular background since the molecular profile of these tumours may have implications in the prognosis and in the response to specific treatments. This review summarizes the main indications for performing a genetic study in patients with GEP-NETs and thoracic NETs, and the methods used to carry it out. Moreover, it offers a description of the main hereditary syndromes associated with these NETs and their molecular background, as well as the clinical implications of the molecular profile.
Silverberg's Principles and Practice of Surgical Pathology and Cytopathology is one of the most durable reference texts in pathology. Thoroughly revised and updated, this state-of-the-art new edition encompasses the entire fields of surgical pathology and cytopathology in a single source. Its practice-oriented format uniquely integrates these disciplines to present all the relevant features of a particular lesion, side by side. Over 4000 color images depict clinical features, morphological attributes, histochemical and immunohistochemical findings, and molecular characteristics of all lesions included. This edition features new highly experienced and academically accomplished editors, while chapters are written by the leading experts in the field (several new to this edition, bringing a fresh approach). Dr Steven Silverberg's practical approach to problem solving has been carefully preserved. The print book is packaged with access to a secure, electronic copy of the book, providing quick and easy access to its wealth of text and images.
Pancreatic neuroendocrine tumors (pNETs) represent a relatively rare disease; however, the incidence has been increasing during the last 2 decades. Next generation sequencing has greatly increased our understanding of driver mutations in pNETs. Sporadic pNETs have consistently presented with mutations in MEN1, DAXX/ATRX, and genes related to the mammalian target of rapamycin pathway. Inherited pNETs have traditionally been associated with multiple endocrine neoplasia type 1, von Hippel-Lindau syndrome, neurofibromatosis type 1, and tuberous sclerosis complex. The current review expands on the existing knowledge and the relevant updates on the genetics of pNETs.
Pancreatic neuroendocrine neoplasms (PanNENs) are rare tumors derived from pancreatic neuroendocrine cells. Recently, the World Health Organization modified and updated the classification of PanNENs, introducing new diagnostic entities and refining prognostic stratification in order to improve potential therapeutic strategies. The aim of this chapter is to provide clinical and pathological knowledge about PanNENs, in order to permit effective diagnostic approach to these particular entities. In particular, the latest changes included in WHO classification are illustrated, and all the new entities are described (PanNENs grade 3, pancreatic neuroendocrine carcinomas, and mixed neuroendocrine non-neuroendocrine neoplasms). All the paragraphs include concise but exhaustive pathologic features of neuroendocrine tumors, along with histopathological, cytological, and clinical diagnostic criteria. Lastly, recent and updated concepts about genetic features and molecular biology of PanNENs are included in every paragraph, offering a useful point of view about new therapeutic frontiers.
Pancreatic cancer is now the second most prevalent gastrointestinal neoplasm after colorectal cancer. Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms that originate from the islet cells of the pancreas. While they only account for approximately 7% of all pancreatic tumors, their incidence has been increasing over the past decade. Pancreatic neuroendocrine tumors are often classified according to functional status and tumor grade. Functional neuroendocrine tumors are those associated with a well-defined or classic syndrome and comprise 10–40% of PNETs. Functional tumors produce high levels of bioactive compounds or hormones including insulin, gastrin, glucagon, vasoactive intestinal peptide (VIP), or somatostatin. Nonfunctional tumors may overexpress various peptides, including neurotensin or calcitonin, yet patients remain largely asymptomatic until the tumor itself causes symptoms through mass effect from local expansion or metastatic disease. Symptoms associated with neuroendocrine tumors, including those produced by hormones, lead patients to pursue diagnoses early and have better survival. The surgical management of PNET varies widely, depending on the size and the location of the disease, as well as the presence of symptoms and the extent of the metastatic disease. A multidisciplinary team best manages PNET patients.
von Hippel Lindau disease (vHL) is caused by a hereditary predisposition to multiple neoplasms, especially hemangioblastomas in the retina and CNS, renal cell carcinomas (RCC), pheochromocytomas, neuroendocrine pancreatic tumours (PNET) and endolymphatic sac tumours. Evidence based approaches are needed to ensure an optimal clinical care, while minimizing the burden for the patients and their families.
This guideline is based on evidence from the international vHL literature and extensive research of geno- and phenotypic characteristics, disease progression and surveillance effect in the national Danish vHL cohort. We included the views and preferences of the Danish vHL patients, ensured consensus among Danish experts and compared with international recommendations.
Recommendations
vHL can be diagnosed on clinical criteria, only; however, in most cases the diagnosis can be supported by identification of a pathogenic or likely pathogenic variant in VHL. Surveillance should be initiated in childhood in persons with, or at risk of, vHL, and include regular examination of the retina, CNS, inner ear, kidneys, neuroendocrine glands, and pancreas. Treatment of vHL manifestations should be planned to optimize the chance of cure, without unnecessary sequelae. Most manifestations are currently treated by surgery. However, belzutifan, that targets HIF-2α was recently approved by the U.S. Food and Drug Administration (FDA) for adult patients with vHL-associated RCC, CNS hemangioblastomas, or PNETs, not requiring immediate surgery. Diagnostics, surveillance, and treatment of vHL can be undertaken successfully by experts collaborating in multidisciplinary teams. Systematic registration, collaboration with patient organisations, and research are fundamental for the continuous improvement of clinical care and optimization of outcome with minimal patient inconvenience.
Von Hippel‐Lindau (VHL) disease is a hereditary cancer syndrome where individuals are predisposed to tumor development in the brain, adrenal gland, kidney and other organs. It is caused by pathogenic variants in the VHL tumor suppressor gene. Standardized disease information has been difficult to collect due to the rarity and diversity of VHL patients. Over 4100 unique articles published until October 2019 were screened for germline genotype‐phenotype data. Patient data was translated into standardized descriptions using Human Genome Variation Society (HGVS) gene variant nomenclature and Human Phenotype Ontology (HPO) terms and has been manually curated into an open‐access knowledgebase called Clinical Interpretation of Variants in Cancer (CIViC). In total, 634 unique VHL variants, 2882 patients and 1991 families from 427 papers were captured. We identified relationship trends between phenotype and genotype data using classic statistical methods and spectral clustering unsupervised learning. Our analyses reveal earlier onset of pheochromocytoma/paraganglioma and retinal angiomas, phenotype co‐occurrences and genotype‐phenotype correlations including hot‐spots. It confirms existing VHL associations and can be used to identify new patterns and associations in VHL disease. Our database serves as an aggregate knowledge translation tool to facilitate sharing information about the pathogenicity of VHL variants. This article is protected by copyright. All rights reserved.
Pancreatic neuroendocrine neoplasms (PanNENs) are the neuroendocrine neoplasms with greatest rate of increase in incidence. Approximately 10% of PanNENs arise as inherited tumour syndromes which include multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 4, von Hippel–Lindau syndrome, neurofibromatosis type1, tuberous sclerosis complex 1/2, Cowden syndrome, and Glucagon cell hyperplasia and neoplasia as well as familial insulinomatosis. In sporadic PanNENs, driver mutations in MEN1, DAXX/ATRX and mTOR pathway genes are associated with development and progression in pancreatic neuroendocrine tumours. The other changes are in VEGF pathway, Notch pathway, germline mutations in MUTYH, CHEK2, BRCA2, PHLDA3 as well as other genetic alterations. On the other hand, pancreatic neuroendocrine carcinomas share similar genetic alterations with ductal adenocarcinomas, e.g., TP53, RB1 or KRAS. In addition, microRNA and changes in immune microenvironment were noted in PanNENs. Updates on these genetic knowledges contribute to the development of management strategies for patients with PanNENs.
Von Hippel-Lindau (VHL) syndrome is a hereditary tumor syndrome associated with germline loss-of-function pathogenic variants (PVs) in the VHL gene. VHL is classically associated with a high penetrance for many different tumor types. The same tumors may be sporadic in the setting of somatic VHL PVs. With more large-scale genome sequencing, variants with low penetrance or variable expressivity are identified. This has introduced challenges in patient management and the clinical interpretation of germline VHL variants identified in non-classic families. Herein, we report individuals from 3 non-classic families with VHL variants who presented with unexpected or non-syndromic phenotypes, but often with a VHL component tumor. In family 1, two siblings, age 61, with pathogenic VHL p.Leu188Val presented with clear cell renal cell carcinoma and lobular breast cancer. In family 2, the proband, age 82, was found to have pathogenic germline VHL p.Tyr98His on testing for metastatic bladder cancer. In family 3, four members carried germline VHL p.Pro81Ser (variant of uncertain significance), after the proband, age 40, presented with cerebellar hemangioblastoma. None of the individuals in the above three families met clinical criteria of classic VHL, suggesting germline VHL p.Leu188Val, p.Y98H, and p.Tyr98His may be low penetrant variants. Large studies are needed to evaluate penetrance and possible effect of genetic and non-genetic modifiers. Somatic sequencing performed on their respective tumors could help discern the etiology of the component tumors, highlighting the role of somatic evaluation in these cases. Paired examination of somatic and germline findings provided a more complete landscape of genome alterations in cancer development.
von Hippel-Lindau disease (VHL) is an inherited neoplastic disorder characterized by the development of tumors in the eyes, brain, spinal cord, inner ear, adrenal gland, pancreas, kidney, and epididymis. The VHL tumor suppressor gene was identified in 1993. Initial studies reported the detection of germline mutations in the VHL gene in 39–75% of VHL families. We used tests that detect different types of mutations to improve the frequency of detection of germline mutations in VHL families. The methods included quantitative Southern blotting to detect deletions of the entire VHL gene, Southern blotting to detect gene rearrangements, fluorescence in situ hybridization (FISH) to confirm deletions, and complete sequencing of the gene. Here we report that we have detected germline mutations in the VHL gene in 100% (93/93) of VHL families tested. In addition, we describe 13 novel intragenic VHL germline mutations. With the methodology described in this article, it is now possible to identify germline mutations in virtually all families with VHL. Hum Mutat 12:417–423, 1998. © 1998 Wiley-Liss, Inc.
Von Hippel-Lindau disease is a rare, autosomal-dominant disorder characterized by CNS hemangioblastomas, retinal angiomas, renal cell carcinomas, pheochromocytomas, and visceral cysts. The occurrence of islet cell tumors in von Hippel-Lindau disease has been noted recently. Because of the coexistence of both islet cell tumors and pheochromocytomas in some patients with this disorder, it has been proposed that there may be a continuum of the multiple endocrine neoplasias. However, no large, multifamily study has been published evaluating the prevalence of islet cell tumors and pheochromocytomas in von Hippel-Lindau disease. To assess the frequency of islet cell tumors in this disorder and its relationship to the multiple endocrine neoplasias, we reviewed the clinical and imaging findings of all patients with von Hippel-Lindau disease evaluated at the Mayo Clinic between January 1979 and December 1989. Forty-three patients with von Hippel-Lindau disease from over 25 kindreds were found. Cross-sectional imaging of the pancreas had been performed in 35. Islet cell tumors were found in six (17%) of these, three islet cell adenomas and three islet cell carcinomas. No patient presented with endocrine-related symptoms; four tumors were detected during screening examinations of the abdomen. Two (33%) of these six patients had a coexisting pheochromocytoma. Our review of a large number of patients from many different families with von Hippel-Lindau disease revealed a high prevalence of islet cell tumors and the frequent coexistence of islet cell tumors and pheochromocytomas. This latter finding supports a continuum of the multiple endocrine neoplastic syndromes.
Common manifestations of the von Hippel-Lindau syndrome, an autosomally dominant inherited cancer-prone disorder, include retinal angiomatosis, hemangioblastoma of the central nervous system, renal cysts, renal cancer, pheochromocytoma, and epididymal cystadenoma. Multiple cysts and microcystic (serous) cystadenomas of the pancreas have also been reported occasionally in patients afflicted with this syndrome. In the large Freiburg study of the von Hippel-Lindau syndrome composed of 66 affected individuals, pancreatic lesions were systematically studied. Fifty-five living individuals were examined by abdominal ultrasound imaging. Abnormal findings were confirmed by computed tomographic scan and/or magnetic resonance imaging. For an additional 11 decreased patients autopsy data were available. Cystic lesions of the pancreas were found in 10 patients (15%). One of these patients presented with multiple pancreatic cysts as the only manifestation of the syndrome. In one patient, a malignant islet-cell tumor was found at autopsy. Because multiple pancreatic cysts did not cause major clinical symptoms and because follow-up examinations over an average period of 5 years did not show significant progression of the lesions, it is concluded that these patients usually do not require surgical treatment. Abdominal ultrasound screening is recommended for patients at risk as a tool to identify potential von Hippel-Lindau syndrome gene carriers with pancreatic manifestations. In all patients with multiple pancreatic cysts, the von Hippel-Lindau syndrome should be included in the differential diagnosis.
The mortality in von Hippel-Lindau disease (VHL) is due to the development of central nervous system or abdominal malignancies, particularly renal cell carcinomas. The abdominal manifestations of VHL discovered in the radiological screening of 22 members of an affected family are described. We discuss the problems of making the diagnosis and of detecting small renal and pancreatic tumours against a background of multiple cystic disease. A radiological screening and surveillance protocol using ultrasound and computed tomography is described.
von Hippel-Lindau (VHL) disease is an autosomal dominant disorder that causes retinal hemangioblastomas, hemangioblastomas of the central nervous system, endolymphatic sac tumors, renal cell carcinomas, pancreatic cysts and tumors, pheochromocytomas, and epididymal cystadenomas, among other less common manifestations. Although this entity has been recognized for almost 70 years, recent developments in the genetics and imaging of VHL disease have greatly improved understanding of the disease and its natural history. This review describes the major events that led to the discovery of the gene for VHL and will familiarize the reader with recent developments in the magnetic resonance Imaging, computed tomographic, and ultrasound findings of this entity. Despite advances in the genetic understanding of this disease, imaging techniques will continue to play a major role in the diagnosis, management, and treatment of VHL.
The purposes of this study were to determine the nature, prevalence, and CT findings of pancreatic lesions in patients with von Hippel-Lindau disease and to determine whether identification of pancreatic cysts and neoplasms is important in establishing the diagnosis of von Hippel-Lindau disease.
The medical records and radiologic images of 52 patients with von Hippel-Lindau disease who were evaluated at our institution between 1976 and 1992, and who at some stage underwent abdominal CT, sonography, or MR imaging, were reviewed. The nature, prevalence, and CT findings of the pancreatic lesions were determined, and the role of the pancreatic abnormalities in establishing the diagnosis of von Hippel-Lindau disease was studied.
Twenty-nine (56%) of the 52 patients had pancreatic lesions. Nineteen patients had pancreatic cysts and no other pancreatic lesion. Four patients had islet cell tumors only, one had a microcystic adenoma only, and three had indeterminate pancreatic masses. One patient had cysts and an islet cell tumor, and another patient had cysts, an islet cell tumor, and a microcystic adenoma. In six patients (12%), pancreatic lesions were the only abdominal manifestation of von Hippel-Lindau disease. In three patients screened because of a family history of von Hippel-Lindau disease, no CNS abnormalities were present, and the only abdominal lesions were in the pancreas (cysts in two cases, islet cell carcinoma in the other). Thus, the pancreatic lesion was an important factor in establishing a diagnosis of von Hippel-Lindau disease in these patients.
Pancreatic lesions may be the only abdominal manifestation of von Hippel-Lindau disease. CT findings include cysts, islet cell tumors, and microcystic adenomas. Pancreatic lesions, including cysts, may precede any other manifestation of von Hippel-Lindau disease by several years, and recognition permits earlier diagnosis in patients being screened for von Hippel-Lindau disease.
Although pancreatic neuroendocrine tumors (NETs) in von Hippel-Lindau (VHL) disease have been reported, their pathological features have not been characterized. In addition, it is unknown whether alterations of the VHL gene are responsible for pancreatic NET development. To evaluate NETs in VHL patients, we performed histopathological analysis of 30 pancreatic tumors in 14 patients. In addition, DNA from NETs and normal pancreatic tissue from 6 patients with documented germ-line VHL gene mutations was studied for allelic deletions of the second copy of the VHL gene by fluorescence in situ hybridization and polymerase chain reaction-based single-strand conformational polymorphism analysis. Morphologically, the tumors were characterized by solid, trabecular, and/or glandular architecture and prominent stromal collagen bands. Sixty percent of the tumors revealed at least focally clear-cell cytology. All tumors were positive for panendocrine immunohistochemistry markers (chromogranin A and/or synaptophysin); 35% of NETs demonstrated focal positivity for pancreatic polypeptide, somatostatin, insulin, and/or glucagon; and no immunostaining for pancreatic and gastrointestinal hormones was observed in 65% of tumors. Dense core neurosecretory granules were evident by electron microscopic examination, and the clear cells additionally revealed abundant intracytoplasmic lipid. All NETs that were subjected to genetic analysis showed allelic loss of the second copy of the VHL gene. We conclude that multiple, nonfunctional pancreatic NETs occur in VHL patients. Stromal collagen bands and clear-cell morphology are important histological features of VHL-associated NETs. The presence of allelic deletions of the VHL gene in pancreatic NETs provides direct molecular evidence for a role of the gene in their tumorigenesis and establishes NET as an independent tumor type of VHL disease.
von Hippel Lindau disease (VHL) is an inherited syndrome characterized by tumors of the kidney, adrenal, central nervous system, and pancreas. The incidence and natural history of pancreatic neuroendocrine tumors occurring in VHL are not known.
From December 1988 through November 1997, 256 patients with VHL were screened with imaging studies, and these data were reviewed from a prospective database.
Thirty (12%) of 256 patients had solid pancreatic lesions consistent with neuroendocrine tumors. Fourteen patients underwent resection, and 4 with metastases on imaging studies underwent biopsy only. Of the 14 patients who underwent resection, 11 remain free of disease, 2 have experienced recurrence, and 1 has died of unrelated causes (mean follow-up, 25 months; range, 3 to 73 months). The size of the primary tumor (median, 5 cm; range, 3 to 8 cm) in patients with liver metastases was significantly larger than the size of the primary tumor (median, 2 cm; range, 1 to 5 cm) in patients without liver metastases (P = .0013).
Solid pancreatic lesions were detected in 12% of patients with VHL. Larger primary tumors were associated with liver metastases. Pancreatic imaging to identify neuroendocrine tumors and resection when they reach 2 to 3 cm may prevent the development of hepatic metastases.
Patients with hereditary forms of renal cancer are at risk for new tumors and metastases. Renal parenchymal sparing surgery has been performed to preserve renal function and quality of life, and prevent metastases. We evaluated a 3 cm. threshold for performing renal parenchymal sparing surgery in patients with von Hippel-Lindau disease and hereditary papillary renal cancer.
Patients with von Hippel-Lindau disease or hereditary papillary renal cancer and renal cancer were identified by screening affected kindred and by kindred history. Patients with small tumors were followed with serial imaging studies until the largest renal tumor was 3 cm., when renal parenchymal sparing surgery was performed. Renal tumors greater than 3 cm. were resected without delay. Parenchymal sparing techniques were used when possible in each group.
The 3 cm. surgical threshold was evaluated in 52 patients with von Hippel-Lindau disease (group 1) at a median followup of 60 months (range 6 to 205). None of these patients had metastatic disease and none has required renal transplantation or dialysis. In 44 patients with von Hippel-Lindau disease (group 2) renal tumors larger than 3 cm. developed. Median followup from the initial radiological diagnosis of renal cancer in this group was 66.5 months (range 0 to 321). Patients in group 1 underwent parenchymal sparing surgery instead of nephrectomy more frequently than those in group 2 (46 of 48 operations or 96% versus 45 of 72 or 63%, Fisher's exact test p <0.0001). In contrast to patients in group 1, metastatic renal cancer developed in 11 of the 44 in group 2 (25%) (Fisher's exact test p <0.0001). A total of 23 patients with hereditary papillary renal cancer were also identified. Median followup in these cases was 44 months (range 0 to 237). Ten patients had tumors less than 3 cm. No patient with tumors less than 3 cm. and 2 of the 13 (15%) with larger tumors had metastases.
Using a 3 cm. renal tumor diameter as an indication for renal surgery no patient with renal cancer and von Hippel-Lindau disease or hereditary papillary renal cancer had metastatic disease regardless of the number of tumors. Using a lesion size of 3 cm. as a threshold for performing renal parenchymal sparing surgery may help to prevent metastatic disease, unnecessary renal damage due to frequent surgery and renal dialysis or transplantation.
Patients with von Hippel-Lindau disease (VHL) may develop pancreatic neuroendocrine tumors (PNETs), which can behave in a malignant fashion. We prospectively evaluated size criteria for resection of lesions and the role of genotype/phenotype analysis of germline VHL mutations in predicting clinical course.
From December 1988 through December 1999 we screened 389 patients with VHL. The diagnosis of PNET was made by pathologic analysis of tissues or by radiographic appearance. Germline mutations were determined by quantitative Southern blotting, fluorescence in situ hybridization and complete gene sequencing.
Forty-four patients with PNETs have been identified; 25 have undergone surgical resection, 5 had metastatic disease, and 14 are being monitored. No patient who has undergone resection based on tumor size criteria has developed metastases. Patients with PNETs were more likely to have missense mutations (58%), and 4 of 5 patients (80%) with metastatic disease had mutations in exon 3 compared with 18 of 39 (46%) patients without metastatic disease.
Imaging for detection and surgical resection based on size criteria have resulted in the successful management of VHL patients with PNETs. Analysis of germline mutations may help identify patients at risk for PNET and which patients may benefit from surgical intervention.
Von Hippel-Lindau disease (VHL) is an autosomal-dominant inherited condition that predisposes patients to develop renal cysts and tumors, most commonly in the second to fourth decades of life. Renal cysts and tumors have historically been a major cause of disease-related morbidity and mortality, so urologists are often called on to manage patients with VHL. Knowledge of the extrarenal manifestations of VHL (hemangioblastomas of the central nervous system and retina, endolymphatic sac tumors, pancreatic cysts, epididymal and broad-ligament cysts, and pheochromocytomas) and integration of nonurologic specialties into management teams for VHL patients will help to achieve successful outcomes. Screening for renal manifestations of VHL, by regular imaging of the abdomen, begins late in the second decade of life. Because renal tumors in VHL can be multifocal and bilateral, management can be complex. Radical nephrectomy removes all tissue at risk for forming renal tumors; however, this necessitates renal replacement therapy. In an effort to control cancer effectively while preserving native renal function and minimizing intervention, some researchers have proposed an observational strategy. Patients are screened until the largest tumor reaches 3 cm in diameter, at which time operative intervention is recommended. Nephron-sparing surgery is undertaken, whenever technically feasible, with the goal of removing all tumors in that renal unit. The role of minimally invasive technologies is currently being evaluated in selected patients with VHL renal masses. Elucidation of molecular pathways associated with VHL renal tumors may facilitate development of effective medical treatments for these lesions in the future.
Improved detection of germline muta-tions in the von Hippel-Lindau disease tumor suppressor gene
- Glenn C G Stolle
- Humphrey B Js Zbar
- Choyke
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- Walther
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Stolle C, Glenn G, Zbar B, Humphrey JS, Choyke PL, Walther MM, et al. Improved detection of germline muta-tions in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 1998;12:417-23.