Benign Meningiomas

Although the majority of meningiomas are benign (World Health Organization [WHO] grade I) and slow growing, they may become large enough over time to cause devastating neurological deficits and morbidity if left untreated. Therefore, therapeutic intervention is needed for most diagnosed tumors. In current clinical practice, surgery is the treatment of choice for the majority of meningiomas. Resection enables histologic diagnosis, relieves mass effect and associated symptoms, alleviates tumor-induced seizures, and achieves high local control rates.

Not all tumors can be resected completely without considerable morbidity. Safe and complete resection is frequently precluded by tumor involvement of the cranial nerves or arteries or invasion of the venous sinuses. Resectability also depends on the site and thus the surgical accessibility of the tumor. Gross total resection (GTR) is often not possible in the cavernous sinus, clivus, cerebellopontine angle, and sellar regions. It is estimated that a third of meningiomas are not fully resectable.¹⁶ In these situations, when complete and safe tumor removal is not possible, an effective strategy is subtotal resection (STR) followed by postoperative RT or RT alone. Clinical follow-up and serial imaging are recommended at annual or semiannual intervals for all patients who have undergone incomplete resection.

For benign meningiomas, the extent of resection is a major clinical predictor of recurrence in the absence of postoperative RT.^17–19 GTR of benign meningiomas is considered definitive treatment (Table 251-1 and Fig. 251-1). Mirimanoff and coauthors reported 5-, 10-, and 15-year recurrence rates of 7%, 20%, and 32% and second operation rates of 6%, 15%, and 20%, respectively, among 145 patients in whom GTR was achieved.¹⁶ These rates were later confirmed in a large series from the Mayo Clinic.²⁰ Additionally, Condra and coworkers confirmed the importance of complete excision but found no association between Simpson grade and local control or cause-specific survival, as long as GTR (Simpson grades 1, 2, and 3) was achieved.²¹ For patients treated by surgery alone, GTR resulted in 5-, 10-, and 15-year actuarial recurrence rates of 7%, 20%, and 24%, respectively.²¹

FIGURE 251-1 Meningioma treatment outcomes by year of publication. Published series with more than 50 patients and at least 3 years’ follow-up were included in this analysis. The addition of postoperative radiation therapy (RT) improves progression-free survival (PFS) in patients with subtotal resection (STR) to levels observed after gross total resection (GTR). It is also worth noting that outcomes of definitive external beam RT (EBRT) alone in the treatment of benign meningiomas are comparable to those after GTR and are associated with minimal morbidity. The impact of computed tomography– and magnetic resonance imaging–based RT planning on PFS is best visualized by comparing treatment outcomes before and after the year 2000; surgical outcomes over the same period remained essentially unchanged, thus suggesting that technologic improvements in RT planning and delivery were largely responsible for the observed improvement in PFS after subtotal resection.

Recurrence rates after STR alone are substantially higher (see Table 251-1 and Fig. 251-1). For example, among 116 patients with STR, Stafford and associates found recurrence in 39% at 5 years and in 61% at 10 years.²⁰ Condra and colleagues documented local recurrence at 5, 10, and 15 years in 47%, 60%, and 70% of patients who underwent STR, respectively.²¹ Overall, it is estimated that local progression develops in 40% to 50% of patients after STR within 5 years, in 60% within 10 years, and in at least 70% within 15 years.^21,22

Because GTR is frequently not possible, RT, whether fractionated external beam RT or stereotactic radiosurgery (SRS), is currently the only accepted nonsurgical treatment option. Historically, meningiomas were considered to be resistant to RT, with authors of many older retrospective studies reporting infrequent radiographic regression.²³ Additionally, concerns about malignant degeneration were cited as a reason to refrain from either definitive or postoperative RT.^24,25 Consequently, many patients with inoperable or subtotally resected meningiomas underwent observation. At present, malignant degeneration has not been explicitly linked to RT; instead, it is believed to be related to the natural history of a subset of meningiomas. Strojan and coauthors reviewed the case files of 170,000 meningioma patients treated in Slovenia over a 31-year period and reported the actuarial risk of a secondary meningioma developing after cranial irradiation to be 0.53% at 5 years and 8.18% at 25 years.²⁶

Most retrospective studies since the 1980s have demonstrated that postoperative RT after STR improves local control (see Table 251-1 and Fig. 251-1) and perhaps even survival.^21,27 Improvement in local control, as well as frequent improvement in tumor-related neurological symptoms, was observed despite the fact that only about a fourth to a third of treated meningiomas exhibit tumor shrinkage (Fig. 251-2; also see Table 251-1).

FIGURE 251-2 Rates of neurological improvement and late post–radiation therapy toxicity as a function of treatment period.

RT can also be used as primary treatment of meningiomas diagnosed radiographically or by biopsy. In one of the earliest reports, Glaholm and associates reported on the outcome of 32 patients treated by primary RT without resection at the Royal Marsden Hospital; a 47% disease-free survival rate was observed at 15 years.^24,25 This was only modestly lower than a corresponding 56% disease-free survival rate in patients treated with STR plus RT. More recent series, however, demonstrate markedly improved local control rates and progression-free survival rates greater than 93% after 5 to 10 years of follow-up (see Table 251-1).^28–31 These outcomes compare favorably with those observed after GTR of benign meningiomas (see Fig. 251-1).

The discrepant outcomes of older studies (before 2000) and more recent RT studies, whether in the postoperative or primary setting, may be attributed to technical advancements in RT treatment planning and delivery techniques. This trend is clearly illustrated in Figure 251-1 for progression-free survival and in Figure 251-2 for RT-related late neurological toxicity, as well as neurological improvement. These observations are more directly supported by Goldsmith and colleagues’ analysis of 140 patients treated at the University of California, San Francisco, with a median dose of 54 Gy in the postoperative setting; a progression-free survival rate of 98% was noted in those treated after 1980 (when computed tomography [CT] and magnetic resonance imaging [MRI] was used for planning therapy) as compared with a rate of 77% for patients treated before 1980, when advanced planning techniques were not available.³²

Newer treatment series also report on the use of intensity-modulated RT (IMRT), as well as fractionated stereotactic RT (FSRT) (see Table 251-1). IMRT techniques allow the delivery of doses via multiple convergent beams (Fig. 251-3), each of which can be divided into zones of different intensities so that the integral dose can tightly conform to the shape of the target. This technique can potentially minimize unnecessary irradiation of surrounding normal tissues, including the critical anterior optic structures. FSRT is a variant of conventional RT characterized by a highly accurate patient immobilization setup, use of a stereotactic coordinate system, and submillimeter mechanical and beam tolerances of the treatment equipment. All modern RT techniques rely on the use of sophisticated imaging for planning treatment and verifying delivery. It is believed, but not yet definitively proved, that these newer treatment methods will continue to improve treatment outcomes and reduce RT-related toxicity.

FIGURE 251-3 A representative intensity-modulated radiation therapy (IMRT) plan for a right cavernous sinus meningioma (World Health Organization grade I) in a 52-year-old patient with a slight right temporal field deficit thought to be related to encroachment of disease on the right portion of the optic chiasm. Gross tumor volume (GTV) is shaded red; a dose of 54 Gy in 30 fractions was prescribed to the 95% isodose line to minimize the risk of injury to the anterior optic structures. Note: The maximal point dose for the plan (56.38 Gy) is located within the tumor volume, and the maximum dose applied to the chiasm is less than 54 Gy.

It is worth noting, however, that serious side effects of modern methods of treatment planning and delivery are already quite uncommon. For example, Debus and coauthors reported on 189 patients treated by FSRT for large skull base meningiomas with median daily fractions of 1.8 Gy to a total mean dose of 56.8 Gy.³³ With a nearly 3-year median follow-up, the rate of clinically significant toxicity (grade 3) was 2.2% (4 patients), and 1.6% (3 patients) in the absence of a preexisting neurological deficit. The neurological deficits reported in the study included reduced vision, a new visual field loss, and trigeminal neuropathy. Goldsmith and coworkers noted complications in 3.6% of 140 patients treated with RT after STR from 1967 to 1990.³² The RT-related toxicity observed in this study included retinopathy, optic neuropathy, and cerebral necrosis. Further analysis of the data by Goldsmith and associates permitted construction of a model to predict that optic nerve tolerance is 890 optic ret, equivalent to 54 Gy in 30 fractions.³⁴ This threshold dose is supported by only rare observations of optic nerve injury with doses lower than 54 Gy, particularly with fractional doses of 2.0 Gy or less.^24,35,36 Additionally, Uy and colleagues reported no anterior optic pathway injury with a median dose of 50.4 Gy in fractions of 1.7 to 2.0 Gy.³⁷ Shrieve and associates further confirmed these findings, as well as the relative benefit of a fraction size of 2.0 Gy or less.³⁸

Other cranial neuropathies (nonoptic) are uncommon with modern treatment techniques but have been reported in older series. For example, Selch and coworkers found no RT-related neuropathy in 45 patients treated for cavernous sinus meningiomas with a median dose of 50.4 Gy (1.8 Gy/fraction).³⁹ Similar findings were noted earlier by Urie and colleagues.⁴⁰ Brain or brainstem injury, including necrosis, is quite uncommon in the modern era with conventional doses and techniques. Similarly, edema is not generally observed after fractionated RT, unlike single-session SRS. For this reason, fractionated RT is preferred over SRS for tumors in locations where edema is likely to lead to significant morbidity (e.g., larger cerebellopontine angle tumors).

Optic Nerve Sheath Meningiomas

Management of optic nerve sheath meningiomas (ONSMs) is almost exclusively nonsurgical. These rare tumors represent less than 2% of all meningiomas and arise from the meningeal lining of the optic nerves.^41,42 They generally grow very slowly within the subarachnoid space and the confines of the optic canal but eventually compress the optic nerve itself, its vasculature, or both. Patients usually have progressive visual loss, although some may exhibit rapid loss of vision. In a small minority of patients, ONSMs are found incidentally on imaging. Less common complaints include visual field defects, loss of or alterations in color vision, and orbital pain.

Resection of ONSMs while keeping the optic nerve in place has been tried^43–47 but carries an unacceptably high risk for visual complications and local recurrence. Resection commonly impairs the blood supply and results in blindness, even though the nerve is left grossly intact. For these reasons, fractionated RT has become the centerpiece of management of ONSM. In one of the largest series published, Turbin and coauthors reported on 64 patients with ONSM and found that fractionated RT alone provided more favorable outcomes than did observation, surgery alone, or even a combination of surgery and RT.⁴⁷ Patients in the RT-only group were the only ones who did not demonstrate a statistically significant decline in visual acuity after a mean follow-up period of 11.5 years (range, 4.75 to 23 years); all other groups, including patients who underwent surgery plus RT, demonstrated a significant decrement in visual acuity, including complete visual loss. Irradiated patients received 40 to 55 Gy of fractionated RT (1.8 to 2.0 Gy/fraction) over an approximately 5-week period. In another study from Japan, Narayan and colleagues evaluated 14 patients with ONSM who were treated with conformal, fractionated RT to a total dose of 50.4 to 56 Gy.⁴⁸ After a median follow-up of 4.1 years, 86% of the treated patients had either improved or stable visual acuity. These studies and six additional ones with similar results established highly conformal, fractionated RT as the treatment of first choice for patients with ONSM. In aggregate, local control is excellent (95%), early visual improvement (<3 months after completion of RT) is attained in about half of the patients (54.7%), and complications of therapy are relatively uncommon.⁴¹ It is our institutional policy to treat all symptomatic ONSM patients with highly conformal, fractionated RT to total doses of 50.4 to 54 Gy in daily fractions of 1.8 Gy; however, there is no uniform agreement on whether patients with stable ONSM and stable vision should be managed by observation or early RT. Patients with bilateral disease are generally treated, whereas those with unilateral tumors are observed, provided that that they can be expected to comply with serial visual field testing and regular clinical and imaging follow-up.

Atypical Meningiomas

Atypical, WHO grade II meningiomas may account for up to 20% of all diagnosed meningiomas.¹⁰ Atypical meningiomas are a heterogeneous group, largely because of the imprecise pathologic classification criteria and varying classification schemes over time. Most investigators have recommended irradiation, irrespective of the extent of resection.^21,49 However, Goyal and coauthors argued that fractionated RT has no significant impact on local control and overall survival.⁵⁰ Their retrospective analysis was based on a cohort of 22 patients, 15 of whom underwent GTR (Simpson grades 1 to 3), 4 underwent STR, and 3 had resection of unknown extent; 8 patients received RT (2 after initial resection and 6 at the time of recurrence). The median radiation dose was 54 Gy (range, 35 to 59.4 Gy). After a median follow-up of 5.5 years, the local control rate was 87% at 5 and 10 years after GTR, and RT had no significant impact on local control or overall survival. This study highlighted some of the difficulties relevant to atypical tumors, including inconsistent use, dosing, and timing of RT, as well as wide variations in the extent of resection.⁴⁹ Hug and coworkers found that that local control of atypical meningiomas was significantly enhanced by cumulative doses of at least 60 cobalt gray equivalents (CGE).⁴⁹ Perry and coauthors reported on 108 patients with atypical meningiomas treated with modern surgical techniques, grading, and postoperative imaging and reported a 5-year recurrence rate of 40% even after GTR.⁵¹ In another study, recurrence rates of atypical meningiomas after either STR or “radical subtotal” resection were 39% and 61% at 5 and 10 years, respectively.²⁰ Because of these unacceptably high recurrence rates, there is a relative consensus that irradiation to a total dose of 59.4 Gy (1.8 Gy/fraction) or 60 Gy (2 Gy/fraction) is appropriate after STR of an atypical meningioma.

Adjuvant treatment recommendations for atypical meningiomas after GTR are more controversial. Many neurosurgeons argue in favor of close radiographic and clinical follow-up after Simpson grade 1 and 2 resection, but not necessarily Simpson grade 3.⁵² In a recent study, Aghi and colleagues retrospectively reviewed the outcomes of 108 patients with atypical meningiomas who underwent Simpson grade 1 GTR at the Massachusetts General Hospital between 1993 and 2004.⁵³ With a mean follow-up period of 3.25 years, the actuarial tumor recurrence rates were 7% at 1 year, 41% at 5 years, and 48% at 10 years. Most recurrences occurred within the first 5 years after surgical resection. Of the 108 patients, 8 received immediate adjuvant RT to a total dose of 59.4 to 61.2 Gy (1.5 to 1.8 Gy/fraction) and experienced no recurrences during the follow-up period. This study could be interpreted as evidence in favor of either immediate postoperative fractionated RT or close clinical and radiographic follow-up (every 3 to 6 months) for the first 5 years, with salvage RT being performed as needed. The key question in this patient subset is whether early adjuvant or late salvage RT is more appropriate; the existing publications do not answer this question.

Recurrent Meningiomas

Recurrent meningiomas, after surgery alone, exhibit markedly increased progression rates over newly diagnosed tumors,^16,21,35,54 with a mean interval to clinical recurrence of 4 years.^16,23 Miralbell and coauthors reported a 78% progression-free survival rate at 8 years in patients treated with surgery plus RT for recurrent tumors as compared with just 11% with surgery alone.³⁵ Similarly, Taylor and colleagues reported on 30 patients in whom recurrent disease developed after their initial treatment; 15 were treated by surgery alone, 10 underwent surgery and RT, and 5 patients either refused treatment or were deemed inoperable.⁵⁴ The reported local control rate was 30% at 10 years in patients who underwent surgery alone for recurrence, whereas the 10 patients treated by salvage RT (with or without resection) had an actuarial local control rate of 89%. The study of Taylor and associates⁵⁴ provides compelling support for the use of salvage RT to cumulative doses of 54 to 59.4 Gy (1.8 Gy/fraction or similar regimens at 2 Gy/fraction), not only because of the superior local control rates but also because of the improved actuarial survival in the salvaged patients (89% for surgery plus RT at 10 years versus just 43% for surgery alone). These data support aggressive treatment of recurrent meningiomas.

Prolactinoma

Prolactinomas are the most common functional pituitary tumors. Nearly 90% of these tumors are entirely intrasellar at diagnosis and rarely increase in size during routine follow-up.⁶⁵ Elevated levels of prolactin can interfere with the normal pulsatile release of gonadotropin-releasing hormone, thereby impeding the secretion of luteinizing hormone and follicle-stimulating hormone. Consequently, the symptoms of prolactinomas are dependent on the sex of the patient. Hyperprolactinemia in women can result in amenorrhea, galactorrhea, and infertility. The majority of prolactinomas in women are microadenomas.⁶⁶ Prolactinomas in men tend to be more aggressive and most are macroadenomas.⁶⁷ Men often report symptoms related to local mass effect such as visual disturbance, neurological dysfunction, and headache with associated hypogonadism, decreased libido, and infertility.

A diagnosis is established by documenting a sustained elevation in serum prolactin above the normal range. Additionally, contrast-enhanced fat-suppressed MRI should be used to confirm a diagnosis. However, a negative MRI scan does not exclude the diagnosis of a prolactinoma in the setting of clinical symptoms, especially in female patients, who are likely to harbor microadenomas.⁶⁸

The goal of treatment of prolactinoma is restoration of sexual/reproductive function, control of galactorrhea, stabilization of serum prolactin levels, and in cases of macroadenoma, relief of neurological symptoms. The standard initial management of prolactinomas is surgery followed by medical therapy with a dopamine agonist if needed. Bromocriptine, pergolide, and cabergoline are ergot alkaloids that bind the dopamine receptor and relieve symptoms of hyperprolactinemia by causing the cessation of prolactin release.⁶⁹ Treatment with bromocriptine has been shown to normalize prolactin levels, relieve symptoms, and cause tumor shrinkage in 80% to 90% of patients with microadenomas and in 70% to 80% of patients with macroadenomas.^69,70

A significant shortcoming of conservative medical management with dopamine agonists is recurrence of disease in almost 90% of patients after cessation of dopamine agonist therapy.^71,72 In a study of 131 patients monitored for an average of 44 months after cessation of bromocriptine therapy, Passos and coworkers reported normalization of prolactin levels in only 20.6% of participants.⁷¹ Many of the reported recurrences were primarily biochemical in nature, but tumor regrowth resulting in compression of the optic nerve and associated visual deterioration was reported in a subset of patients.⁷⁰ These issues argue for an effective adjuvant therapy capable of inducing an extended remission period.

Both surgery and RT have been investigated in this setting. Transsphenoidal pituitary resection is the current second-line therapy and results in 75% to 90% long-term biochemical control in patients with microadenomas.^73–75 Pretreatment prolactin levels are a strong risk factor for recurrence, independent of tumor size. The immediate postoperative prolactin level is also prognostic, with levels of less than 5 ng/mL being associated with an 80.5% remission rate at a mean follow-up of 9.2 years.^76,77 Gillam and coworkers performed an extensive review and meta-analysis of surgical therapy for prolactinoma and demonstrated average remission rates of 74.7% and 33.9% for microadenomas and macroadenomas, respectively.⁷⁰ Remission was defined as normalization of prolactin levels within 12 weeks after surgery. The majority of the recurrences were biochemical without any abnormalities noted on imaging. This analysis confirmed the presence of a macroadenoma as a risk factor for recurrence or persistence of disease.

RT has also been investigated for the treatment of prolactinomas. In the current treatment paradigm, RT is typically a second- or third-line treatment, after medical or surgical interventions (or both) have failed or if the patient is not a surgical candidate. Several studies have addressed the efficacy of conventional RT as postoperative treatment and in the primary setting (Table 251-2). Interpretation of these studies is complicated by the use of different end points and definitions of cure.

Most of the studies investigating the use of primary conventional RT for the treatment of prolactinoma were conducted between 1977 and 2006 (see Table 251-2). Halberg and Sheline observed 28 patients for 2 to 10 years after treatment and demonstrated normalization of prolactin levels in 29%.⁷⁶ They used bilateral coronal arc fields with reversing wedge filters to deliver 45 Gy in 25 fractions to the sella turcica while sparing the eyes altogether. Another study by Grigsby and associates analyzed 17 patients treated with a mean dose of 39.89 Gy (range, 3.94 to 56 Gy) in fractional doses of 0.5 to 2 Gy and reported a 10-year disease-free survival rate of 82.3%.⁷⁸ Patients treated with doses of 45 Gy or greater achieved superior tumor control. Within the treated cohort, 5 of 9 female patients had a return to normal menstrual patterns, and galactorrhea ceased in 4 of 8 patients. Similarly, Rush and Newall reported on 29 patients with a follow-up of 3 to 8 years and reported a 70% rate of prolactin normalization.⁷⁹ Tsang and colleagues conducted the largest postoperative study consisting of 64 patients treated at the Princess Margaret Hospital in Toronto and demonstrated normalization of prolactin levels in 25% at a median follow-up of 7.3 years.⁸⁰ Most patients in this study were treated to a total dose of 50 to 52 Gy via right and left parallel-opposed fields targeting the preoperative extent of adenoma with a 1.0- to 1.5-cm margin. More recently, Jalali and coworkers⁸¹ and Minniti and colleagues⁸² reported on the use of FSRT for the treatment of adenomas. However, these preliminary studies have follow-up that is too limited to permit meaningful interpretation. Table 251-2 lists most major published studies that have examined the role of conventional RT for the treatment of prolactinomas.

The aforementioned studies demonstrate less than satisfactory control rates, especially when compared with the efficacy of primary medical therapy with dopamine agonists, thus suggesting that primary fractionated RT may not offer the best chance for long-term disease remission. It has been hypothesized that these suboptimal outcomes are due to RT-induced damage to the hypothalamus⁸³ and subsequent loss of dopamine release and thus loss of the inhibitory signal for release of prolactin. This leads to a paradoxical increase in prolactin secretion from the anterior pituitary. This hypothesis is supported by observations from studies investigating the treatment of nonsecretory adenomas with RT.⁸³

Many investigations have also looked at the use of RT in conjunction with medical or surgical treatment (or both). Just as in the studies of definitive RT, interpretation of the results is complicated by varied definitions for cure and biochemical remission. In many of these studies, the timing of bromocriptine therapy in the post-RT setting has been poorly documented, thereby confounding analysis of the effects of RT.

In a study investigating the use of intermittent dopamine agonist therapy and RT, Tsagarakis and associates observed 36 female patients for a mean period of 8.5 years. About half of the patients experienced normalization of prolactin levels, and an additional 28% had prolactin levels just above the normal range (378 to 780 mU/L).⁸⁴ Only 1 patient exhibited documented disease recurrence by imaging.

Similarly, Grossman and coworkers investigated the impact of 45 Gy in 25 fractions plus interim dopamine agonist therapy in 36 women with prolactinomas.⁸⁵ Treatment with the dopamine agonist was stopped at a mean of 4.2 years after RT to assess the response in 27 patients, with 26 demonstrating a progressive decline in serum levels of prolactin. Moreover, in patients who were interested in conceiving after treatment, a successful conception rate of 86% was observed. Grigsby and colleagues also analyzed the efficacy of postoperative conventional RT for the treatment of prolactinoma.⁸⁶ Twenty-six patients with prolactinoma had a 10-year disease-free survival rate of 93.3%, with resolution of galactorrhea in 7 of 13 patients and resumption of menses in 8 of 15 patients. Other studies have reported similar and less satisfactory results, thus prompting investigations of the use of SRS for this disease when large, single-fraction doses can be delivered safely.^87,88

In summary, bromocriptine (or other dopamine agonists) is usually sufficient to control the majority of prolactinomas; however, discontinuation of treatment with the drug frequently results in the recurrence of symptoms and necessitates the use of surgery or RT to provide long-term biochemical control. Conventional RT plays a more integral role in the treatment of macroadenomas and lesions causing neurological symptoms as a result of cranial nerve compression or those that are refractory to medical therapy or surgery. The retrospective literature suggests that higher doses of conventional RT (54 Gy in 30 fractions) result in improved local and biochemical control. The toxicity of treatment, secondary to injury to the anterior visual pathway or hypothalamus, may be reduced further as FSRT is adopted and used more widely.

Cushing’s Disease

Cushing’s disease is caused by an adrenocorticotropic hormone (ACTH)–secreting pituitary adenoma and, when associated with signs and symptoms of excess ACTH, is referred to as Cushing’s syndrome. Cushing’s disease causes approximately 70% of cases of Cushing’s syndrome and is characterized by the presence of several of the following symptoms: central obesity, glucose intolerance, hypertension, hirsutism, abdominal striae, moon facies, and a buffalo hump.⁸⁹ Cushing’s disease typically affects men more than women (3 : 1 ratio).⁹⁰ It is diagnosed with a 24-hour urine collection to quantify the amount of urinary free cortisol, a dexamethasone suppression test, or both. Elevated levels of urinary free cortisol, clinical symptoms, and positive findings on imaging can all, in conjunction, lead to a diagnosis of Cushing’s disease.⁹¹ Random measurements of serum cortisol or ACTH (or both) are not diagnostic because of the natural diurnal variations in secretion of ACTH.

Most ACTH-secreting tumors are microadenomas. In up to 25% of patients with this disease, there are no abnormal findings on MRI, and of these patients, about 50% have no identifiable tumor at surgery.⁹² Transsphenoidal resection is currently the first-line therapy and has yielded control rates of 70% to 85% in several retrospective series.^93,94 More recent surgical studies, conducted after 2000, are in line with the historical data and have reported biochemical remission rates ranging from 68.5% to 98%.^95–98 For example, Cavagnini and colleagues observed 300 patients for a median follow-up time of 10 years and found a biochemical remission rate of 70% and a recurrence rate of 15% after surgery alone.⁹⁸ Chen and associates investigated 174 patients treated surgically with a median follow-up of 5 years and found a similar biochemical remission rate of 74%; however, the recurrence rate was just 7% (probably because of a shorter follow-up period).⁹⁵ This study also revealed that a serum cortisol level of 3 µg/dL or less on the morning of postoperative day 3, after an overnight dexamethasone suppression test, was prognostic of up to a 93% biochemical remission rate at 5 years. Flitsch and coworkers evaluated 147 patients and made similar observations regarding the prognostic significance of low postoperative ACTH levels.⁹⁶

RT has also been explored as treatment for patients with Cushing’s disease. In a manner analogous to prolactinomas, most studies evaluating the efficacy of primary, conventional RT for the treatment of ACTH-secreting adenomas were conducted before the year 2000 (Table 251-3). Most recent studies explore the efficacy of SRS instead. Orth and Liddle conducted the largest study of RT involving 44 patients treated before 1971 and demonstrated a control rate of 44% and normalization of cortisol levels in 20% of patients observed for a median period of 9 years.⁹⁹ An analysis by Grigsby and coworkers of 6 patients treated with definitive RT before 1982 showed a 100% tumor control rate with a follow-up ranging from 6 to 29 years.⁷⁸ A dose of less than 40 Gy to the tumor correlated with lower biochemical control rates and a greater risk for recurrence. A more recent study by Hughes and associates analyzed 40 patients and demonstrated a 10-year progression-free survival rate of 59% (see Table 251-3).¹⁰⁰ Large tumor volumes and consequently large treatment fields were found to have a negative prognostic implication.

In a 1997 study, Estrada and coworkers investigated the postoperative use of RT consisting of 50 Gy in 25 fractions and demonstrated an 83% biochemical control rate (normalization or improved symptoms) in 30 patients monitored for a median period of 3.5 years.¹⁰¹ Similarly, Minniti and associates evaluated 40 patients treated postoperatively with RT (45 Gy in 20 fractions or 50 Gy in 28 fractions) and reported a 78% biochemical remission rate at 5 years and an 84% remission rate at 10 years.¹⁰² Not all retrospective studies were similarly successful, however. For example, an older study by Littley and coauthors analyzed 24 patients and found a biochemical remission rate of only 46%,¹⁰³ probably because the postoperative dose of RT was just 20 Gy in 10 fractions. In another study, Tsang and colleagues examined 29 patients who received 50 Gy of postoperative RT and found only a fair biochemical remission rate of 53% at 10 years.⁸⁰ The reasons for these discrepancies among studies are not clear, but it does appear that more modern treatment techniques tend to achieve superior biochemical outcomes.

Nelson’s Syndrome

Nelson’s syndrome is characterized by hyperpigmentation occurring after bilateral adrenalectomy in patients with ACTH-secreting pituitary adenomas.¹⁰⁴ Removal of both adrenal glands eliminates the production of cortisol, and the resultant loss of negative feedback allows preexisting pituitary adenomas to grow unchecked. It is estimated that Nelson’s syndrome will eventually develop in 30% to 50% of patients with Cushing’s syndrome who undergo bilateral adrenalectomy.¹⁰⁵ These adenomas tend to be more aggressive, frequently extend beyond the sella, and thus are more difficult to cure; surgery in this setting is often complex and morbid.

The role of RT for the treatment of Nelson’s syndrome was investigated in a few studies. Howlett and associates conducted a study of 15 patients with Nelson’s syndrome who were treated with definitive, primary RT to a total dose of 45 Gy in 25 fractions and observed post-treatment biochemical improvement in all but 1 patient after a median follow-up of 9.5 years.¹⁰⁶ In 1995, Jenkins and coworkers analyzed the outcomes of 20 patients who underwent “prophylactic” pituitary RT (45 Gy in 25 fractions) at some time after bilateral adrenalectomy and demonstrated that RT reduces the incidence of subsequent Nelson’s syndrome by 50% (75% control rate at a median follow-up of 9.1 years).¹⁰⁷

Acromegaly

Acromegaly is caused by excessive secretion of GH after closure of the epiphyseal plates.¹⁰⁸ The characteristic bone enlargement found in patients with acromegaly usually involves the frontal bones (frontal bossing), nose, mandible (prognathism), hands, feet, and vertebrae (kyphosis). Adults do not generally become taller with excess GH in serum because the epiphyseal plates of the long bones have already closed. The excessive GH leads to an increase in insulin-like growth factor type I (IGF-I), and this results in several other medical comorbidities in addition to simple bone enlargement. Higher rates of cardiovascular complications, hypertension, diabetes mellitus, and colon cancer have all been described in this patient population and lead to significant decreases in life expectancy.^109–111

Because GH secretion varies throughout the day, the diagnosis of acromegaly is established by measuring the GH level after a glucose challenge. A glucose load of 100 g should normally cause marked suppression of GH release, usually below 2 ng/mL.¹¹² Failure to achieve such suppression after a glucose challenge may suggest a presence of a GH-secreting pituitary adenoma. It is also advisable to check serum IGF-I levels because they are less variable throughout the day and may be a more reliable marker for diagnosis.¹¹²

The first-line therapy for GH-secreting pituitary tumors is again surgical resection.¹¹³ Although somatostatin analogues may also be used to control GH and IGF-I levels, this treatment is successful in only 50% to 79% of patients; there is an associated decrease in tumor size by as much as 50% in about half of the patients.^114,115 The concurrent use of dopamine agonists may help reduce GH levels by an additional 10%.¹¹⁶ Both GH and IGF-I levels can be used to monitor the endocrine response (biochemical control) in patients with acromegaly. The goal of therapy is to achieve normalization of GH and IGF-I markers to reduce, stop, or prevent the metabolic complications associated with their elevation.

Transsphenoidal microsurgery is highly successful in the treatment of acromegaly, more successful in the treatment of microadenomas than macroadenomas, just as in other secreting pituitary adenomas. Laws and colleagues analyzed 86 patients treated by microsurgery alone and reported biochemical remission rates of 87% and 51% for microadenomas and macroadenomas, respectively.¹¹⁷ An overall remission rate (normalization of serum IGF-I) of 67% was achieved after 1 year of follow-up. The largest surgical series, by Nomikos and associates in 2005, reported on 688 patients, 506 of whom underwent primary transsphenoidal surgery for their acromegaly.¹¹⁸ An overall biochemical response rate (normalization of serum IGF-I) of 57.3% was achieved in patients treated primarily by surgery during a follow-up period of 10.7 years, with a biochemical recurrence rate of just 0.4%. Again, patients with microadenomas had higher biochemical remission rates than did those with macroadenomas (75% versus 50%, respectively).¹¹⁸

These two large surgical series are representative of outcomes reported in the published literature after transsphenoidal resection of pituitary adenomas for acromegaly. It should be cautioned that a vast range of success rates have been reported in the published literature, principally because of varied definitions of biochemical control or cure. The surgical morbidity in experienced hands is quite low: reported mortality rates are less than 0.5%, and serious complications occur in less than 1.5% of patients.¹¹⁹ Pregnancy after transsphenoidal surgery for microadenomas has been achieved in 86% of women desiring to become pregnant, and the incidence of iatrogenic hypopituitarism in patients with microadenomas is less than 3%.¹¹⁹

Several studies have evaluated the use of conventional RT for the treatment of acromegaly. Table 251-4