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

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Presentazione sul tema: "Neoplasie Endocrine Multiple (MEN) Emanuele Bosi Università Vita-Salute San Raffaele A.A. 2009/10."— Transcript della presentazione:

1 Neoplasie Endocrine Multiple (MEN) Emanuele Bosi Università Vita-Salute San Raffaele A.A. 2009/10

2 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.

3 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: 1.the excess hormone production often results in well- defined 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.

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

5 Classificazione: MEN1 MEN 1 - Wermers 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

6 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 Familiare della Tiroide MEN 2B MTC: Carcinoma Midollare della Tiroide Feocromocitoma Neurinomi delle mucose e gastrointestinali Habitus marfanoide

7 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

8 Classificazione WHO Solcia E, Kloppel G, Sobin LH (2000) Histological Typing of Endocrine Tumours. World Health Organization International Histological Classification of Tumours. Solcia E, Kloppel G, Sobin LH (2000) Histological Typing of Endocrine Tumours. World Health Organization International Histological Classification of Tumours. 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.

9 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. 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.

10 Classificazione WHO: Criteri Parametri patologici Clinica Contesto clinico generale Secrezione ormonale Parametri patologici Clinica Contesto clinico generale Secrezione ormonale

11 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

12 Tumori differenziati Benigni A comportamento biologico incerto Carcinomi Ben differenziati (basso grado di malignità) Scarsamente differenziati (alto grado di malignità) Tumori misti Esocrini-endocrini Tumori Endocrini ben differenziati a comportamento benigno vs i ncerto dimensione (1 cm [2 cm per pancreas e appendice]) e angioinvasione Tumori Endocrini ben differenziati a comportamento benigno vs i ncerto dimensione (1 cm [2 cm per pancreas e appendice]) e angioinvasione Tumori Endocrini vs carcinomi infiltrazione della tonaca muscolare (mesenteriolo per appendice) e presenza di metastasi Tumori Endocrini vs carcinomi infiltrazione della tonaca muscolare (mesenteriolo per appendice) e presenza di metastasi Classificazione WHO

13 MULTIPLE ENDOCRINE NEOPLASIA MEN TYPE 1 Wermers syndrome

14 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. MEN TYPE 1 Wermers syndrome

15

16 Diagnosi Genetica sostituzione C-G in posizione 1561 dellesone 10 [sostituzione AA Arg-Gly in posizione 521] sostituzione T-C in posizione 7257 dellesone 9 [sostituzione AA Phe-Ser in posizione 416 ] sostituzione C-G in posizione 1561 dellesone 10 [sostituzione AA Arg-Gly in posizione 521] sostituzione T-C in posizione 7257 dellesone 9 [sostituzione AA Phe-Ser in posizione 416 ]

17 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 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

18 Hyperparathyroidism Entero-Pancreatic Tumor Pituitary Adenoma MEN %80%50-60% Percent of MEN 1 Clinical Features

19 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

20 Insulinoma: Clinica Neuroglicopenia Cambiamenti di personalità Confusione Epilessia Coma Altri sintomi Appetito Fatica Nausea, vomito Neuropatia periferica Neuroglicopenia Cambiamenti di personalità Confusione Epilessia Coma Altri sintomi Appetito Fatica Nausea, vomito Neuropatia periferica Eccesso di catecolamine Diaforesi Pallore Tachicardia

21 51% 14% 22% Segni e sintomi Distribuzione del tumore Diabete Mellito Sindrome endocrina multipla Eritema necrolitico migrante Sindrome neoplastica Diabete Mellito Sindrome endocrina multipla Eritema necrolitico migrante Sindrome neoplastica Calo ponderale Calo ponderale Diarrea Diarrea Trombosi venosa profonda Trombosi venosa profonda Anemia Anemia Eritema necrolitico migrante Eritema necrolitico migrante Sindrome neoplastica Calo ponderale Calo ponderale Diarrea Diarrea Trombosi venosa profonda Trombosi venosa profonda Anemia Anemia Eritema necrolitico migrante Eritema necrolitico migrante 80% MALIGNI Glucagonoma: Clinica

22 Segni e sintomi Distribuzione del tumore 5% 15% 80% Gastrinoma: Clinica Ulcere Sintomi da reflusso Dolore addominale Diarrea Ulcere Sintomi da reflusso Dolore addominale Diarrea Il gastrinoma origina dalle cellule G, localizzate prevalentemente nel duodeno prossimale (83%) e in minor misura nellantro gastrico, e da popolazioni cellulari denominate D1 a sede pancreatica

23 spesso multifocali dimensioni < 1 cm associati a MEN 1 duodenali spesso multifocali dimensioni < 1 cm associati a MEN 1 duodenali singolo dimensioni > 1 cm sporadico pancreatici singolo dimensioni > 1 cm sporadico pancreatici Gastrinoma: Clinica

24 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

25 MEN1 Screening: when and how

26 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

27 MULTIPLE ENDOCRINE NEOPLASIA MEN TYPE 2

28 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

29 Definition The MEN 2 syndrome has been sub-categorized into two variants called MEN 2A and MEN 2B (formerly MEN 3) MULTIPLE ENDOCRINE NEOPLASIA TYPE 2

30 MEN 2 and its clinical variants or syndromes

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32 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

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34 MEN TYPE 2: diagram of the c-ret protoncogene

35 Percent of MEN 2 Clinical Features by Subtype Subtype Medullary Thyroid Carcinoma Pheochromocytoma Parathyroid Disease MEN 2A 95%50%20-30% FMTC100%0% MEN 2B 100%50%Uncommon

36 Testing Used in MEN 2 Mutation Detection Rate TestTypeTestAvailability MEN 2A 95%DNA-based Clinical Testing FMTC85%DNA-based MEN 2B 95%DNA-based

37 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 patients family members, and genotype- phenotype correlations can help estimate the patients risk of developing additional endocrinopathies (eg, pheochromocytoma, primary hyperparathyroidism), provide prognostic information, and guide the surgical management of MTC.

38 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: Overview

39 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%).

40 MEN 2A Screening: when and how

41 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

42 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

43 Pheochromocytoma Diagnosis confirmed by: Biochemical features CT MRI Scanning with MIBG MEN 2A: Clinical features

44 Introduction The MEN 2B (or MEN 3) syndrome consist of multifocal medullary thyroid carcinoma unilateral or bilateral pheochromocytoma multiple mucosal neuromas marfanoid habitus MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 B 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.

45 Multiple Mucosal Neuromas

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47

48

49 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 MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 B

50 MEN 2B Screening: when and how


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