Pituitary, Parathyroid Pheochromocytomas & Paragangliomas: The 4 Ps of NETs Shereen Ezzat, MD, FRCP(C), FACP Professor Of Medicine & Oncology Head, Endocrine Oncology Princess Margaret Hospital/University Health Network Toronto, Canada
Spectrum of Classic Genetic NET Disorders 4 p27 B
Pituitary tumors
Outline 1) Brief refresher on pituitary physiology, anatomy, radiology 2) Important causes of pituitary disease 3) Approach to pituitary dysfunction in MEN1 4) Therapeutic approaches to pituitary tumor types
What Causes the Pituitary to Malfunction? Tumors» most common are adenomas Inflammation» following pregnancy Infections Injury Cancerous spread
What are Pituitary Tumors? Benign growths or adenomas Cancer is very rare Variable pattern of growth» May be small, hormonally inactive, incidental findings» May be small but cause hormone excess» May be rapidly growing mass lesions
Pituitary Adenomas: Epidemiology A Perplexing Problem! Autopsy incidence: 22.5-27% MRI: 20% of normals Clinical diagnosis:?????» Surgical : 10% of intracranial tumors» Medical:???» Overall:???
Specific pituitary hormone conditions
Prolactin (PRL) Vital to the production of breast milk following delivery Controls the secretion of pituitary hormones responsible for gonadal function Circulates in low levels in non-pregnant women, increasing greatly during pregnancy and stimulating milk production As with most pituitary hormones, prolactin is strictly regulated by hypothalamic hormones
Treatment Options for Hyperprolactinemia Options Observation Dopamine Agonists Transsphenoidal Surgery Radiotherapy Indications Asymptomatic hyperprolactinemia Menopause Symptomatic hyperprolactinemia Increase in tumour volume with medical treatment Refusal of medical treatment Dopamine agonist resistance or intolerance Invasive tumours refractory to medical and surgical therapy
Therapeutic Options Dopamine Agonists first therapeutic option proven efficacy in reducing PRL levels, PRL levels may remain above normal in ~20% of macroprolactinomas and ~10% of microprolactinomas despite dopamine agonist therapy? Long-term use association with valvular heart disease (N Engl J Med; 2007:356-29-38).
Complications of Acromegaly Pulmonary 1 : Abnormal pulmonary function Obstructive sleep apnea Cardiovascular 1,2 : Hypertension Cardiomyopathy Metabolic 3-6 : Insulin resistance Hyperlipidemia Malignancies 6 : Colonic polyps/cancer Neuromuscular 3 : Carpal tunnel Muscle weakness 1. Molitch ME. Endocrinol Metab Clin North Am. 1992;21:597-614. 2. Colao A et al. J Clin Endocrinol Metab. 2002;87:3097-3104.
Effects of Acromegaly on Mortality 1.0 0.9 ( ) Acromegalic patients ( ) Matched controls 0.8 0.7 0.6 0.5 0.4 0 5 10 15 20 25 Length of survival (years) Adapted with permission from Rajasoorya C et al. Clin Endocrinol (Oxf). 1994;41:95-102.
a, visual field compromise is absolute indication for surgery b, consider primary medical therapy if no VF deficit and no chance of surgical cure given cavernous sinus involvement c, re-consider surgery to debulk tumor to improve medical tx response, to reduce medical comorbidities, or due to patient preference d, consider a DA in the setting of modest disease e, consider GH antagonist in setting of persistent disease f, consider RT in patients with residual tumor following TSS
Cushing s Disease
Cushing s or Pseudo? A B Unequivocal identification of an adenoma» evaluation of margins? Crooke s hyaline change in nontumorous gland» correlates with post-resection hypocortisolemia
The Spectrum of Cushing: Subclinical to Overt (Lung, thymus, pancreatic NET)
The problem: establishing the diagnosis Raff H 2003
Parathyroid disease in MEN-1
Spectrum of Genetic Hyperparathyroid Disorders 4 p27 B
Therapeutic Options for Hyperpara Marx SJ; Endo Pract 2011
Establishing the diagnosis of true Primary hyperparathyroidism All potential causes of secondary hyperparathyroidism must be excluded Includes: 25 vitamin D3 insufficiency due to reduced intake or gastrointestinal losses N Engl J Med. 2007;357:266-81
Establishing the diagnosis of Primary Hyperparathyroidism Primary hyperparathyroidism» Elevated intact PTH» Elevated ionized serum calcium» Elevated 24-hour urinary calcium Atypical hyperparathyroidism» Minority with PTH inappropriately normal for serum calcium» A subset have elevated PTH but normal calcium levels
Indications for Surgery National Institutes of Health (NIH) Workshop on Asymptomatic Primary Hyperparathyroidism» Indications for surgery include:» Hypercalcemia (1 mg/dl above the upper limit)» Hypercalciuria (> 400 mg/day)» Renal dysfunction (>30% reduction in Cr. Clearance)» Bone loss (T-score below -2.5 at any site)» Younger age (< 50 years) J Clin Endocrinol Metab. 2002;87:5353-61.
Summary Pituitary and parathyroid tumors complicate MEN Diagnosis requires index of suspicion Management requires a close multidisciplinary team Therapeutic options are perpetually changing with newer meds and surgical techniques
Pheochromocytoma and Paraganglioma
Where are pheo/para located
Clinical Manifestations Multiple manifestations due to single tumor effects Multiple manifestations due to multiple tumor effects
Single Tumor Effects Sympathetic effects:» Headaches, hypertension, palpitations Parasympathetic effects:» Excessive sweating, fatigue
Multiple Tumor Effects Multiple body sites:» Neck» Chest» Abdomen» Brain/spine (metastases, cerebellar/retinal hemangioblastomas) Non-cancerous conditions» Equally as serious» Blood clots» Retinal disease (VHL)
Clinical/Genetic Spectrum of SDH mutations
Regulation of HIF-α: The Molecular Target of SDH/VHL Welander J et al. Endocr Relat Cancer 2011;18:R253-R276 2011 Society for Endocrinology
The Succinate Dehydrogenase (SDH) family of genes
Approach to the Pheo/Para Patient
Management Plans Complete clinical, biochemical, radiographic, and genetic testing Comprehensive multidisciplinary management plan Genetic/family councilling and testing Genetically-based surveillance plans
Surveillance plans: VHL Retinal angioma: Annual ophthalmic examinations (direct and indirect ophthalmoscopy), beginning in infancy or early childhood. CNS hemangioblastoma: MRI of head q12 36 mths, beginning in adolescence. Renal cell carcinoma and pancreatic tumours: MRI (or ultrasound) of abdomen q12 mths, from age 16 years. Pheochromocytoma: Annual BP monitoring and 24-h urine for catecholamines/metabolites and adrenal imaging from age of 8 years in high-risk families