48 Deranged liver function tests 25 Abnormal thyroid function tests 14 \200\22318 Interstitial pneumonitis 10 \200\22313 Cardiac arrhythmias 2 \200\2233 Box 8.1 Treatment of amiodarone-induced hypothyroidism Underlying thyroid abnormality (usually Hashimoto \200\231s thyroiditis) \200 Amiodarone therapy can be continued. \200 Add thyroxine replacement therapy. Apparently normal thyroid \200 Discontinue amiodarone if possible and follow up for resto ration of euthyrodism. \200 If amiodarone cannot be withdrawn, start thyroxine replacement therapy. 08-Draznin-Chap08.indd 64 3/31/2011 2:36:52 PM DIAGNOSIS AND TREATMENT 65 Table 8.4 Treatment of amiodarone-induced thyrotoxico-sis Type 1 AIT Type 2 AIT Methimazole up to 40 mg/day or propylthiouracil 400 mg/day. If possible, discontinue amioda rone* Discontinue amidarone if possible* Prednisone 40 mg/day In mixed forms, add methimazole or pro- pylthiouracil as in type 1 AIT Step 1 Aim: restore euthyroidism Step 2: De \201 nitive treatment Radioiodine treatment or thyroidectomy Follow up for possible spontaneous progression to hypothyroidism If amiodarone cannot be withdrawn and medical therapy is unsuccessful, consider total thyro idectomy. The \201 rst line of treatment is ATDs (methimazole or propylthiouracil). A combination o f corticosteroids and ATDs may be effective in AIT type II. A high dose of prednisone, 40 \200\22360 mg daily, may be required for 8 \200\22312 weeks; studies where steroids have be en discontinued after 2 \200\2233 weeks have been associated with a high relapse rate. Potassium perchlorate may be of additional bene \201 t, but it is currently not available in the United States Radioiodine is not usually effective because of reduced uptake by the thyroid gland, re \202 ecting the iodine load associated with the drug. Surgery remains a very successful form of treatment, with euthyroidism being restored withi n a matter of days. Achieving preoperative euthy- roidism may be dif \201 cult, however. Cardiac function may be compromised by propranolol used in com- bination with amiodarone, s ince this may produce bradycardia and sinus arrest. Further reading Bartalena L, Brogioni S, Grasso L, et al. (1996). Treatment of amiodarone-i nduced thyrotoxicosis, a dif \201 cult challenge: results of a prospective study. J Clin E ndocrinol Metab 81:2930 \200\2232933. Martino E, Bartalena L, Bogazzi F, et al. (2001). The effects of amiodarone on the thyroid. Endocr Rev 22(2):240 \200\223254. Newman CM, Price A, Davies DW, et al. (1998). Amiodarone and the thyroid. Heart 79:121 \200 \223127. Wiersinga WM (1997) Amiodarone and the thyroid. In Weetman AP, Grossman A (eds.), Pharmacot herapeutics of Thyroid Gland . Berlin: Springer-Verlag, pp. 225 \200\223287. 08-Draznin-Chap08.indd 65 3/31/2011 2:36:52 PM CHAPTER 9 Thyroid cancer 66 Thyroid cancer Epidemiology Clinically detectable thyroid cancer is rare. It accounts for <1% of all can- cer and <0.5% of cancer deaths. Thyroid microcarcinoma (diameter <1 cm) may be found in multinodular goi ters. Thyroid cancers are most common in adults aged 40 \200\22350 and are rare in children and a dolescents. Women are affected more frequently than men. See Table 9.1 for classi \201 cat ion of thyroid cancer and Table 9.2 for a comparison of the various types of carcinoma. Table 9.1 Classi \201 cation of thyroid cancer Cell of origin Tumor type Frequency (%) Papillary Differentiated Papillary Follicular Undifferentiated (anaplastic) >80 10 1 \200\2235 C cells Medullary 5 \200\22310 Lymphocytes Lymphoma 1 \200\2235 Table 9.2 Comparison of papillary, follicular and anaplastic carcinomas of the thyroid Characteristic Papillary Ca Follicular Ca Anaplastic Ca Age at presentation 30 \200\22350 (mean 44) 40 \200\22350 60 \200\22380 Spread Lymphatic Hematogenous Hematogenous Prognosis Good Good Poor Treatment Initially: near total thyroidectomy Postoperative TSH suppression High-risk patient: 131 I remnant ablation Postoperative total body radioiodine scan Initially: near total thyroidectomy Postoperative TSH suppression 131 I remnant ablation Po stoperative total body radioiodine scan Total thyroidectomy with lymph node clearance Chemotherapy with doxorubicin and cisplatin E xternal beam irradiation 09-Draznin-Chap09.indd 66 3/31/2011 2:38:14 PM ETIOLOGY 67 Etiology Irradiation There does not appear to be a threshold dose of external irradiation f or thyroid carcinogenesis; doses of 200 \200\223500 rad seem to produce thyroid cancer at a rate of about 0.5%/year. There is no evidence that therapeutic or diagnostic 131 I administration can induce thyroid cancer, although there is a small increase in death rates from thyroid cancer after 131 I. At present it is unclear whether this is due to an effect of 131 I or part of the natural history of the underlying thyroid disease. External irradiation at an age <20 years is asso ciated with an increased risk of thyroid nodule development and thyroid cancer (most common ly papillary). The radioactive fallout from the Chernobyl nuclear explosion in 1986 resulte d in a 4.7-fold increase in thyroid cancer in the regions of Belarus from 1985 to 1993, inc luding a 34-fold increase in children. Most of these were papillary carcinomas. The risk is greater for women and when irradiation occurs at a younger age. There is a latency of at least 5 years with maximum risk at 20 years following exposure, th ough this was not seen following the Chernobyl disaster. Other environmental factors Most investigators agree that iodine supplementation has result ed in a decrease in the incidence of follicular carcinoma. Genetic syndromes and oncogenes RET/PTC1 proto-oncogene abnormalities in the long arm of ch romosome 10 are associated with some papillary tumors (5 \200\22330%), especially after irr a- diation (60 \200\22380%). It is similar to the abnormality associated with medullary thy roid carcinoma in MEN2A. Two new proto-oncogenes have been have been identi \201 ed: RET/PTC2 and RET/PTC3 TRK (less common). The tumor suppressor gene p53 has been found to be mutated in some de-differentiated cancers. Overexpression of the ras and PTTG oncogenes is found in papillary thyroid cancers. These w ere found to be markers for adverse prognosis. c -myc mRNA expression has been correlated w ith histological markers of papillary cancer aggression. Papillary microcarcinoma of the thyroid (PMC) PMC is de \201 ned by the World Health Organ ization (WHO) as a tumor focus of 1.0 cm or less in diameter. It is detected coincidentally on his- topathological examination of resected thyroid Autopsy studies show the following: \200 Prevalence ranges from 1 to 35.6%. \200 No sig ni \201 cant difference in the prevalence rates of PMC has been demonstrated between the sexes. PMC rarely progresses to clinically apparent thyroid cancer with advancing age. 09-Draznin-Chap09.indd 67 3/31/2011 2:38:14 PM CHAPTER 9 Thyroid cancer 68 PMC can be multifocal. \200 Cervical lymph node metastasis from PMC ranges from 4.3 to 18 .2%. \200 Lymph node metastasis was most often associated with multifocal tumors. Althoug h exposure to irradiation increases the likelihood of developing papillary thyroid cancer, the tumors will usually be >1.0 cm in diameter and thus not PMC. Follow-up studies suggest that PMC is a slow-growing lesion that rarely spreads to distant sites and carries a good prognosis. The recommenda- tions for treatment of PMC vary widely: \200 The low morbidity and long survival mean that collection of randomized, prospective data has never been performed and comparisons of therapies are based on retrospective stud ies. \200 The treatment of PMC should not cause more morbidity than the disease process itself. Surgical treatment recommendations range from simple excision to ipsilateral lobectomy. With adjuvant therapy, the consensus is routine use of T 4 but not the use of radioiodine, as there is no difference in the recurrence rate. There is some evidence to keep TSH below the reference range, but robust supporting data are not available. Papillary thyroid carcinoma Papillary carcinoma constitutes approximately 80% of all thyroi d cancers. It is more common in women (3:1). It is rare in childhood Peaks occur in the second and third decades and again in later life (bimodal frequency). Incidence is 3 \200\2235 per 100,000 population. Pathology The carcinoma is slow growing and usually non-encapsulated and may spread through the thyroid capsule to structures in the surrounding neck, especially regional lymph nodes . Recognized variants are follicular, papillary, dorsal, columnar cell, tall cell, and diffuse sclerosing. It is con \201 ned to the neck in over 95% of cases, although 15 \200\22320% have local extra thyroidal invasion. Metastases (1 \200\2232% of patients) occur via lymphatics to local lymph nodes and more distantly to lungs. Histology The tumor contains complex branching papilla that have a \201 brovascular core covered by a single layer of tumor cells. Nuclear features include the following: Large size with pale staining, \200\234ground-glass \200\235 appearance ( Orphan Annie \200\223eye nucleus ) \200 Deep nuclear grooves The characteristic and pathognomoni c cytoplasmic feature is the psammoma body , which is a calci \201 ed, laminated, basophil ic, stromal structure. 09-Draznin-Chap09.indd 68 3/31/2011 2:38:14 PM STAGING OF DTC 69 Staging of DTC TNM See Table 9.3. Table 9.3 Tumor, node, metastasis (TNM) staging Patient age <45 years Patient age >45 years Stage I Any T, any N, M0 T1, N0, M0 Stage II Any T, any N, M1 T2, N0, M0 Stage III T3, N0, M0 T1, N1a, M0 T2, N1a, M0 T3, N1a, M0 Stage IVA T4a, N0, M0 T4a, N1a, M0 T1, N1b, M0 T2, N1b, M0 T3, N1b, M0 T4a, N1b, M0 Stage IVB T4b, Any N, M0 Stage IVC Any T, Any N, M1 09-Draznin-Chap09.indd 69 3/31/2011 2:38:14 PM CHAPTER 9 Thyroid cancer 70 Surgery Indeterminate nodules \200 Lobectomy as initial approach \200 Total thyroidecto my if >4 cm, marked atypia on biopsy, \200\234suspicious for papillary cancer, \200\235 fa mily history of thyroid cancer, history of radiation exposure, bilateral nodular disease Malignancy \200 Lobectomy if <1 cm, low-risk, unifocal, intrathyroidal papillary thyroid carcinomas (PTC) in the absence of prior head and neck irradiation or radiological or clini cally involved cervical nodal metastases Total thyroidectomy if >1 cm unless contraindications Completion thyroidectomy \200 Offer completion thyroidectomy to all patients for whom a t otal thyroidectomy would have been recommended had the diagnosis been available before init ial surgery (all patients with thyroid cancer except those with unifocal subcentimeter dise ase that was completely intrathyroidal and node negative) Neck dissection \200 Central (level VI) dissection for patients with clinically involved central or lateral neck lymph nodes Prophylactic central dissection in patients with T3, T4 PTC \200 No central dissection fo r T1, T2 PTC when noninvasive, clinically node-negative PTCs/most follicular cancer Lateral neck dissection for biopsy-proven metastatic lateral cervical lymphadenopathy Postoperative thyroid hormone therapy For stage TNM I and II disease, the serum TSH concent ration should be at or slightly below the lower half of the reference range (0.1 \200\2232. 0 mU/L). For stage III and IV disease, the serum TSH should be <0.1 mU/L. The presence of h eart disease or low bone density may necessitate a lower level of TSH suppression with smaller doses of thyroxine. The dose also may be decreased to allow the TSH to rise into the nor- mal range in low-risk patients who remain disease-free for 5 to 10 years after primary therapy. 09-Draznin-Chap09.indd 70 3/31/2011 2:38:14 PM RADIOACTIVE IODINE THERAPY 71 Radioactive iodine therapy Postoperative radioactive iodine (RAI) ablation is generally per formed 1 \200\2233 months after total thyroidectomies without remnant thyroid tissue. RAI is indicated for almost all nonpapillary histologies (i.e., follicular, Hurthle) as well as various papillary histologies (Table 9.4). High-risk features (think about when \200\234selective use \200\235) \200 Worrisome hist ological subtypes (tall cell, columnar, insular, solid, poorly differentiated) Intrathyroidal vascular invasion \200 Gross or microscopic multifocal disease \200 Reco mbinant TSH is used for routine RAI remnant ablation \200 Levothyroxine (LT 4 ) withdrawa l is used if patient has known gross residual disease or distant metastases \200 Discontinue LT 4 74 weeks before rechecking t he TSH (must be >30 mU/L) and proceeding with RAI ablation or scanning. \200 Supplement with T 3 25 mcg b id for 2 weeks after stopping T 4 , followed by a 2-week T 3 withdrawal prior to RAI ablati on. LT 4 may be resumed on second or third day after RAI administration. The patient is placed on a low iodine diet for 1 \200\2232 weeks to facilitate the uptake of the radioisotope Pretreatment scan \200 Either 2 \200\2235 mCi 131-I with whole body scan (WBS) 48 \200 \22372 hours later or 1.3 \200\2235 mCi 123-I with WBS 6 \200\22324 hours later (may be ski pped if very low risk of metastases and the goal is to ablate remnants) If using rTSH: obtain a 24-hour 123-I scan on day 3 prior to that day \200\231s administrat ion of RAI ablation. For example: \200 Day 1: rhTSH 0.9 mg IM \200 Day 2: rhTSH 0.9 mg IM + 1.5 mCi 123-I \200 Day 3: pretreatment WBS then 150 mCi 131-I \200 Day 10: post-tr eatment WBS Dosing (maximum lifetime dose: 600 \200\223800 mCi) \200 Low risk: 30 \200\22375 mCi (pri marily patients under age 45 with tumors con \201 ned to the thyroid gland) Intermediate risk: 100 mCi \200 High risk of recurrence or death: 100 \200\223150 mCi \200 Pulmonary metastases: 150 to 200 mCi \200 Skeletal metastases: 200 mCi Post-treatment scan A post-treatment scan is used to con \201 rm tumor uptake of the treat ment dose 2 \200\2238 days later. Directions after treatment: \200 <30 mCi: 5 feet distance for 7 days 09-Draznin-Chap09.indd 71 3/31/2011 2:38:14 PM 0 9 D r a z n i n C h a p 0 7 2 9 . i n d d C H A P T E R 7 2 9 T h y r o d i Table 9.4 Major factors impacting decision making in remnant ablation c a n c e r Expected bene \201 t May faciliate initial staging and follow-up Decreased risk of death Decreased risk of recurrence RAI ablation usually recommended Strength of evidence Factors Description T1 1 cm or less, intrathyroidal or microscopic multifocal No No Yes No E Con \202 icting data a Selective use a 1 \200\2232 cm, intrathyroidal No Yes I Con \202 icting data a Selective use a T2 >2 \200\2234 cm, intrathyroidal No Yes C T3 >4 cm Con \202 icting data a <45 years old No Yes Yes B (cid:2)45 years old Yes Yes Yes Yes B Inadequate data a Selective use a Any size, any age, minimal extrathyroidal extension No Yes I 3 / 3 1 / 2 0 1 1 2 : 3 8 : 1 5 P M 0 9 D r a z n i n C h a p 0 9 . i n d d Expected bene \201 t 7 3 May faciliate initial staging and follow-up Decreased risk of death Decreased risk of recurrence RAI ablation usually recommended Strength of evidence Factors Description T4 Any size with gross extrathyroidal extension Yes Yes Yes Yes B Nx, N0 No metastatic nodes documented No No Yes No I Con \202 icting data a Selective use a N1 <45 years old No Yes C Con \202 icting data a Selective use a >45 years old Con \202 icting data Yes C M1 Distant metastasis present Yes Yes Yes Yes A a Because of either con \202 icting or inadequate data, we cannot recommend either for or against RAI ablation for this entire subgroup. However, selected patients within this subgr oup with higher risk features may bene \201 t from RAI ablation (see modifying factors in the text). Reprinted with permission from Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules. Thyro id 2009; 19(11):1167 \200\2231214. The publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers. R A D O A C T I I V E I O D N E I T H E R A P Y 3 / 3 1 7 3 / 2 0 1 1 2 : 3 8 : 1 5 P M CHAPTER 9 Thyroid cancer 74 >30 \200\223100 mCi: 10 feet distance for 7 days, sleep alone for 2 days, drink \202 uids Avoid IV contrast for 6 \200\2238 weeks, pregnancy for 6 \200\22312 months Side effects \200 Short term: nausea, local neck pain, dry mouth (salivary gland toxicity ), bone marrow toxicity, pulmonary toxicity, gastritis, thyroiditis, salty saliva Long term: salivary and bone toxicity, secondary malignancies, fertility, teratogenicity, d ry eyes/conjunctivitis. If xerostomia occurs, see dentist to avoid dental caries Management of recurrent disease Locoregional metastases \200 Persistent or recurrent disease con \201 ned to the neck: t herapeutic comprehensive lateral and/or central neck dissection Patients with recurrent disease who have already undergone prior comprehensive dissection or external beam radiation therapy (EBRT): limited lateral and/or central neck dissection Aerodigestive invasion \200 Surgery and RAI and/or EBRT Pulmonary metastases \200 RAI therapy 100 \200\223200 mCi repeated every 6 \200\22312 mon ths as long as disease continues to concentrate RAI and respond clinically Bone metastases \200 Surgical resection (especially if age <45), RAI, glucocorticoids. \200 If not amenable to surgery, RAI, EBRT, intra-arterial embolization, radiofrequency ablation (RFA), frequent pamidronate or zolendronate infusions Brain metastases \200 Surgical resection regardless of RAI avidity \200 If not amenable to surgery, EBRT \200 If RAI avid, RAI (with prior EBRT and concomitant glucocorticoid therapy) 09-Draznin-Chap09.indd 74 3/31/2011 2:38:15 PM FOLLICULAR THYROID CARCINOMA (FTC) 75 Follicular thyroid carcinoma (FTC) FTC constitutes 15% of all thyroid cancers. The mean pat ient age in most studies is 50 years. FTC is more common in women (2:1). It is relatively m ore common in endemic goiter areas. Pathology Follicular carcinoma is a neoplasm of the thyroid epithelium that exhibits follic ular differentiation and shows capsular or vascular invasion. Differentiation of benign follicular adenoma from encapsulated low-grade or minimally invas ive tumors is dif \201 cult, particularly for the cytopatholo- gist, and therefore surgery is often necessary for a follicular adenoma. FTC may be minimally invasive or widely invas ive. Metastases (15 \200\22320% cases) are more likely to be spread by hematogen- esis to the lung and bones and less likely to local lymph nodes. Hurthle cell carcinoma is an aggressive type of follicular tumor with a poor prognosis because it fails to concentrate 131 I. Treatment Treatment is as for papillary thyroid carcinoma. 09-Draznin-Chap09.indd 75 3/31/2011 2:38:15 PM CHAPTER 9 Thyroid cancer 76 Follow-up of papillary and follicular thyroid carcinoma For patients with differentiated th yroid cancer (DTC) who undergo subto- tal thyroidectomy or total thyroidectomy without RAI: \200 Follow periodic thyroglobulin (Tg) and perform ultrasound. \200 Rising Tg over ti me is suspicious. For DTC patients after undergoing total thyroidectomy and remnant abla- t ion, the following schedule is recommended. 6 \200\22312 months \200 Clinical examination, serum TSH, free thyroxine, neck ultrasound , thyroglobulin (Tg), and thyroglobulin antibodies while on T4 \200 If the neck ultrasoun d is suspicious for lymph nodes or nodules >5 \200\2238mm, send for biopsy for cytology and Tg wash \200 If biopsy positive, send fo r compartment dissection \200 If biopsy negative, monitor size of lymph nodes or nodules If the ultrasound is negative and TgAb are negative, send for rhTSH or THW Tg stimulation and diagnostic RAI WBS \200 If negative WBS but stimulated Tg>5 \200\22310, send for neck/check CT or PET/CT \200 If imaging negative, consider repeat 1 \200\223131 therapy \200 If imagi ng positive, consider surgery, 1 \200\223131 therapy, EBRT, clinical trial or tyrosine kinase inhibitor therapy If negative WBS and stimulated Tg<5 \200\22310, monitor Tg and neck ultrasound. If Tg rising, consider repeat 1 \200\223131 therapy If positive WBS, consider repeat 1 \200\223131 therapy If the ultrasound is negative but Tg Ab are positive, follow TgAb and neck ultrasound Years 2 \200\22310 \200 Clinical examination, measurements of serum free thyroxine, TSH, and thyroglobulin annually Neck ultrasonography every 1 \200\2232 years or less frequently in low-risk patients with no evidence of disease Thyrogen-stimulated Tg and WBS if serum Tg increases or there is other evidence of recurrence Years 11 \200\22320 \200 Clinical examination and measurements of serum free thyroxine, T SH, and thyroglobulin annually Neck ultrasonography every 1 \200\2233 years or less frequently in low-risk patients with no evidence of disease Thyrogen-stimulated Tg and WBS if serum Tg increases or there is other evidence of recurrence 09-Draznin-Chap09.indd 76 3/31/2011 2:38:15 PM FOLLOW-UP OF PAPILLARY 77 Years 21+ \200 Clinical examination and measurements of serum free thyroxine, TSH, and thyroglobulin annually Neck ultrasonography every 3 \200\2235 years or less frequently in low-risk patients with no evidence of disease Thyrogen-stimulated Tg and radioiodine imaging if serum Tg increases or there is other evidence of recurrence Box 9.1 Thyroid cancer in children \200 Uncommon, with an incidence of 0.2 \200\2235 per million per year \200 >85% are papillary, but with more aggressive behavior than in adult s (local invasion and distant metastases are more common) \200 An i incidence reported in c hildren in Belarus and Ukraine following the Chernobyl nuclear accident in 1986. RET oncogene rearrangements are common in these tumors. Management is similar to that for adults, with a similar controversy as to the extent of initial surgery. Various studies report an overall recurrence rate of 0 \200\22339%; disease- free survival of 80 \200\22393%; and disease-speci \201 c mortality of 0 \200\22310%. Evidence is lacking on the independent risks or bene \201 ts of radioactive iodine or extensive surgery. of thyroglobulin and radionuclide scanning. Many investigators recommend lifelong follow-up with a combination Thyroid cancer and pregnancy The natural course of thyroid cancer developing during pregnan cy may be different from that in nonpregnant women. Any woman presenting with a thyroid nod ule during pregnancy appears to have an i risk for thyroid cancer. Evaluation should be undertaken with FNAC. Radioiodine scan is contraindicated. Lesions <2 cm diameter or any lesion appearing after 24 weeks \200\231 ges- tation should b e treated with TSH suppression and further evaluations carried out postpartum. If FNAC is suspicious or diagnostic, operation should be performed at the earliest safe opp ortunity \200\224generally the second trimester or immedi- ately postpartum. 131 I ablation should be scheduled for the postpartum period and the mother advised to stop breast-feeding. She should avoid pregnancy for 6 months after any 131 I ablation. 09-Draznin-Chap09.indd 77 3/31/2011 2:38:15 PM CHAPTER 9 Thyroid cancer 78 Medullary thyroid carcinoma (MTC) Also see Chapter 92, MEN type 2 (p. 503). Accounts for 5 \200\22310% of all thyroid cancers. Should be managed by a dedicated regional service. Presentation \200 Lump in neck \200 Systemic effects of calcitonin including \202 ush ing and diarrhea Diagnosis \200 FNAC \200 Unsuspected at surgery \200 Comprehensive family history and screening in search for features of MEN-2 is needed. Pathology specimens show immunostaining for calcitonin and staining for amyloid. Management \200 Baseline plasma calcitonin \200 Baseline biochemical investigations for pheochromocytoma and hyperparathyroidism Genetic screening \200 Staging with thoracoabdominal CT/MRI \200 MIBG and pentavalent 9 9m Tc DMSA scintography may also be used. Treatment \200 Total thyroidectomy and central node dissection is the preferred treatment modality. Germline RET mutation carriers should ideally undergo thyroidectomy before 5 years of age. Adjuvant therapy \200 Radioiodine and TSH suppression do not play a role. \200 External radiotherapy and systemic chemotherapy have not been shown to be of bene \201 t. Therapeutic MIBG may help in some cases. Follow-up All patients should have lifelong follow-up at the dedicated regional service. 09-Draznin-Chap09.indd 78 3/31/2011 2:38:15 PM LYMPHOMA 79 Anaplastic (undifferentiated) thyroid cancer \200 Rare \200 Peak incidence: seventh dec ade. 5 : 4 = 1:1.5 \200 Characterized by rapid growth of a \201 rm/hard \201 xed tumo r \200 Often in \201 ltrates local tissue such as larynx and great vessels and so does n ot move on swallowing. Stridor and obstructive respiratory symptoms are common. Aggressive, with poor long-term prognosis \200\2247% 5-year survival rate and a mean survival of 6 months from diagnosis Optimal results occur following total thyroidectomy. This is usually not possible and exter nal irradiation is used, sometimes in association with chemotherapy. Lymphoma \200 Uncommon \200 Almost always associated with autoimmune thyroid disease (Hashimoto \200\231s thyroiditis). Occurs more commonly in women and in patients aged >40 y ears. Characterized by rapid enlargement of the thyroid gland \200 May be limited to thyroid gl and or part of a more extensive systemic lymphoma (usually non-Hodgkin \200\231s lymphoma). Trucut-needle biopsy may be required. Treatment with radiotherapy alone or chemotherapy if more extensive often produces good results. Further reading British Thyroid Association (2007). Guidelines for the Management of Thyroi d Cancer , 2nd ed. London: Royal College of Physicians. British Thyroid Association (nd). Guidelines/statement. Available at: www.british-thyroid-a ssoci- ation.org/Guidelines/ Cooper DS, Doherty GM, Haugen BR, et al., for American Thyroid Association (2009). Revised American Thyroid Association management guidelines for patients with thyroid nodules. Thyro id 19(11):1167 \200\2231214. Hay I, Wass JAH (2008). Clinical Endocrine Oncology , 2nd ed. Blackwell-Wiley. pp. 109 \200 \223171. Mazzaferri EL, Robbins RJ, Spencer CA, et al. (2003). A consensus report of the role of ser um thryoglobulin as a monitoring method for low-risk patients with papillary thyroid carcin oma. J Clin Endocrinol Metab 88(4):1433 \200\2231441. Sherman SI (2003). Thyroid carcinoma. Lancet 361(9356):501 \200\223511. Wartofsky L, Sherman SI, Gopal J, et al. (1998). The use of radioactive iodine in patients with papil- lary and follicular thyroid cancer. J Clin Endocrinol Metab 83:4195 \200\223420 3. Table 9.4 (Contd.) 09-Draznin-Chap09.indd 79 3/31/2011 2:38:15 PM This page intentionally left blank Part 2 Pituitary Janice M. Kerr 10 Pituitary gland anatomy and physiology 11 Imaging 12 Pituitary function testing 13 Hypop ituitarism 14 Anterior pituitary hormone replacement 15 Pituitary tumor basics 16 Prolactin omas 17 Acromegaly 18 Cushing \200\231s disease 19 Gonadotropinomas 20 Thyrotropinomas 21 C raniopharyngiomas and Rathke \200\231s cleft cysts 22 Parasellar tumors 23 In \202 ammator y and in \201 ltrative pituitary diseases 24 Surgical treatment of pituitary tumors 25 Med ical treatment of pituitary tumors 26 Pituitary radiotherapy 27 Diabetes insipidus (DI) 28 Hyponatremia 29 Syndrome of inappropriate ADH (SIADH) 30 Pineal gland 82 86 89 94 98 101 104 110 116 125 128 130 134 136 140 144 147 151 156 159 161 10-Draznin-Chap10.indd 81 3/31/2011 3:19:16 PM CHAPTER 10 Pituitary gland anatomy and physiology 82 Pituitary gland anatomy and physiology Embryology and anatomy The anterior gland comprises 2/3 of the pituitary gland and is deri ved from the oral ectoderm (Rathke \200\231s pouch). The posterior pituitary gland is deriv ed from the diencephalon. The pituitary gland resides in a portion of the sphenoid bone called the sella turcica and is covered by dura (diaphragma sella). The pituitary gland is contiguous with the hypothalamus via the pitu- itary stalk. Anatomic ally, the pituitary gland is adjacent to several critical structures, including the optic c hiasm (superiorally), the cavernous sinuses (laterally, and which contain the internal caro tid arteries and cranial nerves [oculomotor(III), trochlear (IV), abducens (VI) and the tri geminal branches(V1 and V2]) and the sphenoid sinus (inferiorally). The anterior pituitary gland is vascularized by superior hypophyseal arteries that form a c apillary bed (hypophyseal-portal circulation) into which hypothalamic releasing and inhibit ory factors are delivered. The pituitary stalk and posterior pituitary gland receive direct arterial blood supply via the middle and inferior hypophyseal arteries. Supraoptic recess Suprasellar cistern Hypothalamus Optic chiasm Pituitary stalk Sphenoid bone III IV Temporal lobe Internal cartoid artery V1 VI V2 Pituitary gland Sphenoid sinus Fig. 10.1 The sellar region. Reproduced with permission from by Weatherall DJ, Ledingham JG G, and Warrell DA (Eds.) (1996). Oxford Textbook of Medicine, 3rd ed. Oxford: Oxford Univer sity Press. 10-Draznin-Chap10.indd 82 3/31/2011 3:19:16 PM ANTERIOR GLAND PHYSIOLOGY 83 Anterior gland physiology See Table 10.1 . The pituitary gland consists of \201 ve differ entiated cell types that secrete six hormones important for growth, metabolism, stress resp onses and reproductive function. Prolactin (PRL) PRL is a single-chain polypeptide that belongs to the somatotropin/prolac- tin family. PRL has a diurnal pattern of secretion, with a sleep-associated augmentation of PRL levels. Growth hormone (GH) GH is a single-chain polypeptide of which the 22 KDa variant is the maj or isoform. Pulsatile GH secretions are usually undetectable in the serum apart from 5 \200 \2236 noctural bursts, which occur during early sleep stages. Luteinizing hormone and follicle stimulating hormone (LH/ FSH) These are glycoprotein hormo nes with an chain common to LH, FSH, TSH and hCG, but a chain that is speci \201 c f or each hormone. LH and FSH have complex pulsatile secretion patterns, particularly during puberty and across the menstrual cycle. Thyroid stimulating hormone (TSH) TSH is secreted in a circadian pattern and has increased pulse amplitudes at night. Adrenocorticotropic hormone (ACTH) ACTH is derived from a larger precursor polypeptide, pro opiomelano- cortin (POMC), which also encodes for endorphins and melanocyte stimulating hormone. ACTH has a circadian pattern of secretion, with a peak level at 6 \200\2238 A.M. a nd a nadir level between 11 and 12 P.M. (with normal sleep-wake cycles). 10-Draznin-Chap10.indd 83 3/31/2011 3:19:17 PM 1 0 D r a z n i n C h a p 1 8 4 0 . i n d d Table 10.1 Anterior pituitary gland physiology C C H H A A P P T T E E R R 8 4 Cell Type (Hormone) % Pit + Regulation \200\223 Regulation Targets Effects Liver, Cartilage, Muscle, Fat, Skin Linear and somatic growth. Metabolism (lipids and proteins carbohydrates) Insulin-like growth factor (IGF-1) and somatostatin Somatotropes (growth hormone) GH 45 \200\22350 Growth hormone \200\223 releasing hormone (GHRH) 1 1 0 0 P i t u i t a r y 15 \200\22325 (i in pregnancy) Lactotropes (prolactin) PRL Thyrotropin- releasing hormone (TRH) and estrogen Dopamine Breast Lactation g l a n d Gonadotropes (luteinizing hormone and follicle- stimulating hormone) FSH/LH 10 \200\22315 Gonadotropin- releasing hormone (GnRH) Estrogen- late follicular phase of menstrual cycle Estrogen Progesterone Testosterone (on FSH) Inhibin Gonads Sex steroids production. Folliculogenesis and ovulation ( 5) Spermatogenesis ( 4) Thyroid h ormone production a n a t o m y Thyrotropes (thyroid- stimulating hormone) TSH 5 \200\22310 TRH T 4 , T 3 , Somatostatin Thyroid Corticotropes (adrenocorticotropin) ACTH 15 \200\22320 Corticotropin- releasing hormone (CRH) Cortisol Adrenal gland Glucocorticoid and DHEA production a n d p h y s i o l o g y 3 / 3 1 / 2 0 1 1 3 : 1 9 : 1 7 P M POSTERIOR GLAND PHYSIOLOGY 85 Posterior gland physiology The posterior pituitary gland secretes antidiuretic hormone and oxytocin, which are synthesized in the hypothalamic neurons of the supraoptic and paraventr icular nuclei. Antidiuretic hormone (ADH) ADH is a nonapeptide that is released in response to hyperosmoti c and hypovolemic stimuli. ADH acts on V2 renal collecting tubule receptors to mediate free water retention, and acts on V1 blood vessel receptors, at higher concentrations, to cause vasoconstriction. ADH also acts synergis- tically with corticotropin-releasing hormone (CR H) to augment ACTH release. Oxytocin In women, oxytocin facilitates uterine contraction, during parturition, and milk l et-down in the post-partum period. In men, oxytocin has no known function but may aid in se minal vesicle contractions. Further reading Aron DC, Findling JW, Tyrrell JB (2007). Hypothalamus and pituitary gland. In Gardner DG, Shoback D (Eds.), Greenspan \200\231s Basic and Clinical Endocrinology , 8th ed, New York: McGraw Hill, pp. 101 \200\223140. 10-Draznin-Chap10.indd 85 3/31/2011 3:19:17 PM CHAPTER 11 Imaging 86 Imaging Background High-resolution, contrast-enhanced, thin-cut (3mm) magnetic resonance imaging (M RI) provides the optimal evaluation of the sellar and parasellar regions. Coronal and sagittal T 1 -weighted images, before and after gadolinium administration, are recommended. T 2 -weighted imaging is usually unneces- sary, but may assist in the diagnosi s of cystic lesions. In addition, axial imaging may be helpful to de \201 ne lateral exten sion with large tumors. Computed tomography (CT) scans are most useful for patient with contra-indications to MRIs. In addition, they may demonstrate boney destruction and calci \201 cation with some tumor s (e.g., meningiomas and craniopharyngiomas). MRI appearances See Figure 11.1 . The size, shape and signal characteristics of the pituitary gland vary with age, gender and physiological status. Non-contrasted T 1 images of the anterior pituitary gland are isoint ense with cerebral white matter, whereas the posterior pituitary gland appears hyperintense (as a bright spot), in most normal subjects. Following contrast administration, the pituitary gland and stalk enhance, because they are below the blood \200\223brain barrier. 2 There is signi \201 cant overlap in the imaging characteristics of adenomas, and other pituitary diseases such as craniopha ryngiomas, in \202 ammatory/ in \201 ltrative lesions and cysts. 11-Draznin-Chap11.indd 86 3/31/2011 2:39:03 PM PITUITARY ADENOMAS 87 Fig. 11.1 Normal and abnormal pituitary MRI images. A. Normal coronal, post- contrast T 1 i mage showing optic chiasm (OC). B. Normal saggital image showing pituitary stalk (PS) and O C. C. Pituitary macroadenoma with evidence of pituitary gland (PG) compression, left cavern ous sinus invasion, and encroachment of carotid artery (CA). D. Rathke \200\231s cleft cyst \200\224bright T 1 image consistent with mucinous, proteinaceous or blood products. Pituitary adenomas See Figure 11.1 . Microadenomas are best appreciated on contrast-enhanced, T 1 weighted, coronal MRI images. They appear as hypointense signals, and often with associated pituitary gland asymmetry and stalk deviation (contralateral to the tumor). Macroadenomas are characterized radiographically by their size and extrasellar extension. I mportant considerations include the proximity of the adenoma to the optic chiasm and any ra diological evidence for cavern- ous sinus invasion. Macroadenomas are frequently heterogeno us appear- ing and may undergo spontaneous necrotic and/or hemorrhagic changes. On T 1 -wei ghted images: \200 Low-intensity areas indicate necrotic or cystic changes. \200 High-i ntensity signals indicate hemorrhage (particularly after the acute phase, days 1-2). The normal pituitary gland enhances more avidly with contrast than tumors, so is commonly seen as an enhanced signal that is peripherally located. 11-Draznin-Chap11.indd 87 3/31/2011 2:39:03 PM CHAPTER 11 Imaging 88 Craniopharyngioma/Rathke \200\231s cleft cyst Craniopharyngiomas are typically suprasellar in location. They vary in content from cystic to mixed solid/cystic (most commonly) to pred om- inantly solid. Imaging characteristics vary with the tumor composition. Calci \201 cat ions are a distinguishing feature of adamantinomatous craniophar- yngiomas, and are best de tected by CT scans. Rathke \200\231s cleft cysts (RCC) are typically intrasellar, but may extend into the supra sellar space. MRI images vary by cyst content from hypointense (with serous \202 uid), to hyperintense (with mucinous, proteinaceous or blood products) on T 1 -weighted images. Further reading Naidich MJ, Russell EJ (1999). Current approaches to imaging of the sellar region and pituitary. Endocrinol Metab Clin North Am 28:45 \200\22379. 11-Draznin-Chap11.indd 88 3/31/2011 2:39:06 PM THYROTROPES 89 Pituitary function testing Background \200 Pituitary function is best assessed with basal concentrations of the pituitary hormones and their corresponding target gland hormones. \200 Pituitary hormone de \201 ciency is established by a low target hormone level in the setting of a low, or an inappropriately normal pituitary hormone level. In equivocal cases, stimulation tests are used to assess the pituitary hormone reserve (e.g., Insulin tolerance test for GH de \201 ciency). Pituitary hormone excess (or less commonly, resistance to target organ hormone) is established by a high target hormone level in the setting of an inappropr iately normal or a high pituitary hormone level. In equivocal cases, suppression tests are used to assess for a hyper-secretory state. (e.g., OGTT for acromegaly). Lactotropes Basal testing Lactotrope function is best assessed by a fasting PRL level. Dynamic testing None is used. Thyrotropes Basal testing Thyrotrope function is best assessed with concomitant TSH and cir culat- ing thyroid hormone levels (free T 4 and less commonly, T 3 ). Dynamic testing None is used; TRH is not commercially available in the United States. 12-Draznin-Chap12.indd 89 4/1/2011 6:01:34 PM CHAPTER 12 Pituitary function testing 90 Gonadotropes Basal testing Gonadotrope function is best assessed with concomitant gonadotro pin (FSH and LH) and sex steroid levels: estradiol (in females) and testoster- one (in male s). In premenopausal females, because the gonadotropin levels differ signi \201 - cantly acros s the menstrual cycle, hormone testing should be performed in the early follicular phase (d ays 1 \200\2235 after the onset of menses), when the LH and FSH levels are approximately eq ual. In males, testosterone levels are best assessed in the early morning (7 \200\2239 A.M.), which corresponds to normal peak levels. Dynamic testing Gonadotropin-releasing hormone (GnHR) testing is most commonly used to asse ss pubertal disorders, particularly precocious puberty. 12-Draznin-Chap12.indd 90 4/1/2011 6:01:34 PM CORTICOTROPES 91