Handbook of Clinical Neurology, Vol. 124 (3rd series) Clinical Neuroendocrinology E. Fliers, M. Korbonits, and J.A. Romijn, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 12

Nonfunctioning pituitary tumors MARK E. MOLITCH* Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

INTRODUCTION Clinically nonfunctioning adenomas (CNFAs) range from being completely asymptomatic, and therefore detected either at autopsy or as incidental findings on head magnetic resonance imaging (MRI) or computed tomography (CT) scans performed for other reasons, to causing significant hypothalamic/pituitary dysfunction and visual symptoms due to their large size. About three-quarters of CNFAs are actually gonadotroph adenomas, based upon the finding that patients with such tumors produce intact gonadotropins or their glycoprotein subunits (a and/or b) in vivo or in vitro as shown by measurement of these products in the blood, staining on immunohistochemistry, or measurement of the mRNA for these products in the tumors (Young et al., 1996). Rarely, clinically nonfunctioning tumors will be found to stain positively for adrenocorticotropic hormone (ACTH), growth hormone (GH), prolactin (PRL), or thyrotropin (TSH) but do not secrete these hormones in sufficient quantities to cause clinical syndromes; such tumors are referred to as “silent” corticotroph, somatotroph, lactotroph, or thyrotroph adenomas (Yamada et al., 1991). In this discussion, both asymptomatic and symptomatic tumors will be reviewed. A number of other lesions may be found in the sellar area that may mimic a pituitary adenoma, including aneurysms of the internal carotid artery, craniopharyngiomas, Rathke’s cleft cysts, meningiomas of the tuberculum sellae, gliomas of the hypothalamus and optic nerves, dysgerminomas, cysts, hamartomas, metastases, sarcoidosis, eosinophilic granulomas, lymphocytic hypophysitis, sphenoid sinus mucoceles, and focal areas of infarction (Freda et al., 1996; Naidich and Russell, 1999; Valassi et al., 2010; Famini et al., 2011). Some normal individuals statistically must have pituitaries that

exceed the normal size boundary of 9 mm plus three standard deviations in healthy subjects (Doraiswamy et al., 1992; Tsunoda et al., 1997; Elster et al., 1999), and Chanson et al. (2001) have reported several such patients. These individuals with “normal pituitary hypertrophy” had pituitaries that on MRI had homogeneous isointense signals and enhanced homogeneously with contrast (Chanson et al., 2001). Furthermore, surgical specimens showed normal pituitary tissue in two cases (Chanson et al., 2001). Artifacts mimicking pituitary lesions include beam-hardening effects with CT and susceptibility distortions with MRI (Naidich and Russell, 1999). (For more details regarding the radiologic characteristics of adenomas versus other lesions, see Ch. 11.) Recent series have shown that symptomatic pituitary tumors are more common than previously thought (Table 12.1). Daly et al. (2006) found an overall prevalence of 94 cases per 100 000 population in Belgium, with CNFAs comprising 14.7% of these case, for a prevalence of 13.8 cases per 100 000 population of CNFAs. Subsequent similar analyses in Switzerland, the UK, and Finland showed overall prevalences of CNFAs in the same range of 23.8, 13.4, and 25.2 per 100 000 population, respectively (Fontana and Gaillard, 2009; Fernandez et al., 2010; Raappana et al., 2010).

THE ASYMPTOMATIC, INCIDENTAL, CLINICALLY NONFUNCTIONING ADENOMA (PITUITARY INCIDENTALOMA) Autopsy findings Pituitary adenomas have been found at autopsy in 1.5–27% of subjects not suspected of having pituitary

*Correspondence to: Mark E. Molitch, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, 645 N. Michigan Ave., Suite 530, Chicago, IL 60611, USA. Tel: þ1-312-503-4130, Fax: þ1-312-926-8693, E-mail: [email protected]

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Table 12.1 Prevalence of clinical nonfunctioning pituitary adenomas

Series

Country

Overall pituitary adenoma (prevalence per 100 000 population)

Daly et al., 2006 Fontana and Gaillard, 2009 Fernandez et al., 2010 Raappana et al., 2010

Belgium Switzerland

94 80

14.7% 29.5%

13.8 23.8

UK Finland

78 68

17.2% 37.0%

13.4 25.2

disease while alive (see Table 12.2). The average frequency of finding an adenoma for these studies, which examined a total of 21 604 pituitaries, was 10%. The tumors were distributed equally throughout the age groups (range 16–86 years) and between the sexes. In the studies in which PRL immunohistochemistry was performed, 22–66% stained positively for PRL (Kovacs et al., 1980; Burrow et al., 1981; Mosca et al., 1981; Coulon et al., 1983; DeStephano et al., 1984; El-Hamid et al., 1988; Gorczyca and Hardy, 1988; Scheithauer et al., 1989; Marin et al., 1992; Sano et al., 1993; Teramoto et al., 1994; Uie et al., 1994; Camaris et al., 1995; Kurosaki et al., 2001; Buurman and Saeger, 2006; Kim et al., 2007). Buurman and Saeger (2006) provide a detailed breakdown of the 334 pituitary adenomas found in 316 pituitaries of the 3048 autopsy cases they examined, finding 39.5% staining for PRL, 13.8% staining for ACTH, 7.2% staining for gonadotropins or a subunits, 1.8% staining for GH, 0.6% staining for TSH, and 3.0% staining for multiple hormones. In these postmortem studies all but seven of the tumors were less than 10 mm in diameter. The relative lack of macroadenomas in these studies suggests that growth from micro- to macroadenomas must be an exceedingly uncommon event and/or that virtually all macroadenomas come to clinical attention and therefore are not included in autopsy findings. There is a separate report of an additional three macroadenomas being found at autopsy (Auer et al., 1996).

CT and MRI scans in normal individuals Three series have evaluated CT scans of the sellar area in normal subjects who were having such scans for reasons unrelated to possible pituitary disease. Chambers et al. (1982) found discrete areas of low density > 3 mm in diameter in 10 of 50 such subjects. In our study of 107 normal women, we found 7 who had focal hypodense areas and 5 who had focal high density regions > 3 mm in diameter (Wolpert et al., 1984). In a third study, Peyster et al. (1986) found focal hypodense areas > 3 mm in diameter in only 8 of 216 subjects.

Percentage with clinically nonfunctioning adenomas

Clinically nonfunctioning pituitary adenoma (prevalence per 100 000 population)

Two similar studies have been carried out using MRI. Chong et al. (1994) found focal pituitary gland hypodensities 2–5 mm (mean 3.9 mm) in 20 of 52 normal subjects with nonenhanced images using a 1.5 T scanner and 3 mm thick sections. With similar scans but with gadolinium-DTPA enhancement, Hall et al. (1994) found that in 100 normal volunteers focal areas of decreased intensity  3 mm in diameter compatible with the diagnosis of adenoma were present in 34, 10, and 2 volunteers, depending upon whether there was agreement on the diagnosis between 1, 2, or 3 independent reviewing neuroradiologists. Sellar lesions > 10 mm in diameter have not been found in these studies of consecutive normal individuals, similar to the very limited number found at autopsy. However, Nammour et al. (1997) found that of 3550 consecutive CT scans done in men with a mean age of 57 years for the symptoms of change in mental status, headache, or possible metastases, 7 (0.2%) were discovered to have pituitary macroadenomas ranging from 1.0 to 2.5 cm in size; all were thought to be CNFAs after hormonal evaluation. Similarly, when nonenhanced MRI scans were performed without specific views of the sellar area in asymptomatic normal subjects, macroadenomas were found in 0.16% of 3672 subjects in a study by Yue et al. (1997) and in 0.3% of 2000 subjects in a study by Vernooij et al. (2007). Furthermore, macroadenomas have been reported as incidental findings (Chacko and Chandy, 1992). In the nine series of patients reported with pituitary incidentalomas (Reincke et al., 1990; Donovan and Corenblum, 1995; Nishizawa et al., 1998; Feldkamp et al., 1999; Igarashi et al., 1999; Sanno et al., 2003; Fainstein Day et al., 2004; Arita et al., 2006; Aghakhani et al., 2011), 304 of the 454 patients (67%) had macroadenomas (Table 12.3). Several of these patients had tumors 2 cm or more in maximum diameter. This proportion of patients with macroadenomas found clinically, therefore, is much greater than would be expected based on the autopsy findings, suggesting that the mass effects of such tumors may have caused some of the symptomatology causing the patients to have the scans in the first place.

NONFUNCTIONING PITUITARY TUMORS

169

Table 12.2 Frequency of pituitary adenomas found at autopsy

Series{ Susman (1933) Close (1934) Costello (1936) Sommers (1959) Hardy (1968) McCormick (1971) Haugen (1973) Kovacs (1980) Landolt (1980) Mosca (1980) Burrow (1981) Parent (1981) Muhr (1981) Max (1981) Schwezinger (1982) Chambers (1982) Coulon (1983) DeStephano (1984) Siqueira (1984) Char (1986) Gorczyca (1988) El-Hamid (1988) Scheithauer (1989) Kontogeorgos et al., (1991) Marin (1992) Sano (1993) Teramoto (1994) Uie (1994) Camararis (1995) Tomita (1999) Kurosaki (2001) Buurman (2006) Rittierodt (2007) Kim (2007) Furgal-Borzych et al., (2007) Aghakhani (2011) Total { {

Number of pituitaries examined

Number of adenomas found

Frequency (%)

Number of macroadenomas found

Stain for prolactin (%){

260 250 1000 400 1000 1600 170 152 100 100 120 500 205 500 5100 100 100 100 450 350 100 486 251 470

23 23 225 26 27 140 33 20 13 24 32 42 3 9 485 14 10 14 39 35 27 97 41 49

8.8 9.2 22.5 6.5 2.7% 8.8 19.4 13.2 13.0 24.0 26.7 8.4 1.5 1.8 9.5 14.0 10.0 14.0 8.7 10.0 27.0 20.0 16.3 10.4

– – 0 0 0 0 – 2 0 0 0 1 0 – 0 0 0 0 0 0 0 0 0 0

– – – – – – – 53 – 23 41 – – – – – 60 23 – – 30 48 66 –

210 166 1000 1117 423 100 692 3048 228 120 151

35 15 51 36 14 24 79 334 7 7 47

16.7 9.0 5.1 3.2 3.2 24.0 11.4 11.0 3.0 5.8 31.1

0 0 0 0 0 – 1 3 0 0 0

32 47 30 33 44 50 24 40 – 29 –

485 21 604

61 2161

12.6 10.0%

– 7



Each series is identified by the first author and date. Prolactin þ indicates the percentage of tumors that had positive immunostaining for prolactin, indicating that they were prolactinomas.

Endocrinologic evaluation of the asymptomatic incidental mass As the most common lesion in the sella is a pituitary adenoma, it is reasonable to evaluate patients for hormone oversecretion, regardless of the size of the lesion seen. Many of the changes occurring with hormone oversecretion syndromes may be quite subtle and only slowly progressive; therefore, screening for hormonal

oversecretion is warranted even in patients with no clinical evidence of hormone oversecretion. “Silent” somatotroph and corticotroph adenomas have been reported many times but it is not clear whether such patients with minimal clinical evidence of hormone oversecretion are free from the increased risk for the more subtle cardiovascular, bone, oncological, and possibly other adverse effects we usually associate with such tumors. Indeed, there is emerging evidence that subclinical Cushing’s

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M.E. MOLITCH

Table 12.3 Changes in pituitary incidentaloma size Microadenomas

Macroadenomas

Series

Years Total Increased Decreased No change Total Enlarged Decreased No change followed

Reincke et al. (1990) Donovan and Corenblum (1995) Nishizawa et al. (1998) Feldkamp et al. (1999) Igarashi et al. (1999) Sanno et al. (2003) Fainstein Day et al. (2004) Arita et al. (2006) Karavitaki (2007) Dekkers et al. (2007) Anagnostis et al. (2011) Total

7 15 – 31 1 74 11 5 16 – 6 166

1 0 – 1 0 10 1 2 2 – 0 17 (10%)

1 0 – 1 0 7 0 0 1 – 1 11 (7%)

5 15 – 29 1 57 10 3 13 – 5 138 (83%)

7 16 28 19 22 165 7 37 24 28 3 356

2 4* 2* 5 6 20* 1 19* 12 14 1 86 (24%)

0 0 0 1 10 22 0 0 4 8 0 45 (13%)

5 12 26 13 6 123 6 18 8 6 2 225 (63%)

8 6–7 5.6 2.7 5.1 2.3 3.2 5.2 3.6 7.1 4.0

*Seven cases in these series had tumor enlargement due to apoplexy.

syndrome due to adrenal incidentalomas is associated with significantly increased prevalences of diabetes, hypertension, obesity, osteoporosis, and cardiovascular risk (Angeli and Terzolo, 2002). Whether there is a similar increased risk for these comorbidities with “silent” corticotroph adenomas is unknown. Furthermore, some have reported that silent corticotroph adenomas have a worse prognosis than noncorticotroph CNFAs with respect to aggressiveness following initial surgery (Scheithauer et al., 2000; Bradley et al., 2003), but this has not been found in other series (Soto-Ares et al., 2002; Dekkers et al., 2006a). Progression to overt Cushing’s disease over time was reported in 4 of 22 (18%) cases in one series (Baldeweg et al., 2005). It is not clear how many of these patients have nonsuppressible serum cortisol levels or elevated urinary free cortisol levels, but Lopez et al. (2004) have found suppressed ACTH secretion and hypocortisolism in 2 of 12 patients following resection of silent ACTH-secreting adenomas. Screening for hormone oversecretion in such patients has been questioned as to its cost-effectiveness (Chanson and Young, 2003; Krikorian and Aron, 2006; Randall et al., 2010). However, evidence from the series of Fainstein Day et al. (2004) suggests such screening is worthwhile, as 7 of their 46 patients turned out to have prolactinomas, and of the 13 who ended up going to surgery and having immunohistochemistry performed, 2 (15%) were GH positive, 3 ( 23%) were gonadotropin positive, and 4 (31%) were plurihormonal adenomas. A serum PRL should be obtained but it may be difficult to distinguish between prolactin production by a tumor versus hyperprolactinemia from stalk dysfunction in the case of macroadenomas, especially those with

suprasellar extension. For such tumors, PRL levels are usually over 200 ng/mL with prolactinomas, and lower numbers suggest stalk dysfunction (Arafah et al., 1995; Karavitaki et al., 2006; Hong et al., 2010). For very large tumors, the sample should be diluted 1:100 to avoid the “hook effect” (St-Jean et al., 1996; Barkan and Chandler, 1998). An IGF-1 is probably sufficient to screen for acromegaly but if this cannot be performed, it may be necessary to demonstrate nonsuppression of GH levels during an oral glucose tolerance test (Growth Hormone Research Society and Pituitary Society Consensus Conference, 2004). The best screening tests for Cushing’s syndrome have traditionally been the overnight dexamethasone suppression test and the 24 hour urinary free cortisol and, more recently, the assessment of a midnight salivary cortisol (Findling and Raff, 2006; Carroll et al., 2008; Nieman et al., 2008). An abnormal midnight salivary cortisol has been found to have greater than 93% specificity and sensitivity for diagnosing Cushing’s syndrome (Carroll et al., 2008). Because the patients may have little in the way of symptoms, it is likely that the 24 hour urinary free cortisol will be normal and an overnight 1 mg dexamethasone suppression test or a midnight salivary cortisol might be better tests to diagnose early Cushing’s disease. Because of the high variability of ACTH levels, even in patients with overt Cushing’s disease, ACTH levels are probably not worth measuring. However, some participants on the Endocrine Society Taskforce that wrote the pituitary incidentaloma clinical practice guideline of the society felt that measurement of ACTH levels might be useful (Freda et al., 2011). Any abnormality found on such screening would then need to be pursued

NONFUNCTIONING PITUITARY TUMORS with more definitive testing (see Ch. 10). Most clinically nonfunctioning adenomas are gonadotroph adenomas, as shown by immunohistochemistry (Young et al., 1996). However, as gonadotropin oversecretion rarely causes clinical symptoms and the finding of such hormone oversecretion would not influence therapy, there is no reason to screen for this. Microadenomas have generally been thought to not cause disruption of normal pituitary function. Of the 22 patients with suspected microadenomas evaluated in the series of Reincke et al. (1990) and Donovan and Corenblum (1995), all had normal pituitary function. However, Wichers-Rother et al. (2004) found high frequencies of hormone loss in 25 patients with nonfunctioning microadenomas, with deficiencies of GH being present in 80%, of gonadotropins in 24%, of ACTH in 28%, and of TSH in 12%. Yuen et al. (2008) subsequently found deficiencies of one or more pituitary hormones in 50% of 38 patients with clinically nonfunctioning microadenomas. Larger lesions are much more likely to cause varying degrees of hypopituitarism because of compression of the hypothalamus, the hypothalamic–pituitary stalk, or the pituitary itself. Of the various series reported, up to 41% of patients with macroadenomas were found to have hypopituitarism (Reincke et al., 1990; Donovan and Corenblum, 1995; Fainstein Day et al., 2004; Arita et al., 2006). Thus, all patients with macroadenomas should be screened for hypopituitarism but whether all patients with microadenomas should be similarly screened is controversial (Freda et al., 2011). Specifics of diagnostic testing for hypopituitarism can be found elsewhere in this volume (see Ch. 10).

Natural history and follow-up of incidental clinically nonfunctioning adenomas Clinically, patients with incidental macroadenomas are commonly seen in everyday practice. In 11 series totaling 522 patients that have been reported with pituitary CNFAs that were not treated either surgically or medically, thereby giving an indication of their natural history, 356 (70%) had macroadenomas and 166 (30%) had microadenomas (Table 12.3) (Reincke et al., 1990; Donovan and Corenblum, 1995; Nishizawa et al., 1998; Feldkamp et al., 1999; Igarashi et al., 1999; Sanno et al., 2003; Fainstein Day et al., 2004; Arita et al., 2006; Karavitaki et al., 2007; Dekkers et al., 2007; Aghakhani et al., 2011). However, these were not all true incidentalomas. Many had tumors 2 cm or more in diameter and many were symptomatic with hypopituitarism or visual field defects but for a variety of reasons surgery was not carried out. For example, in the series reported by Karavitaki et al. (2007), only one-half of the 24 macroadenomas were incidental findings and 11 had varying degrees of hypopituitarism. In this series,

171

5 of the patients had major visual field defects but did not have surgery either because of major comorbidities (3 patients) or because the patient did not wish surgery (2 patients) (Karavitaki et al., 2007). Similarly, in the series of 28 patients with macroadenomas reported by Dekkers et al. (2007) (62), only 6 (21%) were truly incidentalomas, with 44% having hypopituitarism and 46% having visual field defects. Of the 166 patients with microadenomas reported in these series, 17 (10%) experienced tumor growth, 11 (7%) showed evidence of a decrease in tumor size, and 138 (83%) remained unchanged in size in follow-up MRI scans over periods of up to 8 years (Reincke et al., 1990; Donovan and Corenblum, 1995; Feldkamp et al., 1999; Igarashi et al., 1999; Sanno et al., 2003; Fainstein Day et al., 2004; Arita et al., 2006; Karavitaki et al., 2007; Aghakhani et al., 2011). Of the 356 patients with macroadenomas, 86 (24%) showed evidence of tumor enlargement, 45 (13%) showed evidence of a decrease in tumor size, and 225 (63%) remained unchanged in size on follow-up MRI scans over periods of 8 years (Reincke et al., 1990; Donovan and Corenblum, 1995; Nishizawa et al., 1998; Feldkamp et al., 1999; Igarashi et al., 1999; Sanno et al., 2003; Fainstein Day et al., 2004; Arita et al., 2006; Karavitaki et al., 2007; Dekkers et al., 2007; Aghakhani et al., 2011). In their review of the data from these series, Ferna´ndez-Balsells et al. (2011) expressed the incidence of tumor enlargement per 100 patient-years as 12.53 for macroadenomas and 3.32 for microadenomas. The duration of follow-up of these patients was variable and in their analysis, Dekkers et al. (2007) suggested that with longer follow-up up to 50% of patients with macroadenomas will have an increase in tumor size. It should be mentioned that of the 86 macroadenomas with tumor size increase, in 7 this was due to a hemorrhage into the tumor. The incidence of pituitary apoplexy per 100 patient-years was 1.1 for macroadenomas and 0.4 for microadenomas (Ferna´ndez-Balsells et al., 2011). Attempts have been made to look at the growth rates of those tumors that do grow. Dekkers et al. estimated a growth rate of 0.6 mm per year or 236 mm3 per year (Dekkers et al., 2007). Of their 14 patients who experienced tumor growth, 2 showed evidence of growth by 2 years, 3 more by 3 years, and then 1 each at 4 years, 5 years, 6 years, 7 years, 12 years, 15 years, 17 years, 20 years, and 22 years. In contrast, Karavitaki et al. (2007) found that all but 4 of their 12 patients who experienced macroadenoma regrowth did so by 5 years, although patients also had evidence of tumor growth at 6 and 8 years. Honegger et al. (2008) found tumor volume doubling times ranging from 0.8 to 27.2 years, emphasizing the tremendous variability in tumor size increases; there was no correlation between initial tumor size and the rate of tumor volume doubling. These data

172

M.E. MOLITCH

suggest that at least for patients with macroadenomas, surveillance MRI scans should be carried out for at least 22 years, although the frequency of scanning can certainly be reduced after the first few years if there is no evidence of tumor growth.

Management of incidental clinically nonfunctioning adenomas Therapy is indicated for tumors that are hypersecreting. Therefore, prolactinomas would generally be treated with dopamine agonists and those producing GH or ACTH would be treated with surgery (Biller et al., 2008; Melmed et al., 2009, 2011). For tumors not oversecreting these hormones, the indications for surgery are based primarily on size, size change, and mass effects of the tumors. For patients with microadenomas, the data presented above suggest that significant tumor enlargement will occur in only 10%. Therefore, surgical resection is generally not indicated and yearly repeat scanning for 2–3 years is indicated to detect tumor enlargement; subsequently this can be done at less frequent intervals

(Fig. 12.1). Surgery is done only for significant tumor enlargement. However, the rate of growth is generally quite slow so that the decision and timing of any surgery would depend on the rate and amount of growth as well as any clinical consequences, such as the development of visual field defects. Tumors greater than 1 cm in diameter have already indicated a propensity for growth. A careful evaluation of the mass effects of these tumors is indicated, including evaluation of pituitary function and visual field examination if the tumor abuts the chiasm. If there are visual field defects, surgery is indicated (Freda et al., 2011). Because hypopituitarism is potentially correctable with tumor resection (see below), this is also an indication for surgery. In my opinion, tumors larger than 2 cm should also be considered for surgery simply because of their already demonstrated propensity for growth. Similarly, if a tumor is found to be abutting the optic chiasm, even though testing shows normal visual fields, consideration should be given to surgery (Freda et al., 2011). If surgery is not done, then visual fields should be tested at 6–12 monthly intervals thereafter. If a completely asymptomatic lesion is thought

Evaluation of pituitary function

Hyperfunctioning

Prolactinoma

Other

Dopamine agonist

Surgery

Clinically nonfunctioning

1cm

Visual fields R/O pituitary hypofunction

Repeat MRI at 1, 2, 5 yrs

Repeat MRI at 0.5, 1, 2, 5 yrs

No change

Tumor growth Abnl fields

No further studies (?)

Surgery

Fig. 12.1. Flow diagram indicating the approach to the patient found to have a pituitary incidentaloma. The first step is to evaluate patients for pituitary hyperfunction and then treat those found to be hyperfunctioning. Patients with tumors that are clinically nonfunctioning who have macroadenomas are evaluated further for evidence of chiasmal compression and hypopituitarism. Scans are then repeated at progressively longer intervals to assess for enlargement of the tumors. (Reproduced from Molitch, 2008.)

NONFUNCTIONING PITUITARY TUMORS to be a pituitary adenoma on the basis of radiologic and clinical findings, then a decision could be made to simply repeat scans on a yearly basis, surgery being deferred until there is evidence of tumor growth. Some would obtain the initial follow-up scan at 6 months, to detect potential rapid growers (Freda et al., 2011). As indicated above, significant tumor growth can be expected in approximately 20% of such patients. Hemorrhage into such tumors is uncommon but anticoagulation may predispose to this complication; surgery would prevent such a complication. When there is no evidence of visual field defects or hypopituitarism and the patient is asymptomatic, an attempt at medical therapy with a dopamine agonist or octreotide is reasonable, realizing that only about 10–20% of such patients will respond with a decrease in tumor size (see below). Surgery is indicated if surveillance scans show evidence of tumor enlargement. As with microadenomas, the decision to proceed with surgery is affected by the rate and extent of growth and any clinical consequences, such as compression of the optic chiasm or the development of pituitary hormone deficiencies, as well as the patient’s comorbidities and risks for surgery (Fig. 12.1).

SYMPTOMATIC CLINICALLY NONFUNCTIONING ADENOMAS Presenting symptoms CNFAs usually present because of symptoms due to the mass effects of the tumor. Data from 12 representative series are shown in Table 12.4 (this table is not meant to be comprehensive but to show the range of effects of the tumors). Clearly, the most common symptoms and signs are visual field disturbance, headache, and hypopituitarism, although the last was often only found with detailed testing. Testing of pituitary function in 13 series (Arafah, 1986; Ebersold et al., 1986; Comtois et al., 1991; Tominaga et al., 1995; Colao et al., 1998; Greenman et al., 2003; Nomikos et al., 2004; Wichers-Rother et al., 2004; Dekkers et al., 2006a; Losa et al., 2008; Anagnostis et al., 2010; Brochier et al., 2010; Chen et al., 2011) showed that the loss of hormones was on the order of GH > LH/FSH > ACTH > TSH (Table 12.5). In many older series, testing for GH deficiency in adults was not carried out because they thought that the finding of GH deficiency would not change therapy. However, the multitude of studies carried out in recent years showing potential benefit of GH therapy in GH-deficient adults suggest that GH testing should be done in all such patients if such therapy would be appropriate for the given patient (Molitch et al., 2011). When it is done, the majority of patients will be found to be GH deficient (Table 12.5).

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A number of studies have recently shown that patients with CNFAs have decreased quality of life and some psychological issues, including increased anxiety and harm avoidance (Sievers et al., 2009), increased fatigue, decreased social functioning (Dekkers et al., 2006b), poor sleep quality (Biermasz et al., 2011) and memory (Brummelman et al., 2011). Because these were generally mixed populations of patients with respect to hypopituitarism, hormone replacement, prior surgery, and prior radiotherapy, it is difficult to pinpoint an exact cause for these issues and all of these factors may be important in individual patients.

Diagnostic evaluation MRI with gadolinium is preferred to CT, as it can reveal far more anatomic detail of the lesion itself and its relationship to surrounding structures as well as providing characteristics distinguishing an adenoma from other mass lesions, such as craniopharyngiomas or Rathke’s cleft cysts (Elster, 1993; Naidich and Russell, 1999). MRI can demonstrate the decreased signal of flowing blood and therefore can better determine the presence of aneurysms. Aneurysms and adenomas may coexist, however, and rarely magnetic resonance arteriography may be necessary. Somatostatin receptor imaging shows that most CNFAs have somatostatin receptors (DeHerder et al., 2006) and dopamine receptor imaging shows that many CNFAs have dopamine receptors (DeHerder et al., 2007), but the imaging with these compounds is considerably less sensitive than MRI or CT for showing anatomic detail and as yet does not accurately predict those tumors that might respond to somatostatin analogs or dopamine agonists with size reduction (DeHerder et al., 2006, 2007). The endocrinologic evaluation for hormonal overand undersecretion is discussed above.

Treatment Treatment options for CNFAs include no treatment with careful observation, surgery with or without postoperative radiotherapy, radiotherapy alone, and medical therapy. Transsphenoidal resection is usually recommended for patients with enlarging tumors or tumors with mass effects. Rarely, craniotomy with subfrontal resection is required for very large tumors but this technique is associated with higher morbidity. The effectiveness of each treatment modality can be assessed clinically, with assessment of resolution or amelioration of symptoms (e.g., headache) and signs (e.g., visual field defects), biochemically, with assessment of reversal of pituitary hormonal deficits, and structurally, with assessment of tumor size by MRI. Postoperative MRIs to assess completeness of resection should ideally be done at least 3–4 months after

Table 12.4 Signs and symptoms in patients with clinically nonfunctioning adenomas

Series{ No. of patients Symptoms/signs (%) Visual field defects Hypopituitarism Headaches Visual acuity reduction Ophthalmoplegia Apoplexy

Toronto Erlichman (1979)

Rochester Ebersold (1986)

Montreal Comtois (1991)

Cardiff Shone (1991)

Naples Colao (1998)

Tel Aviv Greenman (2003)

Erlangen Nomikos (2004)

Bonn WichersRother (2004)

Milan Losa (2008)

Paris Brochier (2010)

Beijing Chen (2011)

Thessalonki Anagnostis (2011)

153

100

126

35

84

122

721

155

491

142

385

114

66 58 44 – – –

68 61 36 – 5 5

78 75 56 54 12 8

71 89 17 26 11 –

39 74 75 32 16 –

18 34 29 – 14 4

31 48 19 – – 10

51 85 55 – – –

59 71 – 0 4 10

54 82 25 – – 7

61 61 62 – 15 10

55 50 53 – – 3

{ Each series is identified by the city of the first named hospital as well as the last name of the first author and the year of publication. In the series from Rochester (Ebersold et al., 1986), although all were clinically nonfunctioning adenomas, on immunohistochemistry 82 were null-cell adenomas, 9 were prolactinomas, 2 were silent corticotroph adenomas, 4 were gonadotroph adenomas, 1 was a plurihormonal adenoma, and 2 were not assessed. Hypopituitarism is counted if one or more pituitary hormones were noted to be deficient.

Table 12.5 Frequency of endocrine deficiencies and hyperprolactinemia at presentation in patients with clinically nonfunctioning adenomas

Series{ Number of patients Hormone lost LH/FSH ACTH TSH GH Hyperprolactinemia

Rochester Ebersold (1986)

Cleveland Arafah (1986)

Montreal Comtois (1991)

Hiroshima Tominaga (1995)

Naples Colao (1998)

Tel Aviv Greenman (2003)

Erlangen Nomikos (2004)

Bonn WichersRother (2004)

Leiden Dekkers (2006a)

Milan Losa (2008)

Paris Brochier (2010)

Beijing Chen (2011)

Thessaloniki Anagnostis (2011)

100

26

126

33

84

122

721

155

109

491

142

385

114

36 17 32 NT NT

96 62 81 100 46

75 36 18 NT 65

52 48 19 97 42

56 23 8 93 42

69 27 29 NT 43

78 32 20 0 28

54 32 30 85 –

77 40 47 48 NT

71 24 25 NT 43

75 53 43 77 54

41 33 35 61 NT

26 16 15 55 19

{ Each series is identified by the city of the first named hospital as well as the last name of the first author and year of publication. NT, not tested; LH, luteinizing hormone; FSH, follicle-stimulating hormone; ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone; GH, growth hormone.

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surgery (Steiner et al., 1992; Dina et al., 1993) since the appearance can be deceiving in the immediate postoperative period because of surgical packing, edema, and debris. Once this postoperative baseline has been established, MRIs should be repeated yearly for 3–5 years to detect regrowth and then less frequently if stable. Tumors should be followed by MRI in a similar fashion following radiotherapy or with medical treatment.

SURGERY Outcome data from series in which transsphenoidal surgery was performed are often difficult to analyze, as many series mix results from patients who may or may not have received postoperative radiotherapy, often without an early postoperative scan to determine the presence of residual tumor. Whether patients were cured or not, resection of the bulk of the tumor mass often resulted in improvement of pituitary function with resolution of hyperprolactinemia that was due to stalk dysfunction (Table 12.5). In general, surgical success is highly dependent upon the skill and experience of the neurosurgeon as well as specific tumor characteristics, such as size, invasiveness, and parasellar extension (Ciric et al., 1997; Barker et al., 2003; Dekkers et al., 2008; Roelfsema et al., 2012; Swearingen, 2012). The best way to assess completeness of resection is to obtain an MRI 3–4 months postoperatively and then follow the tumor with serial MRIs, as noted above. Resolution of one or more hormonal deficits by surgery can be expected in 15–50% of patients, with resolution of hyperprolactinemia in more than two-thirds of patients (Table 12.6). Conversely, in 2–15% of patients surgery may induce an additional loss of one or more pituitary hormones when they were normal preoperatively (Losa et al., 2008; Comtois et al., 1991; Gsponer et al., 1999; Nomikos et al., 2004; Brochier et al., 2010; Chen et al., 2011). Transient diabetes insipidus (DI) can be expected in about 20–30% of patients (Nomikos et al., 2004; Chen et al., 2011) but permanent DI occurs

in 0.5–5% (Comtois et al., 1991; Gsponer et al., 1999; Nomikos et al., 2004; Nemergut et al., 2005; van den Bergh et al., 2007; Losa et al., 2008; Anagnostis et al., 2010; Chen et al., 2011). Other complications of surgery occurring in less than 1% of patients each include postoperative CSF leak, meningitis, seizures, rebleeding, cranial nerve injury, and visual function deterioration (Ciric et al., 1997; Barker et al., 2003; Losa et al., 2008; Swearingen, 2012). Mortality remains about 0.3–1.3% and is seen more often in patients with very large tumors who require craniotomy (Ciric et al., 1997; Barker et al., 2003; Losa et al., 2008; Chen et al., 2011). Patients with giant tumors, defined as being > 4 cm in diameter, do particularly poorly, with very low cure rates and relatively high morbidity and mortality rates, and combined transsphenoidal/transcranial approaches are often used (Mohr et al., 1990; Alleyne et al., 2002; Garibi et al., 2002; Mortini et al., 2007; Nishioka et al., 2012).

RADIOTHERAPY Radiotherapy as primary therapy is rarely done and mainly restricted to those patients who would not be able to tolerate surgery. More commonly, radiotherapy is given as adjunctive therapy postoperatively. Prior to the institution of policies of routine surveillance with MRI scans, many series reported postoperative recurrence rates in patients who did or did not have routine postoperative irradiation. In many of those series the criteria for choosing which patient received postoperative irradiation were not specified. Reports from nine series of patients, showed that the recurrence rates for tumors following surgery were 8.0% of 552 patients who received routine postoperative radiotherapy and 16.3% of 428 patients who did not receive such routine radiotherapy (Ebersold et al., 1986; Comtois et al., 1991; Shone et al., 1991; Brada et al., 1993; Bradley et al., 1994; Breen et al., 1998; Colao et al., 1998; Gittoes et al., 1998; Park et al., 2004) (Table 12.6). More recent series have reported similar data stratified by the

Table 12.6 Results of transsphenoidal surgery for clinically nonfunctioning pituitary adenomas on pituitary function

Series{

Cleveland Arafah (1986)

Montreal Comtois (1991)

Madrid Marzuela et al., (1994)

Hiroshima Tominaga (1995)

Naples Colao (1998)

Erlangen Nomikos (2004)

Milan Losa (2008)

Hormone axis normalized LH/FSH ACTH TSH Hyperprolactinemia

32 38 57 58

11 41 14 NT

29 57 13 NT

13 73 67 85

34 10 57 68

15 35 33 95

33 42 36 91

{ Each series is identified by the city of the first named hospital as well as last name of the first author and year of publication. LH, luteinizing hormone; FSH, follicle-stimulating hormone; ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone.

NONFUNCTIONING PITUITARY TUMORS presence or absence of tumor on the initial postoperative MRI (Lillehei et al., 1998; Gsponer et al., 1999; Turner et al., 1999; Woollons et al., 2000; Soto-Ares et al., 2002; Greenman et al., 2003; Alameda et al., 2005; Dekkers et al., 2006a; van den Bergh et al., 2007; Losa et al., 2008; Brochier et al., 2010). For those patients with no visible tumor on postoperative MRI, 1 of 14 (7.1%) who received routine radiotherapy had a recurrence and only 14% of 615 patients who did not receive routine radiotherapy experienced recurrences (Table 12.7). For those patients who had visible tumor on postoperative MRI, 11.2% of 339 patients who received routine radiotherapy had growth of tumor remnants whereas 50.1% of 487 patients who did not receive routine radiotherapy experienced growth of tumor remnants (Table 12.7). Thus, the risk of tumor recurrence/growth is very low when no tumor is visible postoperatively, but such a risk is considerably higher when a tumor remnant is visible

177

and this risk can be substantially reduced with postoperative irradiation. Besides postoperative irradiation, other factors such as the age of the patient, gender, tumor size, invasiveness, and histology were not shown to have consistent prognostic significance with respect to tumor regrowth (Roelfsema et al., 2012). Conventional radiotherapy has substantial complications, including a risk of hypopituitarism in over 50% of patients, a two-fold increase in stroke, and a three- to four-fold increase in the development of brain tumors (Hansen and Molitch, 1998; Gittoes, 2003). However, with respect to this increase in second tumors, there is a clear ascertainment bias due to the routine surveillance MRIs done in patients who have had pituitary irradiation compared to none in the general population (Gittoes, 2003). Cognitive dysfunction is rare when conventional radiotherapy doses are used (Hansen and Molitch, 1998; Gittoes, 2003; Brummelman et al., 2011).

Table 12.7 Regrowth of pituitary adenomas following transsphenoidal surgery with and without postoperative radiotherapy and with and without residual tumor visible postoperatively Series{

Postop MRI status unknown RT

No visible tumor on postop MRI

No RT

RT

Visible tumor on postop MRI

No RT

RT

No RT

Total Regrowth Total Regrowth Total Regrowth Total Regrowth Total Regrowth Total Regrowth Ebersold (1986) Comtois (1991) Shone (1991) Bradley (1994) Colao (1998) Gittoes (1998) Park (2004) Brada (1993) Breen (1998) Lillehei (1998) Turner (1999) Gsponer (1999) Woollons (2000) Soto-Ares (2002) Greenman (2003) Alameda (2005) Dekkers (2006a) Ferrante (2006) van den Bergh (2007) Losa (2008) Brochier (2010) TOTAL {

50

9

10

0

57 63 44 208 120

9 4 1 6 15

552

44 (8%)

42 71 22 73 25 63 132

428

5 15 5 8 4 27 26

90 (16.3%)

11

0

3

1

14

1 (7%)

32 57 21 11 17 30 11 27 73 15

2 13 2 2 0 6 1 0 14 0

279 42 615

36 10 86 (14%)

8 41

0 13

14 22 6 76 76

5 1 0 14 3

81 15 339

1 1 38 (11.2%)

8 21 11 34 78 5 64 77 28

8 9 8 13 41 3 9 45 16

76 85 487

46 46 244 (50.1%)

Each series is identified by the last name of the first author and the year of publication. The numbers shown are numbers of cases. For each category is shown the total number of cases evaluated and the number in whom there was recurrence/regrowth of the tumors. Postop, postoperative; RT, radiotherapy; No RT, no radiotherapy; MRI, magnetic resonance imaging.

178 M.E. MOLITCH Over the past decade, the mode of radiotherapy has Surgery for tumor regrowth has had variable success. changed in most institutions around the world from conIn a series of 42 such patients, Benveniste et al. (2005) ventional to stereotactic (Sheehan et al., 2005; Kanner reported that visual loss improved in only 57%, residual et al., 2009; Jagannathan et al., 2009). With conventional tumor was still present in 75%, and late relapse following radiotherapy, radiation is given through two or three this second surgery occurred in 15%. Stereotactic radioports, 5 days per week for 5 weeks, thereby giving a therapy has also been given to a limited number of total dose of approximately 45 Gy over 25 sessions. patients who have had prior surgery and prior convenWith stereotactic radiotherapy (often referred to as tional radiotherapy who have continued tumor growth “radiosurgery”), after tumor anatomy is defined by or hypersecretion with some success and no increase MRI, radiation is given in a single fraction or fractionin adverse events (Swords et al., 2003). ated either via linear accelerator (LINAC) beams that are shaped or through multiple cobalt sources (gamma MEDICAL THERAPY knife) in higher doses to the tumor with lower doses to the surrounding brain tissue or with protons using proton CNFAs have been shown to have high affinity dopamibeam therapy (for review of these techniques see Kanner nergic binding sites using [3H]spiperone as a radioligand with affinities similar to that seen for normal pituitary et al., 2009). In a recent review summarizing 28 series in tissue and prolactinomas; however, the number of bindwhich 904 patients with CNFAs were treated with these newer stereotactic techniques, tumor growth was coning sites was only 18.8% of that seen in prolactinomas but trolled in 88–97% but this was only over a 4 year period similar to that seen in normal pituitaries (Bevan and of time (Kanner et al., 2009). Because of the short period Burke, 1986). In a more recent study, Pivonello et al. of follow-up, the true long-term tumor size control rate (2004) showed that the dopamine D2 receptor was is as yet unknown. expressed in 67% of 18 cases. Clinically, however, broThe complication rates of stereotactic radiotherapy mocriptine has been shown to be effective in shrinking CNFAs in less than 20% of cases (Grossman et al., are also only beginning to be appreciated after this short 1985; Bevan and Burke, 1986; Van Schaardenburg follow-up period. In one detailed report it was found that after a median of 80.5 months following gamma knife et al., 1989). On the other hand, Greenman et al. radiotherapy, new pituitary hormone deficiencies devel(2005) reported giving bromocriptine to patients with oped in 39% of patients (Gopalan et al., 2011). Overall, CNFAs who had residual tumor on MRI following surthe reported incidences of new hormonal losses varied gery, finding that the tumor mass decreased or remained from 0% in the first few years to up to 66% after 17 years stable in 18 of 20 patients. In this same study, in 13 subfollowing stereotactic radiotherapy (Darzy and Shalet, jects bromocriptine was started when tumor remnant growth became evident during the course of routine 2009). Thus, the ultimate rate for hypopituitarism is likely follow-up and this growth stabilized or decreased in to be quite similar to that for conventional radiotherapy. Although cognitive and memory problems have been 8 (62%) (Greenman et al., 2005). In contrast, tumor size issues with radiotherapy in the past (Hansen and increased in 29 of 47 (62%) subjects who had neither broMolitch, 1998), doses used in recent years with fractionmocriptine nor radiotherapy (Greenman et al., 2005). ated conventional radiotherapy (Brummelman et al., Cabergoline, a long-acting dopamine agonist with 2011) and gamma knife stereotactic radiotherapy (Tooze greater activity on prolactinomas than bromocriptine et al., 2012) do not seem to cause problems. The optic has also been found to have somewhat better in vivo activity on CNFAs. Lohmann et al. (2001) found that nerves and optic chiasm are radiosensitive and so a > 10% (range 10–18%) tumor shrinkage in 7 of stereotactic radiotherapy is not given to tumors < 5 mm from the optic chiasm (Tishler et al., 1993; Leber et al., 13 patients treated with cabergoline 1 mg/week for 1 year, 1998). However, the cranial nerves coursing through and Pivonello et al. (2004) found a more significant the cavernous sinus (III, IV, V1, V2, VI) are much more tumor size reduction (range 28.6–62.4%) in 5 of 9 radioresistant (Tishler et al., 1993; Leber et al., 1998); therepatients with cabergoline 3 mg/week for 1 year. In a fore, stereotactic radiotherapy is quite good for treating review of the literature, Colao et al. (2008) summarized residual tumor in the cavernous sinus. Acute symptoms 13 studies of patients receiving bromocriptine, finding of headache, fatigue, nausea and vomiting, developing that 8 of 128 (6.2%) patients experienced further tumor usually within 2 but up to 10 days following irradiation, growth, 36 of 128 (28.1%) experienced tumor size reduchave been reported in up to 50% of patients (St. George tion, and the remainder showed no change in tumor size; et al., 2002). An MRI should be done to exclude an aposimilarly, in three studies of patients receiving cabergoplexy under such circumstances. Dexamethasone in line, 3 of 23 (13%) patients experienced further tumor doses of about 8 mg per day has been used for these acute growth, 12 of 23 (52.2%) experienced tumor size reduccomplications but results have been variable. tion, and the remainder showed no change in tumor size.

NONFUNCTIONING PITUITARY TUMORS Caution is needed when using high doses of cabergoline, however, in that patients using very high doses (>3 mg/day) for Parkinson’s disease have been found to be at an increased risk for fibrotic cardiac valvular lesions (Schade et al., 2007; Zanettini et al., 2007). Somatostatin receptors are also present in most CNFAs (De Bruin et al., 1992; Duet et al., 1994). Octreotide, a somatostatin analog, has been shown to produce a modest reduction in tumor size with improvement in visual field defects. In their review of 11 studies, Colao et al. (2008) found that visual fields improved in 27 of 84 patients (32.1%) but the changes in tumor volume were much less impressive, with tumor reduction occurring in only 5 of 100 patients, tumor increase occurring in 12 of 100 patients and no size change in the remainder. Interestingly, Andersen et al. (2001) found a 60% response rate with the combination of octreotide 200 mg three times daily subcutaneously and cabergoline 0.5 mg daily, the six responders being those who had elevated blood levels of gonadotropin subunits and the four nonresponders having no elevation of gonadotropin subunits.

MANAGEMENT OF THE SYMPTOMATIC PATIENT Transsphenoidal resection is usually recommended for patients with enlarging tumors, tumors that cause hypopituitarism, or tumors that press on the optic chiasm. Because of its generally limited success, medical therapy would be an option only in those patients with comorbidities so severe as to preclude surgery. Postoperative MRIs should be done 3–4 months after surgery to assess completeness of resection and then repeated yearly for 3–5 years and subsequently less frequently if there is no evidence of growth. If tumor resection is shown to be complete by postoperative MRI scans, routine radiotherapy may well not be needed as the tumor recurrence rate for such patients is only 14% and patients can be followed with periodic MRI scans as stated above. Radiotherapy or repeat surgery, or even medical therapy, can be given at the time tumor size increase is documented. If tumor resection is incomplete, postoperative radiotherapy may be indicated, as radiotherapy can reduce the recurrence rate from 50% to about 11%. However, the recent demonstration by Greenman et al. (2005) regarding the control of postoperative growth suggests that perhaps a trial of a dopamine agonist is reasonable in the patient with a small residual tumor; irradiation (stereotactic) would then only be given to those not responding to the dopamine agonist.

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Nonfunctioning pituitary tumors.

Clinically nonfunctioning adenomas range from being completely asymptomatic, and therefore detected either at autopsy or as incidental findings on hea...
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