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Endocrinology and Metabolism
Peter A. Singer, M.D.
November 26, 2002 11-12 am
PITUITARY TUMORS —Clinical Features, Diagnosis, and Management
Objectives
By the end of this teaching activity, students will be able to:
1. Discuss the differential diagnosis of lesions of the sella turcica.
2. Describe the clinical presentation of pituitary tumors, including both non-functioning
and functioning tumors.
3. Outline a diagnostic approach to pituitary tumors.
4. Describe various treatment options for pituitary tumors, and select appropriate therapies.
Reading – Recommended/Supplemental
1. Harrison’s Online; Chapter 28 (excellent source – this is encouraged)
2. Principles and Practice of Endocrinology and Metabolism, Chaps 12,13,16,17,20-24.
www.usc.edu/nml - ovid - books on file
Points of Integration
Case 5
Introduction
Pituitary tumors, as well as other lesions in the area of the sella turcica, are relatively common. The prevalence of clinically apparent pituitary lesions is estimated to comprise approximately 10 % of all intracranial lesions, while incidental pituitary tumors are detected in approximately 11% of individuals at autopsy. Moreover, CT and MRI scanning performed for disorders unrelated to pituitary disease uncover similar numbers of pituitary lesions, most of which are less than 1 cm in size.
Pituitary tumors (and other sellar masses) result in morbidity by presenting with neurologic symptoms and signs, by hypopituitarism, or by hormonal excess. The purpose of this syllabus material is to outline a clinical approach to the diagnosis and management of such lesions.
Differential diagnosis of sellar lesions
Pituitary tumors are the commonest lesions occurring in the sella turcica. Table 1 provides a differential diagnosis of lesions of the sella, including prevalences of lesions from a surgical series in our clinical practice at USC-University Hospital.
Table: University of Southern California- University Hospital Surgical Experience for Sellar Lesions from 1991 to 2002 (n=833)
Tumor Type Macroadenoma (>10mm) Microadenoma (<10mm) M:F ratio
Non-Functioning 401 4 1.5 : 2
Functioning
ACTH 16 70 1 : 5
GH 86 10 1.5 : 1
TSH 7 1 : 1
Prl 74 68 1 : 1.3
Other Tumors (Lesions) 91 1 : 1
Abbreviations: ACTH=adrenocorticotropin hormone; GH= growth hormone; TSH=thyrotropin hormone; Prl=prolactin; M=male; F=female.
Other tumors include: craniopharyngioma (n=33); Rathke’s cleft cyst (n=31); clivus chordoma (n=6); sellar meningioma (n=18); hyperplasia (n=3); metastatic (0) (breast, prostate, renal); sarcoid – 1 ; fibrosis – 1; hemangioma - 1
Note that among sellar lesions craniopharyngiomas, Rathke’s cleft cysts, and meningiomas are relatively common. Craniopharyngiomas and Rathke’s cysts are outgrowths from remnants of Rathke’s pouch. Meningiomas are benign lesions arising from the meninges. All of these lesions may mimic the clinical findings associated with non-functioning pituitary tumors, namely pressure effects resulting in visual changes, and impairment of secretion of trophic hormones. The other lesions listed in the differential diagnosis are very uncommon, accounting for only a few percent of sellar lesions. Not included in Table 1 (since we haven’t seen cases in our surgical series) are lymphocytic hypophysitis, pituitary abscess, or arteriovenous fistulas of the cavernous sinuses.
Pituitary tumors are virtually always benign adenomas. Pituitary carcinoma has been reported to comprise about 0.5 % of pituitary tumors, although that has not been our experience, having seen only one carcinoma in more than 600 tumors.
Tumors are classified according to size, and function. For example, a tumor less than 1 cm in size is a microadenoma and a lesion 1 cm or larger is a macroadenoma. Most tumors are non-functioning, meaning that they are not hormonally active, while functioning tumors may secrete either prolactin, growth hormone (GH), corticotropin (ACTH), or thyrotropin (TSH). Each of the functioning tumors results in a specific clinical syndrome (see below). Strictly speaking, so-called non-functioning tumors may secrete gonadotropins, but are very infrequently associated with a syndrome of gonadotropin excess, which would include elevated target organ sex steroid levels.
Clinical presentation and diagnosis of specific tumors
• Non-functioning tumors
o Clinical features—non-functioning adenomas are the commonest of the tumors, and, because they are for the most part hormonally inactive, present with pressure symptoms. Bitemporal hemianopsia is the commonest visual abnormality, and results from compression of the optic chiasm by suprasellar extension of the tumor. If chiasmal pressure is severe enough, decreased visual acuity may occur, and if there is extension of the tumor into the cavernous sinus, oculomotor palsies may be present. Unfortunately, tumors grow so slowly that gradual visual changes may not be noticed by the patient, so that vision at times is permanently affected. Headache is a very inconsistent symptom, and presumably occurs from increased sellar pressure; interestingly, most patients, even those with very large tumors, do not complain of headaches—no doubt if they did the diagnosis would be made much earlier.
Hormonal deficiencies occur because of destruction or pressure on normal pituitary tissue (see syllabus section on Hypopituitarism). Hormonal excess may also occur infrequently, since such lesions occasional secrete FSH and LH, and may result in ovarian hyperstimulation, with multiple ovarian cysts and elevated estradiol levels in premenopausal women, or elevated testosterone levels in males. These scenarios are very, very infrequent.
o Diagnostic evaluation—the diagnosis of nonfunctioning tumors depends first of all on recognizing the symptoms of such lesions, such as symptoms of visual impairment and symptoms of pituitary insufficiency, and then proceeding with appropriate imaging tests and hormonal measurements. The imaging procedure of choice for pituitary lesions is magnetic resonance imaging (MRI). MRI has excellent resolution for tumors, and can demonstrate pressure (where present) on the optic chiasm, as well as extension into the cavernous or sphenoid sinuses.
If a tumor is demonstrated on MRI the next step is to determine whether or not the lesion is functioning. Hormonally active lesions causing either acromegaly or Cushing’s disease are often obvious clinically, and whether or not to do tests for those disorders depends on the clinical picture. If patients do not appear clinically to have functioning tumors, hormonal deficiencies should be checked for. Serum gonadotropins and serum testosterone should be measured in men, and gonadotropins (and estradiol in premenopausal women) in women. (The differentiation between primary and secondary hypogonadism is described in the syllabus material on Hypopituitarism). If gonadotropins and either testosterone (males) or estradiol (women) are elevated, the diagnosis would be a functioning gonadotropinoma. In addition, free T4, TSH; and fasting serum cortisol determinations should be performed. Dynamic testing for ACTH or GH reserve is not necessary. It is imperative to measure serum prolactin, and if the prolactin is elevated, but less than 100 ng/ml in a patient with a macroadenoma, the prolactin elevation is almost certainly due to stalk effect in the presence of a non-functioning tumor—i.e., pressure on the pituitary stalk, with inhibition of dopamine.
• Prolactinomas
General comments--Prolactinomas are the commonest pituitary tumors, and are the second-commonest tumors for which patients are referred for pituitary surgery, usually because of side effects from therapy with dopamine agonists (Tables 1 and 2). They are more common in women than men, and may be either macro or microadenomas. Microadenomas appear to be more common in women, and macroadenomas occur more frequently in men. The biochemical hallmark of prolactinoma is an elevated serum prolactin; prolactin may be elevated because of multiple other causes, however, including both physiologic and pathologic, so it is important to know the differential diagnosis of hyperprolactinemia:
Physiologic Hyperprolactinemia Pathologic Hyperprolactinemia
-Pregnancy -Prolactinomas
-Nipple stimulation -Stalk effect (other tumors)
-Stress -Other functioning tumors
(E.g. GH)
-Inflammatory diseases--
(E.g. hypothalamic sarcoid)
-Stalk section, trauma
-Chest wall injury and irritation
-Chronic renal failure
-Drugs (e.g. haloperidol, metoclopramide, phenothiazines, risperidone, estrogen)
-Idiopathic
-Hypothyroidism
Note that “hypothyroidism” is bolded in the list of pathologic elevations of prolactin—this is because it is essential that hypothyroidism be ruled out before embarking on a further work-up for hyperprolactinemia. Indeed, long-standing and pronounced primary hypothyroidism may result in pituitary hyperplasia, and enlargement of the pituitary may lead to an erroneous diagnosis of a pituitary tumor. Serum prolactin elevations from stalk effect are rarely greater than 100 ng/ml, and elevations from hypothyroidism, drugs are rarely greater than 100 ng/ml. Similarly, idiopathic elevations also remain under 100 ng/ml; the likelihood is that such patients have microadenomas too small to detect.
o Clinical manifestations—in premenopausal women the commonest clinical features are oligo/amenorrhea, galactorrhea, and infertility. Since most tumors in younger women are microadenomas, neurologic pressure symptoms and signs do not occur. Such symptoms and signs may occur with macroprolactinomas, though. Hypopituitary symptoms associated with microprolactinomas are related to the degree to which prolactin inhibition of LH secretion lowers serum estradiol levels—the greater the prolactin increase, the lower the estrogen level; symptoms of estrogen deficiency, in addition to oligo/amenorrhea, may include hot flushes and vaginal dryness. In women with macroprolactinomas, pressure effects on the visual apparatus and deficiencies of other pituitary hormones may also be present. In postmenopausal women microprolactinomas rarely cause symptoms, since they are already amenorrheic, and rarely develop galactorrhea.
In men, symptoms and signs of prolactinoma are from pressure effects, including visual changes (if there is suprasellar extension), and hypopituitarism. The commonest endocrine abnormality is related to testosterone deficiency, and decreases in libido, impotence, and infertility, are common symptoms. Such symptoms are frequently overlooked, however, since sexual dysfunction may be ascribed to other issues and stresses. Thus, it may not be until there is significant visual impairment that the diagnosis of prolactinoma is made. Galactorrhea may occur in men, but is uncommon.
o Diagnostic Evaluation—the cornerstone in the evaluation of a woman with amennorhea/galactorrhea, and a man with impotence is the serum prolactin. An elevation in serum prolactin, regardless of the level (and providing that there are no other causes of hyperprolactinemia (see Table above) warrants an MRI scan. As mentioned, a serum prolactin above 100 ng/ml is usually due to prolactinoma, and a level above 200 ng/ml is virtual assurance of the diagnosis. The larger the adenoma, the greater the degree of prolactin elevation, so that some patients with large, invasive tumors have prolactin concentrations in the thousands.
If a macroadenoma is discovered on MRI, additional pituitary endocrine testing should be done (see syllabus material on Hypopituitarism). Patients with microprolactinomas do not have endocrine deficiency due to pressure effects, so no additional workup in such patients is necessary.
• Growth hormone producing tumors
- General comments—Growth hormone producing pituitary tumors cause the clinical syndrome of acromegaly, from excess GH secretion. By far the commonest cause of acromegaly is pituitary tumor; rare causes also include ectopic production of GH from carcinoid or small cell-lung cancer, or from rare tumors secreting growth hormone releasing hormone (GHRH).
GH- producing adenomas account for about one-third of functioning pituitary tumors. Approximately 75% of tumors are macroadenomas, and the mean age at the time of diagnosis is in the mid-40’s. If GH tumors develop during childhood or adolescence, before epiphyseal closure, gigantism results. This is uncommon, though.
Acromegaly results in particularly distressing morbidity for many patients, because of the disfiguring, non-reversible acral changes that occur. Patients often are particularly sensitive about their appearance, and support groups for patients with pituitary tumors consist primarily of patients with acromegaly, because of the psychological issues associated with the tumors.
o Clinical features--The clinical manifestations of GH-producing tumors result primarily from increased serum levels of insulin-like growth factor-1 (IGF-1), which is synthesized in the liver under the influence of GH. Excess GH secretion results not only in growth of various tissues, but in metabolic abnormalities as well. Moreover, since most GH-producing tumors are macroadenomas, pressure symptoms and signs of pituitary tumor may also occur.
Acromegaly tends to develop slowly, often over many years, so that many patients attribute the soft tissue and acral changes to the natural process of aging. It is in retrospect, though, especially when looking at photos, that patients and their families can recognize the slowly-developing changes.
The principle symptoms of acromegaly consist of soft tissue and acral changes. Patients universally admit to an increase in hand and foot size, and complain of difficulty with wearing rings, and the need to purchase ever-larger shoes. (One of my patients went to a local emergency department to have a ring cut off; it had finally become so tight that it was painful. In retrospect he had noticed his ring becoming tighter over the prior 8-10 years). Patients also notice prominence of the jaw, and a change in the bite, and it is not uncommon that visits to the dentist are made. Since bony growth is such a prominent feature of acromegaly, patients commonly develop arthritic symptoms, especially of large joints and the lumbar spine.
It should be noted that while soft tissue and acral changes are the most obvious changes of acromegaly, patients also have generalized symptoms of pituitary macroadenoma, including headache, visual change, and pituitary insufficiency. Indeed, hypogonadism occurs in approximately 50% of patients.
In addition to the obvious acral and soft tissue changes associated with acromegaly, visceromegaly also occurs, including the liver, thyroid, kidneys, and heart. Indeed, cardiovascular disease from both cardiomegaly and hypertension is a prominent cause of morbidity and mortality in untreated patients.
Acromegaly is associated with an increase in benign and malignant tumor development. Women have a much higher prevalence of leiomyomata, and all patients have a significant risk (up to 30%) for the development of premalignant colon polyps (and hence, colon cancer).
Metabolic complications of acromegaly are related primarily to the anti-insulin effects of IGF-1;
impaired glucose tolerance is common, and overt diabetes is present in approximately 25% of patients. Acromegaly is associated with hyperprolactinemia in about one-third of patients, often due to secretion of prolactin itself, rather than just from stalk effect.
It should be stressed that in addition to the obvious somatic changes of acromegaly, that untreated, the
disorder is associated with a significant increase in mortality, principally from cardiovascular disease and cancer. If treated appropriately, mortality should be no different than normal.
o Diagnostic evaluation—the biochemical diagnosis of acromegaly can be established by measuring IGF-1, GH, or a combination of both tests. Since the secretion of GH varies, virtually from minute to minute, obtaining a random GH measurement may result in either false negative or false positive results. IGF-1, on the other hand, does not vary over a 24 hour period of time, and it is therefore the single best test for the diagnosis of acromegaly, and separates normal individuals from those with GH excess. A caveat here is that levels of IGF-1 are age-dependent, with levels gradually decreasing with increasing age.
Growth hormone levels are also elevated in patients with acromegaly,
but because of its pulsatile secretion, “normal” levels may occasionally be encountered. Moreover, GH secretion changes with exercise and sleep (increases), and decreases with eating. Thus, in other than a stable state, GH determinations may lead in an incorrect diagnosis. On the other hand, in the patient with clinical features of acromegaly, a GH level of > 30 ng/ml is virtually diagnostic, but must be confirmed with an IGF-1 determination.
Dynamic testing of GH secretion is employed by some physicians in the diagnosis of acromegaly; oral glucose administration results in suppression of GH within 90-120 min after ingestion in normal subjects, but in those with acromegaly, GH remains unsuppressed, and may even increase following oral glucose. From a practical point of view there is little utility in testing GH suppressibility unless the diagnosis of acromegaly is in doubt.
Measurement of IGFBP-3, the circulating binding protein for IGF-1, tends to be elevated in states of GH excess, although overlap with normals limits its usefulness; nevertheless, some physicians employ this test as well.
Once the diagnosis of acromegaly is established clinically and biochemically, the next step in the evaluation is to obtain an MRI of the pituitary gland. Since virtually all acromegaly is due to pituitary disease, and mostly associated with macroadenomas, the MRI almost always confirms the presence of pituitary tumor. If the MRI does not demonstrate a tumor, ectopic sources must be sought, and imaging of the chest and abdomen are the next steps.
• ACTH producing tumors and TSH producing tumors— these tumors and their clinical syndromes are discussed in the syllabus sections on Adrenal disorders and Thyroid disorders, respectively.
Treatment of Pituitary Tumors
The goal of treatment of pituitary tumors is to remove pressure and relieve neurologic symptoms, and, where abnormal, restore pituitary function to normal. Therapy nowadays consists of three different forms; 1. Surgery, 2. Radiation therapy; and 3. Medical therapy. Some patients require all forms of treatment.
• Surgery—surgery, via the transsphenoidal approach, is the primary form of therapy for patients with non-functioning pituitary tumors, as well as for patients with Cushing’s disease, acromegaly, and TSH secreting tumors; it is also the choice of therapy among some physicians for very young (20’s) women with prolactinomas. With experienced neurosurgeons, cure rates approach 90 % for intrasellar non-functioning tumors, and for patients with functioning microadenomas, initial cure rates for Cushing’s patients and acromegaly approximates 80%, and for those with microprolactinomas, 90%. If tumors are larger, or invade adjacent structures, initial cure rates are significantly lower, and in such patients, adjunctive therapy becomes necessary. For example, since most patients with acromegaly have macroadenomas, initial cure rates overall are likely to be lower than with Cushing’s, where microadenomas are more common. For patients with invasive functioning tumors, surgical cure is the exception, rather than the rule.
Note that I use the term “initial” cure when mentioning functioning tumors. This is because relapses and recurrences occur, especially with Cushing’s disease, even though there has been an evident cure to begin with. Relapse/recurrence is less common in patients with acromegaly or with those who have prolactinomas. Patients who have undergone surgery for pituitary tumor require careful follow-up.
There are biochemical tests which may be obtained the morning after surgery in order to assess the likelihood of surgical cure in patients with functioning adenomas: A serum GH of <2 ng/ml by radioimmunoassay or < 1 ng/ml by immunoradiometric or chemiluminescent assay, a cortisol of < 1 mcg/dl, or a serum prolactin of < 2 ng/ml for patients with acromegaly, Cushing’s, or prolactinomas respectively, is suggestive of cure. Values higher are worrisome, and further testing is necessary. For patients with acromegaly the goal is a serum IGF-1 level in the normal range, but since IGF-1 may remain elevated for 10 days or longer following surgery, early assessment of cure relies on the immediate postoperative GH level.
Some patients with giant, invasive pituitary tumors, and who harbor other lesions in the area of the sella or hypothalamus, such as large invasive craniopharyngiomas, cannot undergo successful surgery via the transsphenoidal route; in such circumstances open craniotomy is performed. Such cases are uncommon, however, and in our experience only approximately 2% of patients have undergone craniotomy.
Complications of transsphenoidal surgery are fortunately uncommon, occurring in less than 5 % of patients, and include cerebrospinal fluid leak, meningitis, intrasellar hemorrhage, injury to the visual apparatus, or injury to he pituitary gland itself, with the development of hypopituitarism. Diabetes insipidus is relatively common, and is nearly always transient, generally lasting only a day or so. In our experience it occurs in approximately 20 % of patients undergoing transsphenoidal surgery. Permanent DI is more likely to occur in patients with craniopharyngiomas, or Rathke’s cleft cysts.
• Radiation therapy—radiation therapy had previously been employed as primary therapy for some patients, but it’s use nowadays is reserved as adjunctive therapy, either following surgery, or in some patients with functioning tumors in whom medical therapy does not control the disease. Radiation is administered either by conventional external beam, fractionated therapy, or in some patients, with stereotactic radiosurgery (gamma knife). Radiation therapy for nonfunctioning tumors is reserved for those individuals with residual tumor, or for those in whom early tumor recurrence is detected. Similarly, radiation is employed for patients with functioning tumors in whom medical therapy is ineffective, or incomplete.
In recent years stereotactic radiotherapy has become increasingly popular, since hypopituitarism occurs much less frequently than with conventional external beam radiation. Patients receiving conventional therapy have an approximately 50% likelihood of developing pituitary insufficiency within 5 years following completion of therapy., Gamma knife radiotherapy also has the advantage of being administered in a single dose, whereas conventional treatment requires daily doses over 4-6 weeks. Pitfalls of both types of therapy is that reduction in hormone levels of functioning tumors may take a few years; moreover, gamma knife has not been used long enough to assess long-term effectiveness.
• Medical therapy—drug therapy is available for patients with functioning adenomas, and is employed as the primary form of treatment for most patients with prolactinomas:
o Prolactinomas—dopamine agonists have been available for the treatment of prolactinomas
in the United States since the late 1970’s. They are an extremely effective form of therapy, since they bind to dopamine receptors, and inhibit prolactin secretion, as well as cause a decrease in tumor size, by binding to dopamine receptors on lactrotrophs. Indeed, patients with visual abnormalities from macroprolactinomas note an improvement in vision within days to weeks after initiating oral therapy, and MRI scans document decreases in tumor size within a few weeks after commencing treatment.
There are currently two dopamine agonists in common use; bromocriptine (Parlodel), and
cabergoline (Dostinex). Bromocriptine is an ergot derivative, and cabergoline is a non-ergot derivative. Cabergoline has gained more favor during the past few years, because it may be administered once or twice a week, while bromocriptine is taken daily, Also, also has less pronounced side effects—both agents may produce nausea, fatigue, postural hypotension. If one drug results in untoward side effects, the other may be tried. If side effects are significant the medication may be given vaginally rather than orally, although side effects persist in most patients.
Dopamine agonists are so effective that they are considered to be the first line of therapy for
most patients with microadenomas, and virtually all patients with invasive macroadenomas. My own method is to offer oral therapy to all patients, but I often recommend transsphenoidal surgery to very young women with microadenomas, since the cure rate is >90%, and the surgery is very low risk, in experienced hands. Since surgery will not cure patients with invasive tumors, drug therapy is the treatment of choice. Surgery is indicated, however, in patients who have significant side effects with drug therapy.
It should be pointed out that drug therapy must be continued indefinitely for patients with
macroadenomas, and for women with microadenomas treatment may be stopped at the time of menopause; while prolactin levels increase again after stopping medication, long-term follow-up of patients with untreated microadenomas shows that the tumors tend to be stable.
The goal of therapy with dopamine agonists is to lower serum prolactin levels to the lower limit
of detectability. Once this has been achieved, and there is MRI evidence of a decrease in tumor size, then patients may be followed with serum prolactin levels alone. An increase in serum prolactin while taking medication may indicate development of resistance to drug therapy, and in such circumstances repeat MR imaging is necessary. In patients with very large, invasive tumors, persistent tumor on imaging is the rule, despite adequate suppression of serum prolactin. In such patients tumors infrequently shrink more than 50%.
Importantly, reductions in serum prolactin often result in reciprocal increases in serum estradiol
in women, and testosterone in men, due to removal of prolactin’s LH-inhibitory effects. Thus, hormonal replacement may not be necessary in patients who had hypogonadism prior to medical therapy of their tumors.
o Growth hormone secreting tumors—medical therapy of patients with acromegaly becomes
necessary all-to-frequently, unfortunately, since most patients have macroadenomas, which are often invasive. As mentioned above, surgical cure rates of such patients are disappointing, so that adjunctive therapy is required. For some patients additional therapy with radiation may suffice, but because of the long duration between undergoing radiation and its peak therapeutic effects, the symptoms and signs of GH excess may persist for several years; fortunately, medical therapy has been available in recent years to decrease GH secretion, and very recently, a peripheral inhibitor of GH (IGF-1) action has become available:
Octreotide and lanreotide (Sandostatin LAR) are analogs of somatostatin (GH-inhibitory hormone), and are effective inhibitors of GH secretion. Octreotide became available during the late 1980’s, while lanreotide first became available for clinical use in the mid 1990’s. Both agents result not only in a decrease in GH, but also in tumor shrinkage. Because of these properties, somatostatin analogues have been advocated as primary therapy in patients with nonresectable tumors. Predictably, patients with smaller tumors fare better than those with larger, invasive tumors, and the response rate in patients with very large tumors in terms of normalizing serum IGF-1 levels, is only about 50%.
Both octreotide, which is short acting, and lanreotide, the long-acting preparation, are given by injection, octreotide several times a day subcutaneously, and lanreotide intramuscularly, once a month. Patients are generally started on the short-acting form for a few weeks in order to see whether or not there are significant untoward side effects, and if not, then lanreotide is substituted. Common side effects include nausea, bloating, and gastrointestinal cramping (usually resolves within a week or so after initiating therapy), and the development of biliary sludge or gallstones. In general, though, therapy is well tolerated. If therapy is stopped, GH and IGF-1 levels increase again, and tumors grow.
Pegvisomant is an analog of GH that was recently developed, and it blocks binding of GH to its receptors, and therefore, inhibits GH action. This agent has shown early promise, and at this time (2002) has yet to be approved for general clinical use. A combination of this agent, along with a somatostatin analog, may prove to be more effective than either agent alone.
Bromocriptine has been used in the treatment of acromegaly, since it inhibits GH release. To be clinically useful, however, very large doses are required, which usually causes significant side effects. I do not use bromocriptine for my patients, either as sole therapy, or in combination with other medical therapies.
o ACTH producing and TSH producing tumors—management of these tumors is discussed in the respective syllabus sections on Adrenal Disorders and Thyroid Disorders.
References
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