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Author:
A better understanding of the biological behavior of organ manifestations of multiple endocrine neoplasia type 1 (MEN1) and increased clinical experience require a revision
of previously published guidelines.
of death after NENs in the thymus.
Therefore, DP-NENs are a major focus for
re-evaluating their diagnosis and treatment recommendations.
Over the past 2 years, more clinical experience has documented follow-up of treated and untreated DP-NENs (natural history).
The goal of the International Federation of Experts in Endocrinology, Genetics, Radiology, Surgery, Gastroenterology and Oncology is to systematically review the literature and make a consensus statement
based on the highest level of evidence.
A review of the literature published over the past decade focused on the diagnosis of F-DP-NENs and NF-DP-NENs in MEN1 syndrome to further standardize and improve treatment and follow-up, and to establish a "journal"
of the diagnosis and treatment of DP-NENs.
This will help further reduce complications and improve long-term treatment outcomes
for these rare tumors.
The following statement of international consensus builds on previously published guidelines for 2001 and 2012 and attempts to complement the recommendations made by
States and international associations.
definition
Multiple endocrine neoplasia type 1 (MEN1) is a rare
by a mutation in the tumor suppressor gene MEN1 gene on the long arm of chromosome 11 (11q13) encoding the menin protein.
Menin, in turn, has multiple roles
in cell division and proliferation, transcriptional regulation, and genome stability.
MEN1 exhibits a high penetrance and can be diagnosed
based on clinical, familial, or genetic characteristics.
Minimum consensus statement on the definition of MEN1
Clinical: Patients present with 2 or more MEN1-related endocrine tumors (i.
e.
, parathyroid adenoma, pancreatic enterotumor, and
Familial: The patient has 1 MEN1-related tumor and is a first-degree relative to
MEN1.
Genetic: Patients with one of the various MEN1 mutations do not exhibit clinical (or biochemical) manifestations
of MEN1 (asymptomatic gene carriers).
In addition to primary hyperparathyroidism (documented up to 100%), duodenal and pancreatic neuroendocrine tumors (DP-NENs) are the second most common manifestation
of MEN1 (30% to 90%).
In addition to neuroendocrine tumors of the thymus, they remain the leading cause of
death.
Other features of MEN1 syndrome are anterior pituitary (30% to 40%) and adrenal (about 20% to 40%) tumors
.
NENs associated with MEN1 are rarely diagnosed in the stomach, thymus, lung, bronchopulmonary airways (3% to 10% of cases), and recently reported in female mammary glands (about 7%)
.
Minimal consensus statement
Patients with MEN1 may develop F-NENs and NF-NENs
of the duodenum and pancreas.
F-NENs produce and secrete high levels of specific gastrointestinal (GI) hormones (i.
e.
,
due to hormone overdose.
The definition of F-NENs is based on clinical symptoms caused by improper hormone secretion, not immunohistochemical results
.
NF-DP-NENs (inactive, clinically asymptomatic, and nonsyndromic) do not secrete typical GI hormones and therefore do not cause endocrine syndromes (asymptomatic DP-NENs).
The aim of the International Expert Alliance is to systematically review the literature listed in PubMed, MEDLINE and Embase (time frame: 2000 to June 2020, and the main literature up to 2000) and to present a consensus statement
based on the best available scientific evidence.
The following consensus statement confirms or modifies previously published recommendations on the diagnosis and treatment of MEN1, while attempting to complement those made by various countries and international associations
.
The level of available evidence (LEs) for the diagnosis of DP-NENs and for clinical and therapeutic outcomes in the MEN1 range is low
for modern evidence-based medicine requirements.
There is a lack of evidence from controlled clinical trials to assess the optimal diagnosis, treatment, and follow-up of
DP-NENs.
Due to the rarity of this disease, they will not be promoted to the clinic in the
near future.
Current recommendations on the need for and value of diagnostic and therapeutic procedures are based on non-randomized, non-prospective investigations and the usual "case-control studies" (LE: III to IV; Recommended grade GR: B/C).
Methodological quality was assessed using LEs and GRs at the Oxford Centre for Evidence-Based Medicine (March 2009).
Epidemiology, penetrance, incidence, and frequency
The estimated prevalence of MEN1 is 1-10 per 100,000.
MEN1 genetic testing contributes to the specific diagnosis of MEN1 and early identification
of asymptomatic carriers.
In most, but not all, patients, MEN1 develops clinical symptoms
after the age of 21 years.
By the age of 50, the clinical penetrance of the disease is close to 100%.
Current guidelines recommend genetic testing for MEN1 starting at age 5 and annual biochemical (and imaging) screening
of affected individuals.
The aim of biochemical and imaging screening is to protect quality of life by early detection of
organ manifestations with malignant behavior (e.
g.
, DP-NET or NEN in the thymus) and, if malignant, to prevent local and distant spread, reduce morbidity and mortality associated with endocrine syndromes.
The techniques applied should be effective
in documenting diagnostic outputs of clinically relevant findings.
Genetic testing is recommended for all patients with clinical suspicion of having MEN1 and all first-degree relatives of MEN1 gene carriers to confirm the diagnosis
.
Genetic and biochemical testing and radiographic imaging are currently being debated until the age of 10~20 years of life
.
The change of genetic and biochemical tests to 16 years of age and the extension of the interval between screening and follow-up are based on the fact that most clinical manifestations begin around
that age.
Prophylactic medications or surgery do not work
in asymptomatic individuals.
Distress regarding psychological burden, positive screening but asymptomatic individuals and their families, cost-effectiveness, genetic and routine screening, and follow-up may be deferred until 16 years of age, but should be applied at least when any clinical symptoms become apparent
, regardless of age.
In addition, since rapid progression of organ manifestations is rarely observed, whether biochemical follow-up and radiological imaging
should be extended if clinically relevant organ manifestations are not detected at initial screening visits and in the home.
This more restrictive screening strategy discourages unnecessary testing
without missing serious findings.
DP-NENs are associated with an early age of onset (LE:4) and are diagnosed
early due to the timely presence of regular screening.
In MEN1, the prevalence of DP-NENs increases
with age.
Based on improved imaging techniques and regular screening, there is evidence that the incidence of DP-NENs in MEN1 reaches >
90% by age 70 years.
Early studies have shown that most DP-NENs are functional
.
NF-DP-NENs were rarely reported in earlier studies and may go undetected
in many cases.
Recent studies have shown that NF-NENs are the most common NENs in MEN1 patients, followed by F-NENs such as gastrinomas and
There was no significant sex difference in DP-NENs, except for men with a higher
prevalence of gastrinoma.
However, gender-appropriate diagnosis and treatment
is not recommended.
Minimum consensus statement of epidemiology, penetrance, incidence, and frequency of F-DP-NENs and NF-DP-NENs
Any patient with a family history of endocrine tumors of the pancreas, pituitary, or parathyroid glands, or other endocrine disorders should consider a diagnosis
of MEN1.
MEN1
should be suspected in patients diagnosed with typical MEN1 manifestations at a young age (< 30 years), in patients with multiple DP-NENs, or in patients associated with DP-NENs associated with
By the age of 50, the clinical penetrance of the disease is close to 100%.
To reduce DP-NENs-related morbidity and mortality, biochemical and imaging screening can be deferred until at least 16 years of age, but must be performed at least clinically apparent, regardless of age (LE:4).
The interval between routine biochemical and imaging screening in asymptomatic patients can be extended from 1 year to 2 to 3 years
.
Diagnosis and follow-up
1.
Biochemical examination
Following current guidelines, a series of biochemical tests
is recommended even in all asymptomatic MEN1 mutation carriers aged 10 years (insulinoma [fasting blood glucose, insulin]) to 20 years (gastrinoma [fasting gastrin level]) or earlier to adapt to the onset of clinical symptoms (LE:3).
In all newly diagnosed MEN1 patients, the purpose of biochemical screening for DP-NENs is primarily to evaluate the presence of F-DP-NENs, primarily in patients with various clinical symptoms (LE:3).
Biochemical testing and follow-up tests are determined by local resources and clinician expertise, and are a lifelong program
that respects the patient's wishes.
In terms of sensitivity and specificity, the value of several biochemical diagnostic tests is controversial (LE:2b).
To date, data
obtained prospectively in randomized trials are lacking.
In particular, general neuroendocrine markers—chromogranin A (CgA), pancreatic
the diagnosis of NF-DP-NENs.
1.
F-DP-NENs
If gastrinoma with Zollinger-Ellison syndrome (ZES) is suspected, fasting serum gastrin (FSG) greater than 10× normal with pH<2 is confirmed
.
After determining that FSG is elevated, gastric pH needs to be assessed when repeating the FSG assay to ensure that FSG elevation is inappropriate
.
Gastric juice pH assessment, increasingly performed during endoscopy, rather than the old method
of using a nasogastric tube.
The current diagnosis of ZES has become more difficult due to increased reliability of commercial gastrin assays, lack of availability of secretions for secretion
in most non-ZES patients.
Unfortunately, elevated FSG may give a false-positive indication of ZES because it may be elevated
in patients with physiologic hypergastrinemia due to hypoacidity/achlorhydria secondary to any cause, such as
In addition, hyperfunction of antral G cells has been reported in MEN1, which can increase FSG levels
with false positives.
Therefore, it is recommended to refer the patient to a specialist center for diagnosis
.
For a long time, the secretinin test (now rarely used) was routinely recommended as an important confirmatory tool
to establish ZES in patients with a <-fold increase in FSG and gastric pH >2.
This is because many other disorders (antral G-cell hyperfunction,
) may be associated with hyperacidity/hypergastrinemia in this range, which can be distinguished
by secretion testing.
Numerous studies have shown that under the right conditions (acidic pH, preferably pH<2), the test is highly sensitive and specific
to ZES.
Clinically suspected insulinoma is usually screened by blood glucose levels and fasting insulin, followed by 72-hour formal evaluation by 72-hour fasting insulin,
when suspicion is established.
For glucagonoma, diagnosis requires evidence of elevated plasma glucagon levels with clinical evidence of glucagon hypersecretion (
.
）
Vasoactive intestinal peptide-secreting tumors (VIP tumors) are manifested by elevated
plasma levels of vasoactive intestinal peptide (VIP).
They cause a particular syndrome, watery
.
Large amounts of VIP cause severe and chronic (secreted) watery diarrhea, characteristic more than 800 mL / day (pancreatic
2.
NF-DP-NENs
Most NF-DP-NENs secrete different regulatory secretory proteins that do not cause functional syndromes
.
CgA and PP are often secreted, and less commonly secreted proteins include glucagon, neuron-specific enolase, human chorionic gonadotropin subhormone,
These neuroendocrine markers may be used for early suspicion of NF-DP-NENs
.
In terms of sensitivity and specificity, the value of several biochemical diagnostic tests is controversial (LE:2b).
In particular, the diagnostic accuracy of general neuroendocrine markers (CgA, PP, and glucagon) for DP-NENs is low, especially in
the diagnosis of NF-DP-NENs.
Minimum consensus statement for biochemical diagnostics of DP-NENs
If biochemical screening is used, it should aim to assess for the presence of
F- and NF-DP-NENs.
Biochemical screening of F-DP-NENs should include a fasting gastrointestinal (GI) hormone profile, including at least insulin levels corresponding to blood glucose, and gastrin (LE:3).
For suspected insulinoma (low fasting blood glucose with elevated insulin), a supervised 72-hour fasting test should be performed to measure glucose, insulin (proinsulin), and C-peptide and analyzed
.
Screening
for sulfonylureas should be checked at the end of fasting.
In suspected gastrinoma (suspicious screening result: elevated FSG), FSG
should be assessed in conjunction with gastric acid pH.
If FSG>10× normal with pH<2, the diagnosis is clearly made with ZES
.
Use this diagnostic method with caution in patients with PPI and atrophic (type A) gastritis—both of which are common and can lead to a diagnosis
of suspected gastrinoma by raising FSG levels and misjudging them.
A secretintest is recommended to confirm ZES in patients with elevated FSG
.
However, secretins
are not available in most countries.
Suspicion of a glucagon tumor should be based on the history and diagnosis based on elevated plasma glucagon levels with clinical symptoms
.
VIP tumors should be diagnosed
by elevated plasma VIP with increased stool output (characteristic > 800 mL/day fasting).
CgA, PP, and glucagon have no added value
for diagnosing NF-P-NENs using a single biomarker.
There are no prospective and/or randomized studies to analyze the value of
individual biomarkers such as CgA, PP, and glucagon in screening for NF-DP-NENs.
2.
Tomography and functional imaging
Various imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and
of DP-NENs.
There is a lack of evidence from controlled clinical trials to assess the best single or combined approach
.
Most retrospective studies in the literature have compared
tomography (CT or MRI) with EUS and/or functional
CT is the most widely used imaging modality
for tumor localization.
It is worth mentioning that the radiation exposure of CT must be taken into account, especially if MEN1 patients are regularly monitored
for CT follow-up examinations.
For screening/imaging of DP-NENs, several groups prefer MRI over CT (LE:3).
MRI has reported identifying > 50% of DP-NENs larger than 30 mm in diameter, but only 5%
if the tumor is smaller than 10 mm.
MRI has the advantage of providing uniform representation
throughout the pancreas.
MRI has no radiation risk compared to other tomography modalities such as CT or PET-CT, which is a major advantage of MRI (LE:3).
SSTRs expressed by NENs can be targeted for radiolabeled peptides for imaging and therapeutics
.
The expression of SSTRs has led to the ability of new imaging techniques for PET-CT or PET-MRI to use radiolabeled somatostatin analogues (SAs) such as gallium-68 (68Ga) 1,4,7,10-tetraazetic acid-octreotide (DOTATATE).
Further research is needed to determine at what age somatostatin-labeled PET-CT/PET-MRI, should initially be used and its status
in the follow-up of MEN1 patients.
68Ga labeled somatostatin PET is superior to other tracer PET
in detecting other tumors.
PET+68Ga-labeled somatostatin is recommended as a diagnostic modality, as assessment provides staging of metastases and may lead to changes in medication and surgical management strategies (LE:2b).
For growing tumors, imaging should be repeated at least annually, and 68Ga-labeled somatostatin PET-CT can be added to the monitoring when tumors > 10 mm are present and/or tumors are growing, allowing metastases
to be detected in time.
However, future prospective studies are needed to validate the effectiveness
of these surveillance protocols for patients with DP-NENs and MEN1 in terms of modalities and intervals.
Combining glucagon-like peptide-1 receptor (GLP-1R) imaging with morphological tomography (CT or MRI) is a valuable tool
to distinguish insulinoma from other P-NENs present in MEN1 patients.
Therefore, GLP-1R imaging can guide successful surgical interventions
.
3.
Selective arterial calcium stimulation and venous blood collection
When F-DP-NENs such as insulinoma (selective arterial calcium injection [SACI]) or gastrinoma (selective arterial calcium or secretin injection) are not detected on tomography, arterial calcium stimulation
can be performed using hepatic venous catheterization in selected patients.
However, this invasive technique can only carry out roughly regionalizing the location, and cannot strictly localize hormone overdose
.
Cross-sectional and functional imaging as the lowest consensus statement for diagnostic and follow-up methods of DP-NENs
Detection, size detection, assessment of progression and presence of metastatic disease of DP-NENs are key elements in
managing MEN1 patients to determine appropriate treatment strategies.
In tomography (CT, MRI), P-NENs are hypervascular.
CT is the most widely used imaging method for the localization of
NENs.
Radiation exposure to CT must be considered, especially when
MEN1 patients are regularly monitored.
MRI should be preferred, and MRI has yielded good results
in DP-NENs with low radiation exposure.
MRI and, if available, EUS should be complementary to MEN1
patients.
Functional imaging of SSTRs targeting SSTRs using PETCT/PET-MRI, appears to add valuable information
for staging and clinical management purposes.
Combining GLP-1R imaging with morphological tomography (CT or MRI) is a useful tool
to distinguish insulinoma from other PNEN in MEN1 patients.
Therefore, GLP-1R imaging can guide successful surgical interventions
.
In terms of follow-up protocols, the surveillance plan should focus on determining the course of disease in
patients with DPNENs.
The frequency of screening should be adjusted
individually according to the rate of growth.
Selective stimulation of pancreatic arterial calcium and determination of insulin or gastrin in hepatic venous effluent may regionalize undetected insulinoma or gastrinoma without definitive localization
.
4.
Endoscopic ultrasound/fine needle aspiration
EUS has a sensitivity and positive predictive value reported of 100% compared to CT with a sensitivity of 81% for P-NENs and a positive predictive value of 97%, and there is a strong correlation between the largest lesions seen on EUS and pathology
.
However, EUS often overestimates the size of MEN1DP-NENs, especially those < 20mm
.
Several previous relatively small studies in MEN1 patients have shown that EUS is a very sensitive method for early imaging of P-NENs; EUS is also recommended as the preferred pancreatic imaging technique for MEN1 patients, as the most sensitive imaging method for NF-P-NENs, which can detect lesions
as small as 2 mm.
However, EUS is limited by availability, invasiveness, time-consuming, and operator experience, especially for MEN1 patients
who require a complete pancreatic examination.
EUS has a decreased
sensitivity to the tail of the pancreas.
In addition, many small NF-P-NENs with no therapeutic consequences have been detected, requiring follow-up and potentially causing psychological burden.
EUS is considered superior to CT or MRI pancreatic lesion detection
.
However, the clinically relevant > 20 mm NF-P-NENs missed by MRI and EUS are similar
.
Therefore, it is concluded that both EUS and MRI can be used interchangeably to detect lesions to ensure maximum sensitivity, should be used as early as possible, and if used in combination, these two modalities may reduce the burden
of invasive EUS.
Due to limited capacity to detect metastatic disease, EUS should always be used in combination with SRS, which is the most reliable method for
detecting metastases.
There are no precise recommendations
in the current literature on whether and when to perform EUS fine-needle aspiration biopsy (FNAB) to confirm a suspected diagnosis and grade of P-NENs in patients with MEN1.
Minimum consensus statement on internal ultrasound/FNAB as a method for diagnosis and follow-up of DP-NENs
Of all available diagnostic imaging modes, EUS is the most sensitive method for diagnosing DP-NENs and should be the test of
choice if specialized EUS is available (LE:2b, GR:C).
EUS is an invasive and not widely used technique, therefore, MRI is a suitable alternative
.
Due to the limited detection capacity of EUS in metastatic disease, nuclear imaging (SRS) should also be used as the most reliable method for detecting metastasis (LE:4, GR:C).
EUS-FNAB testing should not be performed routinely and should be reserved for established indications or cases with diagnostic uncertainty (LE:5, GR:D).
An EUS surveillance system is recommended to assess tumor diameter changes and assess emerging lesions (LE:4, GR:D).
Indications for surgery
1.
Is size an issue?
Current recommendations for surgical resection of NF-DP-NENs are based on tumor size, as patients with larger tumors have a higher
rate of metastasis.
Previous guidelines recommended considering surgical resection of NF-P-NENs larger than 10 mm in size, similar to the reported Uppsala group, the Marburg group, and the MEN collaborative group
in Japan.
The National Comprehensive Cancer Network recommends surgical removal
of tumors larger than 10–20 mm in size and tumors that grow faster within 6–12 months.
There are several different recommendations for treating MEN1 patients
with small NF-DP-NENs.
In a retrospective analysis of the French Oncology Endocrinology Research Group (GTE) database, Triponez et al.
showed a lower
risk of death in patients with small (<20 mm) NF-DP-NENs.
The authors suggest that patients should be conservative in the absence of other clear features, such as rapid advances in imaging studies
.
A recent study by GTE evaluated the likelihood of distant metastasis of NF-DP-NENs and confirmed previous recommendations by Triponez and colleagues, concluding that DP-NENs > 20 mm should be removed to prevent metastasis and improve survival, regardless of their associated secretion (LE:2b).
Regarding F-DP-NENs, the treatment of non-metastatic gastrinomas located in the duodenum is surgical resection, as it has been observed that the disease-related survival of patients with tumors greater than 20 mm improves after surgery (LE:3).
Most gastrinomas are multiple, occur in the duodenum, and most centers perform non-surgical treatment unless NENs (suspected gastrin production) are pancreatic and/or larger than 20 mm, in which case surgery
is recommended.
The prognosis of gastrinoma is related
to tumor size and the presence of liver metastases.
If the biochemical diagnosis is clear and distant metastases are present, some groups recommend a more aggressive approach to prevent metastatic spread (LE:3).
Regardless of size, removal of insulinomas, VIP tumors, and glucagon is
recommended.
Minimum consensus statement regarding size as an indication for DP-NENs surgery
The risk of progression of DP-NENs is related to size (LE:4).
NF-DP-NENs smaller than 20 mm can be followed conservatively in the absence of an aggressive family history or signs of malignancy documented by imaging or metastatic biopsy
.
NF-DP-NENs larger than 20 mm in MEN1 should be surgically removed
.
Most gastrinomas are multiple, occur in the duodenum, and are non-surgical in most centers unless NENs (suspected of gastrin production) are pancreatic and/or larger than 20 mm
.
Regardless of size, surgery
is recommended for insulinomas, VIP tumors, and glucagonomas.
2.
Is histology a problem?
DP-NENs in MEN1 patients develop from multiple clonal unrelated tumors
.
At a macro level, an average of 5 DP-NENs has been described, and the number of tumors detectable under the microscope is much
higher in patients undergoing surgery due to the diversity of diseases.
A subpopulation of these tumors is able to grow to a detectable size and is clinically relevant
.
Currently, the underlying mechanisms are not well understood to predict which tumors will progress.
This progression involves secondary mutations such as those in death domain-associated protein genes/
.
In MEN1, these mutations have been shown to occur only in rare MEN1-associated DP-NENs > 30 mm
.
NENs larger than 20 mm have more chromosomal aberrations
than smaller P-NENs.
The mechanisms involved may include epigenetic changes
.
In addition to size, the second prognostic factor is grading
assessed by proliferation (Ki-67) or mitotic index.
Tumor size ≥ 20 mm appears to be associated with more aggressive MEN-1-associated pancreatic disease, and grade G2 P-NENs should be treated surgically
, regardless of their size.
In some literature, the term "neuroendocrineneoplasm" is used as a synonym
for "neuroendocrineneoplasm.
" In 2018, WHO published a harmonized classification framework
for all NENs.
A key feature of the new classification is to distinguish between "well-differentiated" neuroendocrine tumors (NETs) and "poorly differentiated" neuroendocrine carcinomas (NECs) because they share a common expression
of neuroendocrine markers.
Based on the presence of mitotic count and/or Ki-67 marker index and/or necrosis, NENs can be classified as NETG1 (low), NETG2 (intermediate), or NETG3 (advanced).
NECs are considered "advanced"
by definition.
Minimum consensus statement on histology as an indication for surgery of DP-NENs
The risk of progression of DP-NENs is associated with proliferation (gradation) (LE: 4-5).
When DP-NENs reach size cut-off values (20 mm, primary tumor), tissue samples from these tumors may be recommended to select patients
at high risk of proliferative NENs and may require early surgical intervention to prevent aggressive growth, local and distant metastasis.
DP-NENs graded G2 may be subject to early surgery, regardless of their size
.
3.
Is genetics (genetics) a problem?
Three recent studies have shown that tumor aggressiveness of P-NENs may be related to menin loss of interaction with functional partners (JunD proto-oncogene/JunD and checkpoint suppressor 1/CHES1), and possibly mutations in exon 2
.
On the one hand, in a cohort study of 806 patients, mutations affecting the JunD interaction domain appeared to be associated with a higher risk of death secondary to MEN1 tumors (LE:2b).
On the other hand, a higher risk of aggressive P-NENs (LE:3)
was identified in patients with MEN1 mutations affecting the CHES1 interacting menin domain in a series of 67 patients.
Only recently there is 1 article that has established a genotype-phenotypic correlation
in MEN1.
When exon 2 mutations were present, an increased prevalence of DP-NENs (LE:2b)
was found in a case series of 188 MEN1 patients.
This study describes a 2-fold increased risk of metastasis when an exon 2 mutation is found in patients aged 20-40 years because the JunD domain is known to be partially contained in exon 2 (LE:2b).
For patients with exon 2 mutations, these investigators recommend reducing the recommended size for DP-NET resection to ≥15 mm; However, confirmation
from other independent studies is also recommended.
When indications are in doubt, two specific mutations associated with aggressive DP-NENs may influence the final decision
for surgical resection of the pancreas.
An aggressive phenotype with high penetrance of malignant P-NENs in specific families has been reported (LE:4; LE：4）
。 Both families analyzed in these reports carry germline mutations with complete loss of
menin function.
Belonging to this type of lineage is a reasonable additional factor
in the final surgical decision-making process.
Further international collaborative studies are needed before a recommendation on this topic can be determined, but indications for possible genotype-phenotypic correlation are promising
.
Genetics as a minimal consensus statement for surgical indications for DP-NENs
The risk of progression of DP-NENs appears to be related to genetic factors (LE:5).
There is still no clear evidence of genotype-phenotypic correlation
of DP-NENs in MEN1.
Surgical treatment
Surgical strategies
The surgery of F- and FF-DP-NENs requires a patient-centered, multidisciplinary approach
.
Surgical removal of F-DP-NENs
is generally recommended as long as diffuse unresectable metastatic disease is excluded.
The purpose of initial surgery for NF-D-NENs is to protect the patient's quality of life, prevent further progression or spread of the disease, and provide the longest possible time (LE:3, GR:B)
before any subsequent pancreatic intervention.
1.
Gastrinoma (MEN1-ZES)
MEN1 gastrinoma (irritated ZES) is the most common F-DP-NEN (30%)
.
Gastrinomas in MEN1 originate in the duodenum
.
Thus, all MEN1-ZES patients have duodenal gastrinoma (LE:2b).
P-NENs (which may be present outside of MEN1 gastrinoma) account for the majority
of NF-NENs.
Regardless of size, most gastrinomas exhibit malignant biological behavior
.
The treatment of MEN1 gastrinoma, whether treated with PPIs or surgery, is a highly controversial issue
.
At least 70%-80% of MEN1 gastrinomas have been shown to be malignant at diagnosis and show lymph node and/or liver metastases, but primary D-NEN may be a small gastrinoma as small as 1-2 mm in size (LE:2b).
Recent expert guidelines recommend the medical management of PPIs for most patients because the course of the disease is fairly mild, even without surgery
.
According to the published literature, MEN1-ZES is considered a surgically incurable disease (LE:3b).
At MEN1-ZES, there is no consensus
on indications and timing of surgery.
Most groups recommend surgery only when the tumor size reaches 20–30 mm, as the risk of liver metastases subsequently increases
significantly.
Several groups have suggested that if imaging shows pancreatic lesions > 20~30mm, MEN1-ZES surgery should be performed
.
In MEN1-ZES, the correct interpretation of such imageable "pancreatic tumors" (>20 mm) must be related to NF-P-NENs and not
to gastrinoma.
Nonetheless, the presence of imageable pancreatic lesions > 20 mm in MEN1-ZES, although likely non-functional, may be a useful alternative parameter to indicate surgery, based on good long-term survival (LE:2b)
of up to 100% at 10 years in this setting.
Similarly, there is no consensus
on the type and scope of MEN1-ZES surgery.
Most experts agree that, with the exception of D-gastrinomas, NF-P-NENs should be removed when technically feasible or by formal pancreatic resection (both with systemic lymph node resection
).
Total (duodenum) pancreatectomy (TP) should be avoided as an initial procedure for MEN1-ZES as much as possible, as the resulting "fragile" diabetes (unstable diabetes) significantly reduces the patient's quality of life and is associated with
severe morbidity during long-term survival.
If technically feasible and oncologically justified, complete pancreatectomy
should be avoided.
Any type of MEN1-ZESDP resection should be performed
only by an experienced pancreatic (endocrine) surgeon.
Approximately 24% of patients with MEN1-ZES develop an invasive course with distant metastases, resulting in death (LE:2a).
To date, no reliable markers or parameters have been identified to indicate the invasive course
of MEN1-ZES.
The most important determinant of survival in patients with MEN1-ZES is the presence or development of
liver metastases.
Currently, MEN1-ZES does not have sufficient data to definitively determine in which patient cytoreductive of
liver metastases should be performed.
Hypercalcaemia associated with hyperparathyroidism may increase gastric acid secretion and should be corrected before treatment of MEN1-ZES
.
Minimal consensus statement of surgical strategy for gastrinoma (MEN1-ZES).
There is no consensus on the indications for surgery, as no parameters show an invasive course and long-term survival is good
in about 75% of patients, even without surgery.
Pancreaticoduodenectomy (PPD) performed when biochemical ZES evidence is present, even in the absence of positive images, has a high probability of cure, and the benefits and risks
should be discussed with the patient.
It is agreed that any surgery should include exploration of the duodenum by duodenotomy or even removal of the duodenum in combination with systemic lymph node dissection to provide a cure for hypergastrinemia and reduce the risk of
distant metastatic disease.
Based on very limited data, it is recommended that the indications for re-exploration of MEN1-ZES should be considered with caution, particularly since symptoms are well controlled with medical therapy and long-term survival without distant metastases is excellent
.
Procedures should be individualized
based on preoperative findings, previous DP resection, patient history (e.
g.
, age and pre-existing insulin-dependent diabetes), and patient preference.
If at least 90% or all identifiable tumor burden can be safely removed, surgery
may be considered in patients with MEN1-ZES with advanced disease confined to the liver.
It is recommended to treat hyperparathyroidism before treating MEN1-ZES
.
2.
Insulinoma
MEN1 insulinoma is the second most common F-DP-NEN (15%)
.
The target organ of insulinoma is the pancreas
.
Insulinoma (an endogenous [organic]
.
Insulinomas range
in size from a few millimeters to several centimeters.
Multiple insulinomas
are found in up to 30% of MEN1 patients.
Due to the lack of effective alternative medical treatments, surgical indications
are often advocated.
Most (>90%) exhibit benign biological behavior
.
The precise localization of insulinoma within multiple DP-NENs appears to be helpful in planning an individualized surgical (tissue-sparing) approach
.
It is sometimes difficult to distinguish
insulinoma from other additional P-NENs by preoperative or intraoperative imaging techniques (EUS/CT/magnetic resonance tomography/PET-CT or PET-MRI) or by "regionalization" methods (SACI).
The possibility of classifying P-NEN as an insulinoma must theoretically be entrusted to a specific diagnostic technique
.
EUS-guided FNB may be a reasonable method to locate insulinoma, but it has so far been rarely adopted
.
GLP-1R imaging by 68Ga-exendin-4PET/CT has recently been found to correctly localize insulinoma
in almost all patients affected by MEN1 insulinoma.
Although GLP-1RPET-CT holds promise for selective detection of insulinomas, more experience is needed to validate the effectiveness
of this new imaging technique in a large number of MEN1 patients.
Using the SACI (Selective Arterial Calcium Stimulation) test, insulinoma cannot be definitively "localized" in the pancreas, but small NENs can be "regionalized" in the pancreas, sampling insulin through the hepatic veins, and localizing the insulin-secreting lesions in the right or left pancreatic region
after SACI in the pancreatic aorta.
The choice of surgical type is uncertain
due to the lack of prospective controlled studies.
Depending on the location and size of the suspected insulinoma, an individualized approach
is recommended.
For solitary tumors or 1 dominant tumor (>10 mm) with a few other small DP-NENs (≤ 10 mm), pancreatic eradication or segmental resection with the dominant tumor is recommended to avoid postoperative complications and long-term negative outcomes such as diabetes, persistent organic hyperinsulinemia, or recurrent hypoglycemia (LE:4).
In selected patients with pancreatic (body or) tail insulinoma, distal pancreatectomy with or without removal of other NENs from the head of the pancreas (Thompson procedure)
is recommended.
PPDs with or without pyloric preservation are rarely used and may be appropriate for patients with large insulinomas, which affect a large portion of the pancreatic head, and the size of one or more tumors located deep in the pancreatic tissue close to the main pancreatic duct is independent
of PPD.
3.
Rare F-DP-NENs
Less than 3% of P-NENs secret VIP (VIPoma), glucagon (glucagon) or somatostatin (somatostatinoma).
All of these NENs occur in the pancreas except somatostatinoma, which may also be located in the duodenum or first jejunal loop
.
If the tumor is larger than 30 mm, visceral metastases are usually recorded (highest intrahepatic prevalence) and may be the cause of
death in approximately half of affected patients.
The 10-year survival rate is close to 50%-60%.
Even in advanced stages, surgery
is recommended.
Surgical exploration must be aimed at curative resection
of the primary tumor and its eventual metastases.
The type of pancreatic resection is related
to the localization of the tumor.
Both PPD and distal pancreatic resection are required, and TP can usually be omitted
.
Extensive lymphadenectomy is useful, especially for somatostatin and glucagonoma, which have a tendency for lymph nodes to
spread.
Surgery may be required to remove liver metastases (LE:4).
Minimum consensus statement of surgical strategy for insulinoma (organic hyperinsulinemia)/rare F-DP-NENs
Due to the lack of effective drug therapy, surgery is generally recommended for insulinomas
.
Depending on the location and size of the suspected insulinoma, individualized treatment is recommended, which has a high probability of curing hyperinsulinemia and preserves the exocrine and endocrine functions
of the pancreas at a high rate.
For solitary tumors or 1 dominant tumor (>10 mm) other than some other small DP-NENs (≤5 mm), removal or segmental pancreatic resection with dominant tumor
is recommended whenever technically feasible.
Larger insulinomas, located at the tail of the pancreas, particularly near the main pancreatic duct, should be treated with distal pancreatic resection to reduce complications (e.
g.
, pancreatic fistula) and protect the spleen
.
It is recommended to remove other NENs
from the pancreatic head.
VIPoma, glucagonoma, and somatostatin require surgery, even if only tumor reduction.
4.
NF-DP-NENs
The focus of NF-DP-EN treatment is currently to prevent or delay death from malignancy, balancing the risk of disease with the impact of complex pancreatic surgery
.
Indications for surgery for asymptomatic NF-DP-NENs depend on initial size, imaging findings (signs of invasion, local, and/or distant metastasis), and the rate of further growth of
borderline size tumors during follow-up.
Since MEN1 is a genetic disorder that affects the neuroendocrine pancreas, DP-NENs can always recur
unless the entire gland is removed.
An important area of debate over the past 20 years has been the identification of triggers for malignant behavior in NF-DP-NENs, and subsequent surgical intervention
.
Initial pancreatic surgery should be tailored
to the patient's clinical condition, the location of disease within the pancreas, and the biology of ERN.
The goal of surgery should be to remove all demonstrable tumors in the pancreas and duodenum while preserving the pancreatic parenchyma to maintain normal pancreatic endocrine function
.
Surgery strikes a balance between a given time and scope, the risk of complications and life risks of DP-EN syndrome is complex, and outcome data on which treatment recommendations are based are limited
.
Current surgical indications are NF-DP-NENs>20 mm or those < 20 mm and have significant growth under surveillance to prevent or delay malignant death
.
If surgery is required, the most common procedure is to remove the distal pancreas and remove the tumor in the proximal pancreas or duodenum (Thompson procedure).
This strategy appears to delay, but not completely eliminate, recurrence, reoperation, and death of DP-ENE, while preserving some pancreatic parenchyma to promote endocrine function
.
TP alternatives are mainly used in situations where complete tumor resection is required or recurrent NF-P-NENs
in pancreatic remnants.
In a systematic review of the literature and exploratory meta-analysis, survival rates for tumor enucleation were similar
to those for large pancreatectomy.
However, the former is associated with a lower risk of postoperative endocrine insufficiency and a higher risk of recurrence, and is not associated
with reoperation.
In any case, the significant heterogeneity identified in these data reports requires large-scale, multicenter, prospective, and long-term follow-up comparative studies to determine whether initial surgical intervention for MEN1-related NF-D-NENs is removal or resection
.
Available data suggest that the former may be a better option, in which case it can be done
safely.
Minimum consensus statement on surgical strategies for (asymptomatic) NF-DP-NENs
At MEN1, NF-DP-NENs surgery is indicated for patients with tumor size > 20 mm or tumor progression within the monitoring range (LE:3; GR：B）
。 Striking a balance between the timing and duration of a given surgical procedure, the concomitant risk of complications and the risk to life of P-NENs are complex, and there are limited
outcome data on which treatment recommendations are based.
Initial pancreatic surgery should be tailored
to the site of disease within the pancreas and the patient's clinical condition.
The purpose of the primary surgery is to protect the patient's quality of life, prevent further progression or spread of the disease, and provide as long as possible before
any subsequent interventional pancreatic surgery (LE:3, GR:B).
5.
Endoscopic surgery is safe to perform and allows patients to derive potential benefits from successful minimally invasive surgery (LE:2b) [144-146] if the scope of the procedure is radical (primary tumor, lymph nodes; with/without splenectomy) can be applied
if the patient is performed with open surgery or selected with palliative intent.
。
Laparoscopic enucleation and/or spleen-preserving DP resection can be used for insulinoma and NF-DP-NENs ≤ 20 mm and are the treatment
of choice.
In this case, dissection of enlarged lymph nodes is not recommended because the overall malignant potential is low
.
Oncologically appropriate lymph node dissection
must be performed in all F-DP-NENs and NF-DP-NENs with a high probability of malignancy > 20 mm, or when malignancy is diagnosed.
In the hands of experienced people, this procedure can be performed
laparoscopically.
At the time of diagnosis, about 80% of MEN1 gastrinomas that occur more often in the duodenum have lymph node metastases, so lymphadenectomy is necessary and often concomitant P-NENs appear, which also require treatment
.
Any type of endoscopic mucosal resection or resection without lymph node dissection appears to be insufficiently
oncologically.
The laparoscopic approach (LE:4) should only be performed if the gastrinoma has been well positioned to the anterior duodenal wall before surgery, and the surgeon is familiar with the techniques
of laparoscopic peripancreatic lymphadenectomy.
In the presence of potential multiple insulinomas or multiple NF-DP-NENs, most endocrinologists favor enlarged exploration of the entire gland in open surgery
.
However, surgeons experienced in endoscopic surgery can apply laparoscopic methods to specific patients
.
Experience with intraoperative EUS is necessary to better localize the NEN
within the pancreatic tissue.
Overall, the available evidence for endoscopic surgery (robot or not) for the treatment of MEN1DP-NENs is very limited
.
There were only "case reports" published in the form of "expert opinions" with no clear critical evaluation (LE: 5; GR：D）
。 Laparoscopic and robotic PPD resection may be feasible and safe (LE:3), but they are technically demanding
.
Minimum consensus statement on laparoscopic/robotic surgery techniques
Laparoscopic enucleation and/or splenic-preserving DP resection (with/without robotic assistance) can be applied to insulinoma and NF-DP-NENs ≤ 20 mm and are technically feasible and are currently the surgery
of choice.
Oncologically appropriate lymph node dissection
must be performed in all FDP-NENs with high malignant potential and NF-DP-NENs > 20 mm, or when malignancy is diagnosed.
In the hands of experienced people, this procedure can be performed laparoscopically
.
Endoscopic local resection of duodenal gastrinoma with laparoscopic dilated lymph node dissection should not be performed
.
For MEN1, no final recommendation
can be given for laparoscopic surgery.
6.
Advanced local and distal disease
There are no clear recommendations
for indications, timing, and type of palliative pancreatic surgery in MEN1 patients with locally advanced disease or unresectable liver metastases.
Indications for palliative local and distal surgery should always be discussed within a multidisciplinary team, all treatment (alternative) options considered, and should be recommended for non-surgical treatment of refractory tumors
.
Patients benefit from
radical resection of regional lymph nodes and distant metastases.
Even in the presence of disseminated liver metastases, prognostic benefit
after surgical resection is possible in patients with primary MEN1.
Surgery
should be performed in a low-complication and high-volume referral center.
If at least 90% or all of the identifiable tumor burden can be safely removed, palliative surgery
may be recommended for advanced local or distant disease F- and NF-DP-NENs confined to the liver.
In 80% of patients, liver metastases in MEN1 patients have bicuspid type
.
In the case of surgical removal of liver metastases, the probability of achieving liver R0 resection is low (about 10%)
.
Minimum consensus statement on surgery for advanced local and distal disease F- and NF-DP-NENs
Indications for palliative local and distal surgery should always be discussed within a multidisciplinary team, all treatment (alternative) options considered, and should be recommended for non-surgical treatment of refractory tumors
.
For F- and NF-DP-NENs with unresectable liver metastases, locally radical surgery can be performed in selected cases of high-grade (G1) or moderately differentiated (G2) tumors without extrahepatic metastases and peritoneal spread to reduce local tumor burden (LE:3; GR：B）
。 For patients with locally resectable F-DP-NENs and unresectable liver metastases, the potential benefits of cytoreductive (detumor) surgery are relieving symptoms of hormone overload, limiting the disease to the liver, and preventing life-threatening and obstructive complications such as bleeding,
。 Hepatic resection should be considered the mainstay of treatment
in patients with G1 disease or G2F- and NF-P-NENs, resectable liver metastases, and no extrahepatic metastases.
Natural history - conservative treatment
Natural history of untreated NF-DP-NENs (asymptomatic) and follow-up protocols for treatment of DP-NENs
In addition to thymus NENs, metastatic DP-NENs are the most important cause of
disease-related mortality in MEN1 patients.
Therefore, subsequent follow-up examinations are necessary to prevent disease progression
.
The high prevalence and variable malignancy potential of F- and NF-DP-NENs reduce life expectancy and require a consistent follow-up protocol
.
Management decisions should be made by multidisciplinary teams and MEN1 patients should be followed up
individually by specialists.
Due to the genetic background, F- and NF-DP-NENs may recur, grow, and metastasize
.
In the follow-up and clinical decision making of MEN1-related NF-DP-NENs, the most important prognostic factors are tumor size, grade (mitotic count/Ki-67 index), and annual growth rate
.
Based on the available evidence documenting the overall indolence of NF-DP-NENs, particularly in patients with NENs < 20 mm, once it is determined that tumors do not exhibit a tendency to grow rapidly and the frequency of DP-NENs imaging is likely to be reduced (LE: 2a and 4), intensive follow-up
does not appear to be necessary.
Through EUS and conventional imaging (MRI/CT scan) detection, it was found that the annual growth rate of NF-DP-NENs varied
between 0.
1-1.
32 MM PER YEAR.
Larger tumor sizes appear to be associated
with higher metastasis rates and decreased overall survival.
In a Dutch cohort study, > 80% of DP-NENs were WHO1 grade, 16% were WHO2, and only one tumor was WHO3 HN
.
Grade 2 NF-DP-NENs should be considered high risk
.
A high Ki-67 index/mitotic count in large (>20mm) NF-DP-NENs is associated with
poor prognosis.
The WHO rating based on Ki-67 did not find such an association
.
Regardless of the pain-free course of most DP-NENs, liver metastases
occur in 15% to 19% of patients with NF-DP-NENs.
The presence of liver metastases is the most important prognostic factor
associated with overall survival in patients with MEN1-related DP-NENs.
Patients without liver metastases had 5- and 10-year survival rates of 95% and 86%, respectively, from the diagnosis of DP-NENs, compared with 65% and 50%
of patients with liver metastases.
The optimal radiological follow-up of
NF-DP-NENs has not been established.
EUS has the highest
sensitivity in detecting new NF-DP-NENs.
The joint strategy of EUS and MRI seems to be the most valuable
.
However, MRI appears to be cost-effective for follow-up and can be used alone for patient monitoring
.
If NF-DP-NENs are diagnosed during follow-up to identify metastases, functional imaging (e.
g.
, using 68Ga octreotide/octreotate DOTAPET-CT)
can be added.
Even when combined, tumor markers PP, CgA, and glucagon do not aid MEN1DP-NET screening and follow-up planning
.
However, it seems plausible that after DP-NET diagnosis, these markers can be used for follow-up as a surrogate to detect increased tumor burden or biochemical activity (LE:5).
Consensus statement on the natural history of untreated NF-DP-NENs (asymptomatic) and the protocol for follow-up of treated DP-NENs
Follow-up management should be individualized and based on various expert opinions
.
Initial tumor size, grade (mitotic count/Ki-67 index), and annual growth rate influence follow-up strategies
.
The annual growth rate is between
0.
1-1.
32 mm per year.
A high Ki-67 index/mitotic count in large (>20mm) NF-dpnNENs is associated
with poor prognosis.
To date, no studies in MEN1 patients have focused on the effectiveness
of tumor markers PP, CgA, and glucagon in the follow-up of known tumors.
There is controversy
about the value of various biochemical and radiological follow-up tests.
There is no consensus
on the optimal imaging or EUS screening.
Given the indolent nature of small (<20 mm) DP-NENs, intensive follow-up
does not appear to be necessary once it is determined that tumors do not exhibit growth trends and DP-NENs may be imaged less frequently (LE:2a and 4).
Liver metastases are the most important prognostic factor associated with overall survival, with 5- and 10-year survival rates of approximately 65% and 50%, compared with 95% and 86%
in patients without liver metastases.
Treatment options
1.
F-DP-NENs
Therapeutic surgery is always the initial treatment of choice and may theoretically address the hormonal excess involved in the removal of a given F-DP-ENE
.
To stabilize hormone overdose, medication and treatment for functional tumors is sometimes required before surgery to prevent hormone-related complications
.
Similarly, this therapy is indicated in patients with persistent or recurrent sex hormone hyperactivity after local surgery and in patients with functional (unresectable) distant metastases (LE:2b).
2.
Gastrinoma and ZES
In patients with MEN1-ZES, hypersecretion of gastric acid is almost universal at diagnosis, whereas earlier studies have shown that morbidity and mortality can be very high
if this hypersecretion is not controlled.
Prior to the development of gastric acid antisecretory drugs that were effective in ZES, the leading cause of death in MEN1 patients was a complication of the state of gastric acid secretion, not the malignant nature
of the tumor itself.
Hormonal excess may remain a problem after delayed surgical resection, as MEN1-ZES patients are rarely cured
.
Agents of choice to control gastric acid hypersecretion are PPIs (e.
g.
, omeprazole, lansoprazole, pantoprazole, esomeprazole, and rabeprazole) (LE:2a).
SAs are also used to control acid secretion
by reducing circulating gastrin levels.
Although PPIs are a first-line option for symptom control, they can also be supplemented
by the addition of SAs.
3.
Insulinoma
on insulinoma.
In MEN1 patients with preoperative insulinomas, hypoglycemia can also be controlled
by frequent eating.
Sometimes, long-acting SAs (
are recommended.
4.
Glucagonoma, VIP tumor and somatostatinoma
In other F-DP-NENs, such as glucagonoma, VIP tumors, and somatostatinomas, urgent management of the hypersecretory state (LE:2b)
sometimes associated with severe electrolyte conversion is required prior to any other treatment directed at F-DP-NENs.
For these rare F-DP-NENs, the drug of choice for acute and long-term control of hypersecretory states is long-acting SAs71
in patients with unresectable VIP tumors, glucagonomas, and a small number of clinically specific somatostatinomas.
Hypercalcaemia in
MEN1-ZES.
If parathyroid surgery is not possible, medical therapy for hyperparathyroidism should include administration of a calcium-sensitive receptor agonist such as
.
Minimum consensus statement for conservative (drug) regimens of F-DP-NENs
Medical therapy for hormonal overdose in patients with MEN1F-DP-NENs is similar
to that recommended for patients with sporadic F-DP-NENs.
Demand for antisecretory drugs may change over time, and patients with ZES are advised to check acid secretion control every 6 to 12 months
.
Diazazine should be given an initial dose of 3–8 mg/kg/day divided into 3 or 4 daily doses
.
If ineffective, the analogue can be increased to a maximum daily dose of 15 mg/kg
.
Because SAs also reduce the secretion of glucagon and
before discharge.
Therefore, in patients with F-DP-NENs with uncured hyperparathyroidism, correction of hyperparathyroidism should be considered first, especially if
drug control of hypersecretory states is difficult.
SA treatment in small (≤20mm) NF-(G1/G2)DP-NENs
Although multiple studies have shown that NF-DP-NENs≤20mm reduce oncology risk, and patients who are actively monitored may have the same progression-free survival as those undergoing surgery, concerns about unpredictable tumor progression or distant metastasis can affect patients and their referring physicians, not just after
active monitoring.
During monitoring, SAs experience with MEN1DP-NENs is limited to the occurrence of new DP-NENs, tumor growth, and progression of lymph nodes and/or distant metastases, so no final recommendations
can be given.
Faggiano et al.
evaluated the efficacy of SA lanreotide (LAN group) in a prospective preliminary study that compared patients who did not receive any treatment in the LAN group and the active monitoring group (AS group).
In the LAN group, one patient had an objective tumor response, most patients were stable, and a few patients had tumor progression
.
In the AS group, NEN progression
was recorded for most subjects.
Biotherapy – Targeted Therapy – Radiation Therapy – Targeted
Treatment of locally advanced and/or metastatic F- and NF-DP-NENs associated with MEN1 includes biologic therapies (eg, SAs, receptor inhibitors, and monoclonal antibodies), chemotherapy, and radiation therapy [189].
However, there is a lack of clinical trials in more patients with DP-NENs MEN1 and instead various case reports
revealing the efficacy of these treatment regimens.
High-level F-DP-NENs
Long-acting SAs have been found to control
.
in controlling hypoglycemia in patients with metastatic insulinoma refractory to other therapies.
In glucagonoma, cytotoxic therapy with streptozotocin +
everolimus and sunitinib 。 Such tumors are also sensitive
to peptide radioreceptor therapy (PRRT) using lutetium-177 (177Lu)-DOTATATE and yttrium-90 (90Y)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Tyr3-octreotide (DOTATOC).
Everolimus can also effectively control clinical symptoms
related to VIP production by reducing circulating VIP levels during the treatment of VIPoma.
Finally, PRRT can be applied to these patients with clinical benefits
.
Drug therapy for somatostatin includes the same type of treatment
as NF-DP-NENs.
High-level NF-DP-NENs
Metastatic NF-DP-NENs are usually treated first-line with the cytotoxic drug streptozotocin (plus 5-FU or doxorubicin or temozolomide plus capecitabine
).
Due to problems with access to streptozotocin in many countries, an increasing number of patients are taking everolimus or sunitinib as first-line agents
.
Radiotherapy using SA-based radioactive peptides such as 177Lu and 90Y has achieved significant efficacy
in patients with malignant F-DP-NENs (gastrinoma and insulinoma) and NF-DP-NENs.
PRRT radiation therapy has produced significant clinical benefits in a variety of patients with DP-NENs and therefore represents an effective alternative to
everolimus and sunitinib.
To date, with the exception of 4 case reports, there has been little experience
with PRRT for advanced MEN1F- and NF-DP-NENs as first-line treatment.
In these patients, a good PRRT palliative response was observed without any significant hematologic or nephrotoxicity
.
However, when data from prospective randomized trials of PRRT DP-NENs become available, the optimal sequence
of targeted agents and/or chemotherapy and/or PRRT needs to be determined in advanced F- and NF-DP-NENs (also MEN1).
Recent preclinical studies have identified potential new targeted therapies for the treatment of MEN1-related NENs, such as epigenetic modulators, Wnt pathway targeted β-catenin antagonists, Ras signaling regulators, Akt/mTOR signal modulators, novel SSTR analogues, antiangiogenic drugs, and MEN1 gene replacement therapy
.
DP-NECs（G3）
In a Dutch cohort study, approximately 1% of MEN1 DP-NENs were graded G3 (=NEC).
Important recommendations on DP-NENs have recently been summarized and the concepts
applicable to scattered DP-NECs have been followed.
For NECs, guidelines generally conclude that systemic chemotherapy is indicated for advanced inoperable disease, provided that a given patient has adequate organ function and capacity
.
Minimum consensus statement on conservative regimens of small NF-DP-NENs, locally advanced F- and NF-DP-NENs, and DP-NECs
SAs may be effective antiproliferative therapies in patients with MEN1-associated P-NENs < 20 mm, suggesting the use of these compounds to stop the development of new tumor lesions and delay or avoid pancreatic surgery
.
Currently, everolimus and sunitinib can be considered first-line treatments for advanced NF-DP-NENs, competing
with cytotoxic therapies such as streptozotocin plus 5-FU or doxorubicin and/or temozolomide plus/minus capecitabine.
After the failure of drug therapy, PRRT preparations containing SA, such as 177Lu-DOTATATE and 90Y-DOTATOC
, are recommended.
So far, the value of PRRT as first-line treatment for advanced F- and NF-DP-NENs seems promising
.
DP-NECs are a medical field
.
A combination of cisplatin and etoposide or a replacement of
Choice of drug therapy
It is very rare
for
Only 3 out of 4 women had rough case reports, including gastrinomas or NF-P-NENs
in MEN1 before or during pregnancy.
Taking into account the function, grading, and staging of DP-NENs, pregnancy and
for all patients.
They affect the order of the necessary intervals between diagnostic follow-ups, as well as the treatment, type, and timing
.
Arguments
for and against pregnancy should be discussed with the patient and their family.
Due to its rarity, there are currently no guidelines for young women with genetically confirmed MEN1 on how to plan their pregnancies and, in the event of an unplanned pregnancy, how to follow NENs and pregnancy protocols
.
An individualized, multidisciplinary approach should be developed, involving gynecologists and neonatologists as well as medical oncologists, endocrinologists, surgeons and anesthesiologists
.
In addition, the patient's family should be considered when making pregnancy decisions, taking into account a range of legal, ethical, religious, personal, and emotional factors
.
Minimum consensus statement on F- and NF-DP-NENsMEN1 and pregnancy
Pregnancy does not change the diagnosis and treatment
of gastrinomas and insulinomas.
Symptoms of gastrinoma can be effectively controlled
with gastric antisecretory drugs (prescribed as H2 receptor antagonists or PPIs).
H2 receptor antagonists are the preferred conservative treatment
.
Ideally, if no other treatment options are available, and the benefits outweigh the harms, PPIs should be limited to well-defined indications
.
The use of PPI shows an increased
risk of congenital malformations.
Loss of blood sugar control caused by insulinoma during pregnancy can lead to fetal death
.
Complications
can be avoided by increasing food intake to maintain and monitor reasonable blood glucose levels (if taken regularly).
If conservative treatment fails, diazoxide is the first-line agent
.
Surgery for localized insulinoma remains the only possible cure
.
If conservative treatment fails, it should be planned after 28 weeks' gestation or after delivery
.
There is no clear evidence of functional recurrence
in "surgically cured" F-DP-NENs.
There are no arguments against pregnancy in patients with asymptomatic, localized NENs ≤ 20 mm, as there is no evidence that DP-NENs progress
during pregnancy.
Doctors on the support team should generally advise women with metastatic disease who require ongoing treatment for contraception
.
Hepatic targeted therapy and PRRT therapy with radiopharmaceuticals or chemotherapy drugs and systemic therapy with targeted drugs such as everolimus and sunitinib may cause malformations and increase the risk of
fetal death.
Source: CK Medical Pro
