parathyroid adenoma

approach for suspected parathyroid adenoma and its management

1. APPROACH FOR SUSPECTED PARATHYROID ADENOMA Presenters : Dr Rajendra Moderator :- Prof. Sunil Chumber

2. Historical note Sir Richard Owen 1852: parathyroid gland in a Indian rhinoceros. Vassale and Generali 1896: Introduced the term "parathyroid“ M. Askanazy 1903: Relationship between parathyroid tumors and osteitis fibrosa cystica Erdheim 1906: Relationship between parathyroid glands and calcium metabolism Mandl 1925: Removed a cervical parathyroid adenoma

3. Introduction Embryological development and anatomy of the parathyroid glands: prerequisites for successful surgical strategy.

4. Embryology of Parathyroid Parathyroid glands first appear in amphibia . Branchial arches and Pharyngeal pouches form in the 4 th week Superior Parathyroids - the 4 th Pharyngeal pouch with thyroid Inferior Parathyroids – 3 rd Pharyngeal pouch with thymus 5 Parathyroid Embryology and Anatomy

5. Anatomy of Parathyroid The considerable variability in size, shape, number, location and color of these glands creates unique surgical challenges. Autopsy studies Surgical anatomy Parathyroid Embryology and Anatomy 6

6. Autopsy studies Results 84%- 4 glands 13%->4 glands: supernumerary Majority within the thymus or fat near the normal parathyroid gland More commonly found in MEN1 and Sec. hyperparathyroidism Rudimentary 2% Divided 6% True supernumerary: >5 mg, at some distance 5% 3%-<4 glands Parathyroid Embryology and Anatomy 7 Akerstrom G etal . Surgery 1984;95:14.

7. Parathyroid characteristics Most humans : 4 glands 3 glands: one is missing rather absent Size : avg 5x3x1 mm Weight: 38-59 mg Increases till 5 th decade Lower glands more than upper Increased in mal-absorption and vit D def Parathyroid Embryology and Anatomy 8

8. Parathyroid characteristics Color : depends upon the age, fat content decreases Newborn: grey , semitransparent Children: light pink Adults: yellow Elders: darker Relation with the thyroid Intracapsular : enlarged glands remains in place Extracapsular : tends to migrate in least resistance Intrathyroidal : always maintan a plane of cleavage Parathyroid Embryology and Anatomy 9

9. Vascular anatomy Terminal arteries Arterial supply is solitary 66% Sup parathyroid: -80% ITA -15% STA: post branch -5% Anastomotic branches Inf parthyroid : -90% ITA - 10% STA (ITA agenesis) or anastomotic branches Mediastenal gland: Int mammary 10 Parathyroid Embryology and Anatomy Filament JB, et al. Anat Clin1982;3:279.

10. Relation with recurrent laryngeal nerve 93% of parathyroid glands: predictable relation to RLNs Superior glands lying posterior and superior to the nerve Inferior glands lying anterior to the nerve Parathyroid Embryology and Anatomy 11 Pyrtek LJ, Painter RL. Surg Gynecol Obstet 1964;119:509.

11. Disease spectrum of parathyroid Hyperparathyroidism Primary( adenoma, hyperplasia, carcinoma) Secondary Tertiary Hypopararthyroidism World J Gastroenterol . 2015 May 28

12. Hyperparathyroidism Primary Parathyroid adenoma( 80-85%, most common ) Parathyroid hyperplasia Parathyroid carcinoma Secondary Parathyroid hyperplasia Tertiary Autonomous nodule on top of hyperplasia Overall prevalence of PHPT : 1 in 1000 Higher incidence in patients > 60 years Female : Male - 2 to 3 : 1 Up to 80% - asymptomatic*

13. A novel nomenclature to classify parathyroid adenomas Adherent to the posterior thyroid capsule-normal superior gland location Tracheo -esophageal groove Tracheo -esophageal groove inferior to the inferior thyroid pole Directly over the recurrent laryngeal nerve Close to the inferior thyroid pole-normal inferior gland location Within the thyro-thymic ligament, Intrathyroidal World J Surg (2009) 33:412-416 DOI 10.1007/s 00268-008-9894-0

14. CLINICAL FEATURES The pentad of symptoms — painful bones kidney stones abdominal groans psychic moans fatigue overtones. CLASSICAL FEATURES : osteitis fibrosa cystica , nephrolithiasis , nephrocalcinosis , peptic ulcer disease , gout , pseudogout .

15. CLINICAL FEATURES

16. Syndrome associated with MEN type I (MEN 1 gene) • Parathyroid adenoma, •(earliest & m.c manifestation is PHPT & develops in 80-100% by 40 yrs ) •Pituitary adenoma •Pancreatic islet cell tumor MEN type II •Parathyroid adenoma, •Thyroid medullary carcinoma & • Pheochromocytoma

17. On examination General examination : Ocular : band keratopathy Fibro-osseous tumours- in favour of parathyroid carcinoma. Neck examination-usually normal . Parathyroids are seldom palpable except in patients with profound hypercalcemia (≥14 mg/ dL ).  By Thomas J. Stokkermans , OD, PhD, Pankaj C. Gupta, MD, MSc, and Rony R. Sayegh , MD

18. Investigations S. Calcium- total and ionised S. PTH 24hr urinary calcium S. Phosphate S. ALP 25-OH vitamin D3 Magnesium X-ray : Hand and forearm skull Localization techniques Perioperative Intra-operative

19. X-ray Trabecular bone resorption SALT PEPPER APPEARANCE Subperiosteal bone resorption Phalangeal tufts . Brown tumor ( osteitis fibrosa cystica )

20. L ocalization techniques

21. Ultrasonography First modality after biochemical confirmation With the availability of high resolution USG, detection is easier of small adenomas Enlarged parathyroid glands appear as hypoechoic structures, in sharp contrast to the hyperechoic thyroid tissue. Doppler is performed to test the vascularization of the area and define the arterial branches involved. Concomitant thyroid pathology A  meta-analysis  of  preoperative   localization   techniques  for  patients  with  primary hyperparathyroidism . Cheung K, Wang TS, Farrokhyar F, Roman SA, Sosa JA. Ann Surg Oncol . 2012 Feb;19(2): 577-83

22. Ultrasonography Sensitivity - 72%to 89% , PPV – 93% Facilitates focussed parathyroidectomy Limitations : Small size (<5mm) Ectopic location (especially behind trachea or clavicle) Reoperative localisation

23. Parathyroid Scintigraphy Sestamibi ( methoxy-isobutylisonitrile ),a lipophilic compound, is radiolabeled with 99mTc-pertechnetate . Retained by the mitochondria -rich oxyphil cells in parathyroid longer than in thyroid tissue. Normal functioning parathyroid glands are not visualized . Two protocols : the single isotope-dual phase protocol and the subtraction protocol. Dual phase B. Subtraction Protocol :

24. SPECT Sestamibi -single photon emission computed tomography is a 3D sestamibi scan that provides higher-resolution imaging. Illustrate depth of the parathyroid gland or glands in relation to the thyroid and improve detection of ectopic glands Improves the sensitivity for identifying abnormal parathyroid glands to 92 to 98 %. SPECT-CT helps to discriminate parathyroid adenomas from other anatomic landmarks Specially in retrotracheal parathyroids

25. 4D-CT 4D-CT gives multiplanar images and allows the visualization of differences in the perfusion characteristics of hyperfunctioning parathyroid glands compared with normal glands and other structures Rapid contrast uptake and washout is characteristic of parathyroid adenomas Superior to SPECT-CT Combines both anatomical and functional Sensitivity=88% Disadvantage of 4D-CT - radiation exposure

26. PET Methionine PET scanning has high sensitivity (about 85–90%) Disadvantage - half-life of 11C is very short (20 min) and requires an on-site cyclotron. Useful option in patients with recurrent or persistent PHPT Met-PET / CT scan located a parathyroid adenoma behind the left thyroid lobe

27. 18F- Fluorocholine PET Principle: Choline is part of the phospholipid layer in the cell membrane It is hypothesized that hyperfunctioning parathyroid cells have an increased activity of the phospholipid /Ca2+-dependent protein kinase ( move from cytosol to membrane) Choline gets converted into phosphatidylcholine by the enzyme choline kinase and subsequent incorporation into the cell membrane

28. MRI On MRI parathyroid adenoma has intermediate to low signal intensity on T1 imaging and high intensity on T2 imaging. They may enhance with gadolinium. Usually only as an investigation prior to a re-exploration after failed surgery. Drawbacks-size of detection is limited to adenomas >5 mm, localization of the superior glands is difficult as they lie posterior to the thyroid

29. Invasive Localisation Selective Venous Sampling : For PTH measurement( 1.5 to 2 times) It is a very sensitive test which depends on gland function rather than size. Sampling is done from larger veins such as the jugular vein, innominate vein, superior cava and smaller veins, such as superior, middle, and inferior thyroid veins Sensitivity and specificity of the SVS - 63 to 94.7% and 86 to 100%, respectively

30. Management of hypercalcemia Goals of therapy are aimed at lowering calcium levels. correcting dehydration and thereby increasing renal calcium excretion and decreasing osteoclast mediated bone resorption . Management of the underlying cause of hypercalcemia directs treatment strategy . In the majority of patients, definitive curative therapy requires surgical parathyroidectomy . To avoid factors which exacerbate hypercalcemia .

31. Management of hypercalcemia Hydration Loop diuretics ( avoid thiazides) calcitonin Biphosphonate and other medications Glucocorticoids Dialysis Surgery

32. Management of hypercalcemia Hydration :- NS 2 to 4 L IV daily for 1 to 3 days. Mode of action :- Enhances filtration and excretion of Ca2+ Indication : - Severe ↑Ca++ > 14 mg per dL , Cautions :- May exacerbate heart failure in elderly pt , CKD ,lowers Ca++ by 1 to 3 mg per dL Furosemide (Lasix) 10 to 20 mg IV as necessary upto 100mg/ hr mode of action :- Inhibits calcium resorption in the distal renal tubule indication :- Following aggressive rehydration Caution:-↓K+, dehydration if used before intravascular volume is restored Bisphosphonates Pamidronate , 60 to 90 mg over 4 hours Zolendronic acid 4 mg IV over 15 minutes mode of action :- Inhibits osteoclast action and bone resorption indication :- Hypercalcemia of malignancy cautions:- Nephrotoxicity, ↓Ca++, ↓PO4, rebound ↑Ca++ in hyperparathyroidism Maximal effects at 72 4 mg IV over 15 minutes

33. Management of hypercalcemia Calcitonin Dose 4 to 8 IU per kg IM or SQ every 6 hours for 24 hours Mode of action :- Inhibits bone resorption , augments Ca++ excretion Indication :- Initial treatment (after rehydration) in severe ↑Ca++ Caution:- Rebound ↑Ca++ after 24 hours, vomiting, cramps, flushing Rapid ↑Ca++ within 2 to 6 hours Glucocorticoids dose :- Hydrocortisone, 200 mg IV daily for 3 days mode of action - Inhibits vitamin D conversion to calcitriol Indications :- Vitamin D intoxication, hematologic malignancies, granulomatous disease Caution Immune suppression, myopathy

34. Management of hypercalcemia Gallium nitrate : dose 100 to 200 mg per m2 IV over 24 hours for 5 days Mode of action :- Inhibits osteoclast action ↑Ca++ Indication :- rarely used in severe ca ++ Caution :- Renal and marrow toxicity Dialysis :- Indication :- Ca ++ >16 mg/dl , CHF , Renal failure. Hypercalcemic crisis or refractory hypercalcemia hemodialysis against a low-calcium dialysate is more effective than peritoneal dialysis in lowering serum calcium levels.

35. Surgical indication Symptomatic primary HPT : Polydipsia and polyuria Nephrolithiasis Hypercalciuria (24hr urine calcium >400mg/dl) Impaired renal function (GFR <60cc/min) Osteoporosis (BMD<-2.5),fragility fracture or vertebral compression Pancreatitis , PUD or GERD Neurocognitive dysfunction 2 . Asymptomatic PHPT : Increased parathormone levels without symptoms Age < 50 yrs Serum calcium >1mg/dl above normal/ T score < 2.5. Silent nephrolithiasis / Cr Cl < 60/ Ur Ca > 400 mg/d Unable or Unwilling to comply with surveillance Patient with cardiovascular disease

36. Surgical technique: Open standard approach Minimally invasive parathyroidectomy Open minimally invasive Minimally invasive radioguided Video assisted Purely endoscopic

37. Standard Bilateral exploration-Conventional approach If parathyroid localization studies or IOPTH arent avaialable If localization studies fail to identify any abnormal glands If localization studies identify multiple abnormal glands If concomitant thyroid disorder requires B/L exploration

38. Minimally invasive video assisted parathyroidectomy( MIVAP) First described by Miccoli Indications: <3cm size Previous surgery is relative contraindication BNE can also be performed With 1.5 cm incision in midline Miccoli reported a cure rate of 98.3%

39. Endoscopic parathyroidectomy First described by Gagner With 1.5 cm incision in side of target gland, anterior to the SCM Two 2.5mm incision along it to help CO2 and dissection Specially for posteriorly located parathyroids Help of IOPTH

40. Endoscopic parathyroidectomy

41. VATS For mediastinal parathyroid first described over 20 years ago Procedure of choice with early recovery and less postop pain Avoiding sternotomy Helps early recover

42. IOPTH Short half life= 3-5 min Miami criteria > 50% fall below prexcision value demonstrates successful parathyroidectomy

43. Intraop adjuncts Methylene blue Autofluorescence imaging of parathyroid Near-infrared/ indocyanine green (NIR/ICG) Intraop radioguided surgery Intraop USG

44. Post op complications Hematoma Postoperative hypocalcemia ( transient / hungry bone syndrome ) Permanent hypoparathyroidism Recurrent laryngeal nerve injury(1%) Persistent hyperparathyroidism—5% (PTH never touches baseline -6 mo ) Recurrent hyperparathyroidism—initially PTH decreases but hypercalcaemia recurs 6 months after first parathyroid surgery

45. Parathyroid Embryology and Anatomy 48 Surgical studies Shen W etal . Arch Surg. 1996 ;131(8):861-7. Reoperation for persistent or recurrent primary hyperparathyroidism To analyze the causes and outcomes of reoperation for persistent or recurrent primary hyperparathyroidism. Medical records of 102 patients Reasons for failed parathyroid operations tumor in ectopic position (53%) incomplete resection of multiple abnormal glands (37%) adenoma in normal position missed during previous surgery (7%) regrowth of previously resected tumor (3%). .

46. Post parathyroidectomy follow up Measure calcium and PTH immediate postoperatively Then at three month,6 month and then yearly Correct vitamin D deficiency if present No restriction on daily calcium

47. A total of 196 patients met inclusion criteria with an overall median follow-up time of 9.2 years IQR (interquartile range) [5.4-10.9 years].

48. SUMMARY High index of suspicion is required to diagnose hyper parathyroidism Always send calcium level if patient present with recurrent renal stones Low threshold for parathyroidectomy Reversal of most of the symptoms Surgery remains the treatment of choice in hypercalcemic crisis. Medical therapies can be useful in many situations, but should not be viewed as equivalent to surgery or as a potential replacement for surgery.

49. “The only localization needed for parathyroid is good endocrine surgeon” Thank you Dr John Leo Doppman , M D Interventional Radiologist

50. X-ray Brown tumor ( osteitis fibrosa cystica )  Replacement of bone by vascularized fibrous tissue secondary to PTH stimulated osteoclastic activity  Expansile lytic lesion with well defined non sclerotic margin.  Location: They are usually eccentric

51. Parathyroid Scintigraphy Continue .. Two protocols : the single isotope-dual phase protocol and the subtraction protocol. Dual phase B. Subtraction Protocol : Based on the differential sestamibi retention between parathyroid and thyroid tissue. After injection of 99mTc-sestamibi , tracer retention is prolonged in parathyroid hyperfunctioning lesions whereas it washes out more rapidly from normal thyroid tissue. 20 mCi iv is given and images are taken. Early (15 min post injection) and delayed images (at 1 and 2–3 h) depending on thyroid washout.

52. B. Subtraction Protocol : 99mTc-sestamibi is used in conjunction with another radionuclide specific to the thyroid like 99mTc-pertechnetate (t1/2- 6hrs) or 123I (t1/2- 13hrs tc99 123I Subtraction