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- 1. MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 SUPERVISED BY DR. BASSAM NSHEWAT BALQEES MAJALI
- 2. INTRODUCTION • Medullary thyroid cancer • Pheochromocytoma • Parathyroid hyperplasia • MEN2A with cutaneous lichen amyloidosis (CLA) • MEN2A with Hirschsprung disease (HD) MEN2A • Medullary thyroid cancer • Mucosal neuroma • +/- pheochromocytoma MEN2B • Medullary thyroid cancer alone FMTC
- 3. Syndrome MTC Pheochromocytoma Parathyroid hyperplasia Intestinal ganglioneurom as Mucosal neuromas MEN2A Yes Yes Yes No No MEN2B Yes Yes No Yes Yes FMTC Yes No No No No Clinical Findings Associated With MEN2 Syndromes
- 4. ETIOLOGY MEN2A syndrome affects 60% to 90% of MEN2 families while MEN2B affects only 5% of MEN2 families. All of these conditions are due to one of the several RET proto-oncogene mutations which play an important role in the growth and differentiation of the structures mostly evolved from neural crest cells
- 6. EPIDEMIOLOGY The prevalence of all MEN2 worldwide is 1 in 35,000, while in the United States, it is 1 in 30,000 to 50,000. The epidemiology of MEN2B is unknown. The prevalence of MEN2B is estimated to be between 1 in 600,000 to 1 in 4 million. In MEN2A patients, 50% of those with RET gene mutations develop disease by age 50 years, and 70% develop the disease by age 70 years. MTC has been detected shortly after birth in MEN2B
- 7. MEDULLARY THYROID CANCER medullary thyroid carcinoma is a tumor of the parafollicular cells (C cells) derived from the neural crest. It is characterized by an amyloid stroma. Many medullary tumors produce high levels of serum calcitonin and carcinoembryonic antigen, Levels fall after resection and rise again with recurrence making it a valuable tumor marker in the follow up of patients with this disease
- 8. MTC Clinical presentation : • Neck mass usually a firm, smooth and distinct lump in the neck, indistinguishable from any other form of thyroid solitary nodule • Pain or aching is more common in these tumors when compared to others • Dyspnea , dysphonia , dysphagia in case of local invasion • Diarrhea is a feature in 30% of cases and this may be due to 5-hydroxytryptamine or prostaglandins produced by the tumor cells occurs in affected individuals with a plasma calcitonin concentration >10 ng/mL and implies a poor prognosis • Flushing Diagnosis : Usually made by FNA
- 9. MTC In general 10-20% of all cases of MTC are familial The familial form frequently affects children and young adults whereas sporadic cases occur at any age with no sex predominance If it occurs in combination with hyperparathyroidism and pheochromocytoma = MEN 2A When the familial form is associated with prominent mucosal neuromas involving the lips tongue and inner aspects of the eyelids with marfanoid habitus = MEN 2B Involvement of lymph nodes occurs in 50-60% of cases and blood borne metastases are common It is not TSH dependent and do not take up radioactive iodine The prognosis is variable and depends on the stage at diagnosis
- 10. MTC TREATMENT • total thyroidectomy • prophylactic or therapeutic resection of the central and bilateral lymph nodes In general • detected by genetic screening for RET gene mutations • Estimation of serum calcitonin levels in the basal state and after stimulation by Ca • If there is a rise in calcitonin after stimulation test thyroidectomy should be done • Prophylactic surgery is now recommended for infants with genetic trait Familial cases • In all cases before embarking upon thyroid surgery, pheochromocytoma must be excluded by measurement of urinary catecholamine levels Other measures
- 12. PHEOCHROMOCYTOMA These are tumors of the adrenal medulla and sympathetic ganglia that are derived from chromaffin cells and most commonly produce supraphysiological levels of circulating catecholamines. Pheochromocytoma, a typically benign adrenal medullary tumor (usually bilateral and multicentric), occurs in 40% to 50% of patients with MEN2A or MEN2B; the frequency and penetration highly depend on the specific type of mutation Usually, it is identified as a part of the screening process in the patients with known or suspected MEN2
- 13. PHEOCHROMOCYTOMA – PATHOLOGY • Phaeochromocytomas are greyish-pink on the cut surface and are usually highly vascularised. Areas of hemorrhage or necrosis are often observed • Microscopically, tumor cells are polygonal but the configuration varies considerably • These tumors produce calcitonin, ACTH, vasoactive intestinal polypeptide (VIP) and parathyroid hormone-related protein (PTHrP). • In patients with MEN 2, the onset of phaeochromocytoma is preceded by adrenomedullary hyperplasia, sometimes bilateral. • Phaeochromocytoma is rarely malignant in MEN 2
- 15. PHEOCHROMOCYTOMA CLINICAL MANIFESTATIONS Symptom Prevalence % Hypertension 80-90 Continues 30 Paroxysmal 50-60 Headache 60-90 sweating 50-70 palpitation 70-70 pallor 40-45 Weight loss 20-40 hyperglycemia 40 nausea 20-40 Psychological effects 20-40
- 16. PHEOCHROMOCYTOMA – DIAGNOSIS -metanephrine and normetanephrine level, in a 12 or 24-hour urine collection,) -determination of plasma-free metanephrine and normetanephrine levels localisation of the phaeochromocytoma. MRI is preferred because contrast media used for CT scans can provoke paroxysms. Classically, phaeochromocytomas show a ‘Swiss cheese’ configuration - (SPECT) will identify about 90% of primary tumours and is essential for the detection of multiple extra-adrenal tumors and metastases - (PET) for metastases - (DOPA) is yet more sensitive in detecting metastatic foci.
- 17. Magnetic resonance imaging of a sporadic phaeochromocytoma of the left adrenal gland (arrowheads). Meta-iodobenzylguanidine (MIBG) single- photon emission computed tomography scan of a phaeochromocytoma of the left adrenal gland (arrow) in the same patient as in
- 18. PHEOCHROMOCYTOMA- TREATMENT Laparoscopic resection is now routine in the treatment of pheochromocytoma If the tumor is larger than 8-10cm or radiological signs of malignancy are detected an open approach should be considered
- 20. Pre-op • α- adrenoreceptor blocker (phenoxybenzamine) should be used • β-blockade is required if tachycardia or arrhythmias develop Per-op • A central venous catheter and invasive arterial monitoring are used. Special attention is required when the adrenal vein is ligated as a sudden drop in blood pressure may occur • The infusion of large volumes of fluid or administration of noradrenaline can be necessary to correct postoperative hypotension in the presence of unopposed α- blockade. Post-op • Patients should be observed for 24 hours in the intensive care (ICU) or high dependancy unit as hypovolaemia and hypoglycaemia may occur. • Lifelong yearly biochemical tests should be performed to identify recurrent, metastatic or metachronous phaeochromocytoma
- 21. HYPEPARATHYROIDISM PHPT occurs in approximately 20% of patients and is associated with mutations in codon 634 in the RET proto-oncogene The majority of patients will be asymptomatic, with a mild elevation in calcium and asymmetrically enlarged parathyroid glands It is extremely important that the presence of a phaeochromocytoma is excluded prior to surgical intervention Surgery is usually performed for medullary thyroid carcinoma (MTC), with the parathyroid enlargement often being a coincidental intraoperative finding In this setting, with extensive surgery for MTC, the primary aim of treatment is to avoid hypoparathyroidism. A conservative stance is adopted with resection of grossly enlarged glands, but with preservation of parathyroid tissue where possible and identification with a marking stitch in the neck
- 23. OTHER MANIFESTATIONS Patients with MEN2B tend to have mucosal neuromas, which are often located on the lips, tongue, and buccal mucosa. Other manifestations include various skeletal and ophthalmologic anomalies. Marfanoid habitus, congenital dislocation of the hip, pes planus, pes cavus, pectus excavatum, and kyphosis can all be seen.
- 25. MEN2A CLA Cutaneous lichen amyloidosis (CLA) also termed lichen planus amyloidosis (LPA), is a rare skin condition that is associated with MEN2A. It is thought to be a primary neuropathy and presents with pruritic, pigmented, scaly papules usually in extensor surfaces of extremities and interscapular region. Histology has shown amyloid deposition
- 26. MEN2A HD Hirschsprung disease (HD), also known as chronic aganglionic megacolon, also is associated with MEN2A. It is characterized by the absence of autonomic ganglion cells within the parasympathetic chain of the sigmoid colon, resulting in peristalsis, chronic obstruction, and megacolon
- 27. EVALUATION AND PRIMARY PREVENTION
- 28. CLINICAL CRITERIA MEN2A • is diagnosed clinically by the occurrence of two or more specific endocrine tumors ( MTC, pheochromocytoma, or parathyroid adenoma/hyperplasia) in a single individual or in close relatives. FMTC • is diagnosed in families with four or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. MEN2B • is diagnosed clinically by the presence of early-onset MTC, mucosal neuromas of the lips and tongue, as well as medullated corneal nerve fibers, distinctive facies with enlarged lips, and an asthenic, marfanoid body habitus.
- 29. ESTABLISHING THE DIAGNOSES When the phenotypic and laboratory findings suggest the diagnosis of MEN 2, molecular genetic testing approaches can include single-gene panel testing or use of a multigene panel Molecular Genetic Testing Used in MEN 2 : Gene 1 Method 2 Proportion of Probands with a Pathogenic Variant 3 Detectable by Method MEN 2A FMTC MEN 2B RET Sequence analysis 4, 5 >98% 6, 7 >95% 6, 8 >98% 9 Sequence analysis of select exons 98% 6, 10 95% 6, 8 Targeted analysis for pathogenic 98% 9
- 30. EVALUATION FOLLOWING INITIAL DX Referral to an endocrinologist Consultation with a clinical geneticist and/or genetic counselor Biochemical evaluations: Plasma calcitonin Plasma catecholamines and metanephrines Serum calcium and parathyroid hormone Evaluation for metastatic disease in individuals with MTC CT with contrast for chest and abdomen MRI of liver in the presence of nodal disease or calcitonin >400 pg/mL
- 31. PREVENTION OF PRIMARY MANIFESTATIONS For MTC * Prophylactic thyroidectomy is the primary preventive measure for individuals with an identified germline RET pathogenic variant * Prophylactic thyroidectomy is safe for all age groups; however, the timing of the surgery is controversial For all individuals with a RET pathogenic variant who not had a thyroidectomy, annual biochemical screening is recommended with immediate thyroidectomy if results are abnormal Annual serum calcitonin screening should begin at age: - Six months for children with MEN 2B; - Three to five years for children with MEN 2A or FMTC.
- 32. Pheochromocytoma annual biochemical screening is recommended, followed by MRI and/or CT if the biochemical results are abnormal MEN 2A. Annual biochemical screening beginning at age eight years has been recommended for individuals with a pathogenic variant in codons 630 and 634 and at age 20 years for a pathogenic variant in all other codons FMTC. Screening as for MEN 2A is indicated, as not all families classified as FMTC are MTC- only MEN 2B. Annual screening should begin at age eight years .
- 33. Parathyroid adenoma or hyperplasia Annual biochemical screening is recommended for affected individuals who have not had parathyroidectomy and parathyroid autotransplantation. MEN 2A. Screening should start at age eight years for individuals with a pathogenic variant in codons 630 and 634, and by age 20 years for individuals with other RET pathogenic variants FMTC. Periodic screening should begin at age 20 years MEN 2B. Screening is unnecessary as individuals with MEN 2B are not at increased risk for hyperparathyroidism.
- 34. SUGGESTED FOLLOW UP (SUMMARY) Biochemical Screening Indication for imaging Imaging Indication for Surgery MTC Annual calcitonin (or stimulated calcitonin) • Rise in calcitonin • Palpable lump Ultrasound/CT/M RI, 99mTc Sestamibi scanning • At presentation in adulthood (exclude Phaeo first) Phaeo Annual 24hr urinary metanephrines • 3-5 yearly • Or if meta nephrines elevated CT/MRI, MIBG • Positive scan Parathyroid Annual PTH and ionised calcium • Development of hyperparathyroid ism • And renal calculi, osteoporosis, symptomatic hypercalcaemia, or patient preference
- 35. GENETIC COUNSELING Genetic counseling is the process of providing individuals and families with information on the nature, mode of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.
Notas del editor
- Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary canc MEN 2A is diagnosed clinically by the occurrence of two or more specific endocrine tumors (medullary thyroid carcinoma [MTC], pheochromocytoma, or parathyroid adenoma/hyperplasia) in a single individual or in close relatives. FMTC is diagnosed in families with four or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. MEN 2B is diagnosed clinically by the presence of early-onset MTC, mucosal neuromas of the lips and tongue, as well as medullated corneal nerve fibers, distinctive facies with enlarged lips, and an asthenic, marfanoid body habitus er syndrome associated primarily with tumors of the adrenal gland, thyroid and parathyroid.
- Point mutations associated with MEN2A and the FMTC-only subtype have been identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists. Classical MEN2A is associated with germline missense mutations in RET codons 609, 611, 618, or 620 of exon 10 or codon 634 of exon 11, which map to the receptor’s extracellular cysteine-rich domain. MEN2A with cutaneous lichen amyloidosis is nearly always associated with mutation of codon 634, while patients with MEN2A and Hirschsprung disease typically harbor mutations involving RET exon 10. [10] Approximately 75% of MEN2B cases are sporadic and affected patients have de novo RET mutations, while 25% of cases occur in families with previous or current manifestations of MEN2B. Approximately 95% of patients with MEN2B have RET germline mutations in exon 16 (codon M918T) and fewer than 5% have RET germline mutations in exon 15 (codon A883F). [1] The rearranged during transfection (RET) protein is a receptor tyrosine kinase that is localized to chromosome 10q11.2. It appears to transduce growth and differentiate signals in several tissues, particularly those arising from neural crest cells. Some cytogenetic mutations have been reported; these may involve intracellular and extracellular domains of the RET protein signaling pathway. The germline RET mutations in MEN2 result in a gain of function of this tyrosine kinase receptor. This is different from many other inherited predispositions to neoplasia that are due to heritable "loss-of-function" mutations that inactivate tumor suppressor proteins.
- Levels fall after resection and rise again with recurrence making it a valuable tumour marker in the follow up of patients with this disease
- Treatment is by total thyroidectomy and prophylactic or therapeutic resection of the central and bilateral lymph nodes Familial cases are detected by genetic screening for RET gene mutations Medullary thyroid carcinoma (MTC). Standard treatment for MTC is surgical removal of the thyroid and lymph node dissection [Kloos et al 2009, National Comprehensive Cancer Network 2015]. Current NCCN guidelines recommend consideration of therapeutic external beam radiation therapy or intensity-modulated radiation therapy for incomplete tumor resection or extrathyroidal extension with positive margins [National Comprehensive Cancer Network 2015]. Several kinase inhibitors – vandetanib, cabozantinib, and BLU-667 – have improved progression-free survival and in some cases cause disease regression in unresectable or advanced metastatic MTC [Elisei et al 2013, Wells et al 2013, Subbiah et al 2018]. All individuals who have undergone thyroidectomy need thyroid hormone replacement therapy. Autotransplantation of parathyroid tissue is not typically performed at the time of thyroidectomy unless there is evidence of hyperparathyroidism [
- Usually, it is identified as a part of the screening process in the patients with known or suspected MEN2. One must always take care of bilateral or extra-renal pheochromocytoma. Although it is rare for pheochromocytoma to appear before MTC, it can be the initial manifestation of MEN2 with the classic symptoms of pheochromocytoma such as paroxysmal attacks of a headache, anxiety, diaphoresis, and palpitations. The mean age of presentation is 25 to 32 years, and it may appear as early as 8 to 12 years of age.[6]
- Phaeochromocytomas are greyish-pink on the cut surface and are usually highly vascularised. Areas of haemorrhage or necrosis are often observed Microscopically, tumour cells are polygonal but the configuration varies considerably produce calcitonin, ACTH, vasoactive intestinal polypeptide (VIP) and parathyroid hormone-related protein (PTHrP). patients with MEN 2, the onset of phaeochromocytoma is preceded by adrenomedullary hyperplasia, sometimes bilateral. Phaeochromocytoma is rarely malignant in MEN 2.
- Symptoms and signs are caused by catecholamine excess and are typically intermittent (Table 52.2). In total, 90% of patients with the combination of headache, palpitations and sweating in the presence of an adrenal tumour have a phaeochromocytoma. Paroxysms may be precipitated by physical training, induction of general anaesthesia and numerous drugs and agents (contrast media, tricyclic antidepressive drugs, metoclopramide and opiates). Hypertension may occur continuously, be intermittent or absent. A subset of patients are asymptomatic. More than 25% of apparently sporadic phaeochromocytomas are caused by germline mutations in the RET, SDHB, SDHC, SDHD and NF1 genes; genetic testing for these and other genes is therefore recommended, particularly in those patients aged under 50 years
- Diagnosis The first step in the diagnosis of a phaeochromocytoma is the confirmation of excessive catecholamine levels in the patient either by the measurement of adrenaline and noradrenaline breakdown products, metanephrine and normetanephrine level, in a 12 or 24-hour urine collection, (levels that exceed the normal range by 2–40 times will be found in affected patients) or by determination of plasma-free metanephrine and normetanephrine levels. Biochemical tests should be performed at least twice. The biochemical diagnosis is then followed by localisation of the phaeochromocytoma. MRI is preferred because contrast media used for CT scans can provoke paroxysms. Classically, phaeochromocytomas show a ‘Swiss cheese’ configuration (Figure 52.11). 123I-MIBG(metaiodobenzylguanidine) single-photon emission computed tomography (SPECT) will identify about 90% of primary tumours and is essential for the detection of multiple extra-adrenal tumours and metastases (Figure 52.12). Positron emission tomography (PET) scanning using fluorodeoxyglucose (FDG) or dihydroxyphenylalanine (DOPA) is yet more sensitive in detecting metastatic foci. T
- Pheochromocytomas detected by biochemical testing and radionuclide imaging are removed by adrenalectomy, which may be performed using video-assisted laparoscopy. Historically, some specialists recommended bilateral adrenalectomy at the time of demonstration of tumor on just a single adrenal gland because of the strong probability that the other adrenal gland would develop a tumor within ten years. However, because of the risk for adrenal insufficiency and Addisonian crisis following bilateral adrenalectomy, most experts now recommend unilateral adrenalectomy in unilateral tumors and cortical-sparing adrenal surgery with close monitoring of the remnant tissue in persons with one remaining adrenal gland or bilateral pheochromocytoma [Kloos et al 2009, Neumann et al 2019]. Hypertensive treatment prior to adrenalectomy often involves the use of α- and β-adrenergic receptor blockade [Pacak et al 2005], although some centers do not pretreat with α-blockade and use nitroprusside to control blood pressure during surgery [Neumann et al 2019]. The operative approach is laparoscopy or retroperitoneoscopy. Unilateral or bilateral subtotal resection may be feasible, which retains the healthy part of the gland and prevents postoperative dependence on cortisol and mineralocorticoid supplementation Further phaeos can develop in the remnants that are left so continued surveillance is required.
- α- adrenoreceptor blocker (phenoxybenzamine) should be used to block the effects of catecholamine excess and its consequences during surgery. Additional β-blockade is required if tachycardia or arrhythmias develop; this should not be introduced until the patient is α-blocked. With adequate α-blockade preoperatively, anaesthesia should not be more hazardous than in patients with a non-functioning adrenal tumour A central venous catheter and invasive arterial monitoring are used. Special attention is required when the adrenal vein is ligated as a sudden drop in blood pressure may occur The infusion of large volumes of fluid or administrationof noradrenaline can be necessary to correct postoperative hypotension in the presence of unopposed α-blockade. Patients should be observed for 24 hours in the intensive care (ICU) or high dependancy unit as hypovolaemia and hypoglycaemia may occur. Lifelong yearly biochemical tests should be performed to identify recurrent, metastatic or metachronous phaeochromocytoma
- Parathyroid adenoma or hyperplasia diagnosed at the time of thyroidectomy is treated either with resection of the visibly enlarged parathyroid gland(s), subtotal parathyroidectomy, or total parathyroidectomy with forearm autograft [Kloos et al 2009]. However, in most individuals with MEN 2A, hyperparathyroidism is diagnosed many years after thyroidectomy. Individuals with biochemical evidence of primary hyperparathyroidism who have undergone prior thyroidectomy should have preoperative localization with excision of the localized hypertrophied parathyroid glands and forearm autotransplantation. Therapy with medications to control primary hyperparathyroidism should be considered in individuals with a high risk for surgical mortality, limited life expectancy, or persistent or recurrent primary hyperparathyroidism after one or more surgical attempts [Kloos et al 2009]. MEN 2A-associated hyperparathyroidism MEN 2A consists of medullary thyroid carcinoma, unilateral or bilateral phaeochromocytomas and PHPT. PHPT occurs in approximately 20% of patients and is associated with mutations in codon 634 in the RET proto-oncogene. The majority of patients will be asymptomatic, with a mild elevation in calcium and asymmetrically enlarged parathyroid glands. It is extremely important that the presence of a phaeochromocytoma is excluded prior to surgical intervention. Surgery is usually performed for medullary thyroid carcinoma (MTC), with the parathyroid enlargement often being a coincidental intraoperative finding. In this setting, with extensive surgery for MTC, the primary aim of treatment is to avoid hypoparathyroidism. A conservative stance is adopted with resection of grossly enlarged glands, but with preservation of parathyroid tissue where possible and identification with a marking stitch in the neck
- Parathyroidectomy with exposure of the left superior and inferior parathyroid glands (white arrows) in situ (a) and left superior gland mobilised on its vascular pedicle (b). To reduce the risk of postoperative hypocalcemia, remove only grossly abnormal parathyroid glands. If all parathyroid glands are enlarged, a subtotal parathyroidectomy is advocated, leaving an approximately 60-mg remnant. Perform a cervical thymectomy because of the increased risk of supernumerary parathyroid glands. [20]
- Multiple endocrine neoplasia type 2 (MEN 2) includes the phenotypes MEN 2A; familial medullary thyroid carcinoma (FMTC), which may itself be a variant of MEN 2A; and MEN 2B. MEN 2A should be suspected in individuals with one or more specific endocrine tumors: medullary thyroid carcinoma (MTC), pheochromocytoma, or parathyroid adenoma/hyperplasia. FMTC should be suspected in families with more than one individual diagnosed with MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. MEN 2B should be suspected in individuals with distinctive facies including lip mucosal neuromas resulting in thick vermilion of the upper and lower lip, mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, marfanoid habitus, and MTC. MEN2A and MEN2B should be suspected in any patient diagnosed with MTC or pheochromocytoma, particularly when the age of presentation is very young (younger than 35). MTC most commonly presents with a solitary thyroid nodule and/or cervical lymphadenopathy. Any patient with diagnosed MTC or family history of MTC should be tested for RET proto-oncogene mutations for both MEN2A and MEN2B. The patients who are diagnosed with pheochromocytoma at the age earlier than that of its sporadic forms should be tested for MEN2A and MEN2B. The classic symptoms of pheochromocytoma are the paroxysms of a headache, anxiety, diaphoresis and palpitations, and high blood pressure. The presence of these symptoms in the third decade, particularly in between 25 and 32 years, should prompt to screen for MEN2. A detailed history of the presence of associated conditions (described above) in the patient or the family members should be taken. Other possible physical examination findings include marfanoid habitus (decreased upper to lower body ratio), mucosal neuromas (red papules) over lips and tongues, and joint hyperlaxity associated with MEN2B. The patients typically lack lens dislocation or aortic abnormalities, unlike Marfan syndrome. MEN2A also is suspected in patients with clinical features like purity, scaly, pigmented papules in the interscapular region as these are features of CLA that have an association with MEN2A.
- Patients with classic clinical manifestations of MEN2 are evaluated for two main reasons: To screen for other associated common tumors to decrease overall morbidity and mortality To screen for genetic mutation so that other family members should be tested and provided adequate prophylactic medical and surgical care such as prophylactic thyroidectomy The diagnosis of MEN 2 is established in a proband with the following clinical criteria. Identification of a heterozygous germline RET pathogenic variant by molecular genetic testing (see Table 1) establishes the diagnosis if clinical features are inconclusive.
- To establish the extent of disease and needs in an individual diagnosed with multiple endocrine neoplasia type 2 (MEN 2), the following evaluations are recommended if they have not already been completed: Patients should be monitored on a lifelong basis for evidence of recurrent disease. After an initial follow-up visit, patients may be evaluated at 6 months, then yearly if they are asymptomatic. Evaluations should include the following: Physical examination 24-hour urine catecholamine, metanephrine and vanillylmandelic acid levels CEA level Calcitonin level Serum calcium level. If recurrent hypercalcemia is suggested, consider patients for repeat cervical exploration. If pheochromocytoma is suggested, evaluate patients for surgical resection. This tumor is likely in the remaining contralateral adrenal, although workup should include a CT scan and an MIBG scan to evaluate for recurrence at the resected area or at an extra-adrenal site. Recurrences in the resected area are more common if a subtotal adrenalectomy had been performed initially. The management of patients with calcitonin/CEA elevations has been controversial. Resect any palpable cervical disease. Some practitioners have advocated routine cervical ultrasonography with exploration for any evidence of recurrence. Many patients remain asymptomatic with elevated calcitonin levels for 20 years or longer.
- So here we are talking about patients who have been detected to have the gene mutations but noplasms have not yet developed So there are some prophylactic measures that can be taken to prevent the development of these neoplasms primarly Prior to any surgery, the presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening in any individual with MEN 2A or MEN 2B. In a prospective study of at-risk family members with the pathogenic variant, 8% had pheochromocytoma detected at the same time as MTC [Nguyen et al 2001]. If pheochromocytoma is detected, adrenalectomy should be performed before thyroidectomy to avoid intraoperative catecholamine crisis [Lee & Norton 2000].
- Parathyroid adenoma or hyperplasia. Annual biochemical screening is recommended for affected individuals who have not had parathyroidectomy and parathyroid autotransplantation. MEN 2A. Screening should start at age eight years for individuals with a pathogenic variant in codons 630 and 634, and by age 20 years for individuals with other RET pathogenic variants FMTC. Periodic screening should begin at age 20 years MEN 2B. Screening is unnecessary as individuals with MEN 2B are not at increased risk for hyperparathyroidism.