Treatment paradigms for pituitary adenomas: defining the roles of radiosurgery and radiation therapy

Pituitary adenomas represent one of the most common types of intracranial tumors. While their macroscopic appearance and anatomical location are relatively homogeneous, pituitary tumors have the potential to generate a wide variety of clinical sequelae. Treatment options for pituitary tumors include medical therapy, microscopic or endoscopic surgical resection, radiosurgery, radiation therapy, or observation depending on the biochemical profile and clinical status of the patient. Radiosurgery and external beam radiation therapy (EBRT) are most commonly as adjunctive treatments following incomplete surgical resection leaving residual tumor, tumor recurrence, or failure of medical therapy. We present a comprehensive literature review of the radiosurgery series for pituitary tumors including nonfunctioning adenomas, ACTH- and GH-secreting adenomas, and prolactinomas. While post-radiosurgery radiographic tumor control for nonfunctioning adenomas is excellent, typically around 90 %, the rates of biochemical remission for functioning adenomas are lower than the tumor control rates. The highest endocrine remission rates are achieved patients with Cushing’s disease and the lowest in those with prolactinomas. Although EBRT has been largely supplanted by radiosurgery for the vast majority of pituitary adenomas cases, there remains a role for EBRT in select cases involving large tumor volumes in close proximity to critical neural structures. By far the most common complication after radiosurgery or EBRT is delayed hypopituitarism followed by cranial neuropathies. The effect of suppressive medications on radiosurgery outcomes remains controversial. Due to the rare but well-documented occurrence of late recurrence following endocrine remission, long-term and rigorous clinical and radiographic follow-up is necessary for all pituitary adenoma patients treated with radiosurgery or EBRT.     

Integration of surgery with fractionated stereotactic radiotherapy for treatment of nonfunctioning pituitary macroadenomas

OBJECTIVE: To evaluate the efficacy of fractionated stereotactic radiotherapy (FSRT) after surgery in the management of residual or recurrent nonfunctioning pituitary adenomas with respect to tumor control and the development of complications. METHODS AND MATERIALS: The clinical records of patients with nonfunctioning pituitary adenomas who underwent FSRT were retrospectively analyzed. For newly diagnosed tumors, transsphenoidal surgery was performed, and, if residual tumor was identified at 3 months, FSRT was performed. If significant tumor volume persisted, transcranial surgery was performed before FSRT. We originally initiated FSRT with 2-Gy fractions to 46 Gy. We escalated the dose to 50.4 Gy thereafter. As a final modification, we dropped the daily dose to 1.8-Gy fractions delivered within 6 weeks. High-dose conformality and homogeneity was achieved with arc beam shaping and differential beam weighting. The radiographic, endocrinologic, and visual outcomes after FSRT were evaluated. RESULTS: The 68 patients included 36 males and 32 females with an age range of 15-81 years. The median follow-up was 30 months (range, 2-82 months), and the median tumor volume was 6.2 cm(3). Of the 68 patients, 20 were treated to 46 Gy and 48 to 50-52.2 Gy. Most were treated to 50.4 Gy. Eleven patients had recurrent tumors, 54 had residual tumors, and no surgery was performed in 3 patients before FSRT. We noted no radiation-induced acute or late toxicities, except for radiation-induced optic neuropathy in 2 patients. At latest follow-up, the tumor had decreased in size in 26 patients and remained stable in 41 of the 42 remaining patients. Of the 68 patients, 4 (6%) developed hypopituitarism at 6, 11, 12, and 17 months after FSRT. Reviewing available serial Humphrey visual fields, visual fields were objectively improved in 28 patients, and remained stable in 24 patients, and worsened in 2 patients. CONCLUSION: The findings of this analysis support the use of surgery followed by FSRT as a safe, effective, and integrated treatment for nonfunctioning pituitary adenomas. Additional follow-up is needed to document the long-term tumor control rates, preservation rates for vision and pituitary function, and neurocognitive outcomes.     

Intensity-modulated radiotherapy for pituitary adenomas: the preliminary report of the Cleveland Clinic experience

PURPOSE: Intensity-modulated radiotherapy (IMRT) is being increasingly used for the treatment of pituitary adenomas. However, there have been few published data on the short- and long-term outcomes of this treatment. This is the initial report of the Cleveland Clinic's experience. METHODS AND MATERIALS: Between February 1998 and December 2003, 34 patients with pituitary adenomas were treated with IMRT. A retrospective chart review was conducted for data analysis. RESULTS: With a median follow-up of 42.5 months, the treatment has proven to be well tolerated, with performance status remaining stable in 90% of patients. Radiographic local control was 89%, and among patients with secretory tumors, 100% had a biochemical response. Only 1 patient required salvage surgery for progressive disease, giving a clinical progression free survival of 97%. The only patient who received more than 46 Gy experienced optic neuropathy 8 months after radiation. Smaller tumor volume significantly correlated with subjective improvements in nonvisual neurologic complaints (p = 0.03), and larger tumor volume significantly correlated with subjective worsening of visual symptoms (p = 0.05). New hormonal supplementation was required for 40% of patients. Younger patients were significantly more likely to require hormonal supplementation (p = 0.03). CONCLUSIONS: Intensity-modulated radiation therapy is a safe and effective treatment for pituitary adenomas over the short term. Longer follow-up is necessary to determine if IMRT confers any advantage with respect to either tumor control or toxicity over conventional radiation modalities.     

Fractionated stereotactically guided radiotherapy and radiosurgery in the treatment of functional and nonfunctional adenomas of the pituitary gland

We evaluated survival rates and side effects after fractionated stereotactically guided radiotherapy (SCRT) and radiosurgery in patients with pituitary adenoma.

Between 1989 and 1998, 68 patients were treated with FSRT (n = 63) or radiosurgery (n = 5) for pituitary adenomas. Twenty-six had functional and 42 had nonfunctional adenomas. Follow-up included CT/MRI, endocrinologic, and ophthalmologic examinations. Mean follow-up was 38.7 months. Seven patients received radiotherapy as primary treatment and 39 patients received it postoperatively for residual disease. Twenty-two patients were treated for recurrent disease after surgery. Mean total dose was 52.2 Gy for SCRT, and 15 Gy for radiosurgery.

Overall local tumor control was 93% (60/65 patients). Forty-three patients had stable disease based on CT/MRI, while 15 had a reduction of tumor volume. After FSRT, 26% with a functional adenoma had a complete remission and 19% had a reduction of hormonal overproduction after 34 months’ mean. Two patients with STH-secreting adenomas had an endocrinologic recurrence, one with an ACTH-secreting adenoma radiologic recurrence, within 54 months. Reduction of visual acuity was seen in 4 patients and partial hypopituitarism in 3 patients. None of the patients developed brain radionecrosis or radiation-induced gliomas.

Stereotactically guided radiotherapy is effective and safe in the treatment of pituitary adenomas to improve local control and reduce hormonal overproduction.     

Long-term outcomes of radiotherapy for pituitary adenomas

PURPOSE: To evaluate long-term local control and toxicity for pituitary adenomas treated with fractionated radiotherapy (RT). METHODS AND MATERIALS: The records of 100 patients with pituitary adenomas treated between 1983 and 2003 were retrospectively reviewed. Thirty-one patients had hormone-secreting tumors; 69 patients were treated with surgery and postoperative RT. Median follow-up was 6.7 years (range, 0.6-20.2 years) for all patients and 6.2 years (range, 2-20.2 years) for living patients. The mean dose delivered was 45 Gy (range, 43-50.4 Gy). RESULTS: The 10-year actuarial local control rates for nonsecreting and secreting adenomas were 98% and 73%, respectively (p = 0.0015). Actuarial 10-year cause-specific survival (CSS) rates were 95% and 88%, and overall survival rates were 66% and 79% for nonsecreting and secreting adenomas, respectively. Involvement of the sphenoid sinus was found to be significantly associated with decreased 10-year CSS (p = 0.0453). When compared with the two- or three-field techniques, stereotactic RT was associated with improved CSS (p = 0.0775). CSS was not significantly associated with hormone excretion, extent of surgery, or whether RT was administrated postoperatively or for salvage after a postsurgical recurrence. New cases of hypopituitarism occurred in 35 patients. One patient experienced vision loss, and one patient developed a post-treatment glioma. CONCLUSIONS: This is one of the most mature series in the literature that documents excellent results with fractionated RT for pituitary adenoma. We recommend 45 Gy at 1.8 Gy per fraction using stereotactic noncoplanar fields.     

Instructions for Authors

Pituitary adenomas in the elderly represent an increasing proportion of pituitary tumors, making the surgical management of these patients of special importance. We therefore decided to review our experience with transsphenoidal surgery (TSS) in this age group, in order to better evaluate its efficacy, safety and outcome.A retrospective study was performed on 39 patients aged more than 70 years at the time of surgery (mean age 74.1 ± 2.9 years) and with a minimum follow-up duration of 4 years at the time of the study. Thirty-one had a nonfunctioning pituitary adenoma, 5 had a GH-secreting adenoma and 3 a macroprolactinoma, respectively. The commonest presenting symptom was visual deterioration (60%), whereas hypopituitarism were present in 41% of patients. All patients underwent TSS without any major peri- and post-operative complications. Visual fields improved in 74% of patients. Post-operative radiotherapy was performed in 17 patients with partial surgical resection and/or persistent hormonal hypersecretion, whereas 22 patients with subtotal or total surgical resection were treated by surgery only. Long-term follow-up (mean 9.1 ± 2.7 years) showed evidence for tumor regrowth in one irradiated (5.9%) and 3 non-irradiated patients (13.6%), respectively. A noticeable complication of radiotherapy was progressive hypopituitarism, which worsened or developed in 65% of patients.We conclude that TSS is safe and well tolerated even in elderly patients, with a low incidence of minor complications. The indications for post-operative radiotherapy in patients with incomplete tumor resection should be better defined.     

Visual outcome after fractionated stereotactic radiation therapy of benign anterior skull base tumors

To determine visual outcome including the occurrence of radiation induced optic neuropathy (RION) as well as tumor control after fractionated stereotactic radiation therapy (FSRT) of benign anterior skull base meningiomas or pituitary adenomas. Thirty-nine patients treated with FSRT for anterior skull base meningiomas and 55 patients treated with FSRT for pituitary adenomas between January 1999 and December 2009 with at least 2 years follow-up were included. Patients were followed up prospectively with magnetic resonance imaging scans, visual acuity and visual field examinations. RION was found in four (10 %) patients with anterior skull base meningiomas and seven patients (13 %) with pituitary adenomas. The five-year actuarial freedom from 25 % RION visual field loss was 94 % following FSRT. Actuarial 2-, 5- and 10-year tumor control rates were 100, 88.4 and 64.5 % for anterior skull base meningiomas and 100, 98.2 and 94.9 % for pituitary adenomas, respectively. Patients with an impaired visual field function pre-FSRT were more likely to experience worsened function (p = 0.016). We found that RION, was a relatively uncommon event, in a large prospective cohort of patients that were systematically monitored following FSRT of benign anterior skull base tumors. Long term tumor control was favorable, especially for pituitary adenomas.     

Safety and efficacy of the direct endonasal transsphenoidal approach for challenging sellar tumors

Introduction The direct endonasal approach to pituitary microadenomas is relatively atraumatic, rapid, and carries a lower complication rate than the sublabial approach. Large macroadenomas (3–4 cm) can still be addressed with this simple, unmodified direct endonasal approach. We present our experience with this unique and challenging patient population. Methods About 64 consecutive patients with large (3–4 cm) pituitary adenomas and craniopharyngiomas were treated by the senior author (SK) using the direct endonasal approach from May 2001 to July 2004. The hospital course, endocrinological function, radiographic imaging, and outpatient follow-up were retrospectively reviewed for each patient. Results The mean volume of these lesions was 31.5 cm³ (range, 10.3–168 cm³). Tumor pathologies included 2 craniopharyngiomas, 16 functional, and 46 nonfunctional pituitary adenomas. Suprasellar extension of tumor was evident in all patients and 10 had cavernous sinus invasion. Gross total resection was achieved in 30 patients, near-gross total in 6 patients, and subtotal resection in 26 patients. Eight patients (12.5%) demonstrated postoperative complications, with diabetes insipidus for less than 1 year (n = 4) being the most common. There was no incidence of CSF leak, new panhypopituitarism, or worsened vision. Five patients (7.8%) had tumor residual requiring radiation therapy. Additionally, after a mean clinical follow-up of 24.5 months, 4 patients (6.3%) demonstrated recurrent disease. Conclusions Direct endonasal transsphenoidal surgery enables safe and effective resection of large sellar masses while maintaining a favorable morbidity profile.     

Long-term Results of Radiation Therapy for Pituitary Adenoma

Purpose. Local control for pituitary adenomas treated with external beam radiation therapy was retrospectively analyzed to evaluate the efficacy of radiation. Materials and methods. Thirty-eight patients treated with radiation therapy between 1979 and 1994 were analyzed. The median age was 46. Nineteen newly diagnosed tumors were treated with surgery and radiation therapy, while the others were recurrent cases. Twenty-two tumors were non-functioning, while 10 produced growth hormone (GH) and three each were prolactin-, and adrenocorticotropic hormone (ACTH)-producing tumors. The median radiation dose was 50Gy in 25 fractions. Results. Non-functioning adenomas and prolactin-producing adenomas were completely controlled, judging from the absence of tumor progression on neuroimaging studies and clinical symptoms, and normalization of the serum prolactin level (<25ng/ml). On the other hand, local control was obtained in only one of the 3 patients with ACTH-producing adenomas, and the control rate at 10 years was only 46% for GH-producing adenomas. Panhypopituitarism developed in 35% of the patients after radiation therapy. No other serious complications were noted. Conclusion. Non-functioning pituitary adenomas and prolactin-producing adenomas were well controlled with external radiation therapy combined with surgery. However, dose escalation might be necessary to control GH- or ACTH-producing tumors. It is important to replace corticosteroid hormone and thyroid hormone in many patients.     

The efficacy of conventional radiation therapy in the management of pituitary adenoma

Purpose: To evaluate the efficacy of conventional radiotherapy for reducing tumor size and endocrine hypersecretion of pituitary adenomas.

Methods and Materials: We reviewed the records of 91 patients with pituitary adenoma, who were first treated between 1969 and 1994 and had been followed for more than 2 years (median, 8.2 years.) Of these patients, 86 had received postoperative radiotherapy, and 5 had received radiotherapy alone. The median total dose was 51 Gy. Clinical symptoms related to mass effects or endocrine hypersecretion were assessed. The efficacy of radiotherapy was evaluated before treatment and during the follow-up period (1–14 years; median, 3 years) by estimating tumor size on computed tomography or magnetic resonance imaging in 56 patients, as well as by endocrine testing in the 22 patients who had secreting adenomas. Local control rate, prognostic factors, and side effects were analyzed.

Results: Mass-effect symptoms improved in 72% and 79% of patients who had such symptoms due to nonsecreting adenomas and secreting adenomas, respectively. Symptoms of endocrine hypersecretion abated in 67% of patients who had such symptoms. Excessive hormone levels normalized in 74% of patients who showed endocrine hypersecretions. The greatest size reduction was seen 3 years after the completion of radiotherapy (24% CR, 62% PR, 12% NC, and 3% PD in nonsecreting adenomas, and 32% CR, 36% PR, 27% NC, and 5% PD in secreting adenomas). Three patients with secreting adenomas (2 with prolactinoma and 1 with Cushing’s disease) showed a mismatch between reduction in tumor size and normalization of endocrine hypersecretion. The 10-year local control rates were 98%, 85%, 83%, and 67% for nonsecreting adenoma, growth-hormone-secreting adenoma, prolactinoma, and Cushing’s disease, respectively. Univariate analyses showed that disease type and radiation field size were significant prognostic factors. Brain necrosis occurred in 1 patient who received a 60-Gy dose of irradiation.

Conclusion: We conclude that conventional external radiotherapy with 50 Gy is safe and sufficient to control pituitary adenoma. Careful observation is required in the management of secreting adenomas because the effects on tumor size and endocrine hypersecretion may be mismatched in some secreting adenomas.     

Stereotactic radiosurgery for patients with ACTH-producing pituitary adenomas after prior adrenalectomy

PURPOSE: To review the results of stereotactic radiosurgery for patients with adrenocorticotropic hormone (ACTH)-producing pituitary adenomas after bilateral adrenalectomy. METHODS AND MATERIALS: Eleven patients with ACTH-producing pituitary adenomas after bilateral adrenalectomy underwent radiosurgery between 1990 and 1999. Nine patients had documented tumor growth, hyperpigmentation, and elevated ACTH levels (median 920 ng/mL) at the time of radiosurgery. Five of these patients had tumor enlargement despite prior fractionated radiotherapy (median dose 50 Gy). Two patients were treated prophylactically within 1 month of their adrenalectomies to prevent future tumor growth. The median follow-up was 37 months (range 22-74). RESULTS: Tumor growth control was achieved in 9 patients (82%); 2 patients had had continued tumor growth after radiosurgery. The ACTH levels decreased a median of 66% (range -99% to +27%); 4 patients had normal ACTH levels. Three patients had radiation-related complications, including diplopia (n = 2), ipsilateral blindness (n = 1), testosterone/growth hormone deficiency (n = 1), and asymptomatic temporal lobe radiation necrosis (n = 1): all had received prior radiotherapy. One patient who had undergone three prior resections and radiotherapy died 59 months after radiosurgery despite two additional attempts at tumor resection. CONCLUSION: Although our experience is limited, it appears that radiosurgery provides tumor control for most patients with ACTH-producing pituitary adenomas who have undergone bilateral adrenalectomy.     

Gamma knife radiosurgery for patients with nonfunctioning pituitary adenomas: results from a 15-year experience

PURPOSE: To evaluate the efficacy and complications of stereotactic radiosurgery for patients with nonfunctioning pituitary adenomas (NFA). METHODS AND MATERIALS: This was a retrospective review of 62 patients with NFA undergoing radiosurgery between 1992 and 2004, of whom 59 (95%) underwent prior tumor resection. The median treatment volume was 4.0 cm(3) (range, 0.8-12.9). The median treatment dose to the tumor margin was 16 Gy (range, 11-20). The median maximum point dose to the optic apparatus was 9.5 Gy (range, 5.0-12.6). The median follow-up period after radiosurgery was 64 months (range, 23-161). RESULTS: Tumor size decreased for 37 patients (60%) and remained unchanged for 23 patients (37%). Two patients (3%) had tumor growth outside the prescribed treatment volume and required additional treatment (fractionated radiation therapy, n = 1; repeat radiosurgery, n = 1). Tumor growth control was 95% at 3 and 7 years after radiosurgery. Eleven (27%) of 41 patients with normal (n = 30) or partial (n = 11) anterior pituitary function before radiosurgery developed new deficits at a median of 24 months after radiosurgery. The risk of developing new anterior pituitary deficits at 5 years was 32%. The 5-year risk of developing new anterior pituitary deficits was 18% for patients with a tumor volume of < or = 4.0 cm(3) compared with 58% for patients with a tumor volume >4.0 cm(3) (risk ratio = 4.5; 95% confidence interval = 1.3-14.9, p = 0.02). No patient had a decline in visual function. CONCLUSIONS: Stereotactic radiosurgery is effective in the management of patients with residual or recurrent NFA, although longer follow-up is needed to evaluate long-term outcomes. The primary complication is hypopituitarism, and the risk of developing new anterior pituitary deficits correlates with the size of the irradiated tumor.     

神经内镜经单鼻孔-蝶窦入路直视下切除垂体瘤

目的:探讨神经内镜技术经单鼻孔-蝶窦入路切除垂体瘤的临床应用及手术技巧.方法: 对12例经CT和MRI诊断的垂体瘤患者在神经内镜经单鼻孔入路直视下予以切除.结果: 全切9例,近全切3例.术后2例出现一过性脑脊液漏,尿崩3例.4例内分泌检查正常,7例视力好转,无严重并发症发生.结论: 内镜单鼻孔经蝶窦入路切除垂体瘤具有良好的深部照明、微创、全景化视野等优点,手术创伤小,并发症少、病人恢复快.     

Stereotactic Radiosurgery for Pituitary Adenomas: A Review of the Literature

OBJECTIVE: Pituitary adenomas are very common neoplasms and represent between 10 and 20% of all primary brain tumors. Historically, the treatment armamentarium for pituitary adenomas included medical management, microsurgery, and fractionated radiotherapy. More recently, radiosurgery has emerged as a viable treatment option. The goal of this research is to define accurately the efficacy, safety, and role of radiosurgery for treatment of pituitary adenomas. METHODS: Medical literature databases from 1965 to 2003 were searched for articles pertaining to pituitary adenomas and stereotactic radiosurgery. Each study was evaluated for the number of patients, radiosurgical parameters (e.g. tumor margin dose), length of follow-up, tumor growth control rate, complications, and rate of hormonal normalization in the case of functioning adenomas. RESULTS: A total of 34 published studies including 1567 patients were reviewed. Radiosurgery offers a tumor growth control rate of approximately 90%. The reported rates of hormonal normalization for functioning adenomas vary substantially. This range is in part due to widespread differences in endocrinological criteria utilized for post-radiosurgical assessment. Thus far, the risks of radiation induced neoplasia and cerebral vasculopathy associated with radiosurgery appear to be lower than for fractionated radiation therapy. The incidence of other serious complications following radiosurgery is quite low. CONCLUSIONS: Although surgical resection typically is the primary treatment modality, stereotactic radiosurgery offers safe and effective treatment for recurrent or residual pituitary adenomas. In rare instances, radiosurgery may be the best initial treatment for patients with pituitary adenomas. Refinements in the radiosurgical technique will likely lead to improved outcomes.     

伽玛刀治疗垂体微腺瘤远期对垂体功能的影响

背景与目的：立体定向伽玛刀治疗垂体瘤在临床已经广泛开展，但治疗垂体微腺瘤的报道仍较少，而且伽玛刀治疗远期对垂体功能的影响至今尚不明确，尤其引起垂体功能损害的情况仍令人担忧。回顾性分析伽玛刀治疗垂体微腺瘤的远期对垂体功能的影响，尤其是引起垂体功能低下的情况。方法：随访应用Leksell伽玛刀治疗的垂体微腺瘤患者，获得完整资料109例，进行回顾性分析。所有随访时间超过5年，平均89.40个月。结果：33例在术前存在不同程度垂体功能低下，治疗后28例恢复正常（84．8％）；本组有8例目前存在垂体激素水平低下，但只有1例与本次治疗有明确关系，5名目前无自诉症状，有症状而且需要激素替代治疗有3例（2．7％）。结论：伽玛刀治疗垂体微腺瘤远期引起垂体功能低下的发生率极低，而对改善垂体功能低下有明确的效果。     

Hypofractionated stereotactic radiotherapy with CyberKnife for nonfunctioning pituitary adenoma: high local control with low toxicity

The aim was to evaluate the clinical outcome of hypofractionated stereotactic radiotherapy (SRT) with CyberKnife for nonfunctioning pituitary adenoma. From October 2000 to March 2009, 100 patients with nonfunctioning pituitary adenoma were treated with hypofractionated SRT. Forty-three patients were male, and 57 were female. The patient's ages ranged from 16 to 82 years (median, 59 years). Five patients were medically inoperable, and 1 refused surgery; the remaining 94 were recurrent cases or those receiving postoperative adjuvant SRT. No patients had a history of previous cranial radiotherapy. Tumor volume ranged from 0.7 to 64.3 mL (median, 5.1 mL). The marginal doses were 17.0 to 21.0 Gy for the 3-fraction schedule and 22.0 to 25.0 Gy for the 5-fraction schedule. Toxicities were evaluated with the Common Terminology Criteria for Adverse Events version 4.0. The median follow-up period for living patients was 33 months (range, 18-118.5 months). The 3-year overall survival and local control rates were 98% and 98%, respectively. In-field and out-field tumor regrowth were observed in 3 and 2 patients, respectively. Transient cyst enlargement occurred in 3 cases. A post-SRT grade 2 visual disorder occurred in 1 patient. Symptomatic post-SRT hypopituitarism was observed in 3 of 74 patients who had not received hormone replacement therapy after surgery. CyberKnife SRT involving 21 Gy in 3 fractions or 25 Gy in 5 fractions is safe and effective for surgical treatment of nonfunctioning pituitary adenoma. Hypofractionated SRT appears useful for protecting the visual nerve and neuroendocrine function, especially for tumors located near the optic pathways and large tumors.     

A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery

PURPOSE: To evaluate the risk of clinically significant radiation optic neuropathy (RON) for patients having stereotactic radiosurgery of benign tumors adjacent to the optic apparatus. METHODS AND MATERIALS: We reviewed the dose plans and clinical outcomes of 218 gamma knife procedures (215 patients) for tumors of the sellar and parasellar region (meningiomas, n = 122; pituitary adenomas, n = 89; craniopharyngiomas, n = 7 patients). Previous surgery or radiation therapy was performed in 156 (66%) and 24 (11%) patients, respectively. Median follow-up was 40 months (range 4-115). RESULTS: The median maximum radiation dose to the optic nerve was 10 Gy (range 0.4-16.0). Four patients (1.9%) developed RON at a median of 48 months after radiosurgery. All had prior surgery, and 3 of 4 had external beam radiotherapy (EBRT) in their management either before (n = 2) or adjuvantly (n = 1). The risk of developing a clinically significant RON was 1.1% for patients receiving 12 Gy or less. Patients receiving prior or concurrent EBRT had a greater risk of developing RON after radiosurgery (p = 0.004). CONCLUSION: RON occurred in less than 2% of our patients, despite the majority (73%) receiving more than 8 Gy to a short segment of the optic apparatus. Knowledge of the dose tolerance of these structures permits physicians to be more aggressive in treating patients with sellar or parasellar tumors, especially those with hormone-producing pituitary adenomas that appear to require higher doses to achieve biochemical remission.     

Cyclooxygenase-2 expression in human pituitary tumors

BACKGROUND: Cyclooxygenase-2 (COX-2) plays a role in progression of colon, breast, pancreas, and lung carcinomas. The authors investigated COX-2 expression in pituitary tumors. METHODS: Expression of COX-2 was evaluated in 164 surgically removed human pituitary tumors. Correlation of COX-2 with MIB-1, a cell proliferation marker, as well as angiogenesis, patient age, gender, tumor type, size, invasiveness, and metastatic potential was investigated. RESULTS: Cyclooxygenase-2 immunoreactivity was confined to the cytoplasm of tumor cells, whereas the nuclei were unlabeled. Few normal peritumoral adenohypophysial cells showed slight COX-2 cytoplasmic immunoreactivity. The staining intensity and the percentage of immunopositive cells were higher in tumors. Most pituitary tumors (96%) were COX-2-immunopositive. Expression was strong in 60 (44%), moderate in 39 (28%), and weak in 32 (24%). Male gonadotroph adenomas and null cell adenomas showed a high level of COX-2 expression. Growth hormone-producing adenomas, prolactin-producing adenomas, thyrotropic hormone-producing adenomas, female gonadotroph adenomas, silent adrenocorticotropic hormone-producing adenomas, and silent subtype 3 adenomas had a low level of COX-2 expression. Significant correlation was demonstrated with patient age, but not with tumor size, invasiveness, and MIB-1 labeling indices. Expression was medium to high in 76% of macroadenomas and in only 45% of microadenomas. Strong correlations were noted with angiogenesis markers, such as microvessel density and surface density. CONCLUSIONS: Correlation with angiogenesis suggests that COX-2 may be involved in the regulation of angiogenesis in pituitary tumors. Phamacologic inhibition of COX-2 activity might suppress angiogenesis in pituitary tumors and may provide a novel approach for medical therapy.