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Abstract

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.
435
Cancer February 1, 2022
Consensus Statement
Management Recommendations for Pancreatic Manifestations
of Von Hippel– Lindau Disease
Shachar Laks, MD1,2; Rachel van Leeuwaarde, MD, PhD3; Dhaval Patel, MD4; Xavier M. Keutgen, MD5; Pascal Hammel, MD6;
Naris Nilubol, MD4; Thera P. Links, MD, PhD7; Thorvardur R. Halfdanarson, MD8; Anthony B. Daniels, MD9; and Amit Tirosh, MD 2,10;
The Pancreatic Manifestations Recommendations Development Subcommittee of the VHL Alliance
Von Hippel– Lindau disease (VHL) is a multineoplasm inherited disease manifesting with hemangioblastoma of the central nervous sys-
tem 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 manage-
ment. 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 subcom-
mittee performed a comprehensive systematic review of the literature and conducted panel discussions to reach the current recom-
mendations. 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 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 manage-
ment of VHL- related pancreatic manifestations. Cancer 2022;128:435-446. © 2021 American Cancer Society.
KEYWORDS: neuroendocrine tumor, pancreas, recommendations, surveillance, von Hippel– Lindau.
INTRODUCTION
Von Hippel– Lindau disease (VHL) is a multineoplasm inherited disease with an autosomal dominant trait. The annual
incidence is approximately 1 in 36,000 live births.1,2 VHL is caused by pathogenic variants in the VHL tumor suppressor
gene3 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 neo-
plasms/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- 8 and may have a female predominance.5- 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.
VHL- related pancreatic neuroendocrine neoplasms (PNENs) are clinically distinct from sporadic PNENs in multiple
aspects. The European Neuroendocrine Tumor Society guidelines define a PNEN’s grade on the basis of cell morphology (well
differentiated vs poorly differentiated), and there are 3 grades (G1, G2, and G3) based on proliferative indices such as the mitotic
rate and Ki- 67 expression.10 Compared with sporadic PNENs, VHL- related PNENs are much less often high- grade11,12 or met-
astatic.8 The rarity of high- grade VHL- related PNENs has led the committee to use VHL- related PNET throughout this article.
A PNEN may be functional; that is, it may secrete hormones that cause clinical syndromes. Such syndromes in-
clude recurrent and/or multiple gastroduodenal ulcers (Zollinger- Ellison syndrome) from gastrin oversecretion, recurrent
hypoglycemic episodes from insulin oversecretion, and watery diarrhea syndrome from vasoactive intestinal polypeptide
Corresponding Author: Amit Tirosh, MD, Neuroendocrine Tumors Service, VHL Clinical Care Center, Endocrine Oncology Genomics Laboratory, Chaim Sheba Medical
Center, Sackler Faculty of Medicine, Tel Aviv University, Tel HaShomer, Ramat Gan, Israel (amit.tirosh@sheba.health.gov.il).
1 Surgery C, Chaim Sheba Medical Center, Tel Hashomer, Israel; 2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3 Depar tment of Endocrine
Oncology, University Medical Center Utrecht, Utrecht, the Netherlands; 4 National Cancer Institute, National Institutes of Health, Bethesda, Maryland; 5 Division of
Endocrine Surgery, Department of Surgery, University of Chicago Medical Center, Chicago, Illinois; 6 Department of Digestive and Medical Oncology, Paul Brousse Hospital,
Villejuif, France; 7 Division of Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands;
8 Division of Medical Oncology, Mayo Clinic Cancer Center, Rochester, Minnesota; 9 Division of Ocular Oncology and Pathology, Department of Ophthalmology and
Visual Sciences, Vanderbilt Eye Institute and Vanderbilt- Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; 10 Neuroendocrine Tumors
Service, Division of Endocrinology, Diabetes, and Metabolism, VHL Alliance– Certified Clinical Care Center, Chaim Sheba Medical Center, Tel Hashomer, Israel
DOI: 10.1002/cncr.33978, Received: August 26, 2021; Revised: September 22, 2021; Accepted: September 23, 2021, Published online November 4, 2021 in Wiley Online
Library (wileyonlinelibrary.com)
Consensus Statement
436 Cancer February 1, 2022
oversecretion. Although patients with sporadic PNENs
have a relatively high rate of functional PNETs, VHL-
related PNETs are almost exclusively nonfunctional.4,13
The unique clinical course of VHL- related PNETs af-
fects their management, including the diagnosis, the decision
to intervene and the type of intervention, and the surveil-
lance plan. The high pretest probability for a PNET allows
avoiding a cytopathological diagnosis when there is a typical
radiological appearance. Patients with VHL typically have
multiple tumors; thus, any unnecessary or extensive surgi-
cal resection may lead to an unjustified major parenchymal
sacrifice (early pancreaticoduodenectomy or even total pan-
createctomy is sometimes wrongly proposed). There may be
insufficient consideration by teams of digestive diseases due
to life- threatening tumors that affect other organs during
VHL, such as pheochromocytoma. Finally, misdiagnosis
with other vascularized pancreatic masses may lead to the
wrong clinical decision (mainly pseudosolid pancreatic cys-
tadenomas and, more rarely, pancreatic metastases of RCC).
There are several comprehensive guidelines for the
diagnosis, surveillance, and management of patients with
PNENs.14,15 However, because of the unique characteris-
tics of VHL- related PNETs, as detailed previously, and the
complex context of VHL, in which multiple neoplasms
may develop in parallel to PNETs, there was a need for
VHL- specific recommendations for the management of
these unique neoplasms. During 2018- 2020, the VHL
Alliance (VHLA) gathered several committees of experts
in the various clinical manifestations of VHL to review
the literature and gather evidence on VHL.
In the current report, we detail the results of the dis-
cussion of a group of experts in the pancreatic manifesta-
tions of VHL along with their proposed recommendations
for the clinical surveillance and management of patients
with VHL. The committee produced 2 sets of guidelines.
First, general recommendations are implemented within
the main VHLA guidelines for the surveillance and man-
agement of VHL- related manifestations. These guidelines
are discussed briefly in the first subsection of this arti-
cle (“General Planning of Screening and Surveillance for
PNETs in Patients With VHL”). Second, the committee
recommendations for the diagnosis, surveillance, and
management of VHL- related pancreatic manifestations
are detailed in later subsections of this report.
METHODS
The committee used the best available research evidence to
develop the recommendations and conducted panel dis-
cussions to reach the current recommendations. The level
of evidence was defined according to the Shekelle vari-
ation of the Grading of Recommendations, Assessment,
Development, and Evaluation grading system.16 In ad-
dition to the level of evidence, the committee used the
National Comprehensive Cancer Network’s Categories of
Evidence and Consensus to define the committee mem-
bers’ interpretation of the evidence and degree of consen-
sus.17 None of the committee members had any conflict
of interest with any topic discussed in this article.
DETAILED RECOMMENDATIONS FOR VHL-
RELATED PANCREATIC MANIFESTATIONS
General Planning of Screening and Surveillance
for PNETs in Patients With VHL
Recommendation 1.1— Patients with VHL should be
followed in a VHL clinical care center (CCC) whenever
feasible. (D/2A)
Surveillance of PNETs
Recommendation 1.2— The initiation of screening for
PNETs in patients with VHL should be no later than the
age of 15 years. (C/2A)
Recommendation 1.3— Screening for pancreatic
manifestations of VHL, when no lesions are present yet,
should be performed in 2- year intervals. (C/2A)
Recommendation 1.4— In a patient with VHL and
no pancreatic manifestations detected by the age of 65
years, no further screening for pancreatic manifestations
is required. (C/2A)
Recommendation 1.5— Patients with VHL- related
PNETs should be followed in a VHL CCC whenever fea-
sible. (D/2A)
Recommendation 1.6— All patients with VHL and
specifically patients with VHL- related PNETs should be
in a VHLA- certified CCC. However, when routine sur-
veillance in a VHL CCC is not feasible, the following cri-
teria indicate a referral to a VHLA CCC for consultation:
a patient with a solid pancreatic lesion with an imaging
appearance typical of a PNET. The following criteria in-
dicate a referral to a VHL CCC: a tumor diameter > 1.5
cm, any tumor grow Consensus Statement th between 2
scans, and/or suspected PNET metastases. (D/2A)
As for the age range for screening and surveillance,
the youngest age at diagnosis reported for a patient with
VHL and a PNET was 10 years, and the youngest pa-
tient with a metastatic VHL- related PNET was 11 years
old.9 The median age at disease onset is in the early to
mid- 30s, with ages ranging from the early teenage years to
the seventh to eighth decades.7- 9 The committee defined
Management of VHL- Related PNETs/Laks et al
437
Cancer February 1, 2022
the recommendations so that 95% of PNETs would be
detected, as defined in the goals for all committees, and
co- assessment of visceral manifestations of VHL with a
uniform surveillance protocol would be enabled. Hence,
the committee made the recommendation to initiate
screening no later than the age of 15 years and to cease
screening at the age of 65 years if no pancreatic lesion is
detected by that age.18,19
The pancreatic manifestations in a patient with VHL
are typically a small part of a complex matrix of manifesta-
tions. A VHL multidisciplinary team with experts in various
relevant specialties should preferably provide medical care
for patients with VHL. These specialties include ophthal-
mology, urology, neurosurgery, gastroenterology, oncology,
and neuroendocrinology. The VHLA accredits multidisci-
plinary teams with sufficient capabilities as CCCs after a
thorough review by the VHLA Clinical Council.20 The rec-
ommendation to refer patients with VHL to CCCs stems
from the need to be familiar with all the other manifes-
tations and unique characteristics of VHL- related PNETs.
In the rare cases in which a CCC is not accessible for
routine surveillance, the patient should be referred for con-
sultation and management planning if the tumor is large
(diameter > 15 mm), if there is any tumor growth, or if
PNET metastases are suspected. A VHL specialist consult
may be obtained in situations of uncertainty through expert
networks or the VHLA. Telemedicine may serve to improve
patient care when an in- person evaluation is not possible.
Although most patients with VHL harbor germline
VHL mutations, a subset of patients may be diagnosed
on the basis of disease manifestations and/or their family
history. Thus, in addition to patients with genetic testing,
the committee suggested using the recommendations for
patients diagnosed with VHL on the basis of the interna-
tional criteria, which require the detection of 2 hemangio-
blastomas or 1 hemangioblastoma and a visceral neoplasm,
or on the basis of the Danish criteria, which require the
detection of any 2 VHL- related manifestations.21
Recommendation 1.7— In women planning a
pregnancy, pancreatic protocol magnetic resonance imag-
ing (MRI) should be performed before the planned con-
ception. (D/2A)
Recommendation 1.8— In a pregnant woman with
no known PNETs, no pancreatic imaging is required
during pregnancy. (D/2A)
VHL- related PNETs have an indolent course and
a low risk for metastasis in comparison with sporadic
PNENs. Furthermore, in a series of 52 patients with
VHL (26 women), a lower age- adjusted manifesta-
tion development rate was found in pregnant patients
versus nonpregnant patients, and no appearance or life-
threatening progression of PNETs has been reported in
pregnant patients with VHL.22
On the basis of these data, it will be prudent to per-
form a pancreatic MRI scan for evaluation when a preg-
nancy is being planned as close to conception as possible.
However, in patients with VHL who are pregnant and are
not known to harbor a PNET, the decision to perform
abdominal MRI should be based on specific complaints,
and the low- risk nature of this manifestation and its typi-
cally indolent course should be considered.
Biochemical Biomarkers
Recommendation 2.1— Biochemical biomarkers are not
useful for the screening of VHL- related PNETs. (D/2A)
Recommendation 2.2— Plasma pancreatic poly-
peptide levels may be used for assessing disease burden in
patients with VHL- related PNETs. (C/2A)
Recommendation 2.3— Specific biochemical eval-
uations should be performed for VHL- related PNETs as
clinically indicated. (D/2A)
Although a large subset of sporadic PNETs are func-
tional and necessitate screening for functional status with
a potential impact on patient management,23 in a large
study of 108 patients with VHL- associated PNETs, none
of the patients had biochemically or clinically functional
PNETs.8 Plasma chromogranin A is commonly used as a
biomarker for neuroendocrine tumors but has been found
to not be useful for assessing the burden of VHL- related
PNETs.24 Chromogranin A can be secreted by other
VHL- related neoplasms such as pheochromocytoma,
and increased levels may stem from decreased renal func-
tion, which is commonly encountered in patients with
multiple RCCs.25,26 Tirosh et al27 demonstrated a strong
correlation between the disease burden of VHL- related
PNETs and plasma pancreatic polypeptide levels. The
advantage of this marker is its specificity for pancreatic
lesions in comparison with chromogranin A. The blood
transcriptome– based marker NETest has been validated
as a diagnostic and prognostic biomarker for neuroendo-
crine neoplasms in various scenarios.28- 31 However, in the
context of VHL- related PNETs, there are not sufficient
data to suggest its use at this time point.
Because nearly all VHL- associated PNETs are non-
functional, hormonal screening for functional PNETs
is generally unnecessary. In the infrequent scenario in
which patients with VHL- related PNETs present with
symptoms suggesting a functional PNET, the investiga-
tion should follow the currently available guidelines for
investigating functional PNENs.14
Consensus Statement
438 Cancer February 1, 2022
Imaging Modality
Anatomical imaging
Recommendation 3.1.1— The anatomic imaging mo-
dality of choice for VHL- related PNETs should follow
the imaging methods for sporadic PNETs, preferably
gadolinium- enhanced pancreatic MRI with an early arte-
rial phase. (C/2A)
Recommendation 3.1.2— In patients with VHL-
related PNETs with contraindications for MRI, triple-
phase pancreatic computed tomography (CT) is preferable
to other imaging modalities. (C/2A)
Recommendation 3.1.3— In light of the low risk
of small PNETs in the context of VHL, nonpancreatic
abdominal CT/MRI may be considered for the imaging
of VHL- related PNETs if it is performed for the surveil-
lance/screening of other VHL- related visceral manifesta-
tions. Pancreatic ultrasound has very low sensitivity for
PNETs and is not useful for the screening/surveillance of
VHL- related PNETs. (D/2A)
Recommendation 3.1.4— Endoscopic ultrasound
(EUS) is not recommended as a screening tool and may
be used only when both contrast- enhanced MRI and CT
are contraindicated, there is an indication for biopsy of a
pancreatic lesion (see recommendation 6.1), or there is
doubt about lesions seen on MRI/CT and management
may be changed. (D/2A)
The considerations for the modality of choice for a
PNEN evaluation should follow the currently available
guidelines.32 Contrast- enhanced CT, MRI, or both are the
most frequently used modalities for PNET screening in
patients with VHL. On both CT and MRI, a PNET typi-
cally appears as a hypervascular lesion in early scans (25- 30
seconds) after contrast injection and washes out in the late
phase.33 Studies assessing the diagnostic value of MRI and
CT in head- to- head comparisons in the VHL population
are sparse. A direct comparison between CT and MRI (n
= 27) showed no difference in detecting solid pancreatic
lesions between the 2 modalities.34 Another study (n =
40) demonstrated better sensitivity for CT than MRI for
pancreatic lesions.35 However, a follow- up study reported
comparable detection rates for VHL- related PNETs.24 In
the sporadic PNET population, small PNETs (<1 cm in
diameter) may be missed on CT, with the sensitivity rang-
ing from 29% to 94%,36,37 whereas MRI is more accurate
than CT for the detection of smaller tumors.36
Transabdominal ultrasound is a relatively inexpen-
sive and widely available imaging modality. However,
the reported sensitivities for PNET detection are low
(9%- 64%), mainly when tumors are located at the dis-
tal pancreas and masked by the gastric air bubble.37 EUS
outperformed CT, MRI, and 11C- 5- hydroxytryptophan
positron emission tomography (PET) in detecting PNETs
in 22 patients with VHL, even when tumors > 1 cm were
included.38 However, EUS is an invasive method. Because
of the low risk of small VHL- related PNETs and the po-
tential complications of EUS, its role in screening for
VHL- related PNETs has not been determined.39 Hence,
EUS is the least favorable modality among the 3 possible
modalities suggested for the screening or surveillance of
VHL- related PNETs. Lower radiation exposure is another
advantage of MRI over CT, especially when we consider
the lifelong cumulative radiation exposure due to pancre-
atic imaging in patients with VHL.40
Choosing the imaging modality for patients with
VHL is complex for several reasons. First, patients with
VHL have a high incidence of other visceral neoplasms
with a unique differential diagnosis for any lesion detected.
Second, it is questionable whether missing small tumors
increases morbidity because PNETs smaller than 1.2 to 1.5
cm rarely advance to metastatic disease (see the discussion
and recommendations in the section entitled “Indirect Risk
Stratification of VHL- Related PNETs”). Third, imaging of
the pancreas is often supplanted by imaging required for
the surveillance/screening of other visceral organs, such as
the kidneys and adrenals. In light of the low risk of small
VHL- related PNETs, unless there is a clear indication for
performing pancreas- specific imaging, compromising on
scan sensitivity will be preferred over additional scans.
Functional imaging
Recommendation 3.2.1— In patients with VHL, 68Ga-
DOTATATEc PET/CT imaging is highly sensitive for
detecting PNETs, but it should be reserved for PNET
staging before a planned intervention or for the charac-
terization of a pancreatic mass with radiological charac-
teristics that are not typical for a PNET (nonenhancing
or rapidly growing lesions). (C/2A)
Recommendation 3.2.2—
18F- 2- deoxy- - glucose
(18F- FDG) PET/CT is not helpful for regular characteri-
zation of VHL- related PNETs or their risk stratification.
(C/2A)
Recommendation 3.2.3— Functional imaging in
patients with VHL should be interpreted with consider-
ation of possible pitfalls of VHL by a radiologist or nu-
clear medicine specialist experienced in VHL. (D/2A)
Recommendation 3.2.4—
68Ga- DOTATATE PET/
CT can be used to evaluate VHL- related pancreatic
lesions when metastatic disease is suspected on the basis
of anatomic imaging and/or before a planned interven-
tion, but not for routine screening. (D/2A)
Management of VHL- Related PNETs/Laks et al
439
Cancer February 1, 2022
The optimal functional imaging test for patients
with VHL- associated PNETs has not been clearly
defined. Kitano and colleagues prospectively compared
4 imaging modalities, including 6-
18F- fluoro- - 3,4- di
hydroxyphenylalanine (18F- DOPA) PET/CT, 18F- FDG
PET/CT, CT, and MRI, in a cohort of 40 patients with
VHL- associated PNETs. CT imaging had higher sen-
sitivity than 18F- FDG PET/CT and 18F- DOPA PET/
CT. 24,35 In VHL- related PNETs, the FDG standardized
uptake value was not predictive of metastatic potential
but was reported to identify otherwise unknown meta-
static disease in 3 patients.41
Practically every VHL- related neoplasm has been
shown to have avidity for 68Ga- DOTATATE42- 46 and
particularly for visceral lesions.34 Hence, it is not sur-
prising that the somatostatin receptor– based imaging
68Ga- DOTATATE PET/CT had higher detection rates
than CT for any VHL- related lesions34 and a superior de-
tection rate in another study of 68Ga- DOTATOC PET/
CT. 47
The high sensitivity of these scans should be con-
sidered during interpretation in the context of VHL. For
example, a 68Ga- DOTATATE– avid pancreatic lesion
may be an RCC metastasis, and a parapancreatic 68Ga-
DOTATATE– avid mass may be pheochromocytoma, a
paraganglioma, or a lymph node metastasis of a PNET
or RCC.
18F- FDG PET or 68Ga- DOTATATE can clarify
cases in which solid microcystic serous adenomas are
suspected because this lesion may be difficult to dis-
tinguish from PNETs on CT or MRI.48,49 In light of
the high rate of kidney disease in patients with VHL,
functional imaging studies may be helpful in PNET
surveillance for patients with chronic kidney disease,
in whom contrast- enhanced CT and MRI scans are
contraindicated. An additional confounder unique
to patients with VHL is FDG uptake by brown adi-
pose tissue. This uptake is mediated by norepineph-
rine, which is typically secreted by VHL- related
pheochromocytoma.50
Indirect Risk Stratification of VHL- Related
PNETs
Recommendation 4.1— In patients with VHL, a PNET
whose largest diameter is <1.5 cm confers low risk, and if
it is stable in 2 consecutive scans, it may be followed up
every 2 years. (C/2A)
Recommendation 4.2— In patients with VHL,
a PNET 3 cm in diameter or larger should be resected.
(C/2A) PNETs that are 2 to 3 cm in diameter and located
at the head of the pancreas should be considered for sur-
gical resection. (D/2A)
The high risk for developing PNETs among patients
with VHL enables diagnosing PNETs radiologically with
no need for tissue acquisition. Although this approach
obviates the need for invasive procedures for diagnosis,
the clinician requires an alternative for a tumor grade,
derived from a pathological examination, to define the
risk for tumor progression or metastases. The diameter
of VHL- related PNETs, based on anatomical imaging,
is a consistent and reliable measure for risk stratification.
Several studies reported a very low risk for metastasis or
tumor progression in patients with small PNETs, which
were defined as having a diameter smaller than 1.2 to 1.5
cm.12,51 On the contrary, larger tumors with a diameter
greater than 2.8 to 3 cm were associated with an increased
risk for metastasis.8,9,12 Moreover, tumor growth, mea-
sured by the short tumor diameter doubling time (<500
days), was associated with an increased risk for metastatic
disease,8 but this was not validated and was questioned by
a study demonstrating nonlinear growth of VHL- related
PNETs.24
The genotype- phenotype association described in
the initial reports of VHL led several groups to assess the
association between the type of germline VHL variant and
the phenotype and outcome of patients with VHL- related
PNETs. Variants in exon 3 of the VHL gene were associ-
ated with an increased risk for metastatic diseases in 2 sep-
arate studies from the National Institutes of Health.8,12
A missense variant in codon 167 was found to have a
high risk for metastatic disease,9,52 and a missense vari-
ant was found in 1 study to be associated with the risk
for metastatic disease with a 100% negative predictive
value.12 An algorithm for the surveillance of VHL- related
PNETs, using the germline VHL genotype for patients
with an intermediate risk based on the lesion diameter,
was suggested. However, this algorithm was not validated
prospectively.
The management of VHL- related PNETs 2 to 3 cm
in diameter depends on multiple factors and should be
determined per patient on the basis of the tumor loca-
tion: pancreatic head lesions should be considered for re-
section earlier if enucleation is possible to avoid the need
for Whipple’s procedure. Other VHL- related PNETs may
be followed expectantly.
Indirect risk stratification as a whole is unique for
VHL- related PNETs. The reason is the noninvasive as-
sessment of the lesions, which is aimed at reducing to a
minimum any invasive procedures in patients who un-
dergo multiple surgeries for the various manifestations
Consensus Statement
440 Cancer February 1, 2022
of their disease. Similarly to sporadic PNENs, the lesion
diameter is the main risk- stratifying parameter, and it can
reassure patients with small PNETs. An additional unique
aspect of VHL is the lack of utility for 18F- FDG PET/CT
for the stratification of VHL- related PNETs. Even indo-
lent VHL- related PNETs show 18F- FDG uptake due to
their glycolytic metabolism.
Indications for Tissue Sampling of VHL- Related
PNETs
Recommendation 5.1— In patients with VHL, solid
pancreatic lesions with a radiological appearance typical
of neuroendocrine tumors should not be biopsied. (C/2A)
In patients with VHL- related PNETs, fine- needle as-
piration (FNA)/fine- needle biopsy (FNB) will be required
only in exceptional scenarios. Such intervention should
be performed only after the need for it has been discussed
with a clinician experienced in VHL- related PNETs and
only after radiologists experienced in neuroendocrine
tumor imaging have been consulted. Cases for which
sampling should be considered include the following:
1) a rapidly progressing pancreatic mass, 2) a pancreatic
mass with radiological characteristics that suggest an exo-
crine pancreatic tumor (low vascularity and no uptake on
somatostatin receptor- based imaging), and 3) suspected
metastasis from a different tumor such as RCC. Even in
these specific cases, FNA/FNB should be performed only
if the result will alter the patient’s management.
For patients who are candidates for FNA/FNB of
pancreatic tail lesions, documented normal catechol-
amine and metanephrine profiles are mandatory to en-
sure that the lesion is not a functional paraganglioma or
left adrenal pheochromocytoma. It should be noted that
VHL- related pheochromocytomas are characterized by
a noradrenergic biochemical profile. Thus, normal epi-
nephrine/metanephrine blood/urine levels do not exclude
this diagnosis. If indicated, the modality of choice for the
biopsy of a PNET is EUS- guided FNA.
In contrast to the low risk for a PNEN in non- VHL
patients with a pancreatic mass (3%), in patients with
VHL, the upfront risk for developing a PNET ranges
between 8% and 17% and is much higher when a mass
is detected. Furthermore, because patients with VHL
are prone to develop multiple PNETs throughout their
lifetime, the cumulative risk for complications should be
considered. Hence, a solid pancreatic lesion detected in
patients with VHL should be considered a PNET unless
there are strong parameters to suggest otherwise. The rule
is that FNA/FNB should not be performed unless oth-
erwise indicated. Additionally, a pancreatic cystadenoma
may mimic a PNET in patients with VHL but has a very
low malignant potential.48,53
Interventions
Interventions for localized high- risk lesions
Surgery.
Recommendation 6.1.1— Enucleation rather than for-
mal resection should be attempted for lesions suitable for
parenchyma- sparing procedures. (C/2A)
Recommendation 6.1.2— Total pancreatectomy
should be used rarely, only when all other options for
limited resection have been considered and only after the
presence of distant metastases has been ruled out. (C/2A)
Recommendation 6.1.3— At the time of resection
of a high- risk lesion, additional lesions less than 1.5 cm in
diameter may not be resected. (C/2A)
Previously, no consensus existed for the type of sur-
gical resection that should be used for high- risk PNETs
in patients with VHL. Currently available guidelines
exist for the surgical approach in PNETs.54 The unique
approach to VHL- related PNETs is discussed here.
Treatment options include enucleation versus resection
and laparoscopic approaches versus open approaches.55
Enucleation of VHL- related PNETs is an attractive sur-
gical approach because of the potential for recurrence
and compromised pancreatic function by cystic disease.
Enucleation generally requires a lack of involvement of
the main pancreatic duct and a low risk of harboring re-
gional metastatic disease. Long- term outcomes of enu-
cleation are similar to those for formal resections.8,55 It
is recommended that enucleation be performed along
with regional lymphadenectomy. Certain criteria suggest
resection rather than enucleation, such as the diameter
(>3 cm), the tumor diameter doubling time (500 days),
a mutation in exon 3, and other high- risk genetic char-
acteristics.12,24,51,56 To spare parenchyma, some have ad-
vocated that at the time of resection for high- risk lesions,
additional lesions that are less than 1.5 cm in size be left
alone without significant changes in survival outcomes.51
EUS- guided ablation.
Recommendation 6.1.9— Patients with high- risk lesions
who are unable or unwilling to undergo surgical treat-
ment may be considered for EUS ablation by either radio-
frequency ablation (RFA) or ethanol injection, preferably
in a clinical trial. (D/2A)
Ablation, either by thermal injury or by caustic ma-
terial, has been used to treat PNETs over the last decade.
Theoretical advantages of ablation include its minimally in-
vasive nature when it is applied by EUS or percutaneously.
Management of VHL- Related PNETs/Laks et al
441
Cancer February 1, 2022
A few small retrospective and prospective reports have
indicated that the local control rates and overall survival
are acceptable.57- 60 Limitations of its use are the lack of
associated lymph node sampling, the lack of data about
long- term results, and the occasional severe complications
of pancreatitis and portal vein occlusion.57,61 Furthermore,
the limited series of RFAs has been restricted nearly en-
tirely to a subset of patients with tumors less than 3 cm and
a mix of functional and nonfunctional tumors, and there
is a lack of evidence for patients with VHL- related PNETs.
Advanced disease
Medical intervention.
Recommendation 6.2.1— Systemic treatment for pa-
tients with advanced VHL- related PNETs should follow
the guidelines for sporadic PNETs. (C/2A)
Recommendation 6.2.2— For patients with ad-
vanced, well- differentiated VHL- related PNETs, pazo-
panib may be considered. (C/2A)
The vast majority of PNETs in VHL are well-
differentiated, low- grade tumors. The management of
advanced PNETs in VHL should generally follow ther-
apy paradigms for sporadic PNETs.15,62 It is important
to note that the unique genetic profile of VHL- related
neoplasms63 suggests a distinct response to interventions
in comparison with non– VHL related neuroendocrine
tumors, including sporadic and MEN1- related tumors,
and this should be taken into consideration when one is
weighing the optimal regimen.
A multidisciplinary team should guide the treatment
selection in the context of the status of other VHL- related
manifestations.
Tyrosine kinase inhibitors, including sunitinib,
sorafenib, axitinib, and pazopanib, have been evaluated
for unresectable and/or progressive VHL- related neo-
plasms.64 Among those, sunitinib was evaluated in a pro-
spective randomized controlled trial of sporadic PNETs
and prolonged progression- free survival,65 and it may be
effective for the management of PNETs in patients with
VHL.66- 69 Jonasch et al70 reported the efficacy of pazo-
panib in treating VHL- related neoplasms in a phase 2
study, which included 17 assessed pancreatic lesions, and
there was high efficacy in reducing the size of PNETs.
The most promising therapeutic modalities for
VHL- related manifestations are the HIF2 inhibitors and
specifically belzutifan. VHL deficiency leads to uncon-
trolled HIF1 activity and pseudohypoxia. In light of the
dependence of HIF1 on dimerization with HIF2, HIF2
inhibitors may reverse this effect.71 HIF2 inhibitors
have shown preliminary efficacy in VHL- related renal
tumors.72- 74 In August 2021, the US Food and Drug
Administration (FDA) approved the use of belzutifan for
VHL- related tumors, including VHL- related PNETs. In
regard to VHL- related PNETs, 120 mg of belzutifan once
a day, administered orally, had an overall response rate of
83% for VHL- related PNETs.75
Cystic disease
Recommendation 6.3.1— Patients with pancreatic cysts
who experience pain or an enteric/biliary obstruction
should be considered for intervention. (C/2A)
Recommendation 6.3.2— Patients with pancreatic
cysts in whom the diagnosis of a malignant or premalig-
nant lesion cannot be excluded should be considered for
intervention. (C/2A)
Recommendation 6.3.3— When the indication
for intervention is a biliary/enteric obstruction, a bypass
rather than resection should be preferentially considered
to spare pancreatic parenchyma. (C/2A)
Recommendation 6.3.4— Parenchyma- sparing re-
section with regional lymphadenectomy is suggested for
pancreatic cysts of an uncertain malignant status. (D/2A)
Recommendation 6.3.5— In patients with symp-
tomatic cysts, cyst drainage or marsupialization may be
considered. (D/2A)
Cystic diseases of the pancreas in patients with VHL
are common. According to a systematic review, they are
simple cysts in 47% of screened patients and serous cysta-
denomas in an additional 11% of screened patients. In this
review, when cysts were present, they were multiple in up
to 86% of patients. Symptomatology related to these cysts
appears rare in surveillance series, whereas some studies
have suggested up to a 16% likelihood of symptoms.76
Autopsy series suggest that they may be found in up to
72% of patients with VHL.77 These are essentially never
malignant processes, and intervention should be based
only on symptomatology or an inability to discern them
from other lesions with malignant potential. Specifically,
serous microcystic cystadenomas can mimic intraductal
papillary mucinous neoplasms (IPMNs), mucinous cys-
tic neoplasms, cystic adenocarcinomas, cystic PNETs,
or solid pseudopapillary carcinomas. When symptoms
occur, they are related to the cyst’s mass effect and can
include early satiety, pain, gastrointestinal obstruction,
and jaundice. An institutional review at the Mayo Clinic
from 2000 to 2016 identified 48 patients with VHL with
cystic lesions of the pancreas.78 They confirmed that mul-
tiple cysts were present in 87.5% of the patients. Simple
cysts were found in 71%, serous cystadenomas were
found in 29%, IPMNs were found in 10%, and 4% had
Consensus Statement
442 Cancer February 1, 2022
cystic PNETs. The presence of IPMNs and cystic PNETs
underscores the importance of the appropriate diagnosis
of these cysts and the occasional need for surgical inter-
vention in cases of diagnostic uncertainty due to the pre-
malignant nature of some of these lesions. Eight percent
of the patients reported symptoms, including abdominal
pain and pancreatic insufficiency. One patient required
resection for symptoms of abdominal pain.78
When the indication for surgery is diagnostic un-
certainty, resection is indicated. Parenchyma- sparing pro-
cedures such as enucleation should be preferentially used
but require distance away from the pancreatic duct.
Lymph node dissection should be added to enucle-
ation in cases of suspected malignancy. When the indica-
tion for surgery is biliary or gastrointestinal obstruction,
surgical management options include endoscopic stent
placement; surgical bypasses such as hepaticojejunostomy,
hepaticoduodenostomy, and gastrojejunostomy; and only
then resection.13,79- 82 Hammel et al6 described an alterna-
tive treatment for simple cysts including radiological de-
compression and cyst marsupialization, and it appeared to
have success in the 2 patients described. Another case re-
port described a patient who underwent multiple pancre-
atic cyst fenestrations at the time of enucleation of a PNET,
and it was complicated by severe postoperative ascites.83
UNSOLVED CLINICAL ISSUES AND FUTURE
RESEARCH DIRECTIONS
In recent years, our understanding of the natural course
of VHL- related PNETs has advanced pronouncedly since
the reports of large, prospective natural history studies.
Personalized patient surveillance is closer than ever on ac-
count of robust data on the risk for metastatic disease based
on the lesion diameter and the germline VHL genotype.
However, although follow- up based on these parameters
is possible, no prospective validation studies have enabled
interventions based on certain criteria because the benefit
(or potential harm) has not been assessed yet.
The unique genetic and epigenetic landscape of
VHL- related PNETs may explain the different disease
course in comparison with sporadic PNETs and suggests a
different response to medical interventions. Hence, more
data are required on the efficacy of the various interven-
tions for patients with VHL- related advanced PNETs, in-
cluding tyrosine kinase inhibitors, mTOR inhibitors, and
the much anticipated HIF2 inhibitors.
A collaborative approach to large- scale, retrospective
studies of patients with VHL and even more— the prospec-
tive validation of previously reported data— are needed to
improve the care that we can provide to our patients.
EXECUTIVE SUMMARY
Recommendation 1.1— Patients with VHL should be
followed in a VHL CCC whenever feasible. (D/2A)
Recommendation 1.2— The initiation of screening
for PNETs in patients with VHL should be no later than
the age of 15 years. (C/2A)
Recommendation 1.3— Screening for pancreatic
manifestations of VHL, when no lesions are present yet,
should be performed in 2- year intervals. (C/2A)
Recommendation 1.4— In a patient with VHL and
no pancreatic manifestations detected by the age of 65
years, no further screening for pancreatic manifestations
is required. (C/2A)
Recommendation 1.5— Patients with VHL- related
PNETs should be followed in a VHL CCC whenever fea-
sible. (D/2A)
Recommendation 1.6— All patients with VHL and
specifically patients with VHL- related PNETs should be in a
VHLA- certified CCC. However, when routine surveillance
in a VHL CCC is not feasible, the following criteria indicate
a referral to a VHLA CCC for consultation: a patient with a
solid pancreatic lesion with an imaging appearance typical of
a PNET. The following criteria indicate a referral to a VHL
CCC: a tumor diameter > 1.5 cm, any tumor growth be-
tween 2 scans, and/or suspected PNET metastases. (D/2A)
Recommendation 1.7— In women planning a
pregnancy, pancreatic protocol MRI should be performed
before the planned conception. (D/2A)
Recommendation 1.8— In a pregnant woman with
no known PNETs, no pancreatic imaging is required
during pregnancy. (D/2A)
Biochemical Biomarkers
Recommendation 2.1— Biochemical biomarkers are not
useful for the screening of VHL- related PNETs. (D/2A)
Recommendation 2.2— Plasma pancreatic poly-
peptide levels may be used for assessing disease burden in
patients with VHL- related PNETs. (C/2A)
Recommendation 2.3— Specific biochemical eval-
uations should be performed for VHL- related PNETs as
clinically indicated. (D/2A)
Imaging Modality
Anatomical imaging
Recommendation 3.1.1— The anatomic imaging mo-
dality of choice for VHL- related PNETs should follow
the imaging methods for sporadic PNETs, preferably
gadolinium- enhanced pancreatic MRI with an early arte-
rial phase. (C/2A)
Management of VHL- Related PNETs/Laks et al
443
Cancer February 1, 2022
Recommendation 3.1.2— In patients with VHL-
related PNETs with contraindications for MRI, triple-
phase pancreatic CT is preferable to other imaging
modalities. (C/2A)
Recommendation 3.1.3— In light of the low risk
of small PNETs in the context of VHL, nonpancreatic
abdominal CT/MRI may be considered for the imaging
of VHL- related PNETs if it is performed for the surveil-
lance/screening of other VHL- related visceral manifesta-
tions. Pancreatic ultrasound has very low sensitivity for
PNETs and is not useful for the screening/surveillance of
VHL- related PNETs. (D/2A)
Recommendation 3.1.4— EUS is not recom-
mended as a screening tool and may be used only when
both contrast- enhanced MRI and CT are contraindi-
cated, there is an indication for biopsy of a pancreatic
lesion (see recommendation 6.1), or there is doubt
about lesions seen on MRI/CT and management may
be changed. (D/2A)
Functional imaging
Recommendation 3.2.1— In patients with VHL, 68Ga-
DOTATATE PET/CT imaging is highly sensitive for
detecting PNETs, but it should be reserved for PNET
staging before a planned intervention or for the charac-
terization of a pancreatic mass with radiological charac-
teristics that are not typical for a PNET (nonenhancing
or rapidly growing lesions). (C/2A)
Recommendation 3.2.2—
18F- FDG PET/CT is
not helpful for regular characterization of VHL- related
PNETs or their risk stratification. (C/2A)
Recommendation 3.2.3— Functional imaging
in patients with VHL should be interpreted with con-
sideration of possible pitfalls of VHL by a radiologist
or nuclear medicine specialist experienced in VHL.
(D/2A)
Recommendation 3.2.4—
68Ga- DOTATATE PET/
CT can be used to evaluate VHL- related pancreatic le-
sions when metastatic disease is suspected on the basis of
anatomic imaging and/or before a planned intervention,
but not for routine screening. (D/2A)
Indirect Risk Stratification of VHL-
Related PNETs
Recommendation 4.1— In patients with VHL, a PNET
whose largest diameter is <1.5 cm confers low risk, and if
it is stable in 2 consecutive scans, it may be followed up
every 2 years. (C/2A)
Recommendation 4.2— In patients with VHL,
a PNET 3 cm in diameter or larger should be resected.
(C/2A) PNETs that are 2 to 3 cm in diameter and located
at the head of the pancreas should be considered for sur-
gical resection. (D/2A)
Indications for Tissue Sampling of
VHL- Related PNETs
Recommendation 5.1— In patients with VHL, solid
pancreatic lesions with a radiological appearance typi-
cal of neuroendocrine tumors should not be biopsied.
(C/2A)
Interventions
Interventions for localized high- risk lesions
Recommendation 6.1.1— Enucleation rather than for-
mal resection should be attempted for lesions suitable for
parenchyma- sparing procedures. (C/2A)
Recommendation 6.1.2— Total pancreatectomy
should be used rarely, only when all other options for
limited resection have been considered and only after the
presence of distant metastases has been ruled out. (C/2A)
Recommendation 6.1.3— At the time of resection
of a high- risk lesion, additional lesions less than 1.5 cm in
diameter may not be resected. (C/2A)
Recommendation 6.1.9— Patients with high- risk
lesions who are unable or unwilling to undergo surgical
treatment may be considered for EUS ablation by either
RFA or ethanol injection, preferably in a clinical trial.
(D/2A)
Advanced disease
Recommendation 6.2.1— Systemic treatment for pa-
tients with advanced VHL- related PNETs should follow
the guidelines for sporadic PNETs. (C/2A)
Recommendation 6.2.2— For patients with ad-
vanced, well- differentiated VHL- related PNETs, pazo-
panib may be considered. (C/2A)
Cystic disease
Recommendation 6.3.1— Patients with pancreatic cysts
who experience pain or an enteric/biliary obstruction
should be considered for intervention. (C/2A)
Recommendation 6.3.2— Patients with pancreatic
cysts in whom the diagnosis of a malignant or premalig-
nant lesion cannot be excluded should be considered for
intervention. (C/2A)
Recommendation 6.3.3— When the indication
for intervention is a biliary/enteric obstruction, a bypass
Consensus Statement
444 Cancer February 1, 2022
rather than resection should be preferentially considered
to spare pancreatic parenchyma. (C/2A)
Recommendation 6.3.4— Parenchyma- sparing re-
section with regional lymphadenectomy is suggested for
pancreatic cysts of an uncertain malignant status. (D/2A)
Recommendation 6.3.5— In patients with symp-
tomatic cysts, cyst drainage or marsupialization may be
considered. (D/2A)
FUNDING SUPPORT
This work was supported in part by the National Institutes of Health/
National Eye Institute (5K08EY027464- 02 to Anthony B. Daniels).
CONFLICT OF INTEREST DISCLOSURES
Xavier M. Keutgen reports a research grant from the Cancer Research
Foundation, a Basic/Translational Science Investigator Award from the
North American Neuroendocrine Tumor Society, and consulting for
TerSera. Pascal Hammel reports payments or honoraria from AstraZeneca,
Erythec, Halozyme, Servier, and Viatris and support for attending meetings
and/or travel from AstraZeneca and Erythec. Anthony B. Daniels is a clini-
cal advisory board member of the VHL Alliance. Amit Tirosh reports a pilot
research grant from the VHL Alliance and the Israeli Cancer Research Fund
and is a member of the Pancreas Committee for the VHL Alliance Clinical
Council. The other authors made no disclosures.
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... Von Hippel-Lindau (VHL) is an autosomal dominant neoplasia syndrome that is caused by germline mutations of the tumor suppressor gene VHL and predisposes individuals to the development of multiple benign and malignant neoplasms ( Table 1). The annual incidence of VHL is approximately 1 in 36,000 live births [1]. Patients harbouring a germline pathogenic variant in the VHL gene are at high risk of developing tumors in several organs, including the central nervous system (CNS) and retinal hemangioblastomas, pheochromocytomas and paragangliomas, (PPGLs) renal cell carcinomas (RCC), pancreatic neuroendocrine neoplasms (PanNENs), endolymphatic sac tumors and cysts in the kidneys, pancreas, liver, testicles and broad ligament [2]. ...
... The prevalence of PanNENs in patients with VHL syndrome (vPNENs) ranges between 8% and 17% displaying a female predominance, while in 7.6% of VHL patients only the pancreas is affected [1,8,[18][19][20]. The development of vPNENs has been reported from an earlier age of life compared to sporadic PanNENs, most commonly starting from the second decade of life [18]. ...
... However, EUS is an invasive method while small vPNENs, not revealed with CT or MRI, have a low metastatic potential. Therefore, EUS is recommended only when CT/MRI are contraindicated or in rare cases when biopsy of the pancreatic lesion is required [1]. ...
Article
Full-text available
Purpose of Review The purpose of this review is to outline the current knowledge on epidemiology, diagnosis and management of neuroendocrine neoplasms (NENs) that develop in the context of Von Hippel-Lindau (VHL) syndrome. Recent Findings Pancreatic NENs develop in 8–17% of VHL patients (vPNENs) and are mostly multi-focal, cystic and non-functioning. Surgical resection is recommended for vPNENS > 3 cm that exhibit higher metastatic potential or in tumors with short doubling time while in the 20% of cases with metastatic disease the HIF-2 A inhibitor belzutifan is considered a promising option. Pheochromocytomas arising in VHL type 2 are often bilateral and have a noradrenergic phenotype while they are associated with increased risk of recurrence. High-specific activity [¹³¹I]-MIBG and sunitinib are the treatment options with the highest level of evidence whereas studies on belzutifan are evolving. Summary Life-long surveillance and management in the context of a multidisciplinary team are suggested to achieve the best clinical outcome.
... Von Hippel-Lindau (VHL) is an autosomal dominant syndrome due to mutations of the VHL gene, a tumor suppressor gene located at chromosome 3p25 that predisposes individuals to the development of multiple benign and malignant neoplasms. The annual incidence of VHL is approximately 1 in 36,000 live births [89]. VHL is related to tumors in several organs, including the central nervous system (CNS) and retinal hemangioblastomas, pheochromocytomas and paragangliomas, renal cell carcinomas (RCC), PanNETs, endolymphatic sac tumors and cysts in the kidneys, pancreas, liver, testicles, and broad ligament [90]. ...
... Normally, the VHL protein (pVHL) plays a key role in the ubiquitination of the α subunit of the hypoxia-inducible factor (HIFα) under normal oxygen levels, leading to its degradation. Under hypoxic conditions, HIFα constitutively accumulates and forms heterodimers with HIF1β, acting as transcription factors that drive cell proliferation, angiogenesis via Vascular Endothelial Growth Factor (VEGF) upregulation, and erythropoiesis by upregulating the erythropoietin encoding gene (Figure 1) [89]. In VHL disease, the low levels of pVHL lead to an unregulated accumulation of HIFα, in a state called pseudohypoxia, with subsequent upregulation of proangiogenic peptides and development of highly vascular neoplasms [90,91]. ...
... In VHL disease, the low levels of pVHL lead to an unregulated accumulation of HIFα, in a state called pseudohypoxia, with subsequent upregulation of proangiogenic peptides and development of highly vascular neoplasms [90,91]. The diagnosis of VHL is based on clinical criteria, with or without the presence of a relevant hereditary history or the molecular diagnosis that can be established by the identification of a pathogenic variant of VHL gene [89,92]. The clinical diagnosis of VHL requires the presence of two hemangioblastomas or one hemangioblastoma and a visceral neoplasm based on the presence of at least two VHLrelated manifestations [93]. ...
Article
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Pancreatic neuroendocrine tumors (PanNETs) and lung NETs (LNETs) represent a rare but clinically significant subgroup of neoplasms. While the majority is sporadic, approximately 17% of PanNETs and a subset of LNETs develop in the context of monogenic familial tumor syndromes, especially multiple endocrine neoplasia type 1 (MEN1) syndrome. Other inherited syndromes associated with PanNETs include MEN4, von Hippel-Lindau (VHL) syndrome, neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). These syndromes are highly penetrant and their clinical manifestations may vary even among members of the same family. They are attributed to genetic mutations involving key molecular pathways regulating cell growth, differentiation, and angiogenesis. Pancreatic NETs in hereditary syndromes are often multiple, develop at a younger age compared to sporadic tumors, and are associated with endocrine and nonendocrine tumors derived from multiple organs. Lung NETs are not as common as PanNETs and are mostly encountered in MEN1 syndrome and include typical and atypical lung carcinoids. Early detection of PanNETs and LNETs related to inherited syndromes is crucial, and specific follow-up protocols need to be employed to optimize diagnosis and management. Genetic screening is recommended in childhood, and diagnostic screening starts often in adolescence, even in asymptomatic mutation carriers. Optimal management and therapeutic decisions should be made in the context of a multidisciplinary team in specialized centers, whereas specific biomarkers aiming to identify patients denoted to follow a more aggressive course need to be developed.
... The patient's asymptomatic retroperitoneal paraganglioma highlights the necessity of biochemical screening and imaging studies as part of routine surveillance. Annual measurement of plasma or urinary fractionated metanephrines is recommended to detect these tumors early [22]. ...
... The management of VHL disease relies heavily on a structured surveillance program, as outlined in international guidelines [11,22]. The lack of adherence to these guidelines in this case resulted in delayed diagnosis and increased risk of morbidity. ...
Article
Full-text available
Von Hippel-Lindau (VHL) disease is a rare autosomal dominant hereditary syndrome characterized by the development of multiple neoplastic and cystic lesions across various organs, including the central nervous system (CNS), retina, kidneys, pancreas, and adrenal glands. Renal cell carcinoma (RCC) is a significant cause of morbidity and mortality in VHL patients. Adherence to surveillance protocols is crucial for early detection and management of associated complications. We report the case of a 37-year-old Iranian male with a 5-year history of VHL disease, initially diagnosed following the resection of a cerebellar hemangioblastoma at age 17. Two years prior to the current evaluation, at age 35, he experienced acute visual impairment, and MRI revealed a retinal capillary hemangioma. Given the combination of CNS and retinal lesions, along with a family history of VHL-associated tumors, genetic testing via targeted sequencing confirmed a heterozygous pathogenic variant c.223_232del (p.Leu75_Leu81del) in exon 1 of the VHL gene (VHL). Despite the diagnosis, the patient did not adhere to recommended surveillance protocols. Recently, he presented with abdominal discomfort and hematuria. Multidetector computed tomography identified multiple pancreatic cysts, renal cysts, and two enhancing lesions in the left kidney consistent with clear-cell RCC. Additionally, a retroperitoneal solid-cystic mass suggested an extra-adrenal paraganglioma. Biopsy confirmed RCC. The patient is currently under active surveillance, with plans for potential surgical intervention if disease progression occurs. Over 9 months of follow-up, he remains stable with preserved renal function and no new lesions. This case highlights the critical importance of adherence to surveillance guidelines in VHL disease. Early and regular monitoring can facilitate timely detection and management of associated malignancies, potentially preventing complications. The case underscores the need for comprehensive, multidisciplinary care and patient education to improve outcomes in VHL disease.
... На момент выявления у 50% пациентов уже наблюдаются симптомы заболевания, которые клинически проявляются гемангиобластомами центральной нервной системы (ЦНС) и сетчатки, феохромоцитомой надпочечников, почечно-клеточным раком, НЭО опухолями ПЖ, кистами ПЖ, уха, широкой связки матки у женщин и яичек у мужчин. Спектр клинических проявлений может включать до 40 вариантов поражений различных органов [33,34,35]. Наиболее частыми поражениями и причиной смерти больных являются гемангиобластомы ЦНС (чаще мозжечка) и почечно-клеточный рак. ...
... Если размер опухолей невелик, возможна их лазерная коагуляция или криотерапия. При более значительных размерах опухолей применяется лучевая терапия или их хирургическое удаление [7,34,35]. ...
Article
Introduction. The article provides a literature review on the epidemiology, diagnosis, and treatment of neuroendocrine tumors. The morpho-functional classification by WHO 2022 is presented with the division of neuroendocrine tumors into three groups. Justifications are given for the choice of instrumental methods of topical diagnostics and the need for determining universal and specific biochemical markers in blood serum or plasma. The principles are indicated for choosing the advanced methods of treating neuroendocrine tumors. Aim. To review the scientific literature on neuroendocrine tumors, providing our own clinical observations. Materials and Methods. Russian- and English-language literature sources on this disease were searched for in the databases, such as PubMed, Medscape, Cochrane Library, and eLibrary. Clinical case of our female patient V., 36 years old, with von Hippel-Lindau disease (heterozygous mutation R167W of the VHL gene). Results and Discussion. As an example, we describe a clinical case of surgical treatment followed by long-term use of interferons in a female patient with neuroendocrine pancreatic cancer with metastases to the liver and retroperitoneal lymph nodes. Histological examination of the surgical material revealed highly differentiated neuroendocrine cancer with low malignant potential. A screening examination of the genetic syndrome components revealed a heterozygous mutation R167W of the VHL gene. Her survival under treatment exceeded 9.5 years, including more than 4.5 years from the start of interferon therapy. This pathology occurred in a young woman with one of the rare genetic multiorgan hereditary forms of neuroendocrine tumors, Von Hippel-Lindau disease that manifested itself as a combination of benign (retinal angiomatosis of both eyes and adenomas of both adrenal glands) and malignant diseases (pancreatic cancer). Conclusions. The given clinical example demonstrates that in a patient with highly differentiated metastatic pancreatic cancer, after distal subtotal resection of the pancreas, splenectomy, retroperitoneal lymphadenectomy, followed by treatment with interferons, life expectancy was more than 9.5 years, including more than 4.5 years from the start of therapy with interferons only. Despite the numerous side effects of interferons described in the literature, the patient tolerated the treatment well. At the same time, a connection between the hypothyroidism detected in the patient and treatment with interferons cannot be ruled out, since dysfunction of the thyroid gland is one of its side effects.
... VHL-associated serous cystic neoplasm (WHO classification) present with lesions that are indiscernible at histology from sporadically occurring serous cystic tumors [23]. VHL is a multi-tumor inherited autosomal dominant disease [24]. VHL is caused by mutations in the VHL tumor suppressor gene and is characterized by the presence of hemangioblastoma of the central nervous system and retina, adrenal pheochromocytoma, renal cell carcinoma (RCC), pancreatic neuroendocrine tumors and cysts, cystadenomas, and mixed tumors, and other organ involvement [24]. ...
... VHL is a multi-tumor inherited autosomal dominant disease [24]. VHL is caused by mutations in the VHL tumor suppressor gene and is characterized by the presence of hemangioblastoma of the central nervous system and retina, adrenal pheochromocytoma, renal cell carcinoma (RCC), pancreatic neuroendocrine tumors and cysts, cystadenomas, and mixed tumors, and other organ involvement [24]. In VHL disease, almost 7.6% of patients may have pancreatic manifestations alone, while 11.5% of patients show combined lesions [25]. ...
Article
Full-text available
Pancreatic cystic neoplasms are lesions comprised of cystic components that show different biological behaviors, epidemiology, clinical manifestations, imaging features, and malignant potential and management. Benign cystic neoplasms include serous cystic neoplasms (SCAs). Other pancreatic cystic lesions have malignant potential, such as intraductal papillary mucinous neoplasms and mucinous cystic neoplasms. SCAs can be divided into microcystic (classic appearance), honeycomb, oligocystic/macrocystic, and solid patterns based on imaging appearance. They are usually solitary but may be multiple in von Hippel–Lindau disease, which may depict disseminated involvement. The variable appearances of SCAs can mimic other types of pancreatic cystic lesions, and cross-sectional imaging plays an important role in their differential diagnosis. Endoscopic ultrasonography has helped in improving diagnostic accuracy of pancreatic cystic lesions by guiding tissue sampling (biopsy) or cyst fluid analysis. Immunohistochemistry and newer techniques such as radiomics have shown improved performance for preoperatively discriminating SCAs and their mimickers. Graphical Abstract
... The prevalence of panNETs in patients with VHL syndrome is lower, and they are usually multiple, almost exclusively non-functioning. It is important to initiate the screening of panNETs early, no later than 15 years old, as they occur in young age; the screening should be performed until the age of 65 years old [81,82]. Early detection, a coordinate care team and screening appropriate to the age of the patient are the key to good management of this disease. ...
Article
Full-text available
Opinion Statement The vast majority of neuroendocrine 'neoplasms (NENs) are sporadic, although recent evidence has indicated that a subset of these cancers may also originate as a result of genetic germline mutations. To date, 10% of these cancers can be linked to an inherited genetic syndrome. Genetic diagnosis is crucial for patients with a suspected hereditary NEN syndrome, as it recognizes patients carrying germline mutations and allows for personalized clinical follow-up, considering the higher risk of developing other tumours. The potential for early genetic detection has significant implications for the treatment of patients with hereditary NEN syndrome, as it may facilitate the delivery of precision therapy that differs from that typically provided to other patients. Thus, the integration of genotypic and phenotypic diagnostic methods help clinicians to provide more informed treatment and to extend appropriate prevention to family members.
... The management of VHL disease requires a multidisciplinary approach that involves close collaboration between healthcare providers, patients, and their families [91][92][93]. Therefore, optimizing the management of VHL patients requires a comprehensive consideration of treatment strategies, follow-up, and monitoring for different types of tumors. ...
Article
Full-text available
Von Hippel-Lindau Syndrome (VHL) is a rare genetic disorder characterized by tumors in multiple organs, including the kidneys, pancreas, and central nervous system. This comprehensive review discusses the genetic basis and clinical manifestations of VHL, as well as recent advancements in understanding the molecular mechanisms that lead to tumor formation. The authors highlight the role of hypoxia-inducible factors and the ubiquitin-proteasome system in VHL-associated cancer development .The review also discusses the potential clinical implications of these findings, such as the development of targeted therapies for VHL-associated cancers. However, the authors note the challenges associated with developing effective treatments for this complex disease, including limited patient availability for clinical trials due to its rarity .Overall, this review provides valuable insights into our current understanding of VHL and offers important avenues for future research aimed at improving the diagnosis, treatment, and management of VHL patients. By illuminating the molecular underpinnings of VHL-associated cancers, this work may ultimately help to develop more effective treatments and improve outcomes for patients with this challenging disease.
... SSAs like octreotide and lanreotide, are employed based on symptoms and tumor location. SSAs are typically recommended for carcinoid syndrome, with evidence indicating slowed tumor growth and extended time to progression [64][65][66]. Regarding the safety and feasibility of SSAs in pregnancy, available data are sparse, primarily derived from acromegalic patients. While most reported cases are reassuring, uncertainty persists about SSAs' safety during pregnancy. ...
Article
Neuroendocrine neoplasms (NEN) are rather rare tumors, but their incidence is constantly rising in recent years. Although NEN guidelines summarize the recommendations for the diagnosis and treatment of this heterogeneous group of neoplasms, their handling during pregnancy is not well defined. NEN are rare entities during pregnancy, and their prevalence increases because of an earlier diagnosis also in genetic syndromes. Their diagnosis in gestation can be challenging due to their symptoms that can easily be confused with symptoms of pregnancy. The radiation exposure poses further diagnostic problems as several modalities cannot be applied during pregnancy. Surgery remains the mainstay of NEN treatment, but anesthesia in combination with secretory syndromes such as carcinoid syndrome requires specific approaches. Pharmacological treatments are not well established in pregnant patients with NEN and are so far only applied in specific settings, with somatostatin analogues being mostly tested to date. Collaborative efforts across specialties such as endocrinology, obstetrics gynecology, surgery, oncology and anesthesia are essential to devise effective treatment strategies. Critical considerations include the selection of appropriate medical therapies, timing of surgical interventions, decisions regarding delivery methods and timing, and evaluation of anesthesia protocols. The present paper aims to concisely summarize the complexity of diagnosis and treatment of NEN during pregnancy with focus on a variety of real-life scenarios and on the many unmet needs to be carefully considered in the clinical practice.
Article
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Objectives Medical research continues to be extensively devoted to investigating the pathogenesis and treatment approaches of hereditary renal cancer. By aspect including researchers, institutions, countries, journals, and keywords, we conduct a bibliometric analysis of the literature pertaining to hereditary renal cancer over the last 23 years. Methods From the Web of Science Core Collection, we conducted a search for publications published between January 1, 2000 and November 28, 2023. Reviews and original articles were included. Results A cumulative count of 2,194 publications met the specified criteria for inclusion. The studies of the included articles involved a collective of 2,402 institutions representing 80 countries. Notably, the United States exhibited the highest number of published documents, constituting approximately 45.49% of the total. The preeminent institution in this discipline is the National Cancer Institute (NCI), which maintains a publication volume of 8.98%. In addition to being the most prolific author (125 publications), Linehan WM’s works received the highest number of citations (11,985). In a comprehensive count, 803 journals have published related articles. In the top 10 most recent occurrences were the terms “hereditary leiomyomatosis” and “fumarate hydratase.” Conclusion This is the first bibliometric analysis of the literature on hereditary renal cancer. This article offers a thorough examination of the present status of investigations concerning hereditary renal cancer during the previous 23 years.
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