Nelson \200\231s syndrome is caused by an enlargement of a pituitary adenoma (often aggress ively), and may occur in up to 30% of Cushing \200\231s disease patients who have undergone a bilateral adrenalectomy. These tumors are associated with a marked increase in ACTH leve ls, hyperpigmentation and mass effects. Monitoring should be performed annually with a basa l ACTH measurement and pituitary MRI (as indicated for signs and symptoms of mass effects o r a markedly elevated ACTH level). Transsphenoidal surgery and radiation therapy are the ma in treatment options. 18-Draznin-Chap18.indd 122 3/31/2011 9:37:47 PM TREATMENT 123 Table 18.1 Drug treatments for Cushing \200\231s syndrome Drug Dose Action Side effects Nausea, i androgenic and mineralcorticoid precursors lead to hirsutism and hypertension Neu tropenia. 11B- hydroxylase inhibitor Metyrapone 1 \200\2234 g/day (usually given in 4 divided doses) Ketoconazole 200 \200\223400 mg tid \201 rst line in children. Avoid if taking H2 antagonists as acid is required to metabolize active compound Direct inhibitor of P450 enzymes at several different sites Abnormalities of liver function (usually reversible). Gynecomastia Mitotane (o-p- DDD) 4 \200\22312 g/day (begin at 0.5 \200\2231 g/day and gradually increase dose) Inhibits steroido- genesis at the side-chain cleavage, 11- and 18-hydroxylase and 3B-hydrox y- steroid dehydrogenase. Adrenolytic Nausea & vomit- ing, Cerebellar disturbance, Somnolence, Hyper- cholesterolemia. May increa se clearance of steroids. May be teratogenic. Avoid if fertility desired. RU486 (mifopristone) 400 \200\2231000 mg/ day Glucocorticoid Antagonists Amenorrhea Hypokalemia (antagonizes progesterone and androgen receptors) 0.03 mg/kg IV, followed by infusion of 0.1 mg/kg/h Inhibits side- chain cleavage and 11B- hydroxylase Etomidate 18-Draznin-Chap18.indd 123 3/31/2011 9:37:47 PM CHAPTER 18 Cushing \200\231s disease 124 Follow-up \200 After a successful transsphenoidal tumor resection, periodic assessment of basal and stimulated cortisol levels are indicated to monitor for recovery fr om central adrenal insuf \201 ciency (which is typically prolonged [>1 year]). Monitor periodically for disease recurrence, particularly in patients at high risk for CD recurrence (i.e., non-suppressed post-op cortisol levels, rapid glucoco rticoid taper, macroadenomas and/or failed intraoperative adenoma detection). ACTH-secreting macroadenoma are generally not cured with TSS and require subsequent radiati on therapy medical therapies. In addition, \200\234silent \200\235 ACTH adenomas are am ong the most aggressive tumors with 730% recurrence rates. Further reading Biller BK, Grossman AB, Stewart PM, Melmed S, et al. (2008). Treatment of a drenocorticotropin- dependent Cushing \200\231s syndome: a concensus statement J Clin Endoc rinol Metab 93:2454 \200\2232462. Ilias I, Torpy DJ, Pacak K, Mullen N, et al. (2005). Cushing \200\231s syndrome due to ecto pic corticotropin secretion: twenty years \200\231 experience at the National Institute of Health. J Clin Endocrinol Metab 91(2):371 \200\223377. Nieman LK (2002). Medical therapy of Cushing \200\231s disease. Pituitary 5:77 \200\22382. Nieman LK, Biller BM, Findling JW, Newell-Price J, et al. (2008). The diagnosis of Cushing \200\231s syn- drome. An Endocrine Society clinical practice guideline. J Clin Endocrinol M etab 93:1526 \200\2231540. Patil CG, Prevedello DM, Shivanand P, Vance ML et al. (2008). Late recurrences of Cushing \200\231s disease after initial successful transphenoidal surgery. 93:358 \200\223362. 18-Draznin-Chap18.indd 124 3/31/2011 9:37:47 PM CLINICAL FEATURES 125 Gonadotropinomas Epidemiology Gonadotropinomas are the most common non-functioning pituitary tumors and acco unt for 740 \200\22350% of all pituitary macroadenomas. They are most commonly diagnosed in middle-aged men. Pathology \200 Gonadotropinomas synthesize but generally do not ef \201 ciently secrete intact glycoprotein hormones (FSH, LH) or their free (A or B) subunits. Null cell tumors are de \201 ned by the absence of immunoreactive hormone expression and l ikely represent poorly differentiated gonadotrope cells. Clinical features Mass effects \200 Headache \200 Visual \201 eld defects (uni- or bitemporal quadranta nopia or hemianopia) \200 Ophthalmoplegia (III, IV and VI cranial nerve palsies) \200 V ision loss (optic nerve atrophy) \200 Cerebrospinal \202 uid rhinorrhea (rarely) \200 Hypopituitarism. At diagnosis, > 50% of patients are growth hormone and/or gonadotrope de \201 cient. Adrenal and thyroid insuf \201 ciencies are less common (<30%). Hormone effects Rarely, gonadotropinomas can present with hormone hypersecretory syn- drome s, such as ovarian hyperstimulation syndrome, testicular enlarge- ment or precocious pubert y. 19-Draznin-Chap19.indd 125 3/31/2011 2:46:25 PM CHAPTER 19 Gonadotropinomas 126 Investigations \200 Pituitary imaging: Usually presents as a macroadenoma on MRI/CT \200 Visual \201 elds assessment: Vision \201 eld defects are observed in 760 \200\22370% of patients. PRL: Mild hyperprolactinemia is common due to stalk compression. 0 Pituitary function: Gona dotropinomas rarely present with elevated serum FSH, LH, and/or A-subunit levels, but may b e confused with pri- mary gonadal failure and or the postmenopausal state. Headaches, visua l \201 eld disturbances and hypopituitarism are distinguishing features of a large gonado tropinoma. Management Surgery Transsphenoidal resection is the preferred therapy in most cases. Radiotherapy Radiation therapy is indicated for invasive or recurrent tumors, after initial surgical resection, or for patients who are deemed poor surgical candidates. Conventional fractionated or stereotactic radiotherapies are effective at controlling tumor growth in (>80 \200\22390% of cases). XRT carries a long-term risk of hypopituitarism (750% at 5 \200\22310 years with conventional XRT). Medical treatment Medical therapies, such as dopamine agonists, somatostatin analogs and Gn RH agonist/antagonists are ineffective for gonadotropinomas. Hormone replacement therapy is required for any hypopituitarism ( b see p. 98). Follow-up and prognosis \200 Surgical gross-total resection rates for gonadotropinomas ar e 760 \200\22370%, with experienced neurosurgeons. Risk of tumor recurrence and growth are estimated at 75 \200\22310% at 5 years following gr oss-total resection of gonadotropinomas, and 20 \200\22350% at 10 years with subtotal resec tion. Most patients with gonadotropinomas lack a detectable serum hormone marker (e.g., FSH/LH), so must be followed clinically and radiographically (with MR Is). For patients with asymptomatic/residual tumors or microadenomas, a watchful waiting approac h with annual imaging is recommended Consideration should be given to repeat TSS, or XRT, f or evidence of signi \201 cant interval tumor growth. 19-Draznin-Chap19.indd 126 3/31/2011 2:46:25 PM FOLLOW-UP AND PROGNOSIS 127 Further reading Chaidarun SS, Klibanski A (2002). Gonadotropinomas. Semin Reprod Med 20:339 \200\223348. Dekkers OM, Pereira AM, Romijn JA (2008). Treatment and follow-up of clinically nonfunction ing pituitary macroadenoma. J Clin Endocrinol Metab 93:3717 \200\2233726. Jaffe CA (2006). Clinically non-functioning pituitary adenomas. Pituitary 9:317 \200\223322 . 19-Draznin-Chap19.indd 127 3/31/2011 2:46:25 PM CHAPTER 20 Thyrotropinomas 128 Thyrotropinomas Epidemiology \200 Less than 2% of pituitary adenomas are thyrotropinomas (TSH- secreting). Female predominance-10:1, 5 : 4 . \200 Thyrotropinomas are frequently misdiagnosed and tr eated as primary hyperthyroidism. Clinical features \200 Hyperthyroidism ( b see p. 17) \200 Most thyrotropinomas are mac roadenomas at the time of diagnosis and present with mass effects, including headaches (20% ), vision defects (25%) and hypopituitarism (50%). Goiter is common at presentation. Differential diagnosis of elevated free T 4 /T 3 and non- suppressed TSH \200 TSH-secreti ng tumor \200 Thyroid hormone resistance \200 Inherited abnormalities of thyroid-bindin g globulin proteins Investigations \200 Elevated Free T 4 and T 3 levels with an inappropriately normal or elevated TSH level Elevated glycoprotein hormone A-subunit/TSH molar ratio \200 PRL and/or GH may be elevate d in mixed tumors (725%). \200 Elevated sex hormone binding globulins (hyperthyroid effec t) \200 Failed suppression of TSH with T 3 (80 \200\223100 mcg x 8 \200\22310 days) with TSH-secreting tumor \200 Pituitary imaging MRI Management Surgery \200 First-line therapy, with >80% cure rates for microadenomas and 750% cure rates for macroadenomas 20-Draznin-Chap20.indd 128 3/31/2011 2:47:40 PM MANAGEMENT 129 Medical therapies Somatostatin analogs b See Medical therapies for pituitary tumors (p. 144). \200 Somatost atin analogs, including octreotide LAR and lanreotide, are second-line therapy after failed or incomplete surgical resection. \200 Normalizes TSH secretion in >80% of patients and decreases tumor size in 740 \200\22350% of patients. Antithyroid medications \200 Short-term use only, for preoperative normalization of thyro id hormone levels. Long-standing use has potential adverse effects of tumor growth. B-blockers as needed for symptomatic hyperthyroidism. Radiotherapy Radiation therapy is use d as adjuvant therapy following incomplete surgical resection or inadequate medical respons e. Further reading Beck-Peccoz P, Persani L (2008). Thyrotropinomas. Endocrinol Metab Clin Nor th Am 37:123 \200\223134. 20-Draznin-Chap20.indd 129 3/31/2011 2:47:40 PM CHAPTER 21 Craniopharyngiomas & Rathke \200\231s cleft cysts 130130 Craniopharyngiomas and Rathke \200\231s cleft cysts Craniopharyngiomas Epidemiology Craniopharyngiomas comprise 72 \200\2235% of all intracranial tumors and 710% of all intracranial tumors in children. There is an equal gender prevalence, and a bimodal distribution, with peaks at ages 5 \200\22314 years and 50 \200\22374 years. Pathology Tumors arise from squamous epithelial remnants of Rathke \200\231s pouch. Histolo gical classi \201 cation includes two sub-types: \200 Adamantinomatous \200\224predomina ntly affects the young. Calci \201 cations are common. Papillary \200\224adult predominance. Calci \201 cations are rare. 2 Although craniopharyn giomas are benign tumors, they are biologically aggressive tumors which have a proclivity t o invade and adhere to critical neurovascular structures (i.e., the hypothalamus and the th ird ventricle). Clinical features \200 Mass effects: headaches, vision loss or visual \201 eld de \201 cits, cranial nerve palsies and obstructive hydrocephalus (in children) Pituitary disturbances: Children commonly present with growth failure and delayed puberty. Adults commonly present with hypopituitarism. \200 DI occurs in 715 \200\22320% of cases. Hypothalamic syndrome: hyperphagia, severe obesity, cognitive impairment, thirst and water/electrolyte imbalances, temperature dysregulation and sleep di sturbances. 21-Draznin-Chap21.indd 130 4/1/2011 6:30:41 PM FOLLOW-UP 131 Investigations \200 MRI/CT (CT better depicts boney erosions and calci \201 cations) \200 Visual \201 eld testing \200 Anterior and posterior pituitary assessment \200 N europsychological testing (particularly in children) Management \200 Surgical resection is \201 rst-line therapy for most cases. The surgica l approach (transfrontal vs. transsphenoidal) is dependent on the tumor size and suprasellar extension. Gross-total resection is feasible only for relatively small tumors with a predominantly intrasellar location. Subtotal resection, followed by adjuvant radiation therapy, is preferred over aggressive resection to minimize the potentially devastating effects of hypothalamic d amage (see Hypothalamic syndrome, p. 130). Craniopharyngiomas are radiosensitive, and therefore radiation therapy is indicated for residual disease, recurrent tumor growth, or for patients who are deemed poor surgical candidates. Data regarding additional adjuvant therapies, including: intracavitary irradiation (brachytherapy), bleomycin and systemic chemotherapy are limited. Restoration of pituitary hormone de \201 ciencies is unlikely following surgery, and the need for lifelong pituitary hormone replacement is common. Follow-up \200 Craniopharyngiomas have a high recurrence rate following surgery (730% at 10 years), with most occurring in the \201 rst 3 years. Radiation therapy is ver y effective at constraining tumor growth. The recommended frequency of clinical evaluation, imaging and anterior pituitary hormone as sessment depends on the disease status. In general, imaging is recommended initially at 6- to 12-month intervals. Patients who have received radiotherapy should undergone pituitary hormone testing biannually in anticipation of developing hypopituitarism. For pat ients on a stable pituitary hormone regimen, annual testing is usually suf \201 cient. 21-Draznin-Chap21.indd 131 4/1/2011 6:30:41 PM CHAPTER 21 Craniopharyngiomas & Rathke \200\231s cleft cysts 132 Rathke \200\231s cleft cysts (RCC) Epidemiology Rathke \200\231s cleft cysts account for 71% of primary intracranial tumors. T here is a female predominance (2:1 5: 4), and the mean age at presentation is 738 years. Pathology RCCs are derived from the remnants of Rathke \200\231s pouch and are lined by epi thelial cells (ciliated cuboidal/columnar epithelium). Squamous meta- plasia is associated with a higher risk of RCC recurrence. Clinical features \200 RCCs are usually asymptomatic \200 Large cysts (>1 cm) can be as sociated with mass effects, including headaches (765 \200\22385%) and vision problems (720 \200\22340%). Rarely, RCCs are associated with apoplexy (see b Apoplexy, p. 95). \200 Pituitary dysfunc tion, with large cysts occurs in 30 \200\22360% of cases, with hyperprolactinemia and hypogonadism being the most common abnormalities. DI is uncommo n. Investigations MRIs with variable signals characteristics are observed, depending on the cy st content (see b Imaging, p. 88). RCCs may be indistinguishable from cystic adenomas or cy stic craniopharyngiomas. Management \200 Transsphenoidal surgery is recommended for RCCs associated with mass effe cts (i.e., headaches or vision defects or pituitary hormone insuf \201 ciency). \200 Con servative decompression (cyst drainage and cyst wall biopsy) is preferred over aggressive c yst wall resection to minimize the risk of DI and hypopituitarism. Transsphenoidal surgery results in >80% symptomatic improvements in headaches and vision defects and with low complication rates (see b Transsphenoidal surg ery, p. 140). Hyperprolactinemia and hypogonadism commonly normalize after surgery whereas other pre-existing pituitary hormone abnormalities less commonly improve. 21-Draznin-Chap21.indd 132 4/1/2011 6:30:41 PM FOLLOW-UP 133 Follow-up Recurrence rates for RCC vary by surgical procedure, de \201 nition of recur- re nce, and length of follow-up, but are generally low (<10% symptomatic recurrence rates at 5 years) at experienced neurosurgery centers. Further reading Kanter AS, Sansur CA, Jane JA, Laws ER Jr (2006). Rathke \200\231s cleft cy sts. In Laws ER, Sheehan JP (eds.), Pituitary Surgery \200\224A Modern Approach. Frontiers of Hormone Research, Vol 34. Basel: Karger Press, pp. 127 \200\223157. Karivitaki N, Cudlip S, Adams CB, Wass JA (2006). Craniopharyngiomas. Endocr Rev 27:371 \200\223393. Karavitaki N, Waas JA (2008). Craniopharyngiomas. Endocrinol Metab Clin N Am 37:173 \200 \223193. Oskouian RJ, Samii A, Laws ER Jr (2006). The craniopharyngioma. In Laws ER, Sheehan JP (Eds .), Pituitary Surgery \200\224A Modern Approach. Frontiers of Hormone Research , Vol 34, Ba sel: Kager Press, pp. 105 \200\223126. Lillehei KO, Widdel L, Arias-Astete C, Wierman ME, et al (2010). J Neurosurg Transphenoidal resection of 82 Rathke cleft cysts; limited value of alcohol cauterization in reducing rec urrence rates. 27:1 \200\2238 21-Draznin-Chap21.indd 133 4/1/2011 6:30:41 PM CHAPTER 22 Parasellar tumors 134 Parasellar tumors See b Table 15.1, Lesions of the sellar turcica and parasellar region (p. 101). Meningiomas \200 Most common benign tumors of the sellar region, after adenomas \200 Pe ak incidence between the ages of 40 \200\22370 years \200 Strongly associated with previo us radiation therapy \200 Usually present with vision disturbances and occasionally with pituitary dysfunction Enhancing \200\234dural tail \200\235 on contrasted T 1 MRI is highly characteristic of this tumor type. Management is surgical, when possible, and/or radiation therapy for persistent or recurrent tumors. Rarely transforms to malignant tumors (poor prognosis) Germ cell tumor (GCT) \200 Malignant tumors that most commonly present in the \201 rst two decades of life GCTs are classi \201 ed as germinomas or nongerminomatous. \200 Most develop around the third ventricle (80% in the region of the pineal gland), followed by suprasellar/hypothalam ic locations. \200 For pineal gland involvement and treatment, see b Pineal gland (p. 161). Suprasellar GCT typically presents with DI, hypopituitarism and vision disturbances. Diagnosis is based on histological con \201 rmation (gold standard) or elevated tumor markers (B-hCG, A-fetoprotein in germinomas) and imaging characteristics. A multimodal treatment approach, from among surgical resection, radiation therapy and chemotherapy, is used depending on tumor type and stage. Gangliocytomas \200 Neuroepithelial tumors comprised of ganglion cells either alone (gang liocytoma) or in combination with glial cells (ganglioglioma) \200 Frequently found in as sociation with hormonally active pituitary adenomas, particularly growth hormone tumors Surgical resection is usually \201 rst-line therapy. 22-Draznin-Chap22.indd 134 3/31/2011 2:49:40 PM METASTATIC TUMORS TO THE PITUITARY 135 Chordomas/condrosarcomas \200 Cartilaginous tumors originating from the primitive notocho rd. \200 Incidence: chordomas > chondrosarcomas \200 Both tumors are locally aggressive and cause extensive boney destruction. Clinically, patients most commonly present with vision complaints (diplopia) and headaches. The preferred treatment is surgical resection followed by radiotherapy in most cases. Hamartomas \200 Hypothalamic hamartomas are congenital, neuronal-derived heterotopic tumors. They typically present in childhood with seizures \200\224commonly gelastic (laughing). They may release GnRH, leading to precocious puberty, or very rarely secrete GHRH, leading to gigantism Treatment consists of surgical resection and medical therapies when indicated by harmonl hypersecretion (see b ,p. 214). Metastatic tumors to the pituitary \200 Most commonly includes colon, lung and breast can cers (in 2/3 of the cases). Typically these tumors present in the sixth to seventh decades of life as part of widespread metastatic disease. DI is common (>70% of cases) and is a distinguishing characteristic. \200 Mass effects an d hypopituitarism are less commonly observed (<30%). \200 Treatment is mainly palliative. Surgical debulking and radiation therapy are rarely indicated for pituitary mass effects. Pituitary hormone replacement, particularly dDAVP, glucocorticoids and thyroid hormone, as indicated for these de \201 ciencies. Further reading Kaltsas GA, Evanson J, Chrisoulidou, Grossman AB (2008). The diagnosis and management of para- sellar tumors of the pituitary. Endocr Relat Cancers 15:885 \200\223903 . Komninos J, Vlassopoulou V, Protopapa D, Kor \201 as S, et al. (2004). Clinical case semin ar. Tumors metastatic to the pituitary gland: case report and literature review. J Clin End ocrinol Metab 89:574 \200\223580. 22-Draznin-Chap22.indd 135 3/31/2011 2:49:40 PM CHAPTER 23 In \202 ammatory & in \201 ltrative pituitary diseases 136 In \202 ammatory and in \201 ltrative pituitary diseases Background In \202 ammatory, in \201 ltrative and granulomatous diseases of the hypothala - mus and pituitary gland are uncommon but should be considered in cases of systemic illnes ses that are associated with pituitary enlargement, mass effects (e.g., headaches, vision d isturbances) and neurogenic diabetes insipidus. Box 23.1 Classi \201 cation of hypophysitis Lymphocytic hypophysitis \200 Lymphocytic adenohypophysitis (LAH) \200 Lymphocytic infu ndibuloneurophysitis (LINH) \200 Lymphocytic panhypophysitis (LPH) Xanthomatous \200\224c haracterized by foamy histiocytes Granulomatous \200 Idiopathic \200\224giant cell \200 Infectious \200\224tuberculosis ( TB) \200 Systemic granulomatous disease Sarcoidosis \200 Wegner \200\231s granulomatosis Systemic histiocytosis Langerhan \200\231s cell histiocytosis \200 Erdheim \200\223Chester disease Infectious disease (e.g., viral, fungal, syphilis) 23-Draznin-Chap23.indd 136 4/1/2011 6:36:52 PM LYMPHOCYTIC HYPOPHYSITIS 137 Investigations In \202 ammatory lesions typically appear as an enlarged pituitary gland an d stalk and may mimic a pituitary mass. In contrast to adenomas, how- ever, these lesions t ypically show marked enhancement on contrasted T 1 -weighted MRI images. Biopsy of the pitu itary lesion, by a transsphenoi- dal approach, may be indicated for a de \201 nitive diagn osis. Lymphocytic hypophysitis Lymphocytic hypophysitis is a disease characterized by lymphocytic in \201 ltra- tion of the hypothalamus and/or pituitary gland and is an autoimmune (T cel l \200\223mediated) process. \200 It varies between focal (adenohypophysitis) and diffuse (panhypophysitis) processes. Lymphocytic hypophysitis is associated with other autoimmune conditions (e.g., Hashimoto \200\231s thyroiditis, Addison \200\231s disease, pernicious an emia) in >30% of cases. Anti-pituitary antibodies, although variably present, are not sensitive or speci \201 c markers. Clinical presentation LAH is associated with pregnancy (last trimester and within 1 year po st- partum) in 770 \200\22380% of cases. LINH has an equal gender distribution. \200 Mass effects; headaches (60%) and visual disturbances (40%) \200 1 Hypopituitarism-ACTH and T SH de \201 ciencies are slightly more common (60 \200\22365%), than gonadotropin and GH de \201 ciencies (40 \200\22354%) \200 PRL levels are variable: frequently elevated with mass effects (20 \200\22340%), or may be low with a destructive/in \201 ltrative process. DI is common with neurohypophyseal involvement (e.g., LINH, LPH). Treatment An empiric trial of pharmacological glucocorticoids, early in the disease process (<6 months), has been advocated in the setting of mass effects and progressive pituitary d ysfunction, although data are limited regarding its true bene \201 t relative to the disea ses \200\231 natural history. \200 Transsphenoidal surgery is sometimes indicated for dia gnostic con \201 rmation and mass effects. Adjuvant therapies such as other immunosuppressive agents (e.g., azathioprine, methotrexate , cyclosporine A) and radiation therapy have been tried in selective cases and with variabl e success. Pathology Histopathology is the gold standard for the diagnosis and shows a lym- phocytic i n \201 ltration of T cells, particularly CD4 cells. Natural history Outcomes vary between spontaneous resolution and normal pituit- ary gland f unction to progressive pituitary gland \201 brosis and permanent hypopituitarism. 23-Draznin-Chap23.indd 137 4/1/2011 6:36:53 PM CHAPTER 23 In \202 ammatory & in \201 ltrative pituitary diseases 138 Sarcoidosis Sarcoidosis is a chronic, multisystem disease of unknown etiology that is chara cterized by the presence of granulomas. Clinical features \200 Sarcoidosis affects young and middle-aged adults most commonly and has an equal gender prevalence. Most cases have multivisceral (e.g., lungs, cardiac, sinonasal, eye, skin) involvement at the time of diagnosis. Isolated CNS disease occurs in 75% of cases and can involve the hypothalamus, pituitary gla nd, cranial nerves and leptomeninges. \200 Hypopituitarism is common, including gonadotro pe de \201 ciencies, hyperprolactinemia and diabetes insipidus as early manifestations. \200 Hypothalamic involvement may also manifest with disturbances in sleep, thirst (primar y polydipsia/adipsia), appetite and temperature regulation. Investigations Serum and CSF angiotensin-converting enzyme (ACE) levels may be ele- vated, although these tests are not sensitive or speci \201 c for neurosarcoido- sis. MRI \201 ndings are as described earlier under Investigations (see p. 137). In addition, MRI may dem onstrate meningeal enhancement. Management Glucocorticoid therapy is the mainstay of treatment. \200 Pharmacological dose s of glucocorticoid (e.g., 1 mg/kg/day prednisone for 2 \200\2234 weeks) are recommended fo r initial treatment. Subsequent steroid dosage and duration are dependent on the disease re sponse and severity. Adjuvant therapies, including azathioprine, methotrexate, in \202 iximab, and radiation th erapy, have been tried in selective cases and with variable success. Natural history The disease course varies from monophasic (66% of cases) to relapsing/ remi tting to progressive disease. Glucocorticoid therapy generally does not reverse the hormona l de \201 ciencies. 23-Draznin-Chap23.indd 138 4/1/2011 6:36:53 PM HEMOCHROMATOSIS 139 Langerhans \200\231 cell histiocytosis This rare, multisystemic disease is characterized by aberrant proliferation of dendritic cells (called Langerhan \200\231s cells ). Clinical features and treatment \200 Incidence is 3 \200\2235 cases per million. \200 M ost cases occur in children; up to 50% manifest with pituitary disease, with DI and growth hormone de \201 ciencies being the most common abnormalities. In adults, diffuse disease (e.g., skin, bone, lung) is usually present at the time of diagnosis and is associated with a 20% mortality rate. Standard Langerhan \200\231s-directed therapy of vinblastine and steroids does not reverse pituitary hormone de \201 ciencies. Hemochromatosis This disorder is characterized by increased iron absorption and multi-or- g an deposition, including the heart, liver, pancreas and the pituitary gland. Clinical features and treatment \200 Hypogonadotropic hypogonadism is the most common pit uitary manifestation of hemochromatosis and re \202 ects a predilection for iron deposition in go nadotrope cells. MRI may show decreased T 1 and T 2 signaling from paramagnetic iron deposition. Phlebotomy is the mainstay of treatment and may reverse the pituitary dysfunction, although long-term sex steroid replacement is frequently required. Further reading Carpinteri R, Patelli I, Casanueva FF, Giustina A (2009). In \202 ammatory and granulomatous expansive lesions of the pituitary. Best Pract Res Clin Endocrinol Metab 23:639 \200\223650. Molitch ME, Gillam MP (2007). Lymphocytic hypophysitis. Hormone Res 68:145 \200\223150. 23-Draznin-Chap23.indd 139 4/1/2011 6:36:53 PM CHAPTER 24 Surgical treatment of pituitary tumors 140 Surgical treatment of pituitary tumors Transsphenoidal surgery (TSS) Minimally-invasive, endonasal TSS is the preferred approach, for pituitary tumors, and accounts for 795% of pituitary surgeries. See Box 24.1 for indica tions. Compared to craniotomy, TSS has the following advantages: \200 Reduced associated morbidity and mortality \200 Better visualization of small tumors \200 Reduced duration of hospital stay Preoperative management \200 Optimize medical comorbidities. \200 In apoplexy, correct \202 uid, electrolyte and hormone de \201 ciencies (as indicated), with an emphasis on glucocorticoid and thyroid hormone replacement. In macroadenomas, assess and treat hypopituitarism, particularly glucocorticoid and thyroid hormone de \201 ciencies as indicated. Box 24.1 Indications for transsphenoidal surgery (TSS) \200 Nonfunctioning pituitary aden omas (usually macroadenomas) Gonadotropinomas \200 Null cell adenomas Functioning pituitary adenomas \200 GH-secreting adenoma \200 ACTH-secreting tumor \200 Prolactinoma \200\224if patient is dopamine agonist resistant or intolerant TSH-secreting adenoma \200 Nelson \200\231s syndrome Pituitary apoplexy \200 Recurrent pituitary tumors \200 Parasellar tumors Craniopharyngioma \200 Rathke \200\231s cleft cyst \200 Chordoma \200 Arachnoid cyst Pituitary biopsy for de \201 nitive diagnosis (e.g., hypophysitis, pituitary metastases) 24-Draznin-Chap24.indd 140 3/31/2011 2:50:54 PM TRANSSPHENOIDAL SURGERY (TSS) 141 Discontinue antiplatelet therapies and substitute anticoagulants as needed. \200 Consider preoperative medical treatment for severe Cushing \200\231s disease. \200 Consider medic al treatment of acromegalic patients with signi \201 cant preoperative comorbidities (e.g., congestive heart failure [CHF], OSA). Establish euthyroid status for thyrotropinomas associated with hyperthyroidism. Perioperative management \200 Prophylactic antibiotics are given perioperatively to reduc e the risk of meningitis. Immediate postoperative issues include monitoring for DI and neuro- ophthalmalogic complications. 2 Patients with Cushing \200\231s disease require peri- and postoperative gluco- corticoid treatment because of persistent secondary adrenal insuf \201 ciency with successful tumor resection (see b, Cushing \200\231s disease, p. 116). \200 DVT prophylaxis is necessary f or Cushing \200\231s patients because hypercortisolism induces a hypercoagulable state. Complications of transsphenoidal surgery (see Table 24.1 ) \200 The complication risks ar e highly dependent on the neurosurgeon and correlate inversely with TSS experience. \200 For experienced neurosurgeons (>200 transsp henoidal surgeries), mortality rates are low (<1%). Morbidity related to \202 uid and electrolyte balances, such as DI, complicates an estimated 10 \200\22315% of transsphenoidal surgeries, but is usually transi ent. Table 24.1 Potential complications of pituitary surgery Complications of any surgical procedure Anesthesia related Venous thrombosis and pulmonary embolism Immediate Hemorrhage/hematoma Hypothalamic damage Carotid injury Meningitis Transient DI CSF rhinorrhea Visual deterioration Epistaxis/septal perforation Sinusitus SIADH Permanent Visual deterioration or loss Cranial nerve damage Hypopituitarism DI 24-Draznin-Chap24.indd 141 3/31/2011 2:50:54 PM CHAPTER 24 Surgical treatment of pituitary tumors 142 Newer surgical techniques such as computerized navigation, endoscopy, and intraoperative imaging are used in selected cases and centers, although they are still not widely available. Postoperative management \200 Clinical evaluation on postoperative days 14, to assess for symptomatic improvement and to exclude complications (e.g., hyponatremia and sinusitis). Pituitary hormone function is preserved in most patients with preoperative normal function and may improve in 730% of patients with pre-operative hypoprt urtarism. This percentage is likely higher with an experienced neurosurgeon and for hypogon adism caused by hyperprolactinemia-related stalk effects. Vision improves in >80% of patients following optic nerve decompression but varies by disease duration and severity and may take several months to fu lly recover. A postoperative MRI and pituitary hormone testing (basal dynamic) are recommended at 3-m onth initially, and then annually for the \201 rst \201 ve years. Box 24.2 Postoperative disorders of \202 uid balance \200 Acute and transient DI \200 Hyponatremia from excessive hypotonic \202 uid administration or SIADH Permanent DI \200\234classic triphasic DI response: \200\235 initial DI due to axon shock (hours \200\223days) followed by antidiuretic phase due to uncontrolled release of ADH from damaged posterior pituitary (2 \200\22314 days) followed by DI due to depletion of ADH. Pe rmanent DI complicates <2% of TSS. Isolated SIADH phase, delayed hyponatremia at 7 \200\22310 days postoperative, usually mild and self-limiting. More common in the elderly population. 24-Draznin-Chap24.indd 142 3/31/2011 2:50:54 PM TRANSFRONTAL CRANIOTOMY 143 Transfrontal craniotomy Indications Craniotomy is often the preferred surgical approach for a giant pituitary tumor (>4 cm) or a purely suprasellar location (e.g., craniopharyngiomas, meningiomas). Complications (see Table 24.1) Craniotomy has higher complication rates than does TSS. The potential complications are as listed for TSS (Box 24.1), and include the following: \200 Brain retraction may lead to cerebral edema or hemorrhage. \200 Manipulation of the opti c chiasm may lead to visual deterioration. \200 Damage to the olfactory nerve. Perioperative management \200 Recovery is typically slower than after transsphenoidal sur gery. \200 Prophylactic anticonvulsants are commonly used. \200 Patients are typically given dexamethasone over 1 \200\2232 weeks to minimize the risk of brain edema. Further reading Joshi SM, Cudlip S (2008). Transsphenoidal surgery. Pituitary 11:353 \200 \223360. Laws ER, Thapar K (1999). Pituitary surgery. Endocrinol Metab Clin N Am 28:119. Vance ML (2003). Perioperative management of patients undergoing pituitary surgery. Endocri nol Metab Clin N Am 32:355 \200\223365. Ciric I, Ragin A, Baumgartner A, Crain PA Pierce D (1997). Complications of transphenoidal surgery:results of a national survey, review of the literature and personal experience. Neu rosurgery 40:225 \200\223237. 24-Draznin-Chap24.indd 143 3/31/2011 2:50:54 PM CHAPTER 25 Medical treatment of pituitary tumors 144 Medical treatment of pituitary tumors Dopamine agonists (DA) For indications for use see Prolactinomas (p. 107) and Acromegaly (p . 114). DA formulations/doses \200 Bromocriptine (Parlodel): short-acting, non-ergot derivative. Usually administered orally, twice daily. Therapeutic daily dose for prolactinomas ranges b etween 5.0 and 30 mg; usual dose is 10 mg a day. Bromocriptine is the preferred medication in women seeking fertility because of the greater safety data during pregnancy. \200 Cabe rgoline (Dostinex): long-acting ergot derivative. Usually administered twice a week. The usual therapeutic dose is 1.0 mg a week. \200 Better side- effect pro \201 le and more ef \201 cacious than bromocriptine Pergolide (Permax): no longer available in the United States Mechanism of action DAs activate D 2 receptors, which are coupled to inhibitory G proteins, and decrease cAMP production. Side effects Side effects, particularly with bromocriptine, may be minimized by starting a low dose (e.g., 1.25 mg/day), and titrating up slowing. In females, vaginal administration can be tried if GI intolerance is dose limiting. Common side effects (>10%) \200 Nausea \200 Fatigue \200 Headache Less common side effects (<10%) \200 Postural hypotension, dizziness, nasal stuf \201 ne ss, constipation and a Raynaud-like phenomenon in the hands. Very rarely, patients develop hallucinations and psychosis (usually at higher doses). Uncommon side effects The problems of cardiac valvulopathy, as noted in Parkinson \200\231s patients on high-dose cabergoline (>3 mg/day), is uncommon in prolactinoma patients on sta ndard cabergoline doses ( < 2 mg/week). 25-Draznin-Chap25.indd 144 3/31/2011 2:51:14 PM SOMATOSTATIN ANALOGS 145 Somatostatin analogs Box 25.1 Uses of somatostatin analogs \200 Acromegaly \200 Carcinoid tumors \200 Panc reatic neuroendocrine tumors \200 TSH-secreting pituitary tumors Indications for use See Acromegaly (p. 114). Mechanism of action \200 Analogs of the naturally-occurring GH inhibitor somatostatin, bu t with increased serum half-lives and higher somatostatin receptor af \201 nities. \200 The somatostatin analogs signal predominantly through somatostatin receptors subtypes 2 and 5. Formulations/doses \200 Octreotide LAR (Sandostatin LAR) (10 \200\22330 mg intramuscul ar [IM]) administered every 4 \200\2236 weeks Lanreotide Autogel (Somatuline) (60 \200\223120 mg deep subcutaneous [SC]) administered every 4 \200\2236 weeks SC octreotide (50 \200\223200 mcg) administered 3 \227 daily. \200 Lanreotide SR (30 mg IM) administered every 7 \200\22314 days. Side effects \200 Gallstones or sludge develops in 720 \200\22330% of patients, but only 1%/year develop symptomatic cholecystitis. Abdominal cramps, bloating and mild steatorrhea, due to inhibition of motor activity and pancreatic enzymes secretion, commonly occur early in treatment, alth ough symptoms usually improve, or resolve, over the \201 rst few months. Transient worsening of diabetes (from inhibition of B-cell function). \200 Injection site pain is minimized by allowing the medication to warm to room temperature before administration. Hair loss (<10%) Issues \200 The long-acting somatostatin analogs have similar ef \201 cacies and side- effect pro \201 les. The need for dose titrations should be assessed at 3 month intervals, based on the IGF-1 levels. IGF-1 levels, but not GH-OGTT suppression tests, are recommended to monitor the therapeutic response to somatostatin analogs in acromegaly. 25-Draznin-Chap25.indd 145 3/31/2011 2:51:15 PM CHAPTER 25 Medical treatment of pituitary tumors 146 Growth hormone receptor antagonists Indications for use include medical therapy for acromeg alic patients who are incompletely responsive to, or intolerant of, somatostatin analogs. Mechanism of action \200 Mutated GH molecule that binds to peripheral GH receptors (predo minantly on the liver) and blocks GH receptor signaling Formulations and doses \200 Pegvisomant (Somavert) 40 mg SC loading dose, followed by 10 \200\22340 mg SC administered daily Side effects \200 Abnormal liver function tests (transaminitis), in 75%, but are usually transient Injection site reactions (i.e., atopic reactions or lipohypertrophy) Issues \200 High cost \200 Successful weekly and biweekly administrations of pegvisoman t have been reported, based on its long half-life (70 hours). 2 Therapeutic response is assessed by IGF-1 levels only (GH levels are elevated on GH antag onist therapy). \200 The need for dose titrations should be assessed at 73-month interval s. \200 Medication has no effect on tumor size. MRI of the pituitary is indicated 6 months after starting therapy and then annually thereafter. Long-term studies i ndicate a low risk for tumor growth (<5 % over 5 years). Pegvisomant can be given concomitantly with somatostatin analogs to control GH hypersecretion. Further reading Higham CE, Bidlingmaier M, Drake WM, Trainer PJ (2009). Successful use of w eekly pegvisomant administration in patients with acromegaly. Eur J Endocrinol 161:21 \200 \22325. Melmed S, Colao A, Barkan M, Molitch M, et al. (2009) Guidelines for acromegaly management: an update. J Clin Endocrinol Metab 94:1509 \200\2231517. Trainer PJ (2009). ACROSTUDY: the \201 rst 5 years. Eur J Endocrinol 161:S19 \200\223S24. Trainer PJ, Drake WM, Katznelson L, Freda PU, et al. (2000). Treatment of acromegaly with t he growth hormone receptor antagonist pegvisomant N Engl J Med 342:1171 \200\2231177. 25-Draznin-Chap25.indd 146 3/31/2011 2:51:15 PM TECHNIQUES TECHNIQUES 147 Pituitary radiotherapy