What is endocrine neoplasia?

Endocrine Neoplasia: Types, Genetics, and Clinical Features

Endocrine neoplasia refers to tumors that develop in hormone-producing tissues, with Multiple Endocrine Neoplasia (MEN) syndromes representing hereditary forms characterized by tumors in multiple endocrine glands, each with distinct genetic causes and clinical manifestations. 1

Types of Endocrine Neoplasia

Multiple Endocrine Neoplasia Syndromes

• MEN1: Autosomal dominant disorder caused by pathogenic variants in the MEN1 gene (11q13), characterized by parathyroid adenomas, pancreatic islet tumors, and anterior pituitary neuroendocrine tumors 1
• MEN2A: Caused by pathogenic RET variants (10q11.21), characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid tumors 1, 2
• MEN2B (formerly MEN3): Caused by RET mutations, characterized by medullary thyroid carcinoma, pheochromocytoma, marfanoid habitus, mucosal neuromas, and intestinal ganglioneuromatosis 3, 2
• MEN4: Caused by pathogenic CDKN1B variants (12p13.1), characterized primarily by parathyroid and anterior pituitary tumors, similar to MEN1 but with different genetic basis 1, 4
• HPT-JT Syndrome: Caused by pathogenic CDC73 variants (1q25), characterized by parathyroid tumors and ossifying fibromas of the jaw 1

Sporadic Neuroendocrine Tumors

• Gastroenteropancreatic neuroendocrine tumors (GEP-NETs): Heterogeneous group of tumors originating from neuroendocrine cells of the embryological gut 1
• Functioning tumors: Produce hormones causing clinical syndromes (e.g., carcinoid syndrome) 1
• Non-functioning tumors: May present with mass effect rather than hormonal symptoms 1

Genetics and Pathophysiology

• MEN syndromes follow autosomal dominant inheritance patterns with high but variable penetrance 1, 4
• MEN1 gene encodes menin, a scaffold protein involved in cell division, genome stability, and transcription regulation 4
• RET proto-oncogene mutations in MEN2 result in gain-of-function alterations 2
• CDKN1B gene encodes p27kip1, a cell cycle inhibitor activated by histone methylation 4
• CDC73 gene encodes parafibromin, with mutations leading to HPT-JT syndrome 1
• Disease follows Knudson's two-hit hypothesis with germline and somatic mutations in affected tissues 4

Clinical Features and Manifestations

MEN1

• Primary hyperparathyroidism (95% of patients) - most common presenting feature 1
• Pancreatic islet tumors (commonly gastrinomas, insulinomas) 1
• Anterior pituitary tumors (predominantly prolactinomas) 1
• Dermatologic manifestations: angiofibromas, lipomas, collagenomas 1
• Adrenocortical adenomas (35% of patients) 1
• Other manifestations: leiomyomas, CNS neoplasms 1
• Disease penetrance: 45% by age 30,82% by age 50,96% by age 70 1

MEN2

• Medullary thyroid carcinoma (defining feature) 2
• Pheochromocytoma 2
• Primary hyperparathyroidism (in MEN2A) 2
• Cutaneous lichen amyloidosis and Hirschsprung's disease (in some MEN2A cases) 2
• Marfanoid habitus and mucosal neuromas (in MEN2B) 3

MEN4

• Primary hyperparathyroidism (100% of reported cases) 1
• Pituitary adenomas (somatotroph, corticotroph, non-functioning) 1
• Other possible manifestations: gastroenteropancreatic neuroendocrine tumors, uterine neoplasms, adrenocortical masses 1

Classification and Diagnosis

• WHO classification of GEP-NETs 1:

  • NET G1: Ki-67 ≤2%
  • NET G2: Ki-67 3-20%
  • NEC G3: Ki-67 >20%
  • Mixed adenoneuroendocrine carcinoma (MANEC)

• Diagnosis requires 1:

  • Histopathological confirmation with immunohistochemistry for neuroendocrine markers (chromogranin A, synaptophysin)
  • Ki-67 proliferation index assessment
  • Genetic testing for suspected hereditary syndromes
  • Biochemical evaluation for hormone production
  • Imaging studies (CT, MRI, somatostatin receptor imaging)

Clinical Implications and Management

• Early genetic and clinical diagnosis is crucial for improved outcomes 5
• Pre-symptomatic screening of at-risk individuals allows earlier detection and intervention 1
• Surveillance recommendations differ by syndrome type and should begin in childhood for hereditary forms 1
• No clear genotype-phenotype correlation exists, necessitating comprehensive surveillance for all mutation carriers 6
• Mortality is primarily due to malignant neuroendocrine tumors, particularly in MEN1 5

Surveillance Considerations

• MEN1 surveillance should begin at age 5 years 5
• MEN2 surveillance timing depends on specific RET mutation and risk classification 1
• MEN4 surveillance should focus on hyperparathyroidism and pituitary tumors 1
• HPT-JT surveillance should include screening for parathyroid tumors, jaw tumors, and renal anomalies 1

Endocrine neoplasia represents a complex group of disorders requiring multidisciplinary expertise for optimal management, with early genetic diagnosis and systematic surveillance being key to reducing morbidity and mortality.