multiple endocrine neoplasia

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Slide 1 : Multiple Endocrine Neoplasia Moderator Prof. Anand Kumar Speaker Shashi Prakash
Slide 2 : Definition Neoplasms in two or more endocrine tissues in a single patient. Previously known as Multiple Endocrine Adenopathy or Pluriglandular Syndrome.
Slide 3 : Disease Associations in the Multiple Endocrine Neoplasia (MEN) Syndromes
Slide 4 : Introduction In MEN genetic changes in – tumour suppressor gene (MEN-I) or proto-oncogenes (MEN-II). Neoplastic changes in target endocrine tissues Pathological changes in non endocrine tissues. Tumours - benign or malignant; synchronous or metachronous. Diffuse preneoplastic hyperplasia typically precedes development of carcinoma.
Slide 5 : Multiple Endocrine Neoplasia Type I Most common. Prevalence - 2–20 per 100,000 population. No age or sexual preponderance. No geographic, ethnic or racial variation. Incidence – -0.25% from random post-mortem studies. -1-18% with primary hyperparathyroidism -16-38% with gastrinomas -<3% with pituitary tumours Presentation in 80% by fifth decade
Slide 6 : Neoplasms in at least two target endocrine tissues. Familial MEN I- at least one tumour in a 1st degree relative, in addition. Multiple parathyroid tumours – in 98% to 100% affected. Duodenopancreatic NETs (potentially malignant ) - 30% to 80%. Pituitary tumours in 15% to 50%. At autopsy - pathologic involvement in all three endocrine tissues in essentially all.
Slide 7 : Genetics and Pathogenesis  Autosomal dominant. MEN1 gene chromosome 11q13. Chandrasekharappa et al. (1997 ) - genetic mutation for MEN1 by position cloning. Development of nonhereditary endocrine tumours due to Loss of MEN1 gene. Unregulated cell growth or neoplastic transformation. Brake on cellular growth and proliferation Putative tumour suppressor gene product Complete elimination of its function
Slide 8 : MEN1 gene Menin, expressed ubiquitously (endocrine and nonendocrine). Menin - early development - regulation of cell growth -transcriptional regulation - DNA processing, repair and cytoskeletal integrity. - physically interacts with diverse variety of other proteins. Role in tumorigenesis not clear.
Slide 9 : Evident pathologies Principal feature - hypercalcemia due to multiglandular parathyroid tumours. NETs of pancreas and duodenum. Adenomas of anterior pituitary. Bronchial and thymic carcinoids, thyroid nodules, adrenocortical nodular hyperplasia. Lipomas, ependymomas, and cutaneous angiofibromas.
Slide 10 : Familial MEN 1 syndrome – - concurrent neoplasms in multiple endocrine tissues. - atleast one organ in 1st degree relative - earlier age onset - multifocal within a target endocrine tissue Clinical manifestations depend on - endocrine tissue involved , excess hormones - local mass effect - malignant progression of neoplasm
Slide 11 : Parathyroid gland in MEN-I ~ 100% penetrance, earliest manifestation Most common (>98%) ; multiglandular. Tumours are clonal. Enlargement asymmetric. Hypercalcemia first biochemical abnormality. Renal lithiasis and skeletal complications - uncommon.
Slide 12 : BIOCHEMICAL EVIDENCE serum calcium; PTH. 24-hour urine calcium excretion. Onset of hypercalcemia-as early as 11 to 14 years in genetically positive. RADIOLOGICAL EVALUATION Preoperative imaging not necessary. Nuclear (sestamibi) scanning and ultrasound - useful for localization before reoperation.
Slide 13 : Surgical Mx of hyperparathyroidism Indications for surgery: Symptomatic or marked hypercalcemia Nephrolithiasis Diminished bone density / osteopenia Severe gastric ulcers 20 to gastrinoma (hypercalcemia increase release of gastrin & worsens hypergastrinemia and parathyroidectomy reduces gastrin secretion** -- however PPI’s work well. Aim: minimise incidence of recurrent hypercalcemia and complication of permanent hypoparathyroidism.
Slide 14 : Therapy for Primary Hyperparathyroidism Subtotal parathyroidectomy (removal of 3.5) or Total parathyroidectomy with Transcervical near-total prophylactic thymectomy Parathyroid remnants in situ OR autograft implanted into forearm Endoscopic parathyroidectomy not appropriate b/c difficulty in identifying all four glands
Slide 15 : Results Temporary hypocalcemia common. 4% risk permanent hypoPTH. 30% risk persistent/recurrent hyperPTH. Autotransplantations successful in >90%. High rate of recurrence after successful surgical therapy unlike sporadic 67% @ 8yrs. Autotransplantation to forearm - recurrent hyperparathyroidism managed by excision under LA. Delayed transplantation of cryopreserved parathyroid for permanent postoperative hypocalcemia
Slide 16 : Entero-pancreatic tumors in MEN-1 Gastrinomas Insulinomas Glucagonomas VIPomas Somatostatinomas Pancreatic Polypeptide-Producing tumors
Slide 17 : General principals Establish diagnosis biochemically. Evaluate for familial syndrome – MEN, VHL. Treat symptoms of hormone excess. Tumor localisation – CT, EUS, Angiogram. Prepare for resection – pneumococcal vaccine, somatostatin analog.
Slide 18 : Entero-pancreatic tumors 2’nd most frequent. Clinically evident in 30%-80% Nonfunctioning or PP secreting Pancreatic NETs most frequent in MEN 1. Pathologic change - multifocal, diffuse islet cell hyperplasia and microadenoma in areas of pancreas distant gross tumor. Micro/macroadenomas ? invasive ? metastatic carcinoma Malignant potential of entero-pancreatic lesions in MEN-1, life threatening now.
Slide 19 : Gastrinoma Commonest functional NET in MEN I In 4th decade, small & multiple lesions. Mostly in duodenum; 50% metastasized at Dx Significant malignant potential if associated with intrathoracic carcinoids Poor prognosis -- pancreatic, mets, higher gastrin level C/F - recurrent severe peptic ulcers - perforation & cachexia major contributors to mortality. Hypergastrinemia, or Zollinger-Ellison syndrome (ZES)- epigastric pain, reflux esophagitis, secretary diarrhoea, weight loss.
Slide 20 : Gastrinoma (cont) Biochemical diagnosis: - gastric acid hypersecretion (>15 mEq/L without, or >5 mEq/L with prior ulcer surgery), - elevated fasting levels of serum gastrin (>100 pg/mL). - abnormal secretin test confirms. Imaging: -CT or angiography may not localize preoperatively. -Endoscopic U/S localizes gastrinomas within wall of duodenum or head of pancreas. -Octreotide scan, portal venous sampling MEDICAL Rx: PPI’s – Omeprazole (DOC)
Slide 21 : Gastrinoma (cont) SURGICAL TREATMENT: Solitary sporadic gastrinoma - complete resection MEN1 gastrinomas freq. mult. / mets. – controversial role. Intraop US “Gastrinoma triangle” – pancreas/ duodenum /CBD Duodenotomy Tumors head pancreas-enucleated Tumors body/tail pancreas– distal pancreatectomy +- splenectomy Liver mets - wedge resection
Slide 22 : Gastrinoma (cont) METASTATIC GASTRINOMA: 25-90% of ZE patients ChemoRx – streptozocin & 5 FU Hepatic arterial chemoembolization Octreotide Interferon ? Aggressive debulking surgery
Slide 23 : Insulinoma Hypoglycemia after fast/exertion improve with glucose intake & inappropriately elevated insulin (Whipples Triad) 90% solitary and benign Head, body and tail pancreas Malignancy - size > 6cm or liver/nodal mets. Enucleation/Distal pancreatectomy (minimum) MEDICAL TREATMENT: Control Sx prior to surgery Frequent small CHO meals until operated on Diazoxide or Octreotide
Slide 24 : Insulinoma (cont) SURGERY FOR MALIGNANT INSULINOMA : Curative Whipple’s or subtotal pancreatectomy-splenectomy, excision of liver metastases Palliation for metastatic disease - Radioablation Chemotherapy Chemo-embolization Alcohol injection, cryotherapy, radiofrequency ablation
Slide 25 : Glucagonoma Necrolytic migratory erythema Type II DM, muscle wasting, cachexia, DVT/PE Tail of Pancreas most common site Surgical removal treatment of choice 50-80% with mets at time diagnosis Optimize medical conditions - TPN, octreotide Chemotherapy - 5FU, streptozotocin, dacarbazine
Slide 26 : VIPoma Watery diarrhoea, hypokalaemia, achlorhydria- WDHA correct dehydration Surgical management - distal pancreatectomy curative Somatostatinoma Duodenum/pancreas Steatorrhoea, cholelithiasis, type II DM, hypochlorhydria Resect primary, debulk hepatic mets, cholecystectomy
Slide 27 : Pancreatic Polypeptide-Producing tumors Non-functioning , most common Malignant and large at time of Dx Extrahepatic bile duct obstruction, GI bleeding, GI obstruction Surgical resection ChemoRx for residual disease
Slide 28 : Anterior Pituitary tumors 15-60% in MEN-1 1’st manifestation in 25%; 2/3 microadenomas (<1cm) Prolactinomas 60%, somatotrophinomas 20%, corticotrophinomas and null cell tumors 15% Amenorrhea, galactorrhea, infertility; impotence in men; acromegaly or cushing’s disease CT/MRI Medical T/t - Dopamine agonist Trans-sphenoidal resection
Slide 29 : Multiple Endocrine Neoplasia Type II Uncommon; Autosomal dominant MEN 2A, MEN 2B, and FMTC. Germline mutations in RET protooncogene; chromosome 10 MTC is hallmark-multifocal, bilateral, young age. Complete penetrance of MTC. Other tumors - incomplete penetrance. Abraham Lincoln suffered from MEN IIB.
Slide 30 : Clinical Features of Sporadic MTC, MEN 2A, MEN 2B, and FMTC SABISTON
Slide 31 : MEN IIA- MTC multifocal, bilateral, with C-cell hyperplasia. Pheochromocytomas in 42%; multifocal, bilateral with adrenal medullary hyperplasia. Hyperparathyroidism in 10% to 35%; asymmetrical hyperplasia. Cutaneous lichen amyloidosis- macular amyloidosis (brownish plaques of multiple tiny papules), interscapular area. Microscopically, hyperplastic epidermis, acanthosis, lymphocytic infiltrate, amyloid goblets. Hirschsprung's disease infrequent (obstruction and megacolon)
Slide 32 : MEN II- B MTC and mucosal neuromas in all. 40% to 50% pheochromocytomas. MTC at very young age (in infancy), most aggressive form of hereditary MTC. Once presents clinically, rarely curable. Distinct physical appearance- prominent mid-upper lip, everted eyebrows, multiple tongue nodules, marfanoid body habitus, long limbs. Mucosal neuromas- un-encapsulated, thickened proliferations of nerves lips, tongue; gingiva, buccal mucosa, nasal mucosa, vocal cords, conjunctiva.
Slide 33 : Intestinal Ganglioneuromas- submucosal and myenteric plexus. Megacolon and chronic bowel problems in all. Intestinal dysfunction-poor feeding, failure to thrive, constipation, or pseudo-obstruction early in life. Adults-dysphagia (oesophageal dysmotility). Toxic megacolon rarely, no Hirschsprung's ds. FMTC- MTC without other endocrinopathies. MTC-later age of onset, more indolent course. MTC- Dx occasionally by biochemistry and histological evaluation of thyroid.
Slide 34 : Medullary Carcinoma Thyroid 25% - hereditary in MEN II. Origin- parafollicular cells, or C cells, of thyroid. In MEN II, C-cell hyperplasia, a precursor lesion. Histologically, MTC- calcitonin staining, presence of amyloid. Basal and stimulated serum calcitonin levels correlate tumour burden. Always elevated with palpable thyroid.
Slide 35 : Secretory diarrhoea, flushing- paraneoplastic manifestations ( calcitonin) Early Dx in hereditary MTC, critical (early mets) Genetic testing in childhood; MEN 2A or FMTC; thyroidectomy; Lymph node mets rare. Sporadic MTC and hereditary o/w - neck mass, LN mets. Diagnosis- biopsy (FNAC), calcitonin. Spreads within central compartment (B/L) to perithyroidal and paratracheal LN (VI).
Slide 36 : Upper mediastinal (VII), jugular (II, III,IV), posterior triangle (V), and supraclavicular nodes. Lower tracheobronchial lymph nodes outcome as distant metastases. Involve trachea, RLN, JV,carotid-direct invasion or compression. Resulting stridor, upper airway obstruction, hoarseness, dysphagia, and bleeding or arterial stenosis or occlusion Localized pain and tenderness-MTC or cervical mets. Distant metastases- liver, lung, bone, soft tissues, including breast.
Slide 37 : Diagnosis Thyroid mass Bx- MTC mostly in MEN II. MEN 2A and FMTC Dx- screening, or thyroid nodule on examination. + F/H- Screening (calcitonin or RET mutation) MEN 2B >50% patients have normal parents, neck mass, screening of less importance. Rarely, diagnosed earlier by characteristic phenotype Cervical adenopathy in >50% with palpable MTC.
Slide 38 : Respiratory complaints, hoarseness, and dysphagia in 13% 12%- palpable MTC with e/o distant metastasis. Test RET mutations- all MTC patients. Genetic counselling- risks and benefits of genetic testing should precede. F/H- hypertension, hyperparathyroidism, Hirschsprung's disease, or thyroid and adrenal tumours. Systemetic review- f/o pheochromocytoma or hyperparathyroidism.
Slide 39 : RET mutation found on screening, first-degree relatives counselled and tested. Mutation in RET proto-oncogene-biochemical testing for pheochromocytoma before thyroidectomy Catechol surge on induction-malignant hypertension. Calcitonin, invaluable serum marker in screening and follow-up. CEA also elevated in >50% patients with MTC. Calcitonin levels- basal or after secretagogues-calcium or pentagastrin.
Slide 40 : Treatment Surgical treatment influenced by- More aggressive than differentiated, recurrence and mortality. Radioactive iodine; radiation, chemotherapy ineffective. Multicentric in 90% with hereditary forms. Adequacy of surgical extirpation - postoperative stimulated calcitonin levels. If e/o pheochromocytoma; adrenal surgery with perioperative a-blockade precedes.
Slide 41 : Preventive Surgery Preventive Sx, in hereditary MTC before malignant transformation or spread beyond thyroid Total thyroidectomy earliest possible — before 6 months(pref. first months) of life in MEN IIB. Before 5 to 6 years of age in MEN IIA. Mx central neck nodes and parathyroids according calcitonin levels and type of mutation. FMTC- thyroidectomy before 5 to 10 years of age or depending on calcitonin levels.
Slide 42 : MEN 2A or FMTC; age<8 years, normal calcitonin level; extremely low likelihood of nodal metastases Routinely remove and autotransplant parathyroids with central node dissection. Autotransplant into- muscle of nondominant forearm (MEN 2A) or Sternocleidomastoid (FMTC or MEN 2B). Calcium and vitamin D for 4-8 weeks postoperatively.
Slide 43 : Surgery for Palpable Disease Extensive nodal metastasis; >75% cervical. Persistent disease, in >50% postop.( calcitonin). Surgery only Rx, no effective adjuvant therapy. Define or predict extent of spread at Dx, plan appropriate resection. Total thyroidectomy, parathyroidectomy with autotransplantation, central neck dissection (B/L levels VI and VII), and ipsilateral level II to V node dissection. B/L level II to V node dissections, assess intraop.
Slide 44 : Persistent or Recurrent Disease Radiation or chemotherapy therapy no role Reoperation: curative or palliative. Distant metastase- C/I to surgery unless palliative Palliation to- - Prevent invasion or compression of airway, - Debulk large tumours causing profuse, intractable diarrhoea secondary to hormone secretion. Re-exploration with completion of node dissection if no e/o distant mets, no previous cervical node dissections.
Slide 45 : Metastatic workup- neck, chest, and abdominal CT or MRI Dx laparoscopy distant metastases before reoperating neck. If distant metastases- - Observe clinically negative neck. - Neck reoperation if gross cervical recurrence. No e/o metastasis on laparoscopy and imaging, re-exploration to remove residual nodal tissue. May continue observation as well.
Slide 46 : Chemotherapy in MTC Vandetanib – 300mg monotherapy in advanced MTC MOA - anti-RET TK - anti-VEGFR - anti-EGFR Sorafenib - rapid response in advanced MTC (RET TK and VEGFR inhibitor) still under clinical trials
Slide 47 : Pheocromocytoma Rarely precede C-cell abnormalities in MEN 2 syndrome. Incidence with age. Triad- Diaphoresis, Tachycardia, Headaches(>50%) HTN, Tremulousness, Weight loss, Palpitations, Orthostatic hypotension Rarely malignant and extra-adrenal; MIBG no use Dx- Biochemical screening-plasma or 24 hr urine catecholamines and metanephrines. Opposed-phase chemical-shift MRI-pheochromocytoma from adrenal adenoma.
Slide 48 : Treatment Partial or complete adrenalectomy after medical stabilisation. Preoperative a-blockade by phenoxybenzamine (40-200 mg/day), 5 days to 2 weeks preop. Tachycardia or cardiac arrhythmia, add ß-blocker. Short-acting, sodium nitroprusside or phentolamine- intraoperative paroxysmal hypertension. Laparoscopic adrenalectomy ideally suited.
Slide 49 : Parathyroid Disease Parathyroid hyperplasia, without of hyperparathyroidism, common in MEN 2A. Rarely initial presentation. Not in sporadic MTC or MEN 2B syndrome. Diagnosis-MEN 2A carriers screened annually by serum calcium measurements, PTH if serum calcium high or borderline. Treatment- Isolated rare; routine total parathyroidectomy with auto transplantation with thyroidectomy.
Slide 50 : Thank you

 


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