Serum Prolactin Levels and Mortality in Adults Without Prolactinoma: A Meta-Analysis.

CONTEXT: Prolactin (PRL) is a highly versatile, multifunctional hormone synthesized and secreted by lactotroph cells of the anterior pituitary. Its metabolic role has been extensively studied even in normoprolactinemic populations. Recently, a wealth of observational data have outlined the potential prognostic value of PRL in various clinical settings. OBJECTIVE: This systematic review aims to systematically evaluate and quantitatively synthesize the association between serum PRL levels and risk of mortality in adults without prolactinoma. METHODS: A systematic literature search was conducted up to June 10, 2023, to identify studies reporting the association of serum PRL levels with clinical outcomes of adults without prolactinoma. A random-effects meta-analysis was conducted to quantify the adjusted hazard ratios [(a)HRs] for all-cause and cardiovascular death (CVD) during follow-up. RESULTS: Twenty-eight studies were deemed eligible reporting the outcomes of adults without prolactinoma, in whom serum PRL levels were measured for risk-stratification. Fourteen studies reported appropriate data for meta-analysis encompassing a total of 23 596 individuals. Each unit of PRL increase was independently associated with increased risk of all-cause (pooled aHR = 1.17 [1.08-1.27]; I2 = 48%) and CV mortality (pooled aHR = 1.54 [1.14-2.09]; I2 = 89%). Individuals belonging to the highest PRL category had significantly higher risk for all-cause (pooled aHR = 1.81 [1.43-2.30]; I2 = 65%) and CV (pooled aHR = 1.59 [1.04-2.42]; I2 = 82%) mortality compared to their lowest-PRL category counterparts. The association between PRL levels and in-hospital death did not reach statistical significance. CONCLUSION: PRL levels seem to be an independent predictor for mortality. Further validation is warranted before its role as a risk-stratification tool can be delineated in clinical practice.

Galectin-3 and Estrogen Receptor Alpha as Prognostic Markers in Prolactinoma: Preliminary Results From a Pilot Study.

Introduction: Prolactin-secreting pituitary tumors (PRL-omas) are generally benign neoplasia. However, a percentage of cases show aggressive behavior. Prognostic markers may allow for the identification of aggressive cases. In this study, we investigated the prognostic role of galectin-3 and the estrogen receptor alpha (ERα), as predictive biomarkers of aggressiveness and poor prognosis. Patients and Methods: A mono-centric and retrospective study was conducted on consecutive cases of PRL-omas that underwent first line treatment with surgery and were followed-up for at least five years. The immunohistochemical expression of ERα and galectin-3 was investigated in each case. Results: 36 patients were enrolled. Galectin-3 resulted positive in 11 patients (30.6%). The median expression of ERα was 85% (IQR: 37). Among the group of 21 patients who underwent radical surgery (58.3%), recurrence occurred in 12 cases (33.3%). 27 patients were treated post-surgery with a dopamine agonist (DA) (12 for recurrence and 22 for a history of partial surgery). 13 patients (48.1%) were responsive to DA. Six of 11 cases positive for galactin-3 underwent partial surgery (54.5%, p<0.001). Recurrence occurred in all five cases that underwent radical surgery, which were also positive for galectin-3 (p=0.03). Galectin-3 resulted positive in 9 patients resistant to DA treatment (81.1%, p=0.01). ERα expression was lower in tumors positive for galectin-3 (p<0.001), with mitotic activity (p=0.012), with higher Ki67 Li (p<0.001), and in males with post-surgical recurrence (p<0.001). Conclusion: Galectin-3 and ERα play as markers of aggressiveness and prognosis in PRL-omas and may be tested to identify the aggressive forms of the disease.

Somatic SF3B1 hotspot mutation in prolactinomas.

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 (SF3B1R625H) in 19.8% of prolactinomas. These patients with mutant prolactinomas display higher prolactin (PRL) levels (p = 0.02) and shorter progression-free survival (PFS) (p = 0.02) compared to patients without the mutation. Moreover, we identify that the SF3B1R625H mutation causes aberrant splicing of estrogen related receptor gamma (ESRRG), which results in stronger binding of pituitary-specific positive transcription factor 1 (Pit-1), leading to excessive PRL secretion. Thus our study validates an important mutation and elucidates a potential mechanism underlying the pathogenesis of prolactinomas that may lead to the development of targeted therapeutics.

Pediatric prolactinoma: initial presentation, treatment, and long-term prognosis.

Prolactinoma is a rare pituitary adenoma secreting prolactin. Studies on diagnostics, treatment, and prognosis in pediatric prolactinoma patients are rare. We analyzed clinical presentation, response to treatment, and prognosis of 27 pediatric prolactinoma patients (10 m/17 f. based on patients' records. Tumors included 6 microadenomas (tumor volume: median 0.2 cm3, range 0.01-0.4 cm3; serum prolactin at diagnosis: median 101 ng/ml, range 33-177 ng/ml), 15 macroadenomas (volume: median 3.3 cm3, range 0.4-25.8 cm3; prolactin: median 890 ng/ml, range 87-8624), and 3 giant adenomas (volume: median 44.5 cm3, range 38.6-93.5 cm3; prolactin: median 4720 ng/ml, range 317-10,400); data for 3 patients were not available. Dopamine agonist treatment (n = 22) was safe and effective, leading to reductions in tumor size (p < 0.01) and prolactin levels (p < 0.01). Threat to vision was the indication for decompressing surgery in three of seven operated patients. No patient was irradiated. Long-term functional capacity was not impaired when compared with other sellar masses (n = 235). CONCLUSION: In pediatric prolactinoma, diagnosis is based on hyperprolactinemia and imaging. Dopamine agonist treatment is effective and safe. Overall survival and functional capacity as a measure of quality of survival were not impaired, indicating an optimistic prognosis. Surgery should be considered only in emergency situations of threatened visual function, not presenting a fast response to dopamine agonist treatment. Severe side effects of medication and lack of efficacy should be considered as contraindications. What is Known: • In pediatric prolactinoma-a very rare pediatric neuroendocrinological disease-gender-related differences in terms of clinical presentation at initial diagnosis are known. • Due to the rareness of the disease, reports on long-term outcome and prognosis after childhood-onset prolactinoma based on prospective follow-up are not published. What is New: • Dopamine agonist treatment is efficient and safe for tumor volume reduction in pediatric prolactinoma and surgical interventions are recommended only for decompression of the optic chiasm in case of threat to vision. In case of inefficient response to medication, side effects or parental refuse, alternative therapeutic options should be considered. • Quality of life in terms of survival and functional capacity was not impaired in pediatric prolactinoma patients when compared with 235 long-term survivors of different sellar masses.

Long-Term Follow-Up of Primary Medical Versus Surgical Treatment of Prolactinomas in Men: Effects on Hyperprolactinemia, Hypogonadism, and Bone Health.

OBJECTIVE: In men with prolactinomas, impaired bone density is the principle consequence of hyperprolactinemia-induced hypogonadism. Although dopamine agonists (DAs) are the first-line approach in prolactinomas, surgery can be considered in selected cases. In this study, we aimed to investigate the long-term control of hyperprolactinemia, hypogonadism, and bone health comparing primary medical and surgical therapy in men who had not had prior DA treatment. METHODS: This is a retrospective case-note study of 44 consecutive men with prolactinomas and no prior DAs managed in a single tertiary referral center. Clinical, biochemical, and radiologic response to the first-line approach were analyzed in the 2 cohorts. RESULTS: Mean age at diagnosis was 47 years (range, 22-78 years). The prevalence of hypogonadism was 86%, and 27% of patients had pathologic bone density at baseline. The primary therapeutic strategy was surgery for 34% and DAs for 66% of patients. Median long-term follow-up was 63 months (range, 17-238 months). Long-term control of hyperprolactinemia required DAs in 53% of patients with primary surgical therapy, versus 90% of patients with primary medical therapy (P = 0.02). Hypogonadism was controlled in 73% of patients. The prevalence of patients with pathologic bone density was 37% at last follow-up, with no differences between the 2 therapeutic cohorts (P = 0.48). CONCLUSIONS: Despite control of hyperprolactinemia and hypogonadism in most patients independent of the primary treatment modality, the prevalence of impaired bone health status remains high, and osteodensitometry should be recommended.

Phosphorylation of kinase insert domain receptor by cyclin-dependent kinase 5 at serine 229 is associated with invasive behavior and poor prognosis in prolactin pituitary adenomas.

Pituitary adenomas constitute 15-20% of intracranial neoplasms. Previously we reported that cyclin-dependent kinase 5 (CDK5) is upregulated in pituitary tumors associated with activating protein p35, and plays an essential role in pituitary adenomas progression. Here we explored the mechanisms of CDK5 signaling in prolactin pituitary adenomas. Our data indicate that p35 expression and CDK5 activity are both significantly increased in human invasive prolactin pituitary adenomas as compared to noninvasive forms of pituitary adenomas. Inhibition of CDK5 activity suppressed cell migration and invasive ability in GH3 rat pituitary cells. We identified that CDK5 phosphorylates serine 229 residue (Ser-229) of kinase insert domain receptor (KDR), also known as VEGFR-2, in prolactin pituitary adenomas. Phosphorylation of Ser-229 is required for proper KDR surface localization. Phosphorylated Ser-229 in KDR (pSer-229) levels are significantly higher in noninvasive and invasive prolactin pituitary adenomas compared to normal pituitary tissues. In addition, our data indicated that higher KDR pSer-229 correlates with worse prognosis in patients with prolactin pituitary adenomas. In summary, our results illustrated that CDK5-mediated KDR phosphorylation controls prolactin pituitary adenoma progression and KDR pSer-229 serves as a potential prognostic biomarker for both noninvasive and invasive pituitary adenomas.

The role of Ki-67 in women with a resistant prolactinoma: a retrospective analysis in 199 hospitalized patients over a period of 5 years.

Proliferation-associated antigen Ki-67 is used for the histological evaluation of different tumors. Few studies have been conducted on women with a resistant prolactinoma. To better define the characteristics and to evaluate the differences between patients with different Ki-67 labeling index (LI), a retrospective study was designed to recruit 199 females with a resistant prolactinoma. The patients were divided into two groups, patients with Ki-67 LI≥3% and patients with Ki-67 LI<3%. Tumors in the LI>3% group were also larger (p=0.043), had a higher rate of invasion (p=0.014), and were associated with more frequent polyuria and polydipsia (p=0.008) compared to the LI<3% group. The pre- and post-operative PRL levels in the LI>3% group remained significantly higher compared to patients with LI<3% (p<0.05). The incidences of transient diabetes insipidus and hyponatremia in the LI>3% group were also significantly higher (p=0.037, p=0.041). Additionally, the postoperative PRL normalization rate was lower in patients with LI>3% compared with patients with LI<3% (p=0.028). The recurrence rate in the LI>3% and LI<3% groups were 27.27% and 8.47%, respectively. In conclusion, high Ki-67 LI is predictive sign of a poor prognosis in women with resistant prolactinoma.

El adenoma hipofisario de Percy Wyndham Lewis (1882-1957) / No disponible

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Long-term outcome of patients with macroprolactinomas initially treated with dopamine agonists.

OBJECTIVE: Dopamine agonists are the first line therapy for the treatment of prolactinomas. The aim of this study was to assess the outcome of macroprolactinomas during long-term follow-up after initial treatment with dopamine agonists. DESIGN: Retrospective follow-up study. PATIENTS: We included 72 consecutive patients (age 39+/-17 years, men 46%) diagnosed with macroprolactinoma, and initially treated with dopamine agonists between 1980 and 2004. RESULTS: Initial presentation included headache in 49%, and visual field defects in 38% of the patients. Nine patients were already treated with dopamine agonists at presentation. Median prolactin level of the untreated patients was 460 microg/L (range 96-35,398 microg/L) at presentation. Hypopituitarism, other than hypogonadism, was present in 6% of the patients. Mean duration of follow-up was 10.2+/-6.1 years. Additional transsphenoidal surgery was necessary in 35% of the patients, because of resistance and/or intolerance of dopamine agonists. Postoperative radiotherapy was provided to 18% of all patients. During long-term follow-up, normoprolactinemia was present in 85% of the patients, but biochemical remission (normal prolactin levels in the absence of dopamine agonists) was present in only 22% of the patients. Tumor shrinkage was evident on MRI in 57% of the patients. Hypopituitarism developed in 39% of the patients, especially in those who received additional surgery with or without radiotherapy. CONCLUSION: Dopamine agonists are effective in normalizing prolactin values, and inducing tumor shrinkage. However, in one-third of the patients, additional therapy was necessary due to dopamine agonist resistance and/or intolerance, associated with a high incidence of hypopituitarism.

Gender-related differences in prolactinomas. A clinicopathological study.

BACKGROUND/AIMS: Prolactinomas are the most common tumors of the pituitary gland. Only few studies have documented gender-related differences in the growth and presentation of these tumors, but nothing is known about their effects on their subsequent surgical outcome and prognosis. PATIENTS & METHODS: Twenty-six patients with prolactinomas, that met strict immunohistochemical and electron microscopic criteria and were surgically treated between January 1990 and June 1997, were retrospectively reviewed. The patient charts, as well as histological (mitotic index) immunohistological (MIB-1 labeling-index) and electronic microscopical staining were analyzed. RESULTS: Nineteen patients were women, and seven were men; the female-to-male-ratio was 2.7:1. Men were significantly older, both at diagnosis and surgery. Menstrual abnormalities were the most common presenting symptom in women, whereas impotence predominated in men. Psychological symptoms were significantly more common in men than in women. Men had a significantly shorter preoperative duration of symptoms and higher preoperative serum prolactin levels than women. The preoperative prolactin levels and proliferative activities (mitotic index, MIB-1 labeling index) were lower in women compared to men and showed a direct correlation to postoperative outcome. The overall outcome was significantly better in women than in men. In women, age less than 35 years was a beneficial prognostic factor, and preoperative bromocriptine treatment was associated with a significantly worse long-term-outcome. CONCLUSION: The biology and the clinical course of prolactinomas seem to differ in women and men. In men, the preoperative durations of symptoms is shorter, the tumors are larger and more invasive at surgery, and the outcome is worse than in women. Based on proliferative activities (mitotic index, MIB-1 labeling index), the predominance of marcoadenomas in men is due to a high frequency of rapidly growing tumors, which are often invasive and frequently correlated with a worse outcome. Our findings may justify a more aggressive therapeutic approach to prolactinomas in men than in women.

The characteristics of quality of life impairment in adult growth hormone (GH)-deficient survivors of cancer and their response to GH replacement therapy.

We studied 50 (27 women and 23 men) GH-deficient (GHD) cancer survivors and 47 (24 women and 23 men) GHD patients with pituitary pathologies. All GHD patients were considered for GH replacement on the basis of subjectively poor quality of life (QOL). Primary outcome measures were scores of QOL instruments psychological general well-being schedule (PGWB) and assessment of GH deficiency in adults (AGHDA) at baseline and early (6-13 months) and long-term (24-77 months) treatment follow-up. Of secondary interest were six PGWB domains. Linear mixed effect regression was used to model each QOL outcome. The groups differed with respect to three covariates: age, gender, and body mass index. These variables were included in all fitted models. Baseline scores for PGWB and AGHDA were not different between groups. Ranking of PGWB domains were similar between groups at baseline (lowest domain, vitality). The pattern of change in mean scores for all outcome measures from baseline did not differ between groups (P = 0.86). All QOL variables improved significantly with treatment [estimated mean change +/- se: PGWB, 16.2 +/- 1.7; AGHDA, -6.2 +/- 0.6; PGWB domains (transformed percentage scales): anxiety, 12.4 +/- 1.7; depression, 14.1 +/- 2.1; health, 12.4 +/- 1.7; self-control, 11.3 +/- 2.0; well-being, 15.2 +/- 1.7; vitality, 22.5 +/- 2.0 (vitality, greatest change)]. There was no evidence of group difference in early follow-up or long-term follow-up means for any outcome variable. The QOL in adult GHD cancer survivors was comparable to that in GHD adults with pituitary pathologies and improved with GH replacement in a similar manner. We conclude that QOL impairment in adult GHD cancer survivors appears mainly related to GHD rather than cancer diagnosis and treatment.

Radiation therapy in the multimodal treatment approach of pituitary adenoma.

BACKGROUND: Pituitary tumors are relatively uncommon, comprising 10-12% of all intracranial tumors. The treatment consisting of surgery, radiotherapy and drug therapy or a combination of these modalities is aimed at the control of tumor cell proliferation and--in endocrine active tumors--the reduction of hormone secretion. However, the slow proliferation characteristics of pituitary tumors necessitate long-term studies for the evaluation of the treatment results. In the last decade there has been continuous improvement in surgical procedures, radiotherapy techniques and drug generation. In this paper, literature will be reviewed to assess the role of modern radiotherapy and radiosurgery in the management of pituitary adenomas. MATERIAL AND METHODS: Nowadays, magnetic resonance imaging for the definition of the target volume and a real three-dimensional (3-D) treatment planning with field conformation and the possibility for non-coplanar irradiation has to be recommended. Most groups irradiate these benign tumors with single doses of 1.8-2.0 Gy up to a total dose of 45 Gy or 50.4 Gy in extensive parasellar adenomas. Adenomas are mostly small, well circumscribed lesions, and have, therefore, attracted the use of stereotactically guided high-precision irradiation techniques which allow extreme focussing and provide steep dose gradients with selective treatment of the target and optimal protection of the surrounding brain tissue. RESULTS: Radiation therapy controls tumor growth in 80-98% of patients with non-secreting adenomas and 67-89% for endocrine active tumors. Reviewing the recent literature including endocrine active and non-secreting adenomas, irradiated postoperatively or in case of recurrence the 5-, 10- and 15-year local control rates amount 92%, 89% and 79%. In cases of microprolactinoma primary therapy consists of dopamine agonists. Irradiation should be preferred in patients with macroprolactinomas, when drug therapy and/or surgery failed or for patients medically unsuitable for surgery. Reduction and control of prolactin secretion can be achieved in 44-70% of patients. After radiotherapy in acromegaly patients somatomedin-C and growth hormone concentrations decrease to normal levels in 70-90%, with a decrease rate of 10-30% per year. Hypercortisolism is controlled in 50-83% of adults and 80% of children with Cushing's disease, generally in less than 9 months. Hypopituitarism is the most common side effect of pituitary irradiation with an incidence of 13-56%. Long-term overall risk for brain necrosis in a total of 1,388 analyzed patients was estimated to be 0.2%. Other side effects are rare too, and do also depend on the damage produced by tumor itself or preceding surgery. They include deterioration of vision in 1.7% of all cases, vascular changes in 6.3%, neuropsychological disorders such as dementia in 0.7% and secondary malignancies in 0.8%, if single doses of 2.0 Gy and total doses of 50 Gy are not exceeded. CONCLUSION: Conventional radiation therapy of pituitary adenoma is highly effective. It is recommended after subtotal resection of primary tumors such as macroadenomas, after gross total resection from endocrine active adenomas with postsurgical hormone secretion and for recurrent tumors. Radiosurgery seems to be a possible treatment alternative in experienced centers, and only in patients with adenomas smaller than 25-30 mm with a minimum distance of 2-3 mm to the chiasm.

Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group.

BACKGROUND: Four retrospective studies have reported premature mortality in patients with hypopituitarism with standard mortality ratios (SMRs) varying between 1.20 and 2.17. Patients with hypopituitarism have complex endocrine deficiencies, and the mechanisms underpinning any excess mortality are unknown. Furthermore, the suggestion has emerged that endogenous growth-hormone deficiency might account for any excess mortality. We aimed to clarify these issues by doing a large prospective study of total and specific-cause mortality in patients with hypopituitarism. METHODS: We followed up 1014 UK patients (514 men, 500 women) with hypopituitarism from January, 1992, to January, 2000. 573 (57%) patients had non-functioning adenomas, 118 (12%) craniopharyngiomas, and 93 (9%) prolactinomas. SMRs were calculated as the ratio of observed deaths to the number of deaths in an age-matched and sex-matched UK population. FINDINGS: The number of observed deaths was 181 compared with the 96.7 expected (SMR 1.87 [99% CI 1.62-2.16], p<0.0001). Univariate analysis indicated that mortality was higher in women (2.29 [1.86-2.82]) than men (1.57 [1.28-1.93], p=0.002), in younger patients, in patients with an underlying diagnosis of craniopharyngioma (9.28 [5.84-14.75] vs 1.61 [1.30-1.99], p<0.0001), and in the 353 patients treated with radiotherapy (2.32 [1.71-3.14] vs 1.66 [1.30-2.13], p=0.004). Excess mortality was attributed to cardiovascular (1.82 [1.30-2.54], p<0.0001), respiratory (2.66 [1.72-4.11], p<0.0001), and cerebrovascular (2.44 [1.58-4.18], p<0.0001) causes. There was no effect of hormonal deficiency on mortality, except for gonadotropin deficiency, which, if untreated was associated with excess mortality (untreated 2.97 [2.13-4.13] vs treated 1.42 [0.97-2.07], p<0.0001). Multiple regression analyses identified age at diagnosis, sex, a diagnosis of craniopharyngioma, and untreated gonadotropin deficiency as independent significant factors affecting mortality. INTERPRETATION: Patients with hypopituitarism have excess mortality, predominantly from vascular and respiratory disease. Age at diagnosis, female sex, and above all, craniopharyngioma were significant independent risk factors. Specific endocrine-axis deficiency, with the exception of untreated gonadotropin deficiency, does not seem to have a role.

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 50 Gy 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 (< 25 ng/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.

Role of radiation therapy in clinical hormonally-active pituitary adenomas.

BACKGROUND AND PURPOSE: The outcome following radiation therapy (RT) of hormonally-active pituitary adenomas was assessed. The purpose of this analysis was to determine the control rate after radiation, identify any prognostic factors and evaluate the late toxicity. MATERIALS AND METHODS: From 1972 to 1986, 145 patients received RT for hormonally-active pituitary adenomas. The median age was 39 years (range 15-76), with 81 males and 64 females. There were 52 patients with acromegaly, 64 with prolactinoma, and 29 with Cushing's disease. The median follow-up was 7.3 years. RT was given as primary treatment in 17 patients, after initial surgery in 65 patients, and as part of salvage therapy in 63 patients. The median total dose was 50 Gy (daily fraction: 2 Gy). Tumor control was defined as normalization of basal hormonal level and lack of progression of adenoma assessed by imaging studies. The following factors were analyzed for prognostic significance in tumor control: age, sex, tumor type, direction of tumor extension, radiation dose, and radiation field size. RESULTS: The 10-year actuarial proportion of patients with persistent elevated hormone level were 61% following RT alone, and 44% with the addition of medical management. The progression-free rate was 96% at 10 years. Of the 20 deaths, three patients died with uncontrolled pituitary adenoma and three died of treatment complications. The actuarial 10-year overall and cause-specific survival rates were 86% and 97%. The actuarial rates of radiation-induced hypopituitarism were 35%, 22% and 22% at 10 years for thyroid, glucocorticoid and gonadal functions, respectively. None of the factors examined were found to be significant predictors of tumor control. CONCLUSIONS: Post-operative external beam RT is highly effective in preventing recurrence of space-occupying effects of hormonally-active pituitary adenomas. However, long-term biochemical remission is observed only in approximately 40% of patients (at 10 years), with an additional 20% requiring medical therapy. Malignancies of the CNS can develop as an infrequent late event.

Results of treatment of pituitary disease in multiple endocrine neoplasia, type I.

OBJECTIVE: The aim of the present study was to examine the clinical and pathological features of pituitary disease in patients with multiple endocrine neoplasia, Type I (MEN I) and to assess the prognosis. METHODS: Fifty-two patients with pituitary disease and MEN I were studied retrospectively. Medical records were reviewed, and all of the patients known to be alive were sent a questionnaire to ascertain current disease status. RESULTS: In 12 patients, pituitary disease was the initial manifestation of MEN I. The most common lesion was prolactinoma, followed, in frequency, by acromegaly and nonsecretory adenoma. Thirty-four of the patients had surgical treatment at the Mayo Clinic, Rochester, MN, as primary treatment, 3 had radiotherapy, and 12 received no specific therapy. Twelve patients had adjunctive radiotherapy postoperatively. Of the 34 patients receiving surgical treatment, 33 had adenoma and 1 had adenoma and pituitary hyperplasia. Immunocytochemical examination demonstrated that many tumors showed reactivity for more than one pituitary hormone. On survival analysis, no excess pituitary-related mortality was found, either in the surgically treated group or in the group as a whole. CONCLUSION: On the basis of this study, we conclude that pituitary disease is frequently the initial manifestation of MEN I; that adenomas, particularly prolactinomas, are the rule and hyperplasia is rare; that a significant proportion of tumors are plurihormonal; and that excess pituitary-related mortality is not a factor in patients with MEN I.

External irradiation of macroinvasive pituitary adenomas with telecobalt: a retrospective study with long-term follow-up in patients irradiated with doses mostly of between 40-45 Gy.

PURPOSE: Published dose recommendations for radiotherapy in patients with pituitary macroadenomas vary. Therefore, we retrospectively analyzed the results in our patients from the treatment period 1973-1992. METHODS AND MATERIALS: From a total of 89 patients with macroinvasive adenomas, 66 received radiation therapy immediately following subtotal surgical removal (combined treatment modality), and 22 were irradiated as primary treatment or after surgical recurrence. Only one patient was reirradiated. The surgical interventions have been performed by the same surgeon. For the majority of patients (79 out of 89) with a mean follow-up of 8.1 years (0.5-19 years) the total tumor dose ranged between 40-45 Gy at a dose per fraction of 1.8-2.25 Gy. All patients had bilateral opposed fields with telecobalt. Eleven patients had an additional arc rotation. RESULTS: The 10-year progression-free survival for all 89 patients independent of treatment modality was 88.1%. The 10-year progression-free survival for patients treated by surgery and adjuvant radiation therapy (40-45 Gy at 1.8-2.25 Gy, 60 out of 79) was 90.3%, and for radiation therapy alone (40-45 Gy at 1.8-2.25 Gy, 19 out of 79), 100% (p = 0.32). The prognostic factors for progression-free survival were the subtype of adenoma, the presence of visual symptoms at the time of diagnosis, the suprasellar extension, and the initial hormone levels. The presence of infiltration of adenoma cells in the basal dura or in the mucosa of the sinus sphenoidalis do not represent prognostic factors showing the special biological behavior of pituitary adenomas. Signs of x-ray-induced cerebral necrosis have not been observed in any patient. Long-term visual complications developed in four patients. This could be due to scar formation in the treated region, which can compress the optic nerve and provoke disturbance similar to an empty-sella syndrome. The latter occurred prevalently years after treatment, even though surgical methods of sellar plugging were used. The incidence of hypopituitarism after combined treatment modality at time of last follow-up (irradiated between 40-45 Gy at 1.8-2.25 Gy) was low (36%, 21 out of 60). CONCLUSION: In patients with pituitary macroadenomas, radiotherapy with a total dose of 40-45 Gy at 1.8-2.25 Gy per fraction resulted in a high local tumor control without serious morbidity.