مدیریت بیماران با آدنوم نان-فانکشن هیپوفیز

: مخاطبین : رزیدنتهای محترم داخلی و فلوهای محترم غدد

مختصر و مفید  از:
UPTODATE 21.2

Treatment of gonadotroph and other clinically nonfunctioning adenomas
MANAGEMENT APPROACH
treatment should be promptly instituted for those with impaired vision, and considered for those at high risk for loss of vision (marked suprasellar tumor extension). Standard first-line therapy is transsphenoidal surgery ( TSS ) , followed by radiation therapy if there is considerable residual adenomatous tissue.
Long-term monitoring is necessary because the risk of tumor regrowth is significant, particularly after surgery alone.
Radiation therapy is also indicated for patients whose adenoma recurs.
Life-long management of pituitary hormone deficiencies is required in many patients.
Goals of treatment —
• Relief of visual impairment or other neurologic symptoms
• Removal of pituitary macroadenoma (as complete as possible to avoid recurrence)
• Management of hormonal deficiencies due to compression of nonadenomatous pituitary cells by the macroadenoma
Surgical approach — TSS is the treatment of choice for initial therapy.
TSS reduces the size of the adenoma and its hormonal hypersecretion ( > 90 % of cases) ; it improves vision > 80 % .
Preoperative preparation —
• Identifying one of these biochemical markers can also be used to monitor the response to surgery and subsequent therapy.
• Identifying a highly experienced pituitary surgeon.
• Identifying any pituitary hormone deficiencies that need to be treated preoperatively,

Perioperative management —
An MRI on postoperative day 1 gives an initial view of how much of the adenoma has been removed, even though a more accurate view is provided when the artefacts of surgery have regressed 3-6 months later.
Perioperative hormonal management should be directed toward abnormalities of cortisol and vasopressin.
Hypocortisolism —

patients should be treated with 100 mg of hydrocortisone beginning at the induction of anesthesia. The dose should be gradually decreased during the next few days.

We recommend a replacement dose (eg, 15 to 25 mg/day) following discharge until the initial postoperative evaluation four to six weeks after discharge.

Others recommend measuring serum cortisol on the third postoperative day, 24 hours after the previous dose of hydrocortisone, and if the value is low (less than 4 mcg/dL [110nmol/L]) or borderline (5 to 17 mcg/dL [138 to 469 nmol/L]),prescribing replacement hydrocortisone on discharge .

Diabetes insipidus and SIADH —

DI is more common, occurring in 18.5 %- 54.2 %
It usually occurs within the first 24 hours postoperatively and is usually transient but is sometimes permanent. In the series of 319 patients, almost 50 percent had remitted in one week and about 80 percent in three months .
SIADH is less common, occurring in 8.8 – 23 %
SIADH occurs between day 4 – 10.
Sometimes a patient experiences only diabetes insipidus, but less often the patient experiences diabetes insipidus followed by SIADH and, even less often, the SIADH is followed once more by diabetes insipidus .

any patient who has TSS be assessed daily postoperatively by inquiring about thirst and measuring I/O , serum sodium, and urine SG .

If DI has not occurred by the time of discharge, the serum sodium should be repeated as an outpatient on day 7.

DI that occurs in the first day after surgery, when absorption through the nasal mucosa is variable, should be treated with dDAVP IV in doses from 0.25 to 1.0 mcg every 12 to 24 hours, titrated to keep urine volume and serum sodium normal.

If DI has not remitted by the time of discharge, the dDAVP can be given as a nasal spray.

If the condition is partial or the patient is very sensitive to dDAVP, it can be administered orally, 0.1 to 0.2 mg at bedtime alone or more often.

SIADH is treated by fluid restriction until it remits, usually by postoperative day 10.

Short-term monitoring —

Four to six weeks after discharge from the hospital, the patient should be evaluated for the following:
• Amount of residual adenoma.
• by monitoring the serum concentration of FSH or the free alpha subunit, that had been elevated before surgery.
• Visual function (by acuity and visual fields).
• Hormonal function of the nonadenomatous pituitary, regardless of whether it was normal or abnormal prior to surgery. This evaluation should include measurements of:
• Serum thyroxine.
• Early morning serum cortisol 24 hours after the previous dose of hydrocortisone . If the serum cortisol value is ≤3 mcg/dL (83nmol/L), the patient has secondary adrenal insufficiency (ACTH deficiency); if it is ≥18 mcg/dL (497 nmol/L), the patient has normal adrenal function; if it is between 4 and 17 mcg/dL (110 and 469nmol/L) on three occasions, a test of (ACTH) reserve, such as a metyrapone test, should be performed.
• cosyntropin test should not be used in these patients because it may give a falsely normal result
• Serum testosterone in a man or serum estradiol in a premenopausal woman.
• 24-hour urine volume if the patient has significant nocturia. A water deprivation test should be performed if the urine output is above 3L/day; values above 6 L/day are almost always due to diabetes insipidus.

Residual adenoma —
o Although results are widely variable by center and surgeon, in a meta-analysis of 58 case series of patients with nonfunctioning pituitary adenomas undergoing TSS , complete removal of the adenoma, as judged by the surgeon, was achieved in only 20% of cases . More experienced surgeons and high volume centers have higher rates of complete removal (approximately 65 to 75 % ) .

 20 % of adenomas recur after TSS alone ;

 if there is evidence of residual adenoma in MRI , the addition of radiation therapy lowers the risk of subsequent recurrence.
 Radiation therapy is typically started if an MRI performed 6 to 12 months after surgery shows substantial residual adenoma tissue or if residual adenoma tissue shows progressive growth in the months or years after surgery.

Visual function —
TSS improves visual function in 80% of patients ;
improvement can be seen in the first few days after surgery .
If visual function was abnormal before surgery, it should be reevaluated a month or two afterward and less often until no further change occurs.

Hormonal abnormalities —
improvement in pituitary function is less likely.
30 % of patients experienced an improvement in some hormone deficiency .
However, most patients are left with long-term deficiencies that need replacement.
the approximate frequencies of postoperative hormone deficiencies were :
• GH – 83 percent
• LH/FSH – 60 percent
• TSH – 30 percent
• ACTH – 30 percent
Complications —
the mortality rate in the immediate postoperative period was 1% .
Serious complications occurred in < 5% of patients, and included cerebrospinal fluid leakage, fistula, meningitis, and new visual field defects.

Adjuvant radiation therapy —
 is useful in preventing regrowth of residual adenoma tissue following TSS .

 Indication is based on the amount and location of the residual tissue, an assessment of the aggressiveness of the adenoma, and the patient’s age and general health status.

 If the postop day 1 MRI shows a large amount of residual adenoma tissue, the decision to radiate could be made a month after surgery, but otherwise the decision is usually made by an MRI performed three to six months after surgery, when artefacts of surgery have regressed.

 Radiation is also useful when there is evidence of adenoma regrowth in the months or years after surgery.
 When administered for adenoma regrowth, conventional radiation therapy results in 10 year control rates, defined as lack of progression clinically and radiologically, of 80 % .
 Radiation therapy is usually not employed as primary therapy for gonadotroph and other clinically nonfunctioning pituitary adenomas

“Conventional” radiation therapy —
administered in 23 to 25 daily doses of 2 Gy each, without stereotactic mapping.
Side effects of conventional and stereotactic radiation therapy can occur both during therapy and up to 10 years later.
• Symptoms that occurred during treatment include nausea, lethargy, loss of taste and smell, and loss of hair at the radiation portals. The first two remit within one to two months, and the last two usually remit within six months.
• The most common late complication was hypopituitarism .
• There was an 50% likelihood that at least one pituitary hormone that was normal prior to radiation became subnormal within the ensuing 5 years .
• Neurologic complications were less common but more serious. Optic neuropathy has been reported .
• as well as second, malignant brain tumors .
• increased risk of cerebrovascular disease, but there is little documentation.
Stereotactic radiation —
 The Several series have now reported the results of fractionated radiotherapy using a linear accelerator or proton in patients

 These results seem relatively good, but no better or worse than conventional radiation therapy.
 Overall, single-dose radiation also appears to give good results, but not clearly superior to those previously reported with conventional radiation.

Unproven therapies —

 Bromocriptine therapy for nonfunctioning adenomas has been disappointing ;
 cabergoline may have some effect .
 octreotide
 Unfortunately, administration of GnRH agonist analogs to patients with gonadotroph adenomas usually has either an agonist effect or no change in gonadotropin secretion and does not affect adenoma size .

Long-term follow-up —
include testing every 6 to 12 months initially to detect growth of residual adenoma tissue and the adequacy of hormonal replacement.

Adenoma regrowth —
 Evaluation for tumor regrowth should include measurement of whatever serum marker was elevated before surgery and an MRI ;
 if there is no regrowth after a year or two, the interval between scans can be lengthened.
 Early detection permits appropriate use of radiation therapy to minimize the need for repeat surgery.

 patients who undergo subtotal resection of an adenoma with suprasellar extension are at high risk for recurrence . These patients benefit from adjuvant radiotherapy.

 If MRI six months after TSS shows little adenoma tissue or the residual tissue is not in a location of clinical significance, we recommend observation only by MRI, initially yearly.

Quality of life — (QOL)
 QOL reduced after long-term cure of functioning pituitary adenomas .
 Patients with nonfunctioning pituitary macroadenomas treated successfully by TSS alone or combined with radiotherapy also have impaired quality of life .

 patients commonly experience increased fatigue and daytime somnolence

 The impaired QOL and fatigue appear to be due to the underlying hypopituitarism that is present in many patients , as well as impaired sleep quality and abnormal distribution of sleep stages .

ASYMPTOMATIC ADENOMAS —

o Gonadotroph adenomas that are asymptomatic and not an immediate threat to vision may not require surgery , although hormonal deficiencies should be treated, and reevaluation of adenoma size and pituitary function should be performed at yearly intervals.

o Limited data are available on the natural history of nonfunctioning macroadenomas because most patients undergo surgery. However, in studies that have monitored growth of these tumors for more than four to five years, approximately 50 percent of patients experienced adenoma growth .

o Thus, although watchful waiting may be appropriate in some cases, long-term follow-up is necessary as tumor growth can be anticipated in 50 percent of patients.

o In a small percent of cases, nonfunctioning adenomas may spontaneously regress. In a review of 10 series, this occurred in 34 of 304 patients (11 percent) , and was thought to be due to silent ischemia, while in an individual series of 37 patients with five years of follow-up, four experienced pituitary apoplexy .

تصویر پروفایل نویسنده:دکتر علی میرزاپور
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