DÄ internationalArchive14/2021The Interdisciplinary Management of Newly Diagnosed Pituitary Tumors

Review article

The Interdisciplinary Management of Newly Diagnosed Pituitary Tumors

Dtsch Arztebl Int 2021; 118: 237-43. DOI: 10.3238/arztebl.m2021.0015

Jaursch-Hancke, C; Deutschbein, T; Knappe, U J; Saeger, W; Flitsch, J; Fassnacht, M

Background: The increasing use of cranial tomographic imaging has led to the more frequent discovery of pituitary tumors. In this review, we discuss the clinical symptoms that point toward a pituitary tumor, the required diagnostic studies, the potential need for follow-up studies, and the indications for neurosurgical treatment.

Methods: This review is based on pertinent publications from the years 2005-2020 that were retrieved by a selective search in PubMed, as well as on the current German S2k guideline, which was created with the present authors playing a coordinating role, and on further guidelines from abroad. Relevant information from older reviews was also considered.

Results: The reported prevalence of pituitary tumors varies depending on the method of data acquisition. Autopsy studies yield a figure of 10.7%, while population-based studies reported 77.6–115.6 cases per 100 000 inhabitants. These lesions are nearly always benign, and 85% of them are pituitary adenomas. Pituitary adenomas measuring less than 1 cm in diameter are called microadenomas, while those measuring 1 cm or more are called macroadenomas. According to magnetic resonance imaging (MRI) studies, the prevalence of microadenomas in the general population is in the range of 10–38%, while that of macroadenomas is 0.16–0.3%. Pituitary adenomas can be either hormonally inactive or hormonally active. Half of all patients with hormonally inactive microadenomas display no endocrine abnormality, while 37–85% of patients with hormonally inactive macroadenomas manifest at least partial pituitary insufficiency. The clinical spectrum of pituitary tumors ranges from a fully asymptomatic state to visual disturbances, neurologic deficits, severe hormone excess (e.g., in Cushing disease), and life-threatening pituitary insufficiency. Pituitary adenomas are often diagnosed only after a latency of many years, even when they are symptomatic. If an imaging study shows the tumor to be in contact with the visual pathway, an ophthalmological evaluation should be performed. There are clear indications for surgery, e.g., imminent loss of vision, but most asymptomatic pituitary tumors can be observed only.

Conclusion: The manifestations of pituitary tumors are first recognized by primary care physicians. The further diagnostic evaluation of these patients should be carried out in standardized and interdisciplinary fashion.

LNSLNS

Pituitary tumors account for 10–15% of all intracranial neoplasms and constitute the third most common cranial tumor entity in adulthood (1, 2). Their prevalence is higher than previously reported. In population-based studies, pituitary tumors were found in 77.6–115.6 persons per 100 000 inhabitants (3, 4). These lesions are benign, with only rare exceptions, and 85% of them are pituitary adenomas (Table) (5). Pituitary adenomas measuring less than 1 cm in diameter are called microadenomas, while those measuring 1 cm or more are called macroadenomas. Pituitary tumors can be either hormonally inactive or hormonally active. Tumors of the latter type are characterized by excessive hormone secretion: of prolactin in 69–80% of cases, growth hormone (GH) in 13–20%, adrenocorticotropic hormone (ACTH) in 5–10%, and thyroid-stimulating hormone (TSH) in 1–2% (6).

Tumors of the pituitary gland and the sellar region in the German pituitary tumor registry, 1996–2005
Table
Tumors of the pituitary gland and the sellar region in the German pituitary tumor registry, 1996–2005

The increasing use of cranial tomographic imaging—magnetic resonance imaging (MRI) and computed tomography (CT)—in the diagnostic evaluation of non-specific symptoms such as dizziness, headache, and other neurological or general medical complaints has led to the more frequent discovery of pituitary tumors as incidental findings (“incidentalomas”) (7). Some of these will remain asymptomatic for the patient’s lifetime, while others can cause both non-specific and hormone-specific manifestations over the course of many years. The reported frequency of incidental pituitary tumors depends on the particular imaging modality used (MRI or CT) and on whether cystic lesions are counted as well. It is recommended in the current guidelines that incidental cystic lesions should be counted along with incidental lesions that have the typical imaging features of an adenoma (8).

In the most comprehensive meta-analysis of autopsy studies, the mean prevalence of pituitary incidentalomas was 10.7% (range across studies: 1.5–31%), with an even distribution in the two sexes and across age groups (9). The age distribution has no peak. Some studies have shown a slight rise in prevalence with increasing age (10, 11). Only 3.5 of all pituitary tumors are diagnosed up to the age of 18 years (12). In MRI studies of the general population, pituitary microincidentaloma frequencies ranging from 10% to 38% have been reported. In contrast, the prevalence of macroincidentaloma is low: 0.16–0.3% in MRI studies, 0.2% in CT studies (7).

Nonetheless, despite the increasing use of neuro-imaging and laboratory testing, it can still take many years before a pituitary adenoma is revealed as the cause of the patient’s symptoms. According to current data, several years often elapse from the first symptoms to the correct diagnosis even in patients with hormonally active adenomas that oversecrete GH (acromegaly) or ACTH (Cushing’s disease), whose clinically evident effects presumably become manifest earlier than those of hormonally inactive tumors. In acromegaly, the time to diagnosis is 5 years on average (and in 24% of patients even more than 10 years); in ACTH-producing adenomas the average time to diagnosis is 2–6 years (11, 12).. In Germany, the mean latency to the diagnosis of Cushing’s disease is four years (13). This situation has not changed appreciably in recent decades, despite the intensive efforts of national and international specialist societies with the dedicated participation of patient organizations. For example, the mean latency to the diagnosis of acromegaly was five years in 2001 and this latency remained unchanged until 2020 (14).

The more time elapses until the definitive diagnosis, the higher the mortality (15). One reason for the long diagnostic latency is the slow development of the symptoms and their resemblance to those of common conditions such as diabetes mellitus, hypertension, overweight, and non-specific joint pain (11). Patients with pituitary adenomas have an increased mortality compared to the normal population not only if the adenoma is hormonally active, but also if it is hormonally inactive (16). On the other hand, persons harboring lesions of no clinical significance that are incidentally revealed by neuroimaging can be subjected to unnecessary worry by the subsequent unnecessary endocrinological and neuroradiological follow-up examinations. For this reason, competent medical advice has to play a key role (17).

The first goal of this review is to present the clinically relevant considerations that lead to the diagnosis of a pituitary tumor and to describe the current standard for the required clinical, endocrine, and neuroradiological diagnostic studies, both on presentation and during further follow-up. The second goal is to discuss the procedures to be followed when a clinically asymptomatic pituitary lesion is discovered incidentally.

Methods

This review is based on pertinent publications from the years 2005–2020 that were retrieved by a selective search in PubMed, as well as on the current German S2k guideline, which was created with the present authors playing a coordinating role (18), and on further international guidelines. Relevant information from older reviews was also taken into account. The searching terms were “pituitary adenoma,” “pituitary incidentaloma,” “pituitary disorders,” “pituitary tumors,” and “pituitary insufficiency.”

The major manifestations of pituitary tumors

The clinical manifestations of pituitary insufficiency or hormone excess due to a pituitary tumor generally develop insidiously over several years, as these tumors tend to grow very slowly (19, 20). Insufficiency of the anterior pituitary lobe is the most common detectable manifestation of hormonally inactive pituitary tumors. As for macroadenomas, a representative meta-analysis (21) has shown that 37–85% of patients have an at least partial hormone deficiency at the time of their diagnosis; the somatotropic axis (GH) is the most commonly affected (61–100% of all patients), followed by the gonadotropic axis (hypogonadism in 36–95% of all patients) (Box 1).

The major symptoms and clinical aspects of pituitary tumors
Box 1
The major symptoms and clinical aspects of pituitary tumors

Among the above manifestations, the clinical signs of hypogonadism most frequently lead to the diagnosis, as growth hormone deficiency in adulthood is characterized by a non-specific impairment of performance ability with a diminished quality of life (i.e., by clinical signs that are difficult to assign to a particular cause). The clinical aspects and major manifestations of pituitary tumors are summarized in Box 1. Loss of function of the posterior pituitary lobe, leading to central diabetes insipidus, is more commonly due to a craniopharyngioma or hypophysitis than to a pituitary adenoma (1).

The manifestations of hormone excess depend on the particular hormone that is oversecreted, and they can be highly variable. The major manifestations of prolactinoma, acromegaly, and Cushing’s disease are presented in Box 1.

Compression of neighboring neural structures by a pituitary tumor can also cause focal neurologic deficits such as diplopia, loss of visual acuity, and visual field defects, typically bitemporal hemianopsia (22, 23). Pituitary tumors can also be accompanied by headache; it is often unclear, however, whether the headache is really due to the pituitary tumor, as headache is a common symptom in the general population, but it is very rarely caused by a pituitary tumor. (18, 23).

Interdisciplinary management

The optimal treatment of patients with pituitary tumors can only be provided by an interdisciplinary team with expertise in the diagnostic evaluation, treatment, and follow-up care of pituitary disorders. Such teams must include endocrinologists, (neuro-)radiologists, and neurosurgeons, as well as—depending on the size of the tumor and the planned intervention—ophthalmologists, (neuro-)pathologists, and radiation oncologists. For specialized questions, experts from other disciplines may need to be consulted as well (e.g., gynecology, neurology, and psychology). It is not always necessary for all of the disciplines to participate in the care of an individual patient, e.g., in cases with a small microadenoma or microprolactinoma. The primary care physician retains the important task of initially assessing the clinical manifestations and setting the stage for interdisciplinary care.

Diagnostic evaluation

Imaging studies

MRI visualizes lesions in the sella turcica and the suprasellar region more precisely than CT and is therefore the current gold standard for the imaging of pituitary adenomas (18). The sensitivity of MRI for microadenomas is 82.6%, compared to 42.1% for CT (24). If a pituitary tumor first becomes evident on a CT scan, or if the sellar region is inadequately visualized on CT, a corresponding MRI scan should be obtained (including dynamic contrast sequences).

The diagnostic evaluation on the initial discovery of a pituitary adenoma

If a patient is found to have a pituitary tumor, whether because of its clinical manifestations (Box 1) or as an incidental finding on cranial imaging, a comprehensive history and physical examination should be performed before any endocrine laboratory studies or functional tests are obtained (8, 18). The history and physical examination enable the detection of clinical signs of pituitary insufficiency and/or hormonal excess conditions, which will put the findings of subsequent studies in an appropriate clinical context. Attention must be paid to concurrent illnesses that can cause manifestations resembling those of pituitary dysfunction, as well as to drugs that can interfere with the reliability of hormonal diagnostic tests.

Endocrine laboratory tests

Endocrine tests serve to document or exclude excessive hormone secretion or pituitary insufficiency. Very small pituitary adenomas can be hormonally active, either with or without impairment of other pituitary functions, or they can be fully asymptomatic. Larger pituitary tumors can cause pituitary insufficiency, or they can be hormonally active or asymptomatic. The overall percentage of persons harboring pituitary micro- and macroadenomas that remain asymptomatic for life can only be estimated indirectly on the basis of findings from autopsy studies; according to a meta-analysis, the mean value is 10.7% (range, 1.5–31 %) (9). It thus makes sense for basic endocrine laboratory testing to be performed in any patient with a newly discovered pituitary tumor, regardless of size, so that hormonal activity can be detected or definitively ruled out. On the other hand, the risk of hormonal insufficiency is directly linked to the size of the tumor: hormonal insufficiency is found accompanying 37–85% of macroadenomas (8, 21) and some larger-sized microadenomas (6–9 mm), but is rare in microadenomas measuring 5 mm or less (8).

In the following paragraphs, we will describe the laboratory tests to be performed in the initial diagnostic evaluation of any pituitary tumor (Box 2).

Obligatory laboratory tests on the initial diagnosis of a pituitary tumor
Box 2
Obligatory laboratory tests on the initial diagnosis of a pituitary tumor

Prolactin

The diagnosis or exclusion of a prolactinoma is an important endocrinological consideration because these lesions account for 40–66% of all hormonally active pituitary tumors (11) and their identification also has major implications for treatment. A prolactin value of >250 μg/L (> 5300 mU/L) is nearly pathognomonic for a macroprolactinoma (21, 25, 26), as long as attention has been paid to the pitfalls of laboratory diagnosis (see below). A hormonally inactive macroadenoma can cause hyperprolactinemia by displacement or compression of the pituitary stalk, which diminishes the inhibitory effect of dopamine on the lactotroph cells of the anterior pituitary lobe. This is the so-called stalk effect, involving disinhibitory hyperprolactinemia; in such cases, the prolactin level, although elevated, generally remains below 100 μg/L (26). The differentiation of a prolactinoma from the stalk effect is important, as only the former can be treated with drugs. Mildly elevated prolactin values (25-100 100 μg/L) can also be caused by dopaminergic medication—above all, psychotropic drugs such as tricyclic antidepressants and serotonin reuptake inhibitors (26, 27). Some medications, such as risperidone and phenothiazines, can also elevate the prolactin level above  200 μg/L (26).

TSH, free T4 (fT4), and free T3 (fT3)

If the TSH value is low or normal, fT4 values in the lower reference range may already indicate thyrotropic insufficiency. In most of such cases, other hormonal axes are affected as well. TSH-producing pituitary adenomas (TSH-omas) are very rare, accounting for only 1–2% of all hormonally active pituitary tumors. A tumor of this type should be suspected if all three values—TSH, fT4, and fT3—are high or in the upper normal range (28).

LH, FSH, total testosterone (in men), and estradiol (in premenopausal women)

The values of luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (in men), and estradiol (in premenopausal women), seen in the context of the clinical manifestations, generally enable the rapid diagnosis or exclusion of gonadotropic insufficiency.

IGF-1

Measurement of the insulin-like growth factor 1 (IGF-1) level is a screening test both for a GH-producing adenoma (acromegaly) and for GH deficiency. The GH concentration itself is affected by multiple external factors and is, therefore, insufficiently informative. A normal IGF-1 value nearly rules out acromegaly. In case of clinical suspicion, further functional diagnostic testing is required (an oral glucose tolerance test to assess GH suppression [6, 18]).

Cortisol

In patients with macroadenomas and larger-sized microadenomas (> 6 mm), corticotropic insufficiency must be ruled out as well (8, 18). If the morning serum cortisol concentration is ≤ 4.0 μg/dL (110 nmol/L), secondary adrenal insufficiency is very likely to be present and requires immediate treatment. On the other hand, values ≥ 15.0 μg/dL (414 nmol/L) indicate that the corticotropic axis is very likely to be functioning adequately. For values in the intermediate range, dynamic functional testing is needed (gold standard: insulin-hypoglycemia test, alternative: metopyrone test, ACTH test, or corticotropin releasing hormone [CRH] test) (29, 30).

1-mg dexamethasone suppression test

This test should be performed in all patients with a pituitary adenoma, so that an ACTH-producing adenoma (Cushing’s disease) cannot be overlooked.

Pitfalls in hormonal diagnosis

The laboratory findings may be misleading if the blood drawing does not take place before 9 am with the patient in the fasting state, i.e., if the circadian rhythm and the effect of food intake are disregarded, leading to errors in the analytic and pre-analytic phases of the evaluation. Attention must also be paid to the effect of drugs such as psychoactive agents, oral contraceptives, steroid injections, and food supplements (e.g., biotin) in the interpretation of the laboratory findings. Physical stress and illness can also affect the hormone values.

If hyperprolactinemia is found but does not fit into the overall clinical picture, e.g., if a female patient’s menstrual cycle is intact or a male patient has normal testosterone values, then the special constellation of macroprolactins is to be suspected; this can be ruled out by precipitation with polyethylene glycol (31, 32). A high-dose hook effect (i.e., a falsely low prolactin level) must also be considered in the appropriate circumstances and ruled out via sequential dilution of prolactin (26).

If secondary hypothyroidism due to a pituitary tumor is suspected, the TSH value, which is used to assess thyroid dysfunction of other causes, is not helpful, as it will not necessarily be low; it may only be lower than it should be, while possibly still lying in what is considered the normal range. Instead, the most informative finding in such situations is a low fT4 value.

Important considerations for cortisol measurement include the circadian rhythm and the fact that drugs including sex hormones (e.g., for contraception or postmenopausal hormone replacement) can elevate the cortisol concentration. On the other hand, the cortisol concentration can be markedly lowered if synthetic glucocorticoids are given for therapeutic purposes, e.g., because of orthopedic problems.

The measured total testosterone value is often falsely low in overweight or obese men and in men with diabetes mellitus, because, in these situations, sexual-hormone-binding globulin (SHBG) is often reduced. To measure testosterone, blood must be drawn in the morning before breakfast, as the reference values are correct only for this period of time (33).

Biotin can lead to further misinterpretations of hormone tests. Biotin—also called vitamin B7 or vitamin H—is freely available without a prescription and is purported to have beneficial effects on metabolism that promote healthy nails, hair, and skin. Intake of biotin can severely alter hormone concentrations, because many immunoassays employ a streptavidin-biotin system (34).

Ophthalmological examination

If an imaging study shows that the pituitary tumor has contact with the visual pathway, an ophthalmological examination is needed, including measurements of the visual acuity, visual field and a funduscopic examination. The patient may not notice a deficit if it has developed slowly and can be compensated for, at least in part, by the other eye (35).

Indications for surgery

After a complete diagnostic evaluation, it will be possible to answer the question whether the pituitary tumor requires surgical treatment. A surgical indication is present in the following situations (Figure) (8, 18):

The typical diagnostic and therapeutic algorithm for pituitary tumors
Figure
The typical diagnostic and therapeutic algorithm for pituitary tumors
  • (imminent) loss of visual function
  • clinically relevant increase in tumor size (especially if in the vicinity of critical structures, such as the visual pathway)
  • pituitary apoplexy with potentially imminent blindness, which may constitute a neurosurgical emergency
  • hormonally active tumor (exception: prolactinoma, which is mainly treated with dopamine agonists)

Surgery can also be considered if clinically significant pituitary insufficiency is present.

The surgical method of choice is a transsphenoidal microsurgical or endoscopic procedure performed by a neurosurgeon with the appropriate experience. In case of recurrent tumor or progression of residual tumor tissue after surgery, a second operation and/or radiotherapy should be considered.

Follow-up examinations

Patients with asymptomatic, hormonally inactive pituitary tumors measuring less than 1 cm in diameter are primarily followed up clinically and with serial imaging (the “wait and scan” method). Tumor size is the main factor determining the further follow-up (Figure). The risk of further growth is lower for a hormonally inactive microadenoma than for a macroadenoma (8, 18). In a German study, only 3.2% of microadenomas grew in their further course, while 26.3% of macroadenomas did (19). In another study, only one of 15 microincidentalomas displayed tumor growth of 1 mm over a follow-up interval of nearly 5 years (36). Patients with asymptomatic, hormonally inactive pituitary tumors measuring > 1 cm can usually—i.e., as long as the tumor is confined to the sella turcica—be followed clinically and with accompanying imaging studies. Only limited data are available regarding the ideal time interval between consecutive endocrinological and imaging follow-up examinations (16). The Figure contains recommendations on this matter, drawn from the relevant guidelines and review articles (6, 8, 17, 18, 37).

For hormonally active tumors with persistent, uncontrolled hormone excess after surgery (and for inoperable tumors), pharmacotherapy is a potential further option beyond the typical options of reoperation and/or radiotherapy (38). If the initial diagnostic evaluation yields the suspicion of pituitary insufficiency and/or a hormonally active tumor, structured patient education and life-long endocrinological follow-up will be needed (18, 39).

Conflict of interest statement

PD Dr. Deutschbein has served as a paid advisory board member for Novo Nordisk and Novartis. He has received reimbursement of meeting participation fees from Novartis and of travel costs from Ipsen, Lilly, Novo Nordisk, and Novartis. He has also received third-party research funding from Ipsen, Novartis, and Shire.

PD Dr. Knappe has received lecture honoraria and reimbursement of meeting participation fees from Novartis.

Prof. Saeger has served as a paid medicolegal consultant with regard to histopathology and has received third-party research funding for a pituitary tumor registry sponsored by Novartis, Ipsen, Novo Nordisk and Pfizer.

Prof. Flitsch has served as a paid advisory board member for Novartis and Ipsen. He has received lecture honoraria and reimbursement of meeting participation fees and travel expenses from Novartis, Ipsen, and Lilly.

Prof. Fassnacht has received reimbursement of travel expenses from Ipsen and third-party research funding from HRA Pharma and Novartis.

Dr. Jaursch-Hancke states that she has no conflict of interest.

Manuscript submitted on 31 March 2020, revised version accepted on 21 September 2020.

Translated from the original German by Ethan Taub, M.D.

Correspondence address
Dr. med. Cornelia Jaursch-Hancke
Endokrinologie
DKD HELIOS Klinik Wiesbaden
Aukammallee 33, 65191 Wiesbaden, Germany
jaurschhancke@icloud.com

Cite this as:
Jaursch-Hancke C, Deutschbein T, Knappe UJ, Saeger W, Flitsch J, Fassnacht M: The interdisciplinary management of newly diagnosed pituitary tumors. Dtsch Arztebl Int 2021; 118: 237–43. DOI: 10.3238/arztebl.m2021.0015

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Department of Internal Medicine/Endocrinology, DKD-Helios Klinik Wiesbaden: Dr. med. Cornelia Jaursch-Hancke
Medicover Oldenburg MVZ: PD Dr. med. Timo Deutschbein
Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany: Prof. Dr. med. Martin Fassnacht, PD Dr. med. Timo Deutschbein
Department of Neurosurgery, Johannes Wesling Klinikum Minden: PD Dr. med. Ulrich J. Knappe
Institute of Neuropathology, UKE Hamburg: Prof. Dr. med. Wolfgang Saeger
Department of Neurosurgery, UKE Hamburg: Prof. Dr. med. Jörg Flitsch
The major symptoms and clinical aspects of pituitary tumors
Box 1
The major symptoms and clinical aspects of pituitary tumors
Obligatory laboratory tests on the initial diagnosis of a pituitary tumor
Box 2
Obligatory laboratory tests on the initial diagnosis of a pituitary tumor
The typical diagnostic and therapeutic algorithm for pituitary tumors
Figure
The typical diagnostic and therapeutic algorithm for pituitary tumors
Tumors of the pituitary gland and the sellar region in the German pituitary tumor registry, 1996–2005
Table
Tumors of the pituitary gland and the sellar region in the German pituitary tumor registry, 1996–2005
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2.Melmed S: Pathogenesis of pituitary tumors. Nat Rev Endocrinol 2011; 7: 257–66 CrossRef MEDLINE
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