Multiple Endocrine Neoplasia Type 1 Flashcards
What is the treatment of adrenocortical tumors in MEN1?
Surgical removal of adrenocortical tumors that exceed 3.0 cm in diameter can prevent malignancy.
MNEMONIC: Remember the greater than symbol you do with your fingers when thinking of AC tumors + scissors for surgical removal.
What are carcinoid tumors, how and when do they typically manifest? Where can they occur?
Typically, non-hormone-secreting (rarely cause the carcinoid syndrome), slow-growing, neuroendocrine tumors which can manifest as a large invasive mass after age 50 years of age.
Sites:
- Thymic
- Brochopulmonary
- Gastric: type II gastric enterochromaffin-like (ECL) carcinoids
What are the risks in pregnancy related to hyperparathyroidism in MEN1?
What are the possible neonatal complications?
- Pregnant women are at increased risk of developing preeclampsia.
- Infants born to women with primary hyperparathyroidism should be monitored for postnatal hypocalcemia.
- Other neonatal complications may include intrauterine growth restriction, preterm birth, and permanent hypoparathyroidism.
MNEMONIC: Babies - milk - calcium - check it, can be low.
What diagnostic workup can be done to confirm a diagnosis of MEN1?
MNEMONIC: Diagnostic criteria - clinical and molecular
- Biochemical testing:
- Primary hyperparathyroidism: increased serum concentration of parathyroid hormone and calcium.
- Prolactinoma: increased serum concentrations of prolactin.
- Tumors of the GEP tract: increased serum concentrations of gastrin, insulin, and VIP. - Imaging:
- For prolactinomas = MRI.
- Neuroendocrine tumors (NETs) are detected by somatostatin receptor scintigraphy (SRS) octreotide scan
- Endoscopic ultrasound (EUS) examination is the most sensitive imaging procedure for the detection of small (≤10 mm) pancreatic endocrine tumors in asymptomatic individuals with MEN1. - Molecular genetic testing of the MEN1 gene:
- Detection of a heterozygous pathogenic variant.
- Who should surveillance for MEN1 be offered to?
2. What does surveillance in MEN1 entail?
Answer 1:
- Those confirmed to have MEN1 - clinically or molecularly (even if asymptomatic)
- Those at risk for MEN1 syndrome-associated tumors (i.e. those with an affected parent who have not undergone molecular genetic testing)
Answer 2:
Surveillance using biochemical testing and imaging should begin in early childhood and continue for life:
A. Yearly biochemical investigations:
1. Serum concentration of prolactin, IGF-1, FASTING glucose, and insulin from age 5 years*,
- FASTING total serum calcium concentration (corrected for albumin) and/or ionized-serum calcium concentration, chromogranin-A, pancreatic polypeptide, glucagon, vasoactive intestinal peptide for other pancreatic NET from age 8 years**, and
(CC - PP - G - VIP)
- FASTING serum gastrin concentration from age 20 years***.
B. Imaging every 3 to 5 years - depending on whether there is biochemical evidence of and/or signs and symptoms of an MEN1-related tumor:
- Head MRI starting at the age of 5 years*,
- Abdominal CT or MRI starting at the age of 20 years***
May consider fasting serum PTH concentration and yearly chest CT**
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For individuals at 50% risk of having MEN1 syndrome in whom genetic status is unknown.
Yearly biochemical investigations, beginning at the specified age:
- Starting at 5 years of age: Serum concentration of prolactin,
- Starting at 10 years of age: FASTING total serum calcium concentration (corrected for albumin) and/or ionized-serum calcium concentration + FASTING serum concentration of intact (full-length) PTH
- Starting at 20 years of age: FASTING serum gastrin concentration IF individual has symptoms of ZES (reflux or diarrhea).
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MNEMONIC: Think of the diagnostic criteria and from head to toe:
- Head, vision is thinking of 5
- Neck, parathyroid = 4 glands = infinity necklace = 8
- Gut where the gum got stuck
MNEMONIC: 50% risk = 5 years - 10 years - 20 years (doubling and only the essentials - do PTH because they’re getting minimal screening anyway, not the whole package and no imaging)
What is carcinoid syndrome?
What is it caused by?
How does it present?
What is the treatment of choice?
What is the treatment for unresectable tumors and those individuals with metastatic disease?
What medication can be administered to control the secretory hyperfunction associated with carcinoid syndrome? (Hint: NETs)
- Carcinoid syndrome is a paraneoplastic syndrome which occurs secondary to carcinoid tumors.
- It is caused by endogenous secretion of mainly serotonin and kallikrein.
- It presents with flushing and diarrhea, and less frequently, vomiting, heart failure, and bronchoconstriction.
MNEMONIC: Carcinoid - Paranoid/Anxious - shit their pants, became flushed, vomited - heart failure, can’t breathe
- Surgical: The treatment of choice for carcinoid is surgical removal, if resectable.
- Medical: Long-acting somatostatin analogs can control the secretory hyperfunction associated with carcinoid syndrome.
- Alternative: For unresectable tumors and those individuals with metastatic disease, treatment with radiotherapy or chemotherapeutic agents (e.g., cisplatin, etoposide) may be used.
MNEMONIC: How do you treat cancer (carcinoid) that can’t be removed?
What is the clinical diagnostic criteria for MEN1 syndrome?
What should clinicians keep in mind?
The presence of two out of the three following endocrine tumors: parathyroid, pituitary, or GEP tract tumors.
NB: Clinicians should keep in mind that non-endocrine tumors may appear before the manifestations of hormone-secreting endocrine tumors.
Mnemonic:
1. Must create the V in W (2 of 3)
What is the management of hyperparathyroidism in MEN1?
- Surgical:
- Initially, subtotal parathyroidectomy and cryopreservation of parathyroid tissue, or
- Total parathyroidectomy and autotransplantation of parathyroid tissue - if patient has extensive disease or initial surgery was unsuccessful; - If surgery is contraindicated or has failed:
- Calcimimetics (i.e., Cinacalcet) are used to treat primary hyperparathyroidism.
- A calcimimetic is a pharmaceutical drug that mimics the action of calcium on tissues and reduces serum levels of parathyroid hormone (PTH) and calcium. - Prior to surgery:
- Bone antiresorptive agents are used to reduce hypercalcemia and limit bone resorption.
- Have any genotype-phenotype correlations been identified in MEN1 syndrome? Clinical variability?
- What protein does the MEN1 gene encode for?
- What does this protein do?
- What class of driver gene does it fall under?
- What is the cytogenetic location of the gene?
- What is the penetrance for all clinical features?
- List the genetically related (allelic) disorders.
- No direct genotype-phenotype correlations have been identified in MEN1 syndrome. A HIGH clinical variability has been described between affected members of the same families (bearing the same MEN1 pathogenic variant) and even between homozygous twins.
- Menin
- A nuclear scaffold protein. It interacts with several transcription factors. It regulates gene transcription by COORDINATING chromatin remodeling.
- It’s considered to act as a tumor suppressor gene.
- 11q13.1
- The AGE-RELATED penetrance for all clinical features surpasses 50% by age 20 years and 95% by age 40 years.
- Familial isolated hyperparathyroidism (FIHP): **which may be associated with an increased risk for parathyroid carcinoma.
- Familial pituitary tumor.
- Sporadic tumors with somatic mutations:
1. Angiofibroma, somatic
2. Lipoma, somatic
3. Parathyroid adenoma, somatic
4. Carcinoid tumor of lung
5. Gastrinoma, insulinoma
6. Adrenal adenoma, somatic
NB: These are occurring as single tumors in the absence of any other findings of MEN1 syndrome frequently harbor somatic pathogenic variants in MEN1 that are NOT present in the germline. In these circumstances, predisposition to these tumors is not heritable.
Mnemonic: Think of WandaVision - holding on and remodeling chromatin - suppresses the bad guys.
What tumors are associated with MEN1?
What is the cancer risk of each?
What is the morbidity and mortality?
The endocrine tumors (adenomas) include:
- Parathyroid tumors
- ANTERIOR Pituitary tumors
- Well-differentiated neuroendocrine tumors of the gastro-entero-pancreatic (GEP-NETs) tract
- Carcinoid tumors
- Adrenocortical tumors
The non-endocrine tumors include:
- Facial angiofibromas,
- Collagenomas,
- Lipomas,
- NB: Other skin findings include café au lait macules in 38%, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6%
- Leiomyomas (fibroids)
- Meningiomas,
- Ependymomas
Mnemonic: WandaVision: From parathyroid to pituitary (yellow stone) - creates a W - remember the gum that passed through his tract - carcinoid - adrenocortical // Think of vision’s skin - brain stuff - fibroids when Wanda got pregnant
Cancer risk:
- Gastrinoma - Multiple - Malignant - Mets
- Glucagonoma - Malignant - Mets (to liver)
- VIPomas - Malignant - Mets (to liver)
- Thymic carcinoid tumors = increased risk of death
- Adrenocortical tumors = risk of malignancy increases with size.
NOTES:
- Parathyroid carcinoma is rare in individuals with MEN1.
- No increased prevalence of pituitary carcinoma is observed in individuals with MEN1.
- **The gastrinomas of MEN1 syndrome are frequently multiple and usually malignant. Half have metastasized before diagnosis.
- Insulinomas are almost always benign.
- ** About 80% of MEN1-associated glucagonomas are malignant and frequently spread to the liver.
- ** VIPomas are malignant and have usually metastasized at the time of diagnosis. Metastases occur most frequently in the liver.
- **Therefore, the presence of thymic tumors is reported to be associated with a significantly increased risk of death in individuals with MEN1 (hazard or odds ratio = 4.29) – this in contrast to the presence of bronchial carcinoids, which have not been associated with increased risk of death.
- **In a study of 715 individuals with MEN1, Gatta-Cherifi et al [2012] estimated the overall incidence of adrenocortical carcinoma at 1%. In individuals with MEN1 who have adrenal tumors larger than 1 cm, the risk of malignancy is about 13%. This risk may be higher in affected individuals whose tumor is greater than 4 cm in diameter.
M&M:
MEN1 syndrome-associated malignancies currently account for approximately 30% of deaths in MEN1 syndrome.
{{XXX}} are the main MEN1-associated endocrinopathy; onset in 90% of individuals is between ages {{XXX}} years with {{symptom - XXX}} evident by age {{XXX}} years.
How do they manifest?
With {{XXX}} which causes:
- {{XXX}},
- {{XXX}},
- {{XXX}},
- {{XXX}},
- {{XXX}}.
{{Parathyroid tumors}} are the main MEN1-associated endocrinopathy; onset in 90% of individuals is between ages {{20 and 25}} years with {{hypercalcemia}} evident by age {{50}} years.
How do they manifest?
With {{primary hyperparathyroidism and hypercalcemia}} which causes:
- {{Lethargy - depression - confusion}},
- {{Anorexia - constipation - nausea - vomiting}},
- {{Diuresis - dehydration - hypercalciuria - kidney stones}},
- {{Increased bone resorption/fracture risk/osteoporosis}},
- {{Hypertension, and shortened QT interval}}.
NB: Parathyroid tumors are usually multiglandular disease with enlargement of all the parathyroid glands rather than a single adenoma.
Multiple endocrine neoplasia type 1 (MEN1) syndrome includes varying combinations of more than 20 {{XXX}} and {{XXX}} tumors.
Multiple endocrine neoplasia type 1 (MEN1) syndrome includes varying combinations of more than 20 {{endocrine}} and {{non-endocrine}} tumors.
Endocrine tumors become evident either by {{XXX}} or by {{XXX}}.
Endocrine tumors become evident either by {{overproduction of hormones by the tumor}} or by {{growth of the tumor itself}}.
The most common pituitary tumors in MEN1 is the {{XXX}}, which manifests as {{XXX}} in females and {{XXX}} in males.
The most common pituitary tumors in MEN1 is the {{prolactinoma = prolactin-secreting anterior pituitary adenomas}}, which manifests as {{oligomenorrhea/amenorrhea and galactorrhea}} in females and {{sexual dysfunction including (reduction of libido or impotence) and (more rarely) gynecomastia}} in males.
Mnemonic: Wanda gave birth to twins - breastfeeding
In MEN1, well-differentiated neuroendocrine tumors of the gastro-entero-pancreatic (GEP-NETs) tract include the following (from most to least frequent) which can manifest as:
- Accounting for {{XXX}} is the {{XXX}} which can be located in the {{XXX}} and causes {{XXX}}
- {{XXX - secreting - location}} — {{XXX}}
- {{XXX - secreting - location}} — {{XXX}}
- {{XXX - secreting - location}} — {{XXX}}
- Accounting for {{XXX}} the most frequently seen tumors in MEN1 syndrome {{XXX}}
- {{XXX}}
In MEN1, well-differentiated neuroendocrine tumors of the gastro-entero-pancreatic (GEP-NETs) tract include the following which can manifest as:
- Accounting for {{40%}} is the {{Gastrinoma: gastrin-secreting tumor}} which can be located in the {{pancreas or duodenum}} and causes {{Zollinger-Ellison syndrome: excess gastric acid can cause peptic ulcers in your stomach and intestine}}
- {{Insulinoma: insulin-secreting pancreatic tumor}} — {{Hypoglycemia}}
- {{Glucagonoma: glucagon-secreting pancreatic tumor}} — {{Hyperglycemia: anorexia, glossitis, diarrhea – venous thrombosis, anemia, and skin rash: necrolytic migratory erythema}}
- {{Vasoactive intestinal peptide [VIP]-secreting pancreatic tumor}} — {{watery diarrhea, hypokalemia, and achlorhydria syndrome, i.e. absence of hydrochloric (HCl) acids in the stomach = WDHA syndrome}}
- Accounting for {{20%-55%}}, the most frequently seen tumors in MEN1 syndrome: {{Non-functioning pancreatic NETs}}.
- {{Gastric carcinoids}}
NB: Average life expectancy of individuals with MEN1 with non-secreting tumors was shorter than life expectancy of individuals who did not have pancreaticoduodenal tumors.
