Hereditary Endocrine Cancers Lecture Notes

Flashcards covering hereditary endocrine cancers, including MEN1, MEN2, thyroid cancers, paraganglioma, and pheochromocytoma syndromes, derived from lecture notes.

What does the endocrine system do?

Network of glands that produce and secrete hormones (chemical messengers) directly into the bloodstream. Regulate nearly metabolism, growth and development, tissue function, sexual function, reproduction, sleep, and mood.

What is an endocrine tumor?

Originates from an endocrine gland or hormone-producing tissue. May lead to functional abnormalities, such as hyperfunction or hypofunction or non-functional.

What are neuroendocrine cells?

Cells with characteristics of both nerve cells and hormone-producing endocrine cells.

Receive nerve input (or secrete neurotransmitters) and release hormones etc. directly into the bloodstream→ abundant in the gastrointestinal tract, pancreas, and lungs.

What are neuroendocrine tumors (NETs)?

Tumors able to produce and secrete various hormones, etc., which can lead to specific clinical syndromes (e.g., carcinoid syndrome).

NETs can occur in almost any organ system, but most commonly the gastrointestinal tract, pancreas, and lungs.

What are examples of endocrine tumors?

Adrenal gland tumors→ adrenal gland, adrenocortical tumors

Thyroid→ medullary, papillary, follicular

islet cell tumors→ VIPomas, glucaganomas, insulinoma, gastrinoma, etc.

Parathyroid tumors

Pituitary gland tumors

What are carcinoid tumors?

Carcinoid tumors are typically slow-growing neuroendocrine tumors that most commonly originate from enterochromaffin cells in the gastrointestinal tract (e.g., appendix, small intestine, rectum), but can also occur in the lungs or other sites. They often secrete a variety of bioactive substances, notably serotonin, but also histamine and bradykinin. The excessive secretion of these substances can lead to 'carcinoid syndrome,' characterized by symptoms such as flushing, diarrhea, and bronchospasm. While often sporadic, some carcinoid tumors are linked to hereditary syndromes like Multiple Endocrine Neoplasia Type 1 (MEN1).

What are pheochromocytomas?

A neuroendocrine tumor, located in the adrenal medulla (the inner part of the adrenal glands).

Most secrete excessive amounts of catecholamines, primarily epinephrine and norepinephrine.

Classic sx→ tachycardia, sustained hypertension, severe headaches, palpitations, excessive sweating, pallor, anxiety, panic attacks.

Approximately 30-40% of cases are associated with RET, VHL, NF1, or SDH complex genes.

What is Multiple Endocrine Neoplasia Type 1 (MEN1) syndrome?

Coccurrence of tumors in multiple endocrine glands, as well as some non-endocrine neoplasms.

MEN1 gene

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It is caused by a germline inactivating mutation in the $MEN1$ tumor suppressor gene. The most common tumors involve the parathyroid glands (leading to primary hyperparathyroidism), the pituitary gland (e.g., prolactinoma), and the enteropancreatic neuroendocrine system (e.g., gastrinoma, insulinoma).

What is the function of the MEN1 gene?

The $MEN1$ gene, located on chromosome 11q13, encodes a 610 amino acid nuclear localized protein called menin. Menin functions as a critical tumor suppressor, playing vital roles in regulating gene expression, DNA repair, and cell proliferation. Inactivating mutations (loss-of-function) in one germline copy of the $MEN1$ gene predispose individuals to MEN1 syndrome according to the 'two-hit hypothesis,' where a second somatic hit to the remaining normal allele leads to deregulated cell growth and tumor formation.

What is hypercalcemia in MEN1?

Hypercalcemia is a metabolic condition defined by abnormally high levels of calcium in the blood. In the context of MEN1 syndrome, it commonly results from primary hyperparathyroidism, where one or more parathyroid glands become overactive due to hyperplasia or adenoma caused by the underlying $MEN1$ gene mutation. This leads to an excessive production of parathyroid hormone (PTH), which in turn increases calcium reabsorption from bones, absorption from the gut, and retention by the kidneys, driving up serum calcium levels.

What is a prolactinoma?

A prolactinoma is the most common type of pituitary tumor, characterized by the excessive secretion of the hormone prolactin. This hormonal imbalance can lead to various symptoms: in females, oligomenorrhea/amenorrhea (irregular or absent menstruation) and galactorrhea (inappropriate lactation); in males, sexual dysfunction, decreased libido, and gynecomastia (breast enlargement). While most prolactinomas are sporadic, they are a common manifestation of MEN1 syndrome due to the underlying $MEN1$ gene mutation and can also cause symptoms due to their mass effect on surrounding brain tissue.

What are gastrinomas?

Gastrinomas are neuroendocrine tumors that secrete excessive amounts of gastrin, a hormone that potently stimulates gastric acid secretion. Most commonly, these tumors are found in the duodenum ($60-70\%$) or pancreas ($20-30\%$). Their unchecked gastrin production leads to Zollinger-Ellison syndrome, causing severe and recurrent peptic ulcers, gastroesophageal reflux disease, and chronic diarrhea. Gastrinomas are a significant cause of morbidity and mortality in MEN1 patients, directly linked to inactivating mutations in the $MEN1$ tumor suppressor gene.

What is Zollinger-Ellison syndrome?

Zollinger-Ellison syndrome (ZES) is a rare but severe condition characterized by chronic gastrointestinal symptoms, most notably persistent and intractable peptic ulceration, gastroesophageal reflux disease, and diarrhea. These symptoms are caused by an extreme overproduction of gastrin, almost always from gastrinomas (neuroendocrine tumors of the pancreas or duodenum). Approximately $20-30\%$ of ZES cases are a manifestation of Multiple Endocrine Neoplasia Type 1 (MEN1) syndrome, an inherited genetic disorder.

What are insulinomas?

Insulinomas are rare insulin-secreting neuroendocrine tumors that originate from the beta cells of the pancreatic islets. These tumors autonomously produce excessive amounts of insulin, leading to recurrent episodes of hypoglycemia (abnormally low blood glucose levels). Symptoms of hypoglycemia can include neuroglycopenic manifestations (confusion, visual disturbances, seizures, coma) and adrenergic symptoms (tremors, sweating, palpitations, hunger). While most insulinomas are sporadic and benign, they are the second most common functional pancreatic tumor in MEN1 syndrome, linked to mutations in the $MEN1$ gene.

What are glucagonomas?

Glucagonomas are very rare glucagon-secreting neuroendocrine tumors typically arising from the alpha cells of the pancreatic islets. The excessive production of glucagon, a hormone that raises blood glucose, leads to a distinctive constellation of symptoms known as the 'glucagonoma syndrome.' This includes hyperglycemia (high blood glucose), anorexia, glossitis (inflammation of the tongue), anemia, diarrhea, venous thrombosis, and a pathognomonic skin rash called necrolytic migratory erythema. While usually sporadic, some cases can be associated with MEN1 syndrome, reflecting genetic predispositions.

What is a VIPoma?

A VIPoma is a rare neuroendocrine tumor, usually located in the pancreas, that secretes excessive quantities of vasoactive intestinal peptide (VIP). VIP stimulates intestinal water and electrolyte secretion and inhibits gastric acid secretion. This leads to a classic and severe triad of symptoms known as the WDHA syndrome (Watery Diarrhea, Hypokalemia, Achlorhydria/Hypochlorhydria). Patients experience profound, secretory watery diarrhea, dangerously low potassium levels (hypokalemia) due to fluid loss, and diminished gastric acid production (achlorhydria or hypochlorhydria). VIPomas can occasionally be a component of MEN1 syndrome.

What are collagenomas in MEN1?

Collagenomas are benign dermal (skin) lesions characterized by a localized accumulation of excessive collagen. These skin lesions, reported with an incidence of up to $72\%$ in affected individuals, are a common cutaneous manifestation associated with Multiple Endocrine Neoplasia Type 1 (MEN1) syndrome. Their presence can serve as a valuable clinical clue to the underlying genetic disorder, which is caused by germline mutations in the $MEN1$ tumor suppressor gene, affecting mesenchymal cell proliferation.

What are facial angiofibromas in MEN1?

Facial angiofibromas are benign skin lesions that appear as small, flesh-colored to reddish-brown papules (bumps) composed of fibrous tissue and blood vessels. With an incidence reported as high as $88\%$ in MEN1 patients, these are highly characteristic cutaneous findings in Multiple Endocrine Neoplasia Type 1 (MEN1) syndrome. They typically appear on the face, especially around the nose, cheeks, and forehead, and are an important external indicator for the genetically determined MEN1 syndrome, triggered by mutations in the $MEN1$ tumor suppressor gene.

What is papillary thyroid cancer?

Papillary thyroid cancer (PTC) is the most common type of differentiated thyroid cancer, originating from the follicular cells of the thyroid gland and accounting for $80-85\%$ of all thyroid malignancies. V600E BRAF (somatic, RET, SDHB, and RAS mutations. These genetic changes activate signaling pathways that drive uncontrolled cell growth and are crucial for personalized diagnostic, prognostic, and therapeutic approaches.

What is medullary thyroid cancer (MTC)?

Medullary thyroid cancer (MTC) is a distinct type of thyroid cancer that originates from the parafollicular C-cells of the thyroid gland, which are responsible for producing the hormone calcitonin (a key tumor marker for MTC). approximately 25% are due to Multiple Endocrine Neoplasia Type 2 (MEN2) syndromes or Familial Medullary Thyroid Carcinoma (FMTC) due to the RET gene

What is anaplastic thyroid cancer?

Anaplastic thyroid cancer (ATC) is a very rare and extraordinarily aggressive form of thyroid cancer. It is considered 'undifferentiated,' meaning the cancer cells have lost all features resembling normal thyroid cells and exhibit extremely rapid, uncontrolled growth. ATC often arises from pre-existing differentiated thyroid cancers (papillary or follicular types) through the accumulation of additional, highly impactful genetic mutations. It carries a very poor prognosis due to its rapid progression, invasive nature, and general resistance to conventional treatments. Common genetic alterations identified include mutations in oncogenes like $BRAF$ and tumor suppressor genes like $TP53$, as well as $TERT$ promoter mutations.

What is a goiter?

A goiter is an abnormal, often visible, enlargement of the thyroid gland, located in the front of the neck. It is generally a benign condition and can arise from various etiologies, including iodine deficiency, autoimmune diseases (e.g., Hashimoto's thyroiditis, Graves' disease), inflammation (thyroiditis), or the presence of benign thyroid nodules. While most goiters are benign, certain types, particularly rapidly growing or large multinodular goiters, may occasionally harbor or increase the risk for concurrent thyroid cancer within the nodules. Genetic predisposition can influence susceptibility to some forms of goiter.

What is the RET proto-oncogene?

The $RET$ proto-oncogene (Rearranged during Transfection) encodes a receptor tyrosine kinase, a type of cell surface receptor protein that plays a critical role in cell growth, differentiation, and survival, particularly in cells of neural crest origin (which give rise to C-cells of the thyroid, adrenal medulla, and enteric neurons). As a 'proto-oncogene,' $RET$ normally regulates these vital cell processes. However, specific 'activating' (gain-of-function) mutations in this gene cause it to become a constitutively active oncogene, leading to uncontrolled cell proliferation and tumorigenesis. Such mutations are the underlying genetic cause of hereditary medullary thyroid cancer and are central to Multiple Endocrine Neoplasia Type 2 (MEN2) syndromes.

What is Multiple Endocrine Neoplasia Type 2 (MEN2)?

Multiple Endocrine Neoplasia Type 2 (MEN2) is a rare, inherited autosomal dominant cancer syndrome characterized by a very high penetrance for developing specific endocrine tumors. It is exclusively caused by germline activating (gain-of-function) mutations in the $RET$ proto-oncogene. The core clinical components of MEN2 include medullary thyroid cancer (MTC, nearly $100\%$ penetrance), pheochromocytoma (tumors of the adrenal medulla), and parathyroid abnormalities (hyperplasia or adenoma, leading to hypercalcemia). Early genetic testing for $RET$ mutations is crucial for diagnosis, risk assessment, and timely prophylactic thyroidectomy to prevent aggressive MTC.

What is MEN2A (Sipple syndrome)?

MEN2A, also known as Sipple syndrome, is the most common subtype of Multiple Endocrine Neoplasia Type 2. It is an inherited autosomal dominant cancer syndrome caused by specific germline activating mutations in the $RET$ proto-oncogene. MEN2A is classically characterized by the triad of medullary thyroid cancer (MTC), pheochromocytoma, and primary hyperparathyroidism (due to parathyroid hyperplasia or adenoma). Unlike MEN2B, patients with MEN2A typically do not exhibit the distinctive physical features like enlarged lips or mucosal neuromas, making genetic screening and early intervention, particularly prophylactic thyroidectomy based on specific $RET$ codon mutations, vital for management.

What is MEN2B?

MEN2B is a distinct and highly aggressive subtype of Multiple Endocrine Neoplasia Type 2, caused by specific germline activating mutations in the $RET$ proto-oncogene (most commonly a methionine to threonine substitution at codon 918, M918T). MEN2B is characterized by very early-onset and aggressive medullary thyroid cancer (often appearing in infancy), unilateral or bilateral pheochromocytomas, and rarely parathyroid disease. A key distinguishing feature is the presence of distinctive physical abnormalities, including a Marfanoid body habitus (tall, slender build), thickened lips, and numerous benign ganglioneuromas in the gastrointestinal tract and mucosal neuromas on the tongue and oral cavity. Due to the rapid progression of MTC, prophylactic thyroidectomy is typically recommended in the first year of life.

What is Familial Medullary Thyroid Carcinoma (FMTC)?

Familial Medullary Thyroid Carcinoma (FMTC) is considered a subtype of Multiple Endocrine Neoplasia Type 2 (MEN2) that is characterized exclusively by the presence of medullary thyroid cancer (MTC) in two or more family members, without the occurrence of pheochromocytomas or parathyroid disease. FMTC is caused by specific germline activating mutations in the $RET$ proto-oncogene that confer a lower risk for the extra-thyroidal manifestations seen in MEN2A or MEN2B. MTC in FMTC typically presents at a later age and often follows a milder course, though careful genetic counseling and long-term surveillance for MTC remain essential for affected families.

What is Hirschsprung disease?

Hirschsprung disease is a congenital (present at birth) disorder that affects the large intestine, causing functional intestinal obstruction and severe constipation. It is characterized by the absence of ganglion cells (specialized nerve cells crucial for peristalsis) in a segment of the distal colon, which results from incomplete migration of neural crest cells during embryonic development. Approximately $10-40\%$ of patients with Hirschsprung disease have mutations in the $RET$ proto-oncogene; however, unlike in MEN2, these are typically 'loss-of-function' mutations that impair $RET$ signaling, leading to developmental defects rather than oncogenic activation.

What are Hereditary Paraganglioma-Pheochromocytoma Syndromes?

Genes involved:

SDH complex (SDHA, SDHB, SDHC)

THEM127

SDHD, SDHAF2, and MAX have MATERNAL IMPRINTING

Criteria:

Phx of PGL and/or PCC, especially if multiple, multifocal, recurrent, malignant, and/or early onset (<45y)

A phx of gastrointestinal stromal tumors (GIST), especially if <45y.

Fhx of PGL, PCC, or GIST in F/SDR.

Also at risk for: (clear cell) RCC, GIST, and non-medullary thyroid cancer. Pituitary, pNET, and other endo tumors can also be seen.

What is a paraganglioma (PGL)?

A paraganglioma (PGL) is a rare neuroendocrine neoplasm that arises from of the autonomic nervous system (vertebral body from base of skull to pelvis).

These tumors are found in various locations such as the head, neck (e.g., carotid body, glomus jugulare, vagal paraganglia), chest, and abdomen.

Extra-adrenal PGLs of the abdomen, pelvis, or thorax are often sympathetic (secreting) and cause similar sx to pheochromocytomas (excessive sweating, HTN, headaches, panic attacks, tachycardia, etc.)

approximately 20-50% of PGLs are germline mutations. the SDH complex genes (ex. SDHB, SDHC, SDHD, SDHAF2, etc.) are from hereditary paraganglioma-pheochromocytoma syndromes.

What are catecholamines?

Catecholamines are a class of neurotransmitters and hormones that include epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine (a part of sympathetic nervous system). regulate the body's 'fight or flight' response, profoundly influencing heart rate, blood pressure, metabolism, and mood. The excessive release from PCCs or secreting PGLs leads to characteristic sx such as episodic headaches, palpitations, excessive sweating, and often severe hypertension, due to the overstimulation of adrenergic receptors.

SDHB (PGL-PCC syndrome subtype 4)

succinate dehydrogenase (SDH) B, a mitochondrial enzyme complex essential for both the Krebs cycle and the electron transport chain.

Highest risk of malignancy and mortality compared to mutations in other SDH genes.

Higher chance of extra-adrenal sympathetic PGLs and PCCs (dangerous). Highest chance of renal cell carcinoma (RCC), Higher chance of papillary thyroid cancer (also other cancers can occur, gastrointestinal stromal tumors (GIST), astrocytomas.

Tumor risk is 50%.

What are imprinted mutations (SDHD-related)?

only if inherited from the father (paternally expressed aka maternal imprinting).

highest risk for head and neck PGLs which are often parasympathetic. Sx include hoarseness, dysphagia, and tinnitus.