Wieloogniskowa neoplazja endokrynna typu 1 (men 1) – Rokowania, prognozy i postęp choroby

Wieloogniskowa neoplazja endokrynna typu 1 (men 1)
Rokowania, prognozy i postęp choroby

Wieloogniskowa neoplazja endokrynna typu 1 (MEN 1) to autosomalnie dominujący zespół predysponujący do nowotworów gruczołów endokrynnych, głównie przytarczyc, trzustki, dwunastnicy i przysadki mózgowej. Pacjenci z nieleczonym MEN 1 mają skróconą przeżywalność, z 50% ryzykiem zgonu przed 50. rokiem życia, a średni wiek zgonu wynosi 55-60 lat. Najczęstszą przyczyną zgonów są złośliwe nowotwory neuroendokrynne (NET), zwłaszcza niefunkcjonalne NET trzustki (NF-pNET), gastrinoma oraz NET grasicy, z całkowitą penetracją NET dwunastnicy i trzustki sięgającą 80%. Rokowanie NET grasicy jest szczególnie złe (mediana przeżycia 8,4 roku, 10-letnie przeżycie 33%), natomiast NET żołądka i płuc cechują się lepszym przebiegiem. Kluczowymi czynnikami prognostycznymi w MEN 1 są wielkość guza (NF-pNET ≤2 cm obserwacja, >2 cm resekcja) oraz stopień zróżnicowania histopatologicznego (grade 2 oznacza wysoki ryzyko). Przerzuty do wątroby w gastrinoma wiążą się z gorszym rokowaniem, natomiast przerzuty do węzłów chłonnych nie wpływają negatywnie na przeżycie.

Wieloogniskowa neoplazja endokrynna typu 1 (MEN 1) – Prognoza (przewidywanie wyników)

Główne przyczyny zgonów w MEN 1
Czynniki prognostyczne w MEN 1
Znaczenie wczesnej diagnostyki w poprawie rokowania
Znaczenie ośrodków referencyjnych
Cele obserwacji i leczenia
Kolejne rozdziały

Wieloogniskowa neoplazja endokrynna typu 1 (MEN 1) – Prognoza (przewidywanie wyników)

Wieloogniskowa neoplazja endokrynna typu 1 (MEN 1) jest rzadkim dziedzicznym zespołem nowotworowym, przekazywanym w sposób autosomalny dominujący, charakteryzującym się predyspozycją do rozwoju nowotworów gruczołów endokrynnych, głównie przytarczyc, trzustki, dwunastnicy oraz przysadki mózgowej. Pacjenci z nieleczonym MEN 1 mają skróconą oczekiwaną długość życia, z 50% prawdopodobieństwem zgonu przed ukończeniem 50. roku życia.¹² Mimo postępów w diagnostyce i leczeniu nowotworów związanych z MEN 1, średni wiek w momencie zgonu wynosi 55-60 lat.³

Główne przyczyny zgonów w MEN 1

Badania wieloośrodkowe sugerują, że około 70% pacjentów z MEN 1 umiera z przyczyn bezpośrednio związanych z tym zespołem.⁴ Główne przyczyny zgonów zmieniły się na przestrzeni lat – od powikłań związanych z nadmiernym wydzielaniem hormonów (szczególnie w przypadku gastrinoma) do złośliwych nowotworów neuroendokrynnych (NET). Obecnie najczęstszymi przyczynami zgonów są złośliwe nowotwory neuroendokrynne, przede wszystkim trzustki (pNET) oraz grasicy (thNET).⁵⁶

Złośliwe nowotwory neuroendokrynne stanowią najważniejszą przyczynę śmiertelności związanej z chorobą, głównie niefunkcjonalne NET trzustki (NF-PanNET), gastrinoma oraz NET grasicy. Całożyciowa penetracja nowotworów neuroendokrynnych dwunastnicy i trzustki sięga 80%.⁷ Nowotwory neuroendokrynne grasicy (występujące u 2-8% pacjentów) rozwijają się głównie u mężczyzn i mają złe rokowanie.⁸

Czynniki prognostyczne w MEN 1

Głównym wyzwaniem w prowadzeniu pacjentów z MEN 1 jest identyfikacja osób zagrożonych agresywnym przebiegiem choroby.⁹ Na podstawie dostępnych danych zidentyfikowano kilka kluczowych czynników prognostycznych:

Czynniki genetyczne

Badania kohortowe z pojedynczych ośrodków zidentyfikowały pewne genotypy związane z bardziej agresywnym przebiegiem choroby (zwłaszcza w odniesieniu do NET trzustki i dwunastnicy), takie jak mutacje w domenie oddziałującej z JUND lub CHES1, czy mutacje nonsensowne/przesunięcia ramki odczytu w porównaniu do mutacji zmiany sensu. Jednakże, ponieważ żadne z tych powiązań nie zostały niezależnie zwalidowane, genotypu nie można wykorzystać do indywidualizacji nadzoru.¹⁰ Brak wyraźnej korelacji genotyp-fenotyp może sugerować potencjalną rolę innych genów modyfikujących i/lub czynników środowiskowych.¹¹

Badania 10 holenderskich rodzin sugerują występowanie antycypacji genetycznej (zmniejszony wiek wystąpienia choroby lub zwiększona ciężkość choroby w kolejnych pokoleniach), zjawiska dotychczas niewyjaśnionego w przypadku genów dziedziczonych autosomalnie dominująco bez ekspansji powtórzeń trinukleotydowych.¹²

Czynniki prognostyczne w niefunkcjonalnych nowotworach neuroendokrynnych trzustki (NF-pNET)

Najważniejszymi czynnikami prognostycznymi wykorzystywanymi w podejmowaniu decyzji klinicznych w przypadku niefunkcjonalnych pNET związanych z MEN 1 są:¹³

Wielkość guza – NF-pNET o średnicy ≤2 cm mogą być zarządzane poprzez uważną obserwację, podczas gdy resekcja chirurgiczna jest zalecana dla NF-pNET >2 cm
Stopień zróżnicowania (grade) – NF-pNET w stopniu 2 powinny być uznawane za guzy wysokiego ryzyka

¹⁴

W badaniu pacjentów poddanych resekcji pNET związanego z MEN1, van Beek i wsp. wykazali, że wskaźnik przeżycia wolnego od przerzutów do wątroby był znacząco niższy u pacjentów z guzami niefunkcjonalnymi niż u pacjentów z insulinoma; szacowany 10-letni wskaźnik wynosił odpowiednio 63% w porównaniu do 87%.¹⁵

Rokowanie w innych guzach związanych z MEN 1

NET grasicy charakteryzują się wyjątkowo złym rokowaniem, co zostało potwierdzone w meta-analizie 99 przypadków thNET związanych z MEN 1: mediana przeżycia wynosiła 8,4 roku, a wskaźnik 10-letniego przeżycia wynosił 33%.¹⁶

Rokowanie w przypadku NET żołądka związanych z MEN 1 jest ogólnie dobre, z przerzutami (regionalnymi i odległymi) zgłaszanymi w 10-30% przypadków i śmiertelnością związaną z chorobą na poziomie 10%.¹⁷¹⁸

Większość NET oskrzeli i płuc związanych z MEN 1 to dobrze zróżnicowane NET (typowe i atypowe rakowiaki); tylko pięć przypadków słabo zróżnicowanych raków neuroendokrynnych zidentyfikowano dotychczas u pacjentów z MEN 1. Ogólnie łagodne cechy histopatologiczne tych nowotworów mogą wyjaśniać ich zwykle dobre rokowanie – duże badania kohortowe wykazały, że NET oskrzeli i płuc nie wpływają znacząco na przeżycie pacjentów z MEN 1.¹⁹²⁰

W przypadku gastrinoma, obecność przerzutów do wątroby wiąże się ze złym rokowaniem. Interesujące jest, że rokowanie nie wydaje się być negatywnie wpływane przez przerzuty do węzłów chłonnych.²¹

Znaczenie wczesnej diagnostyki w poprawie rokowania

Wczesna i dokładna diagnoza MEN 1 ma kluczowe znaczenie dla poprawy wyników leczenia. Umożliwia wczesne wykrycie manifestacji nowotworowych, pozwalając na terminowe leczenie w celu zmniejszenia chorobowości i poprawy przeżycia.²²

Obecnie testy DNA umożliwiają wczesną identyfikację mutacji germinalnych u bezobjawowych nosicieli genu, którym zaleca się rutynowy nadzór (regularne badania biochemiczne i/lub radiologiczne w celu wykrycia rozwoju guzów i zmian związanych z MEN 1).²³

Identyfikacja mutacji MEN 1 u pacjentów i członków rodziny z grupy ryzyka wiąże się z zaleceniem pozostawania pod dożywotnią obserwacją, z co najmniej corocznymi wizytami klinicznymi obejmującymi wywiad, badanie fizykalne, badania biochemiczne oraz badania radiologiczne w określonych odstępach czasu.²⁴

Najnowsze wytyczne praktyki klinicznej dla MEN 1, opublikowane w 2012 roku, podkreślają potrzebę wczesnej diagnostyki genetycznej i klinicznej MEN 1 i zalecają intensywne podejście do nadzoru zarówno dla pacjentów z tym zespołem, jak i bezobjawowych nosicieli, rozpoczynając od 5 roku życia. Celem jest terminowe wykrywanie i leczenie nowotworów związanych z MEN 1, a ostatecznie zmniejszenie chorobowości i śmiertelności związanej z tą chorobą.²⁵²⁶ Racjonalne podejście do intensywnego nadzoru u pacjentów z MEN 1 i bezobjawowych nosicieli opiera się na założeniu, że wczesne przedobjawowe wykrywanie nowotworów związanych z MEN 1 może zmniejszyć związaną z nimi śmiertelność.²⁷

Znaczenie ośrodków referencyjnych

Ze względu na złożoność choroby, zdecydowanie zaleca się, aby pacjenci, jeśli to możliwe, byli obserwowani i leczeni w ośrodkach referencyjnych z odpowiednim doświadczeniem.²⁸ Wiedza na temat mechanizmów rozwoju guzów u pacjentów z MEN 1 znacznie się zwiększyła, jednak nadal pozostaje wiele pracy do wykonania. Ostatecznym celem jest zaoferowanie pacjentom z mutacjami germinalnymi MEN 1 optymalnego programu profilaktyki i leczenia nowotworów.²⁹

Cele obserwacji i leczenia

Główne cele obserwacji i leczenia pacjentów z MEN 1 to:³⁰

Zapobieganie chorobie przerzutowej
Wyleczenie nadmiernego wydzielania hormonalnego
Zapobieganie powikłaniom wynikającym z nadmiernego wydzielania hormonalnego
Minimalizacja powikłań związanych z leczeniem
Zachowanie jakości życia

³¹

W ostatnich dziesięcioleciach nastąpił znaczny postęp w zrozumieniu naturalnego przebiegu guzów związanych z MEN 1, co miało bezpośrednie konsekwencje dla opieki klinicznej nad pacjentami z tym zespołem.³²

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Materiały źródłowe

#1 Multiple Endocrine Neoplasia Type 1 (MEN1): Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/126438-overview
Multiple endocrine neoplasia type 1 (MEN1) is characterized by the combination of parathyroid tumors, pancreatic islet cell tumors, and anterior pituitary tumors. Most MEN1 tumors are not aggressive, and many of them (particularly nonfunctioning tumors) follow a long-term indolent course, remaining asymptomatic for years. Nevertheless, patients with untreated MEN1 have a decreased life expectancy, with a 50% probability of death by age 50 years. […] Malignant pancreatic neuroendocrine tumors and thymic carcinoid tumors have been associated with a marked increase in the risk of death in MEN1 patients. […] The rationale for an aggressive surveillance approach in MEN1 patients and asymptomatic carriers is based on the presumption that the early pre-symptomatic detection of MEN1 neoplasias may reduce the associated mortality.
#2 Multiple Endocrine Neoplasia Type 1 (MEN1) Follow-up: Further Outpatient Care, Prognosis
https://emedicine.medscape.com/article/126438-followup
Untreated multiple endocrine neoplasia type 1 (MEN1) patients have a decreased life expectancy, with a 50% probability of death by age 50 years. The cause of death is usually associated with a malignant tumor or sequelae of the disease. […] One multicenter study suggests that 70% of patients with MEN1 die of causes directly related to MEN1.
#3 Frontiers | Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis
https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00339/full
Despite advances in the diagnosis and treatment of MEN1-associated tumors, patients with this syndrome continue to have a decreased life expectancy compared to the rest of the population, with a mean age of death of 55â60 years. […] The most common cause of death has shifted from the complications of hormone-excess states, primarily due to gastrinomas, to malignant NETs, most notably pNETs and th-NETs. […] The most recent Endocrine Society clinical practice guidelines for MEN1 published in 2012, recommend an intensive surveillance approach for patients with MEN1 and asymptomatic carriers starting at the age of 5 years, based on the assumption that early detection and management of MEN1-associated neoplasms may lead to decreased morbidity and mortality.
#4 Multiple Endocrine Neoplasia Type 1 (MEN1) Follow-up: Further Outpatient Care, Prognosis
https://emedicine.medscape.com/article/126438-followup
Untreated multiple endocrine neoplasia type 1 (MEN1) patients have a decreased life expectancy, with a 50% probability of death by age 50 years. The cause of death is usually associated with a malignant tumor or sequelae of the disease. […] One multicenter study suggests that 70% of patients with MEN1 die of causes directly related to MEN1.
#5 Frontiers | Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis
https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00339/full
Despite advances in the diagnosis and treatment of MEN1-associated tumors, patients with this syndrome continue to have a decreased life expectancy compared to the rest of the population, with a mean age of death of 55â60 years. […] The most common cause of death has shifted from the complications of hormone-excess states, primarily due to gastrinomas, to malignant NETs, most notably pNETs and th-NETs. […] The most recent Endocrine Society clinical practice guidelines for MEN1 published in 2012, recommend an intensive surveillance approach for patients with MEN1 and asymptomatic carriers starting at the age of 5 years, based on the assumption that early detection and management of MEN1-associated neoplasms may lead to decreased morbidity and mortality.
#6 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare autosomal dominantly inherited endocrine tumor predisposition syndrome, caused by mutations in the MEN1 gene. Cardinal manifestations are primary hyperparathyroidism (pHPT), pituitary adenomas (PA), and neuroendocrine tumors (NETs) of the pancreas (PanNET) and duodenum. […] Malignant NETs are the most important cause of disease-related mortality, mainly NF-PanNETs, gastrinomas and thymus NETs. […] Life-time penetrance of duodenopancreatic NETs is 80%. […] The main challenge is to identify patients at risk for an aggressive disease course. Thymic NETs (2-8%) occur predominantly in males and have a poor prognosis. […] Given the complexity of the disease, it is strongly advised that patients, whenever possible, be followed and treated in centers of expertise.
#7 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare autosomal dominantly inherited endocrine tumor predisposition syndrome, caused by mutations in the MEN1 gene. Cardinal manifestations are primary hyperparathyroidism (pHPT), pituitary adenomas (PA), and neuroendocrine tumors (NETs) of the pancreas (PanNET) and duodenum. […] Malignant NETs are the most important cause of disease-related mortality, mainly NF-PanNETs, gastrinomas and thymus NETs. […] Life-time penetrance of duodenopancreatic NETs is 80%. […] The main challenge is to identify patients at risk for an aggressive disease course. Thymic NETs (2-8%) occur predominantly in males and have a poor prognosis. […] Given the complexity of the disease, it is strongly advised that patients, whenever possible, be followed and treated in centers of expertise.
#8 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare autosomal dominantly inherited endocrine tumor predisposition syndrome, caused by mutations in the MEN1 gene. Cardinal manifestations are primary hyperparathyroidism (pHPT), pituitary adenomas (PA), and neuroendocrine tumors (NETs) of the pancreas (PanNET) and duodenum. […] Malignant NETs are the most important cause of disease-related mortality, mainly NF-PanNETs, gastrinomas and thymus NETs. […] Life-time penetrance of duodenopancreatic NETs is 80%. […] The main challenge is to identify patients at risk for an aggressive disease course. Thymic NETs (2-8%) occur predominantly in males and have a poor prognosis. […] Given the complexity of the disease, it is strongly advised that patients, whenever possible, be followed and treated in centers of expertise.
#9 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare autosomal dominantly inherited endocrine tumor predisposition syndrome, caused by mutations in the MEN1 gene. Cardinal manifestations are primary hyperparathyroidism (pHPT), pituitary adenomas (PA), and neuroendocrine tumors (NETs) of the pancreas (PanNET) and duodenum. […] Malignant NETs are the most important cause of disease-related mortality, mainly NF-PanNETs, gastrinomas and thymus NETs. […] Life-time penetrance of duodenopancreatic NETs is 80%. […] The main challenge is to identify patients at risk for an aggressive disease course. Thymic NETs (2-8%) occur predominantly in males and have a poor prognosis. […] Given the complexity of the disease, it is strongly advised that patients, whenever possible, be followed and treated in centers of expertise.
#10 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
Patients with MEN1 suffer from high morbidity and a decreased life expectancy. In the present day and age, MEN1-related malignancy is the main MEN1-related cause of death, particularly due to duodenopancreatic and thymic NETs. A timely and accurate diagnosis of MEN1 is paramount to improve disease outcomes. This enables early identification of tumor manifestations allowing timely treatment to reduce morbidity and improve survival. […] The approximate prevalence of MEN1 has been reported as 1 in 30,000 individuals with no apparent gender bias. MEN1 follows an autosomal dominant pattern of inheritance with 95% penetrance by age 40-50 years. […] Single center cohorts have identified certain genotypes that are associated with a more aggressive course of the disease (especially related to duodenopancreatic NETs), such as mutation in the JUND or the CHES1 interacting domain or nonsense/frameshift versus missense mutations, but since none of these associations have been independently validated, genotype cannot be used to individualize surveillance.
#11 Multiple endocrine neoplasia type 1 | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-1-38
Patients with liver metastases have a poor prognosis for survival. […] Prognosis does not seem negatively influenced by nodal metastases. […] The absence of a genotype-phenotype correlation might suggest a possible role of other modifier genes and/or environmental factors. […] An understanding of the function of MEN1 gene and of menin interacting proteins, in the near future, may help correlation studies and assist clinical management of patients. […] In fact, although the knowledge of the mechanisms of tumour development in patients with MEN1 has grown tremendously, much work lies ahead. The final goal is to offer patients with MEN1 germline mutations an optimal cancer prevention and treatment program.
#12 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
Evaluation of 10 Dutch families suggest genetic anticipation (decreased age of disease onset or an increased disease severity in successive generations), a known phenomenon which to date cannot be explained in autosomal dominant inherited disease genes without trinucleotide repeat expansions. […] The identification of an MEN1 mutation in patients and family members at risk is followed by the advice to remain under lifelong surveillance, with at least annual clinic visits including history, physical examination, biochemical screening, and radiological screening at specific intervals. […] The optimal timing of the initial operation is still a matter of debate, especially in (asymptomatic) children and young adults. […] The initial operation recommended by most experts and guidelines is a bilateral cervical exploration, identifying all four parathyroid glands and performing a subtotal parathyroidectomy with concomitant cervical thymectomy.
#13 Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: a systematic review of literature in: Endocrine-Related Cancer Volume 27 Issue 6 (2020)
https://erc.bioscientifica.com/view/journals/erc/27/6/ERC-19-0372.xml
Metastatic duodenopancreatic neuro-endocrine tumors (dpNETs) are the most important disease-related cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Nonfunctioning pNETs (NF-pNETs) are highly prevalent in MEN1 and clinically heterogeneous. Therefore, management is controversial. Data on prognostic factors for risk stratification are limited. […] We found that the most important prognostic factors used in clinical decision making in MEN1-related NF-pNETs are tumor size and grade. NF-pNETs 2 cm may be managed with watchful waiting, while surgical resection is advised for NF-pNETs 2 cm. Grade 2 NF-pNETs should be considered high risk. […] Based on our systematic review of prognostic factors in MEN1-related NF-pNETs, combined with evidence from sporadic NF-pNETs and MEN1-related pNETs in general, we conclude that the most important prognostic factors to be used in clinical decision making in MEN1-related NF-pNETs are currently tumor size and grade. Based on the available evidence, NF-pNETs 2 cm may be managed with watchful waiting, while surgical resection is advised for NF-pNETs 2 cm. Grade 2 NF-pNETs should be considered high risk.
#14 Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: a systematic review of literature in: Endocrine-Related Cancer Volume 27 Issue 6 (2020)
https://erc.bioscientifica.com/view/journals/erc/27/6/ERC-19-0372.xml
Metastatic duodenopancreatic neuro-endocrine tumors (dpNETs) are the most important disease-related cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Nonfunctioning pNETs (NF-pNETs) are highly prevalent in MEN1 and clinically heterogeneous. Therefore, management is controversial. Data on prognostic factors for risk stratification are limited. […] We found that the most important prognostic factors used in clinical decision making in MEN1-related NF-pNETs are tumor size and grade. NF-pNETs 2 cm may be managed with watchful waiting, while surgical resection is advised for NF-pNETs 2 cm. Grade 2 NF-pNETs should be considered high risk. […] Based on our systematic review of prognostic factors in MEN1-related NF-pNETs, combined with evidence from sporadic NF-pNETs and MEN1-related pNETs in general, we conclude that the most important prognostic factors to be used in clinical decision making in MEN1-related NF-pNETs are currently tumor size and grade. Based on the available evidence, NF-pNETs 2 cm may be managed with watchful waiting, while surgical resection is advised for NF-pNETs 2 cm. Grade 2 NF-pNETs should be considered high risk.
#15 Multiple Endocrine Neoplasia Type 1 (MEN1): Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/126438-overview
Patients with multiple endocrine neoplasia type 1 (MEN1) have a decreased life expectancy, with a 50% probability of death by age 50 years. Half the deaths result directly from a malignant process or the sequela of an endocrine disorder. In a Dutch study, median survival in patients with an identified mutation in the MEN1 gene was estimated at 73 years, versus 87 years in mutation-negative patients diagnosed on the basis of having two of the three main MEN1 manifestations (primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors, and pituitary tumors). […] In a study of patients who underwent resection of a MEN1-related pancreatic neuroendocrine tumor, van Beek et al reported that the rate of liver metastases-free survival was significantly lower in patients with nonfunctioning tumors than in patients with insulinomas; estimated 10-year rates were 63% versus 87%, respectively.
#16 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
Gastric NETs in MEN1 are almost exclusively seen in patients with gastrinoma and usually have an indolent course. […] The prognosis of MEN1-related gastric NETs is generally good, with metastases (regional and distant) reported in 10-30% and disease-related death 10%. […] The poor prognosis of MEN1-related thNET has also been illustrated in a meta-analysis of 99 MEN-1 thNETs: median survival was 8.4 years, and the 10-year survival rate was 33%. […] The treatment of stage IV dpNET in patients with MEN1 is similar to that of patients with sporadic dpNETs. […] The only curative treatment for NF-PanNETs in MEN1 is surgical resection, and the goal of surgical intervention in NF-PanNETs is to prevent metastases and thereby NF-PanNET-related mortality. […] The majority of MEN1-related bpNETs are well-differentiated NETs (typical and atypical carcinoids); only five cases of poorly differentiated neuroendocrine carcinomas have been identified in MEN1 patients until now.
#17 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
Gastric NETs in MEN1 are almost exclusively seen in patients with gastrinoma and usually have an indolent course. […] The prognosis of MEN1-related gastric NETs is generally good, with metastases (regional and distant) reported in 10-30% and disease-related death 10%. […] The poor prognosis of MEN1-related thNET has also been illustrated in a meta-analysis of 99 MEN-1 thNETs: median survival was 8.4 years, and the 10-year survival rate was 33%. […] The treatment of stage IV dpNET in patients with MEN1 is similar to that of patients with sporadic dpNETs. […] The only curative treatment for NF-PanNETs in MEN1 is surgical resection, and the goal of surgical intervention in NF-PanNETs is to prevent metastases and thereby NF-PanNET-related mortality. […] The majority of MEN1-related bpNETs are well-differentiated NETs (typical and atypical carcinoids); only five cases of poorly differentiated neuroendocrine carcinomas have been identified in MEN1 patients until now.
#18 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
The overall benign histopathological characteristics of MEN1-related bpNET may explain their usually good prognosis: large cohort studies have shown that bpNETs do not significantly affect survival in MEN1 patients. […] In patients with MEN1, minimal recommended screening for adrenal lesions as per the current guidelines, is abdominal imaging with CT or MRI every 3 years for those without adrenal lesions. […] The current guidelines recommend that screening be focused on hyperaldosteronism and hypercortisolism, but given that pheochromocytomas do occur in MEN1 as described above and the consequence of missing the diagnosis can be serious, it is prudent to screen for the presence of a pheochromocytoma by either plasma free (nor)metanephrines or urinary fractionated (nor)metanephrines. […] The prognosis of MEN1-related gastric NETs is generally good, with metastases (regional and distant) reported in 10-30% and disease-related death 10%. […] In conclusion, in the past decades there have been great advances in the understanding of the natural course of MEN1-related tumors, which has had direct consequences on clinical care.
#19 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
Gastric NETs in MEN1 are almost exclusively seen in patients with gastrinoma and usually have an indolent course. […] The prognosis of MEN1-related gastric NETs is generally good, with metastases (regional and distant) reported in 10-30% and disease-related death 10%. […] The poor prognosis of MEN1-related thNET has also been illustrated in a meta-analysis of 99 MEN-1 thNETs: median survival was 8.4 years, and the 10-year survival rate was 33%. […] The treatment of stage IV dpNET in patients with MEN1 is similar to that of patients with sporadic dpNETs. […] The only curative treatment for NF-PanNETs in MEN1 is surgical resection, and the goal of surgical intervention in NF-PanNETs is to prevent metastases and thereby NF-PanNET-related mortality. […] The majority of MEN1-related bpNETs are well-differentiated NETs (typical and atypical carcinoids); only five cases of poorly differentiated neuroendocrine carcinomas have been identified in MEN1 patients until now.
#20 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
The overall benign histopathological characteristics of MEN1-related bpNET may explain their usually good prognosis: large cohort studies have shown that bpNETs do not significantly affect survival in MEN1 patients. […] In patients with MEN1, minimal recommended screening for adrenal lesions as per the current guidelines, is abdominal imaging with CT or MRI every 3 years for those without adrenal lesions. […] The current guidelines recommend that screening be focused on hyperaldosteronism and hypercortisolism, but given that pheochromocytomas do occur in MEN1 as described above and the consequence of missing the diagnosis can be serious, it is prudent to screen for the presence of a pheochromocytoma by either plasma free (nor)metanephrines or urinary fractionated (nor)metanephrines. […] The prognosis of MEN1-related gastric NETs is generally good, with metastases (regional and distant) reported in 10-30% and disease-related death 10%. […] In conclusion, in the past decades there have been great advances in the understanding of the natural course of MEN1-related tumors, which has had direct consequences on clinical care.
#21 Multiple endocrine neoplasia type 1 | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-1-38
Patients with liver metastases have a poor prognosis for survival. […] Prognosis does not seem negatively influenced by nodal metastases. […] The absence of a genotype-phenotype correlation might suggest a possible role of other modifier genes and/or environmental factors. […] An understanding of the function of MEN1 gene and of menin interacting proteins, in the near future, may help correlation studies and assist clinical management of patients. […] In fact, although the knowledge of the mechanisms of tumour development in patients with MEN1 has grown tremendously, much work lies ahead. The final goal is to offer patients with MEN1 germline mutations an optimal cancer prevention and treatment program.
#22 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
Patients with MEN1 suffer from high morbidity and a decreased life expectancy. In the present day and age, MEN1-related malignancy is the main MEN1-related cause of death, particularly due to duodenopancreatic and thymic NETs. A timely and accurate diagnosis of MEN1 is paramount to improve disease outcomes. This enables early identification of tumor manifestations allowing timely treatment to reduce morbidity and improve survival. […] The approximate prevalence of MEN1 has been reported as 1 in 30,000 individuals with no apparent gender bias. MEN1 follows an autosomal dominant pattern of inheritance with 95% penetrance by age 40-50 years. […] Single center cohorts have identified certain genotypes that are associated with a more aggressive course of the disease (especially related to duodenopancreatic NETs), such as mutation in the JUND or the CHES1 interacting domain or nonsense/frameshift versus missense mutations, but since none of these associations have been independently validated, genotype cannot be used to individualize surveillance.
#23 Multiple endocrine neoplasia type 1 | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-1-38
Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary cancer syndrome presented mostly by tumours of the parathyroids, endocrine pancreas and anterior pituitary, and characterised by a very high penetrance and an equal sex distribution. […] Currently, DNA testing allows the early identification of germline mutations in asymptomatic gene carriers, to whom routine surveillance (regular biochemical and/or radiological screenings to detect the development of MEN1-associated tumours and lesions) is recommended. […] Hyperparathyroidism is the most common and usually the first clinical manifestation of MEN1. Gastrinoma and carcinoids represent the most frequent causes of mortality. […] The treatment for a non-metastatic gastrinoma is surgical resection. The treatment for multiple and disseminate gastrinomas consists of therapy with a human somatostatin analogue (octreotide), administration of proton pump inhibitors or H2-receptor blockers to reduce gastric acid output, chemotherapy with 5-fluoroaracil and streptozotocin, and surgical excision of all resectable tumours (however, the success rate seems very low).
#24 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
Evaluation of 10 Dutch families suggest genetic anticipation (decreased age of disease onset or an increased disease severity in successive generations), a known phenomenon which to date cannot be explained in autosomal dominant inherited disease genes without trinucleotide repeat expansions. […] The identification of an MEN1 mutation in patients and family members at risk is followed by the advice to remain under lifelong surveillance, with at least annual clinic visits including history, physical examination, biochemical screening, and radiological screening at specific intervals. […] The optimal timing of the initial operation is still a matter of debate, especially in (asymptomatic) children and young adults. […] The initial operation recommended by most experts and guidelines is a bilateral cervical exploration, identifying all four parathyroid glands and performing a subtotal parathyroidectomy with concomitant cervical thymectomy.
#25 Frontiers | Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis
https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00339/full
Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumor syndrome inherited in an autosomal dominant manner and characterized by a predisposition to a multitude of endocrine neoplasms primarily of parathyroid, enteropancreatic, and anterior pituitary origin, as well as nonendocrine neoplasms. […] Despite advances in the diagnosis and treatment of MEN1-associated tumors, patients with MEN1 continue to have decreased life expectancy primarily due to malignant neuroendocrine tumors. […] The most recent clinical practice guidelines for MEN1, published in 2012, highlight the need for early genetic and clinical diagnosis of MEN1 and recommend an intensive surveillance approach for both patients with this syndrome and asymptomatic carriers starting at the age of 5 years with the goal of timely detection and management of MEN1-associated neoplasms and ultimately decreased disease-specific morbidity and mortality.
#26 Frontiers | Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis
https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00339/full
Despite advances in the diagnosis and treatment of MEN1-associated tumors, patients with this syndrome continue to have a decreased life expectancy compared to the rest of the population, with a mean age of death of 55â60 years. […] The most common cause of death has shifted from the complications of hormone-excess states, primarily due to gastrinomas, to malignant NETs, most notably pNETs and th-NETs. […] The most recent Endocrine Society clinical practice guidelines for MEN1 published in 2012, recommend an intensive surveillance approach for patients with MEN1 and asymptomatic carriers starting at the age of 5 years, based on the assumption that early detection and management of MEN1-associated neoplasms may lead to decreased morbidity and mortality.
#27 Multiple Endocrine Neoplasia Type 1 (MEN1): Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/126438-overview
Multiple endocrine neoplasia type 1 (MEN1) is characterized by the combination of parathyroid tumors, pancreatic islet cell tumors, and anterior pituitary tumors. Most MEN1 tumors are not aggressive, and many of them (particularly nonfunctioning tumors) follow a long-term indolent course, remaining asymptomatic for years. Nevertheless, patients with untreated MEN1 have a decreased life expectancy, with a 50% probability of death by age 50 years. […] Malignant pancreatic neuroendocrine tumors and thymic carcinoid tumors have been associated with a marked increase in the risk of death in MEN1 patients. […] The rationale for an aggressive surveillance approach in MEN1 patients and asymptomatic carriers is based on the presumption that the early pre-symptomatic detection of MEN1 neoplasias may reduce the associated mortality.
#28 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare autosomal dominantly inherited endocrine tumor predisposition syndrome, caused by mutations in the MEN1 gene. Cardinal manifestations are primary hyperparathyroidism (pHPT), pituitary adenomas (PA), and neuroendocrine tumors (NETs) of the pancreas (PanNET) and duodenum. […] Malignant NETs are the most important cause of disease-related mortality, mainly NF-PanNETs, gastrinomas and thymus NETs. […] Life-time penetrance of duodenopancreatic NETs is 80%. […] The main challenge is to identify patients at risk for an aggressive disease course. Thymic NETs (2-8%) occur predominantly in males and have a poor prognosis. […] Given the complexity of the disease, it is strongly advised that patients, whenever possible, be followed and treated in centers of expertise.
#29 Multiple endocrine neoplasia type 1 | Orphanet Journal of Rare Diseases | Full Text
https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-1-38
Patients with liver metastases have a poor prognosis for survival. […] Prognosis does not seem negatively influenced by nodal metastases. […] The absence of a genotype-phenotype correlation might suggest a possible role of other modifier genes and/or environmental factors. […] An understanding of the function of MEN1 gene and of menin interacting proteins, in the near future, may help correlation studies and assist clinical management of patients. […] In fact, although the knowledge of the mechanisms of tumour development in patients with MEN1 has grown tremendously, much work lies ahead. The final goal is to offer patients with MEN1 germline mutations an optimal cancer prevention and treatment program.
#30 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
After initial subtotal parathyroidectomy, the 10-year recurrence rate is approximately 50%. […] The treatment of hyperparathyroidism in MEN1 is surgical. […] The optimal timing of the initial operation is still a matter of debate, especially in (asymptomatic) children and young adults. […] The treatment of MEN1-related pituitary adenomas follows the same strategy as sporadic pituitary adenomas. […] The diagnosis of gastrinoma in MEN1 is challenging at present. […] The diagnosis of gastrinoma in MEN1 is challenging at present. […] Presently, as in other MEN1-related dpNETs, surgery is the only potentially curative treatment. […] The cumulative probability of having a dpNET increases with age, however the age of onset varies somewhat per tumor type. […] The goals of follow-up and treatment are to prevent metastatic disease, cure hormonal hypersecretion, and prevent complication from hormonal hypersecretion, while minimizing treatment-related complications and preserving Quality of Life.
#31 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
After initial subtotal parathyroidectomy, the 10-year recurrence rate is approximately 50%. […] The treatment of hyperparathyroidism in MEN1 is surgical. […] The optimal timing of the initial operation is still a matter of debate, especially in (asymptomatic) children and young adults. […] The treatment of MEN1-related pituitary adenomas follows the same strategy as sporadic pituitary adenomas. […] The diagnosis of gastrinoma in MEN1 is challenging at present. […] The diagnosis of gastrinoma in MEN1 is challenging at present. […] Presently, as in other MEN1-related dpNETs, surgery is the only potentially curative treatment. […] The cumulative probability of having a dpNET increases with age, however the age of onset varies somewhat per tumor type. […] The goals of follow-up and treatment are to prevent metastatic disease, cure hormonal hypersecretion, and prevent complication from hormonal hypersecretion, while minimizing treatment-related complications and preserving Quality of Life.
#32 Multiple Endocrine Neoplasia Type 1 – Endotext – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK481897/
The overall benign histopathological characteristics of MEN1-related bpNET may explain their usually good prognosis: large cohort studies have shown that bpNETs do not significantly affect survival in MEN1 patients. […] In patients with MEN1, minimal recommended screening for adrenal lesions as per the current guidelines, is abdominal imaging with CT or MRI every 3 years for those without adrenal lesions. […] The current guidelines recommend that screening be focused on hyperaldosteronism and hypercortisolism, but given that pheochromocytomas do occur in MEN1 as described above and the consequence of missing the diagnosis can be serious, it is prudent to screen for the presence of a pheochromocytoma by either plasma free (nor)metanephrines or urinary fractionated (nor)metanephrines. […] The prognosis of MEN1-related gastric NETs is generally good, with metastases (regional and distant) reported in 10-30% and disease-related death 10%. […] In conclusion, in the past decades there have been great advances in the understanding of the natural course of MEN1-related tumors, which has had direct consequences on clinical care.