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Neoplasie Endocrine Multiple
(MEN)
Emanuele Bosi
Università Vita-Salute San Raffaele
A.A. 2009/10
Multiple Endocrine Neoplasia (MEN)
Le Neoplasie Endocrine Multiple (Multiple Endocrine Neoplasia,
MEN) sono patologie familiari connotate dalla presenza nello
stesso paziente di lesioni iperplastiche, adenomatose o
adenocarcinomatose in due o più ghiandole endocrine.
MEN: general features
The MEN syndromes differ from other hereditary cancer
syndromes in that most tumor growth occurs in hormonesecreting glands.
This feature has two primary consequences of clinical
importance:
1. the excess hormone production often results in welldefined hormonal syndromes with characteristic
symptoms and medical sequelae.
2. the excess hormone production serves as a sensitive
tumor marker that is useful for making a diagnosis,
determining response to therapy, and screening
asymptomatic patients.
Classificazione
In base alle ghiandole endocrine interessate si distinguono le
seguenti forme:
 MEN 1
 MEN2
 Altre (Sindromi miste)
Classificazione: MEN1
MEN 1 - Wermer’s syndrome
• Paratiroidi: Iperplasia o adenoma (paratormone)
• Pancreas endocrino e duodeno: Iperplasia,
adenoma o carcinoma (gastrina, insulina,
glucagone, somatostatina, PP, VIP)
• Ipofisi: Iperplasia o adenomi (prolattina, GH,
ACTH)
• Altre manifestazioni cliniche meno comuni:
carcinoide, feocromocitoma, lipomi sottocutanei o
viscerali
Classificazione: MEN2
MEN 2A
MEN 2B
• MTC: Carcinoma Midollare
della Tiroide
• MTC: Carcinoma
Midollare della Tiroide
• Feocromocitoma
• Feocromocitoma
• Iperplasia o adenoma delle
paratiroidi
• Neurinomi delle
mucose e
gastrointestinali
In associazione a:
- amiloidosi e lichen cutaneo
- malattia di Hirschsprung
- FMTC: Carcinoma Midollare
Familiare della Tiroide
• Habitus marfanoide
Classificazione: altre, forme miste
Carcinoma midollare familiare della tiroide: almeno 4 membri affetti
senza altre endocrinopatie
Von Hippel Lindau: feocromocitoma, emangioblastoma retinico o
SNC, carcinoma cellule chiare del rene, tumori isole
pancreatiche, ..
Neurofibromatosi associate a MEN: feocromocitoma, macchie
caffè-latte, neurofibromi, ..
Sindrome di Cowden: carcinoma non midollare della tiroide
(papillare o follicolare), neoplasie di cute, mammella, mucosa
orale, utero
Carney complex: tumori endocrini (tiroide, ipofisi, corticosurrene),
pigmentazione cutanea, mixomi, schwannomi
Classificazione WHO
A revised clinicopathological classification of neuroendocrine
tumors of the gastroenteropancreatic tract has been
developed under the auspices of the World Health
Organization (WHO) according to advances in the field of
tumor biology.
Solcia E, Kloppel G, Sobin LH (2000)
Histological Typing of Endocrine Tumours. World Health Organization
International
Histological Classification of Tumours.
Classificazione WHO: Novità principali
 Nomenclatura
Abbandono del termine “carcinoide” a favore di tumore o carcinoma:
“instead of carcinoid, the WHO classification published in 2000 uses the
general terms neuroendocrine tumor and neuroendocrine carcinoma”
Utilizzo combinato di dati anatomo-clinici e funzionali
Volume, presenza di metastasi, presenza di angioinvasione, tipo di
secrezione ormonale, presenza o meno di sindrome clinica
associata: “On the basis of localization and of various morphological and
biological criteria, we distinguish between benign neuroendocrine tumors,
tumors with uncertain malignant potential, and tumors showing low-grade
and high-grade malignancy”.
 Suddivisione per sede
Stomaco, pancreas, duodeno, digiuno-ileo, appendice, colon-retto.
Classificazione WHO: Criteri
 Parametri patologici
 Clinica
 Contesto clinico generale
 Secrezione ormonale
Classificazione WHO: Criteri
Parametri patologici (sede, dimensione, coinvolgimento delle tonache di
parete/diffusione extraorgano, indice proliferativo, angio-invasione, linfonodi,
metastasi, residuo di malattia):
Tumori endocrini ben differenziati (benigni/comportamento biologico incerto)  funzionanti
e non funzionanti
Carcinomi endocrini ben differenziati (basso grado di malignità)  funzionanti e non
funzionanti
Carcinomi endocrini scarsamente differenziati (alto grado di malignità)
Carcinomi misti endocrini/esocrini
Clinica:
Funzionanti/non funzionanti
Contesto clinico generale:
(stomaco: tumori endocrini associati o meno ad ipergastrinemia)
Produzione ormonale:
Dimostrabile con metodiche immunoistochimiche
Classificazione WHO
Tumori Endocrini ben differenziati a comportamento
benigno vs incerto Benigni
Tumori
differenziati
A comportamento
biologico

dimensione (1 cm
[2 cm per pancreas
e incerto
appendice]) e
angioinvasione
differenziati
Tumori
Endocrini vs Ben
carcinomi
Carcinomi
(basso grado di
malignità)
dellaScarsamente
tonaca differenziati
muscolare
(alto grado di malignità)
 infiltrazione
appendice) e presenza di metastasi
Tumori
Esocrini-endocrini
misti
(mesenteriolo per
MULTIPLE ENDOCRINE
NEOPLASIA
MEN TYPE 1
Wermer’s syndrome
MEN TYPE 1
Wermer’s syndrome
Genetic
Autosomal-dominant condition that occurs as a result of
inactivating mutations of MEN1 gene
The MEN 1 gene is located at chromosome 11q13 and consist
of 10 exons with a 1830-bp coding region that encodes a
novel 610-amino acid protein, referred to as MENIN.
The presumed unifying mechanism for tumor formation in Men
1 involves loss of MENIN function in a tumor precursor cell.
Diagnosi Genetica
 sostituzione C-G in posizione 1561
dell’esone 10 [sostituzione AA Arg-Gly in
posizione 521]
 sostituzione T-C in posizione 7257
dell’esone 9 [sostituzione AA Phe-Ser in
posizione 416]
MEN1: General features
• Multifocal nature of the disease process within a single
organ.
• Hyperplasia  adenoma  carcinoma
• a neoplastic process in one organ may affect the
progression in another organ (i.e. pancreatic tumor may
stimulate growth of a pituitary tumor).
• the syndrome evolves in 30-40 years and the manifestation
will in large parte on when the syndrome is identified.
•The prevalence of MEN1 has been estimated at 1 in 20-40,000
individuals
Percent of MEN 1 Clinical Features
Hyperparathyroidism
Entero-Pancreatic Tumor
Pituitary
Adenoma
90-100%
80%
50-60%
MEN 1
MEN1: sindromi cliniche da iperplasia,
adenomi, carcinomi endocrini
Paratiroidi: Iperparatiroidismo primitivo
Pancreas endocrino e duodeno:
• Gastrinoma (Zollinger-Ellison)
• Insulinoma
• Glucagonoma
• Somatostatinoma
• VIPoma (Watery Diarrhea Syndrome)
• PPoma, non secernenti
Ipofisi: prolattina, GH, ACTH, non secernenti
Insulinoma: Clinica
 Neuroglicopenia
 Eccesso di catecolamine
 Cambiamenti di personalità
 Confusione
 Epilessia
 Coma
 Altri sintomi
 Appetito
 Fatica
 Nausea, vomito
 Neuropatia periferica
 Diaforesi
 Pallore
 Tachicardia
Glucagonoma: Clinica
Segni e sintomi
Distribuzione del tumore
 Diabete
Mellito
Sindrome
neoplastica
Sindrome
endocrina multipla

Calo
ponderale

Diarrea
Eritema necrolitico migrante
 Trombosi venosa profonda
Sindrome neoplastica

Anemia
Eritema necrolitico migrante
80% MALIGNI
51%
14%
22%
Gastrinoma: Clinica
Segni e sintomi
Distribuzione del tumore
Ulcere
5%
Sintomi da reflusso
Dolore addominale
Diarrea
15%
80%
Il gastrinoma origina dalle cellule G, localizzate prevalentemente nel duodeno prossimale (83%)
e in minor misura nell’antro gastrico, e da popolazioni cellulari denominate D1 a sede pancreatica
Gastrinoma: Clinica
 spesso multifocali
 dimensioni < 1 cm
 associati a MEN 1
 duodenali
 singolo
 dimensioni > 1 cm
 pancreatici
 sporadico
Test genetico
• La MEN1 dovrebbe essere sospettata nei
pazienti con: iperparatiroidismo ad esordio
<30 anni o a base multighiandolare o con
elevata incidenza familiare; tumori endocrini
del pancreas multifocali; Zollinger-Ellison;
due endocrinopatie di pancreas, ipofisi,
paratiroidi
• Test genetico disponibile; utile in fase
precoce per il monitoraggio delle successive
endocrinopatie
Therapeutic considerations
Despite its earlier recognition, MEN 1 is the most challenging of
the MEN syndromes.
Each affected patient can be expected to undergo at least two or
more surgical procedures; it is necessary to recognize the high
probability of recurrent or new neoplasms in potentially affected
organ systems and to balance this likelihood against the possible
side effects of intervention, such as
- Hypoparathyroidism
- Hypopituitarism
- Endocrine and exocrine pancreatic insufficency
MULTIPLE ENDOCRINE
NEOPLASIA
MEN TYPE 2
Overview
The hallmark of MEN2 is a very high lifetime risk of
developing medullary thyroid carcinoma (MTC) more than
95% in untreated patients.
Three clinical subtypes MEN2A, MEN2B, and familial MTC
(FMTC) have been defined based on the risk of:
- pheochromocytoma
- hyperparathyroidism
- the presence or absence of characteristic physical
features
The prevalence of MEN2 has been estimated at 1 in 35,000
individuals
MULTIPLE ENDOCRINE NEOPLASIA TYPE 2
Definition
The MEN 2 syndrome has been sub-categorized into two
variants called MEN 2A and MEN 2B (formerly MEN 3)
MEN 2 and its clinical variants or syndromes
MEN 2 and its clinical variants or
syndromes
MEN 2: genetica e fisiopatologia
 Mutation of the c-ret protooncogene have been identified
in 93 to 95% of pts with MEN 2.
 Two regions of the Ret tyrosine kinase receptor are
mutated
MEN TYPE 2: diagram of the c-ret protoncogene
Percent of MEN 2 Clinical Features by
Subtype
Sub
type
Medullary Thyroid
Carcinoma
Pheochromo
cytoma
Parathyroid
Disease
MEN 2A
95%
50%
20-30%
FMTC
100%
0%
0%
MEN 2B
100%
50%
Uncommon
Testing Used in MEN 2
Mutation
Detection Rate
Test
Type
MEN 2A
95%
DNA-based
FMTC
85%
DNA-based
MEN 2B
95%
DNA-based
Test
Availability
Clinical
Testing
Screening and Risk assessment
• MEN2 accounts for approximately 25% of all cases of MTC
and approximately 7% of individuals presenting with apparently
sporadic MTC.
• RET genetic testing is considered the standard of care for
newly identified MTC patients, regardless of age at diagnosis or
family history.
• The identification of a mutation provides essential risk
information for the patient’s family members, and genotypephenotype correlations can help estimate the patient’s risk of
developing additional endocrinopathies (eg,
pheochromocytoma, primary hyperparathyroidism), provide
prognostic information, and guide the surgical management of
MTC.
MEN 2A: Overview
The MEN 2A syndrome consist of
multifocal medullary thyroid carcinoma
unilateral or bilateral pheochromocytoma
parathyroid hyperplasia or adenoma
Approximately 4% to 5% of cases of apparently sporadic
pheochromocytoma occurring before age 50 years are due to
mutations of RET and are thus associated with MEN2A.
MEN2A-associated pheochromocytomas almost always secrete
epinephrine and may or may not secrete norepinephrines. In
addition, malignancy and extra-adrenal location are extremely rare
in MEN2A.
MEN 2A: Clinical features
Patients with this syndrome can present with manifestations
of a pheochromocytoma, a thyroid nodule, hypercalcemia
or some combination of the three,
but at present
the routine screening of affected families makes early
thyroid C-cell hyperplasia (elevation of circulating
calcitonin), the most common initial presentation (followed
by Pheochromocytoma in about half pts and parathyroid
abnormalities in 10 to 35%).
MEN 2A: Clinical features
Medullary thyroid carcinoma (MTC)
Multicentric neoplasm of parafollicular or C cell of thyroid gland.
The first demonstrable abnormality is hyperplasia of C cells
followed by
Histological progression:
nodular hyperplasia
microscopic medullary thyroid carcinoma
frank medullary thyroid carcinoma
The time required for this progression through these
histologic stages, is not known but the process may
require decades.
MEN 2A: Clinical features
Pheochromocytoma
Adrenal chromaffin tissue undergoes the same
type of histological progression as that observed
for C cell
Histological progression:
- hyperplasia of chromaffin cells
- nodular hyperplasia
- pheochromocytoma
MEN 2A: Clinical features
Pheochromocytoma
Diagnosis confirmed by:
Biochemical features
CT
MRI
Scanning with MIBG
MULTIPLE ENDOCRINE NEOPLASIA
TYPE 2 B
Introduction
The MEN 2B (or MEN 3) syndrome consist of
multifocal medullary thyroid carcinoma
unilateral or bilateral pheochromocytoma
multiple mucosal neuromas
marfanoid habitus
The hallmark of this syndrome is the presence of characteristic
mucosal neuromas on the distal portion of the tongue, the lips and
subconjunctival areas and throught the gastrintestinal tract.
Multiple
Mucosal
Neuromas
Multiple
Mucosal
Neuromas
Multiple
Mucosal
Neuromas
MULTIPLE ENDOCRINE NEOPLASIA
TYPE 2 B
The clinical course of patients with medullary thyroid
carcinoma in MEN 2B is more aggressive than that in MEN
2A.
Metastatic disease can occur in children younger than 1
year age and there is shorter average survival time in
patients with metastatic disease.
The identification of mucosal neuroma phenotype in a
child should alert the physician to the diagnosis of
medullary thyroid carcinoma