Neoplasie endocrine multiple men
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Neoplasie Endocrine Multiple (MEN). Emanuele Bosi Università Vita-Salute San Raffaele A.A. 2009/10. Multiple Endocrine Neoplasia (MEN).

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Neoplasie endocrine multiple men

Neoplasie Endocrine Multiple(MEN)

Emanuele Bosi

Università Vita-Salute San Raffaele

A.A. 2009/10


Neoplasie endocrine multiple men

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 indue o più ghiandole endocrine.


Neoplasie endocrine multiple men

MEN: general features

  • The MEN syndromes differ from other hereditary cancer syndromes in that most tumor growth occurs in hormone-secreting glands.

  • This feature has two primary consequences of clinical importance:

  • the excess hormone production often results in well-defined hormonal syndromes with characteristic symptoms and medical sequelae.

  • 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.


Neoplasie endocrine multiple men

Classificazione

In base alle ghiandole endocrine interessate si distinguono le seguenti forme: MEN 1MEN2 Altre (Sindromi miste)


Neoplasie endocrine multiple men

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


Neoplasie endocrine multiple men

Classificazione: MEN2

  • MEN 2A

  • MTC: Carcinoma Midollare della Tiroide

  • Feocromocitoma

  • Iperplasia o adenoma delle paratiroidi

  • In associazione a:

  • amiloidosi e lichen cutaneo

  • malattia di Hirschsprung

  • FMTC: Carcinoma Midollare Familiaredella Tiroide

  • MEN 2B

  • MTC: Carcinoma Midollare della Tiroide

  • Feocromocitoma

  • Neurinomi delle mucose e gastrointestinali

  • Habitus marfanoide


Classificazione altre forme miste

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


Neoplasie endocrine multiple men

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.


Neoplasie endocrine multiple men

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.


Neoplasie endocrine multiple men

Classificazione WHO: Criteri

  • Parametri patologici

  • Clinica

  • Contesto clinico generale

  • Secrezione ormonale


Classificazione who criteri

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


Neoplasie endocrine multiple men

Classificazione WHO

Tumori Endocrini ben differenziati a comportamento benigno vs incerto

 dimensione (1 cm [2 cm per pancreas e appendice]) e angioinvasione

Benigni

A comportamento biologico incerto

Tumori differenziati

Carcinomi

Tumori Endocrini vs carcinomi

 infiltrazione della tonaca muscolare (mesenteriolo per appendice) e presenza di metastasi

Ben differenziati (basso grado di malignità)

Scarsamente differenziati (alto grado di malignità)

Tumori misti

Esocrini-endocrini


Neoplasie endocrine multiple men

MULTIPLE ENDOCRINE NEOPLASIA

MEN TYPE 1

Wermer’s syndrome


Neoplasie endocrine multiple men

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.


Neoplasie endocrine multiple men

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]


Neoplasie endocrine multiple men

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


Neoplasie endocrine multiple men

Percent of MEN 1 Clinical Features

MEN 1

Hyperparathyroidism

Entero-Pancreatic Tumor

Pituitary Adenoma

90-100%

80%

50-60%


Neoplasie endocrine multiple men

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


Neoplasie endocrine multiple men

Insulinoma: Clinica

  • Neuroglicopenia

    • Cambiamenti di personalità

    • Confusione

    • Epilessia

    • Coma

  • Altri sintomi

    • Appetito

    • Fatica

    • Nausea, vomito

    • Neuropatia periferica

  • Eccesso di catecolamine

    • Diaforesi

    • Pallore

    • Tachicardia


Neoplasie endocrine multiple men

51%

14%

22%

Glucagonoma: Clinica

Segni e sintomi

Distribuzione del tumore

  • Diabete Mellito

  • Sindrome endocrina multipla

  • Eritema necrolitico migrante

  • Sindrome neoplastica

  • Sindrome neoplastica

  • Calo ponderale

  • Diarrea

  • Trombosi venosa profonda

  • Anemia

  • Eritema necrolitico migrante

80% MALIGNI


Neoplasie endocrine multiple men

Gastrinoma: Clinica

Segni e sintomi

Distribuzione del tumore

  • Ulcere

  • Sintomi da reflusso

  • Dolore addominale

  • Diarrea

5%

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


Neoplasie endocrine multiple men

  • spesso multifocali

  • dimensioni < 1 cm  associati a MEN 1

  • duodenali

Gastrinoma: Clinica

  • singolo

  • dimensioni > 1 cm  sporadico

  • pancreatici


Test genetico

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


Neoplasie endocrine multiple men

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


Neoplasie endocrine multiple men

MULTIPLE ENDOCRINE NEOPLASIA

MEN TYPE 2


Neoplasie endocrine multiple men

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


Neoplasie endocrine multiple men

MULTIPLE ENDOCRINE NEOPLASIA TYPE 2

  • Definition

    The MEN 2syndrome has been sub-categorized into two variants called MEN 2A and MEN2B (formerly MEN 3)


Neoplasie endocrine multiple men

MEN 2 and its clinical variants or syndromes


Neoplasie endocrine multiple men

MEN 2 and its clinical variants or syndromes


Neoplasie endocrine multiple men

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


Neoplasie endocrine multiple men

MEN TYPE 2: diagram of the c-ret protoncogene


Neoplasie endocrine multiple men

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


Neoplasie endocrine multiple men

Testing Used in MEN 2

Mutation

Detection Rate

Test

Type

Test

Availability

MEN 2A

95%

DNA-based

Clinical

Testing

FMTC

85%

DNA-based

MEN 2B

95%

DNA-based


Neoplasie endocrine multiple men

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 genotype-phenotype 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.


Neoplasie endocrine multiple men

MEN 2A: Overview

TheMEN 2Asyndrome 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.


Neoplasie endocrine multiple men

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%).


Neoplasie endocrine multiple men

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.


Neoplasie endocrine multiple men

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


Neoplasie endocrine multiple men

MEN 2A: Clinical features

  • Pheochromocytoma

    Diagnosis confirmed by:

    • Biochemical features

    • CT

    • MRI

    • Scanning with MIBG


Neoplasie endocrine multiple men

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.


Neoplasie endocrine multiple men

Multiple Mucosal Neuromas


Neoplasie endocrine multiple men

Multiple Mucosal Neuromas


Neoplasie endocrine multiple men

Multiple Mucosal Neuromas


Neoplasie endocrine multiple men

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 yearage 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


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