The long-term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas

OBJECTIVES We assessed the long-term efficacy and toxicity of conservative surgery and radiotherapy in the control of pituitary adenomas. DESIGN Retrospective study of patients treated at the Royal Marsden Hospital. PATIENTS Four hundred and eleven patients with pituitary adenomas treated with conventional external beam radiotherapy at the Royal Marsden Hospital between 1962 and 1986. Two hundred and fifty-two patients had clinically non-functioning pituitary adenomas, 131 had hormone secreting tumours and in 28 patients the secretory status was not known. Three hundred and thirty-eight patients had surgical intervention of whom only 11 had complete tumour excision. All patients received conventional fractionated external beam radiotherapy to a dose of 45–50Gy in 25–30 fractions. MEASUREMENTS Actuarial progression free survival and overall survival and assessment of toxicity, particularly in terms of vision, requirement for hormone replacement therapy and incidence of second tumours. RESULTS The actuarial progression free survival was 94% at 10 years and 88% at 20 years for all patients and 97% at 10 years and 92% at 20 years for patients with clinically non-functioning adenomas. Only secretory status was an independent prognostic factor for disease control. The 10 and 20-year survivals for all patients were 77 and 58% respectively. When compared with the normal population the relative risk of death was 1 76 (P<0 001) and no prognostic factors for survival were identified. The morbidity of radiotherapy was low. Visual deterioration, assumed to be radiation induced, occurred in 1–5% of patients and the risk of second brain tumour was 1.9% at 20 years. Fifty per cent of patients received hormone replacement therapy by 19 years. CONCLUSION Conventional external beam radiotherapy as described here combined with conservative surgery is safe and effective in the control of pitutary adenomas. These results should form a baseline for comparison with new treatment strategies.     

Somatomammotrophic cells in GH-secreting and PRL-secreting human pituitary adenomas

A morphological study has been carried out on 20 GH-secreting adenomas removed from acromegalic normoprolactinemic patients, on 29 PRL-secreting adenomas removed from hyperprolactinemic patients without signs of acromegaly and on one normal human anterior pituitary gland collected at autopsy. The protein A-gold immunoelectron microscopic technique has been utilized in order to verify the presence of mixed cells producing both GH and PRL (somatomammotrophs) in these pituitary tissues. In the normal pituitary a considerable number of somatomammotrophs (15-20%) was found, thus supporting the idea that these cells are normal components of the human anterior pituitary gland. In 10 GH-secreting adenomas and in 10 PRL-secreting adenomas somatomammotrophs were present in a variable number (from 4 to 20% of the whole cell population in GH adenomas and from 1 to 47% in PRL tumors). It can be concluded therefore that these cells, largely present in all GH/PRL-secreting adenomas, can also be found in GH-secreting and PRL-secreting tumors without clinical evidence of a mixed secretion. Adenomatous somatomammotrophs displayed ultrastructural features of adenomatous somatotrophs and mammotrophs (prominent Golgi complexes, abundant rough endoplasmic reticulum, irregular nuclei). The size and the number of granules were variable. In some cells GH and PRL were stored in distinct secretory granules, in others in mixed granules or both in mixed and distinct granules, thus suggesting that in adenomatous somatomammotrophs the efficiency of the mechanisms of sorting of the two hormones varies from one cell to another.(ABSTRACT TRUNCATED AT 250 WORDS)     

124例伴血催乳素增高的生长激素分泌性垂体腺瘤临床分析

目的探讨伴血催乳素(PRL)增高的生长激素(GH)分泌性垂体腺瘤的临床特点。方法采用回顾性病例研究方法,对北京协和医院1984年至2004年收治的124例伴血PRL增高的GH分泌性垂体腺瘤患者进行临床和激素水平分析,其中87例随诊1年以上。结果124例患者中女性88例,男性36例,男性病程(8.0±7.3)年长于女性(5.5±4.3)年(P<0.01)。男性和女性患者性腺功能低减者分别占71.6%和69.4%。87例随访患者随访(5.5±4.3)年,其中垂体微腺瘤3例,非侵袭性大腺瘤28例,侵袭性大腺瘤56例。肿瘤免疫组化染色呈单纯GH( )占19.6%,其余多呈多激素染色阳性。血PRL水平与肿瘤体积呈正相关(r=0.261,P<0.05)。鞍上型肿瘤中,单纯GH腺瘤的血PRL值(58.7±1.5)μg/L,明显低于多激素染色腺瘤者的(90.3±2.4)μg/L(P<0.05)。87例随访患者的治愈率为27.6%。结论伴血PRL增高的GH分泌性垂体腺瘤好发于女性,性腺功能低减发生率高,治愈率低,血PRL的水平和肿瘤体积有关,是GH分泌性垂体腺瘤中有独特的临床特点及转归的一种特殊临床亚型。     

Disease-specific impairments in quality of life during long-term follow-up of patients with different pituitary adenomas

Objective Quality of life (QoL) is impaired in patients treated for pituitary adenomas. However, differences in age and gender distributions hamper a proper comparison of QoL. Therefore, we compared age‐ and gender‐specific standard deviations (SD) scores (Z‐scores) of QoL parameters in patients treated for pituitary adenomas. Patients and methods We determined Z‐scores for health‐related questionnaires [the Hospital Anxiety and Depression Scale (HADS), Multidimensional Fatigue Inventory (MFI)‐20, Nottingham Health Profile (NHP), and Short Form Health Survey (SF‐36)] in patients during long‐term follow‐up (13 ± 8 years) after treatment for pituitary adenomas. Z‐scores were calculated by comparing the data for 403 patients with acromegaly (n = 118), Cushing's disease (CD; n = 58), prolactinoma (n = 128), and nonfunctioning macroadenoma (n = 99) with a control population (n = 440) for each subscale of the questionnaires and for total QoL score. Results All subscales of the questionnaires and the total QoL score were negatively affected in patients compared to controls. Comparing the Z‐scores, patients treated for acromegaly reported more impairment in physical ability and functioning and more bodily pain compared to patients treated for nonfunctioning macroadenoma and those treated for prolactinoma. Patients with CD reported impairment in physical functioning compared to patients treated for nonfunctioning macroadenoma. Linear regression analysis, with correction for age and gender, confirmed these findings. Additionally, CD was associated with increased anxiety. Hypopituitarism negatively influenced multiple aspects of QoL. Conclusion QoL is impaired in patients during long‐term follow‐up after treatment of pituitary adenomas. Patients with pituitary adenomas should be informed of these persistent adverse effects of their disease on QoL to prevent inappropriate expectations with respect to the long‐term results of treatment.     

Effects of octreotide treatment on the proliferation and apoptotic index of GH-secreting pituitary adenomas.

To investigate the effects of octreotide administration on the growth rate of GH-secreting pituitary adenomas, we measured both the Ki-67 labeling index (LI) and the apoptotic index in tumor specimens from octreotide-treated or matched untreated acromegalic patients. Thirty-nine patients who received octreotide until the day of or the day before surgery and 39 untreated patients matched for sex, age, tumor size, extension, and invasiveness were studied. Immunocytochemical analysis was performed on paraffin-embedded material using a monoclonal antibody (MIB-1) directed against a proliferation-associated nuclear antigen, Ki-67, to measure the growth fraction. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick endlabeling method, using a monoclonal antibody recognizing areas of DNA fragmentation. The Ki-67 LI and apoptosis were counted on separate slides in at least 1000 evaluable cells. Octreotide-treated patients showed a lower Ki-67 LI (1.8 +/- 0.3%) than untreated controls (3.8 +/- 0.7%; P < 0.02). Overall, the mean Ki-67 LI of treated patients was 53% lower than that in untreated patients. The antiproliferative effect of octreotide occurred independently of tumor extension and invasiveness. Octreotide-treated and untreated patients showed similar apoptotic indexes (0.6 +/- 0.2% and 0.8 +/- 0.3%, respectively). There was a positive correlation between the Ki-67 LI and the apoptotic index (r = 0.29; P < 0.03). Our study demonstrates that acromegalic patients receiving chronic octreotide treatment have a lower value of the proliferation marker Ki-67, but no significant difference in the apoptotic index compared with matched untreated patients. The antiproliferative effect of octreotide on GH-secreting adenomas should imply a lower risk of tumor growth during long-term chronic treatment with the drug.     

Surgical management of GH-secreting pituitary adenomas: an outcome study using modern remission criteria.

The results of transsphenoidal surgery as initial therapy for GH-secreting pituitary adenomas in 57 acromegalic patients were analyzed retrospectively. Patients with prior surgery or radiation therapy were excluded from the study. Three different criteria were used to define remission: glucose-suppressed (nadir) GH less than 1.0 microg/liter, a normal sex- and age-adjusted IGF-I level, and postoperative random GH levels of 2.5 microg/liter or less. Additionally, we analyzed the neuropathological data, including immunohistochemistry and ultrastructural categorization, and the surgical complications. The short-term remission rate (6-wk postoperative follow-up visit), as determined by a random GH measurement of 2.5 microg/liter or less, was 48.8%; the remission rate, as determined by nadir GH, was 51.4%. For 57 patients followed for 12 months or more after surgery (mean, 37.7 months), surgical remission was achieved in 70.2%, 66.7%, and 61.1%, respectively, for patients assessed by normal IGF-I, random GH, and nadir GH. One patient (1.1%) developed recurrence of active acromegaly 81 months after initially successful surgical therapy. Extrasellar growth of the tumor (P = 0.04) and dural invasion by the adenoma (P = 0.008) were significant univariate predictors of a poor outcome. Tumor size was significantly greater in patients with persistent or recurrent acromegaly (P = 0.02). Patients with tumors of the ultrastructural categories of mixed GH/PRL cell and mammosomatotroph adenomas had the lowest remission rates (50% and 42.9%, respectively). There were no perioperative deaths, and there was no serious morbidity. The permanent complication rate was 3.3% (1 permanent DI and 2 nasal septal perforations). Surgical management of acromegaly currently provides prompt, effective, and satisfactory initial treatment for the majority of patients. Using stringent criteria for remission, primary transsphenoidal surgery for GH-secreting pituitary adenomas is effective and often definitive therapy for acromegaly. These results provide a benchmark for the contemporary results of surgical management as assessed by modern outcome criteria.     

Serum alpha-subunit levels in patients with pituitary adenomas

OBJECTIVE: We investigated preoperative and postoperative serum alpha-subunit levels and the alpha-subunit response to TRH in patients with various types of pituitary tumour and correlated the data with histological findings in order to clarify the significance of alpha-subunit measurement in pituitary adenomas. PATIENTS: We examined 59 patients with pituitary tumours (22 with GH cell adenomas, 30 with clinically nonfunctioning adenomas and seven with other tumours) treated at Toranomon Hospital between 1996 and 1998. RESULTS: The basal alpha-subunit level was supranormal in six out of 22 (27%) patients with a GH cell adenoma and in nine out of 30 (30%) patients with a nonfunctioning adenoma. A paradoxical alpha-subunit response to TRH was found in seven out of 22 (32%) patients with a GH cell adenoma. These seven patients also showed a paradoxical GH response to TRH administration. In addition, paradoxical response to TRH was found in eight out of 30 (27%) patients with a clinically nonfunctioning adenoma. In contrast, patients with other types of pituitary tumour showed neither a supranormal alpha-subunit level nor a paradoxical response to TRH. The supranormal alpha-subunit level and the abnormal response to TRH were normalized in both GH cell adenoma and nonfunctioning adenoma patients after successful surgery. Immunohistochemical studies showed alpha-subunit positive cells in 51% of GH cell adenomas or nonfunctioning adenomas and there was a good concordance with the serum alpha-subunit levels in both GH cell adenoma and nonfunctioning adenoma patients. CONCLUSIONS: These findings suggest that supranormal serum alpha-subunit levels are mainly due to hypersecretion by the tumour itself, while the paradoxical alpha-subunit response to TRH is an associated phenomenon in patients with a GH cell adenoma or nonfunctioning adenoma. The alpha-subunit level and the response to TRH may be useful indicators for assessing the operative outcome, especially in nonfunctioning adenoma patients who have no other definite endocrine markers.     

Non-functioning pituitary adenomas: indications for postoperative radiotherapy

To determine the indications for postoperative radiotherapy after surgical resection of a nonfunctioning pituitary macroadenoma. A retrospective chart review of 72 patients with histologically proven chromophobe adenoma who presented for pituitary surgery between January 1985 and June 1998, with a minimum follow-up period of 12 months. The study endpoint was tumour recurrence or progression detected either by routine follow-up imaging or by clinical progression with subsequent confirmation by imaging. A proportional hazards model was used to determine independent prognostic factors. Mean follow-up was 64 months. In the radiotherapy group 13 of 50 recurred (or progressed) (26%), while in the nonradiotherapy group 10 of 22 recurred (46%), logrank test, P = 0.025. In patients assessed as having complete excision of tumour (n = 20) only two recurred (10%), both in patients without radiotherapy. No further treatment has been required in either case to date. In patients with residual tumour (n = 52), 41 had radiotherapy with 13 recurrences (32%), while 11 patients had no radiotherapy with eight subsequent recurrences (73%); logrank test, P = 0.007. Further treatment has been required in the majority of these cases. Cox's proportional hazards model analysis showed that only complete tumour removal and postoperative radiotherapy were independent favourable prognostic factors. The goal of surgery should be complete surgical excision where possible. The risk of recurrence in patients with no residual tumour on postoperative imaging is low enough to justify withholding routine postoperative radiotherapy in this group. In patients with residual tumour, conventional external beam radiotherapy administered within 12 months of surgery is effective at reducing recurrence or progression.     

Overview of genetic testing in patients with pituitary adenomas

Clinically-relevant pituitary adenomas occur with a prevalence of one case per 1000-1300 of the general population. Although most are sporadic, there are several inherited conditions that incur an increased risk of developing a pituitary adenoma. Multiple endocrine neoplasia type 1 and Carney complex (due to mutations in MEN1 and PRKAR1A, respectively) are established pituitary adenoma predisposition conditions, while multiple endocrine neoplasia type 4 (due to CDKN1B mutations) is an emerging rare condition. Familial isolated pituitary adenomas (FIPA) is a novel condition not associated with these multiple endocrine neoplasias. Mutations in the aryl hydrocarbon receptor interacting protein gene account for about 15% of FIPA kindreds and are associated with about 10-20% of macroadenomas that occur in children, adolescents and young adults. When treating a pituitary adenoma patient, relevant familial and clinical factors such as associated tumors or syndromic features should be assessed at the outset in order to guide the correct choice of genetic testing in appropriate individuals.     

Absence of mutations in the growth hormone (GH)-releasing hormone receptor gene in GH-secreting pituitary adenomas

OBJECTIVE: GH-releasing hormone (GHRH) is a potent stimulator of somatotroph cell proliferation and GH secretion. GHRH acts via binding to a G-protein coupled receptor (GPCR) (GHRH-R), that activates adenylyl cyclase (AC) and increases growth and function of somatotroph cells. Indeed, a subset (30--40%) of somatotrophic adenomas contain somatic mutations of the GNAS1 gene that encodes the alpha subunit of the G-protein (G(s)alpha) that stimulates AC. As activating mutations of other GPCRs cause development of endocrine tumours, we hypothesized that somatic activating mutations of the GHRH-R might provide the molecular basis for somatotroph cell proliferation in a subset of human GH-secreting pituitary adenomas. DESIGN: We analysed genomic DNA isolated from 26 somatotrophinomas, 17 of which lacked activating mutations in the GNAS1 gene. We individually amplified via polymerase chain reaction all 13 coding exons and the exon-intron boundaries of the GHRH-R gene. We used denaturing gradient gel electrophoresis to search for abnormalities in exons 1 through 11. Abnormally migrating bands were subjected to direct sequencing. Exons 12 and 13, encoding for the intracellular C-terminal domain, were subjected to direct sequencing. RESULTS: Mutations were not detected in any of the tumours, but a rare polymorphism in codon 225 corresponding to the third transmembrane domain (V225I) was discovered. CONCLUSIONS: GHRH-R mutations are absent or rare in somatotrophinomas, and other mechanisms must explain the somatotroph cell proliferation in the adenomas that lack activating mutations in the GNAS1 gene.     

The properties of prolactin secretion in patients with prolactin secreting pituitary adenomas

Plasma prolactin (PRL) responses to several exogenous agents are variable in patients with prolactinomas. In this study the factors determining the responsiveness to exogenous stimuli were investigated in 35 patients with prolactinomas. Among these patients, 14 patients were responder (greater than 150% increase of basal value) to TRH, sulpiride (DA D2-receptor blocker) and arginine, and remaining 21 were non-responder to these three agents. Plasma TSH responses to sulpiride, an indirect indicator of hypothalamic dopaminergic tone on pituitary gland, were similar between responder (delta TSH: M +/- SEM; 5.3 +/- 0.2 microU/ml) and non-responder (delta TSH: 5.6 +/- 0.2 microU/ml), and were greater than those in normal subjects (delta TSH: 0.7 +/- 0.2 microU/ml, n = 18) (P less than 0.001). The plasma PRL responses to dopaminergic agents (L-dopa, CB-154, dopamine) were greater in responders than in non-responders (% of basal: L-dopa, 33.7 +/- 3.7% vs 51.6 +/- 5.6% at 150 min, P less than 0.05; CB-154, 16.5 +/- 2.6% vs 30.9 +/- 2.8% at 6 hr, P less than 0.05; dopamine, 31.7 +/- 5.6% vs 44.9 +/- 4.3% at 90 min, P less than 0.05). When all patients were divided into microadenoma (n = 12) and macroadenoma patients (n = 23), there were no differences in plasma PRL responses to these agents between the two groups. Again, there were no differences in the duration of illness between the responder and non-responder patients (61.9 +/- 13.7 vs 54.1 +/- 12.0 months). During the short term CB-154 treatment (7.5mg/day for 3 approximately 5 weeks) in 8 responders and 15 non-responders, all responder patients showed normalization of plasma PRL levels, while such normalization was observed in only 6 non-responder patients. These results suggest that in prolactinoma patients variable responsiveness to several exogenous agents are depending on the sensitivity to several exogenous agents are depending on the sensitivity of prolactinoma itself, regardless of the endogenous hypothalamic dopaminergic tone, tumor size or duration of the illness.     

Reversible hypopituitarism in patients with large nonfunctioning pituitary adenomas

Detailed pituitary function studies were conducted on 26 patients with large nonfunctioning pituitary adenomas before and 2-3 months after transsphenoidal adenomectomy. Basal serum PRL, GH, TSH, LH, FSH, and ACTH levels were measured, and dynamic studies of their secretion were made. Preoperatively, GH deficiency was found in all 26 patients (100%), hypogonadism in 25 patients (96%), hypothyroidism in 21 patients (81%), and adrenal insufficiency in 16 patients (62%). Serum PRL levels were low (1.5-4 ng/ml) in 5 patients, normal (5-20 ng/ml) in 9 patients, and mildly elevated (21-53 ng/ml) in the remaining 12 patients. After selective adenomectomy, variable improvement in pituitary function occurred in 17 patients, worsening in 1 patient, and persistence of hypopituitarism in 8 patients. After surgery, normal thyroid function was documented in 12 of the 21 patients (57%) who were hypothyroid preoperatively. Similarly, 6 of the 16 patients (38%) with adrenal insufficiency recovered normal adrenal function, and 8 of the 25 patients (32%) with hypogonadism recovered normal gonadal function. GH deficiency persisted in all but 4 patients (15%). Serum PRL levels decreased in all patients, and only 5 had midly elevated levels after surgery. The presence of a normal or mildly elevated serum PRL level before surgery in these patients was of value in predicting possible recovery of pituitary function after surgery; none of the 5 patients with low preoperative serum PRL levels had any improvement in pituitary function after surgery. A rise in serum TSH levels after TRH administration before surgery also was helpful in predicting possible recovery from hypopituitarism. Most patients who had a rise in serum TSH level in response to TRH stimulation preoperatively recovered some pituitary function after adenomectomy. In contrast, no improvement in pituitary function occurred in patients who had blunted responses to TRH preoperatively. Improvement in pituitary function occurred more often in patients with tumors measuring 25 mm or less than in those with larger tumors. In conclusion, significant improvement in pituitary function may occur after surgical adenomectomy for nonsecreting pituitary tumors. A rise in serum TSH levels in response to TRH stimulation preoperatively suggested the presence of viable pituitary tissue in these patients with hypopituitarism. The presence of a normal or mildly elevated serum PRL level before surgery also suggested the presence of functioning pituitary lactotrophs. These observations suggest that compression of the portal circulation is a possible mechanism for hypopituitarism in this setting.(ABSTRACT TRUNCATED AT 400 WORDS)     

External pituitary irradiation as a cause of TRH deficiency in patients with pituitary adenomas

The influence of external pituitary irradiation (XRT) on thyrotroph function and PRL secretion was studied in twenty-five patients with pituitary adenomas, of whom eight had acromegaly. Twenty-one patients had undergone subtotal operative removal of their adenomas 8-190 weeks (median 12 weeks) before XRT. Following irradiation there was a significant reduction in peak serum TSH levels in response to i.v. TRH (P less than 0.05, compared with before XRT). Peak TSH levels returned to normal at 3 months. Similarly a transient reduction in TRH-stimulated beta-TSH release was observed. Serum T3 and T4 concentrations also fell after XRT, the levels at 3 months being significantly lower than control values (P less than 0.02), though no difference was seen at 6 and 12 months. A delayed (hypothalamic) serum TSH response to TRH (60 greater than 20-min level) developed at 6 months. In contrast, PRL concentrations (basal and TRH stimulated) were not altered during the 12 months following XRT. These findings demonstrate that thyrotroph function can be transiently impaired following external pituitary irradiation. None of the patients studied required T4 replacement therapy. The development of a delayed TSH response to i.v. TRH may indicate endogenous TRH deficiency. It was not associated with supra-sellar tumour enlargement in our patients and may be due to hypothalamic damage by irradiation.     

Fractionated stereotactic conformal radiotherapy for secreting and nonsecreting pituitary adenomas

OBJECTIVE: To assess the medium-term outcome in a cohort of patients with residual or recurrent pituitary adenoma treated with fractionated stereotactic conformal radiotherapy (SCRT). PATIENTS AND METHODS: Ninety-two patients (median age 50 years) with a residual or recurrent nonfunctioning (67) or a secreting (25) pituitary adenoma were treated between 1995 and 2003. Eighteen patients had a GH-secreting, five PRL-secreting and two an ACTH-secreting pituitary adenoma. Vision was impaired in 39 patients, with visual field deficit (35) and/or reduced visual acuity (25). Sixty-four patients had partial or complete hypopituitarism before SCRT. The treatment was delivered stereotactically by four noncoplanar conformal fixed fields using a 6-MV linear accelerator to a dose of 45 Gy in 25 fractions. RESULTS: At a median follow-up of 32 months (range 4-108) the 1, 3 and 5 years actuarial progression-free survival is 99%, 98% and 98%, and overall survival is 98%. Three patients recurred 5 months, 1 year and 9 years after SCRT requiring surgery. In secreting adenomas, hormone levels declined progressively, becoming normal in more than a third of patients with GH-secreting and PRL-secreting pituitary tumours. 50% of baseline GH level was achieved in just under 2 years. The treatment was well tolerated with minimal acute toxicity. Hypopituitarism was the most common long-term effect; 22% of patients had worsening of pituitary function. One patient developed unilateral quadrantopia without tumour progression. CONCLUSION: SCRT as a high-precision technique of localized irradiation achieves tumour and hormone control of pituitary adenomas comparable with previously published data on the efficacy of conventional radiotherapy. Despite the potential advantage of reducing the volume of normal brain irradiated, the theoretical benefit over conventional radiotherapy in terms of the reduction in long-term morbidity has not yet been demonstrated and requires longer follow-up. Potential effect on long-term cognitive function has not been tested.