Q J Med 1999; 92: 741-745
© 1999 Association of Physicians
Outcome of surgery for acromegaly—the experience of a dedicated pituitary surgeon
From the Division of Medical Sciences, University of Birmingham, and 1 Department of Otolaryngology, Queen Elizabeth Hospital, Birmingham, UK
Received 23 June 1999 and in revised form 2 September 1999
Professor P.M. Stewart, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH
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Summary |
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Previous large series of outcome following pituitary surgery for acromegaly, including our own, have demonstrated poor results, with cure, defined as GH <5 mU/l, achieved in only 33–42% of patients. In our previous series, surgery was performed by one of eight different surgeons. Largely based on the disappointing results of this previous audit of outcome, our practice since 1990 has been, whenever possible, to refer all patients with acromegaly to a dedicated pituitary surgeon (APJ). The objective of the current study was to re-analyse the outcome of surgical treatment for acromegaly since instituting this change. Tumour size and extension was determined on CT/MRI scanning. Biochemical cure was defined as a basal GH <5 mU/l or a nadir GH of <2 mU/l across an OGTT following initial pituitary surgery. Surgery was performed on 66 patients and 42 (64%) were cured, compared with 26/78 (33%) in our previous study (p<0.0005,
2 test). The cure rate for microadenomas (n=22) was 86%, and for macroadenomas 52%, compared with 54% (p<0.05, 2 test) and 30% (p<0.05, 2 test) respectively, in our previous study. We conclude that surgical outcome for acromegaly is enhanced if patients are operated on by a single experienced surgeon. |
Introduction |
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A number of large epidemiological studies have demonstrated excess mortality due to cardiovascular, respiratory and malignant disease in patients with acromegaly.1–5 Moreover, there is a direct relationship between mortality and post-treatment GH concentrations, such that in treated acromegalic patients achieving a GH<5 mU/l, life expectancy is normal.4–7
Despite the availability of effective long-acting somatostatin analogues, pituitary surgery is, and is likely to remain for the forseeable future, the most appropriate first-line therapy for the treatment of patients with acromegaly. However, acromegaly is a rare condition, with an annual incidence of 3–4 cases per million population.1,8 As such, the experience gained by individual surgeons may be limited, even over a protracted period of time, and this may account for the reported regional discrepancies in surgical cure rates.
Using accepted criteria, overall `cure' rates for acromegaly within the UK have varied between 18% and 76%. Our previous audit of surgical treatment for acromegaly in Birmingham revealed a disappointing overall cure rate of 33%.9 This study represented the outcome of surgery performed by any one of eight surgeons, reflecting our previous referral patterns and the organization of Endocrine/Neuroscience clinical practice across Birmingham. Since 1990, we have revised our strategy and have, wherever possible, focussed the referral of patients with acromegaly to a single dedicated pituitary surgeon. The influence of this change upon surgical cure rates in patients with acromegaly is discussed.
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Methods |
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APJ commenced operating on pituitary adenomas in 1986. A retrospective analysis of outcome was performed on all patients with biochemically-proven acromegaly treated by APJ since this time. No patients had received previous surgery, and none had been pre-treated with pituitary radiotherapy. Pituitary tumours were classified on a size basis according to their maximum diameter as determined by CT or MRI scanning at the time of diagnosis: tumours <1 cm were microadenomas and those
1 cm were macroadenomas. Radiological imaging was also used to assess whether macroadenomas were confined to the sella or extended beyond this region, and were thus classified as: (i) intrasellar tumours; (ii) tumours extending only into the immediate suprasellar region; or (iii) tumours with lateral extension in addition to suprasellar extension. Requirement for pituitary hormone replacement therapies pre-and post-operatively were recorded. Biochemical cure of acromegaly was defined as a basal GH<5 mU/l or a nadir GH of <2 mU/l across an oral glucose tolerance test (OGTT) performed at the patient's most recent clinic visit. We have previously shown a very good correlation between basal GH and nadir GH values across an OGTT.9 Patients who failed to satisfy one of these criteria were subjected to further treatment modalities, and were deemed to represent surgical treatment failures. The GH assay, an in-house double-antibody radioimmunoassay, has not changed during the study period, and interassay coefficients of variation were <10% at 7.5 and 13.6 mU/l.
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Results |
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The mean age at diagnosis of acromegaly among the 66 patients was 47±2 years (mean±SE), and 30 (45%) were female. Macroadenomas were identified in 44 (67%) patients (age at diagnosis 45±2 years; 21 (48%) female), and of these, 19 (43%) were intrasellar tumours, 15 (34%) extended into the immediate suprasellar region and the remaining 10 (23%) exhibited both suprasellar and lateral extension. The age at diagnosis of patients with microadenomas (n=22) was 49±2 years and nine (41%) were female.
Cure rates
Overall, a biochemical cure was achieved after initial pituitary surgery in 42 (64%) patients. Eight (12%) patients who were otherwise `endocrinologically' normal pre-operatively were rendered hypopituitary (requiring replacement of at least one pituitary hormone) as a result of curative surgery. Post-operative morbidity was otherwise low, the commonest complications being permanent diabetes insipidus in four patients (6%) and CSF leak (two requiring further surgical intervention) in four (6%). One patient suffered surgery-related nasal haemorrhage requiring transfusion. There was no peri-operative mortality.
Tumour size and cure rate
Of 22 patients with microadenomas, 19 (86%) were cured (Figure 1
), and four (18%) were rendered hypopituitary as a result of surgery. Two patients who were not cured remained eupituitary and one patient was not cured but was rendered hypopituitary following surgery. A biochemical cure in the presence of a macroadenoma was achieved in a significantly lower proportion of patients (23, 52%) compared with those with microadenomas (p<0.01, 2 test), and six (14%) of those cured were rendered hypopituitary as a result of surgery.
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Cure rates within the group of macroadenomas were also determined with respect to tumour extension (see Table 1
). Of the 19 intrasellar macroadenomas, 12 (63%) were cured, compared with 7/15 (47%) tumours that extended only into the suprasellar space. Ten macroadenomas demonstrated both suprasellar and lateral extension and of these, four (40%) were cured following surgery (p=NS, 2 test, Figure 2).
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Cure rates were compared with results from our previous audit (Table 1
), and showed a significant improvement in all tumour size categories, apart from intrasellar macroadenomas.
Cure rate with respect to year of operation
Patients were grouped according to the year of operation and cure rates were determined within these time periods (Table 2). During 1986–1989, 15 patients (seven [47%] with microadenomas) were operated on and nine (60%) were cured. Since 1990, 51 patients (15 [29%] with microadenomas) underwent surgery and 33 (65%) were cured. When data were analysed according to pituitary tumour size, there was a suggestion of improved cure rates with time amongst macroadenomas (38% vs. 56%), during the time periods 1986–1989 and 1990–1998, respectively, although this observation did not reach statistical significance.
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Discussion |
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There is considerable debate as to the definition of cure post-treatment in a patient with acromegaly. Because of this, together with the published data on normalization of mortality rates, our practice has been to define a `safe' level of GH post-treatment as 5 mU/l. Pituitary surgery is the most appropriate first-line treatment modality for patients with acromegaly. Even in experienced hands, however, a GH of <5 mU/l is achieved in only approximately 60% of cases. The chance of surgical cure in the presence of a microadenoma is significantly better than in macroadenomas, although the majority of GH-secreting adenomas are macroadenomas. As a result of our previous experience of relatively poor cure rates of acromegaly when up to eight surgeons performed pituitary surgery,9 we changed our practice in 1990 and referred all patients whenever possible to a single dedicated pituitary surgeon.
The surgical cure rate from our current cohort of patients compares favourably with those of recently published studies (Table 3), and more specifically, represents a significant improvement in outcome compared to our previous series of patients (64% cured in the current series vs. 33% previously, p<0.0005, 2 test) operated on by one of eight different surgeons.9 Although our previous cohort of patients included a greater proportion of patients with macroadenomas (77% vs. 67% in the current series), this disparity is not sufficient to account for the observed discrepancy in cure rate. Moreover, the difference in cure rates remained when tumours were analysed specifically as micro- and macroadenomas.
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The only tumour category that did not show a significant improvement in cure rates when operated on by a single surgeon was intrasellar macroadenomas. Technically these tumours are easier to cure, whereas those with more extensive spread are often more difficult to completely excise. The cure rate for selective microadenomectomy was also significantly improved when a single surgeon performed the operation. The pattern of improvement of cure rates in subtypes of GH-secreting tumours is therefore consistent with the proposal that the skill and experience of the surgeon determines the improved outcome. Another factor that may contribute to the improved cure rate is the advance in pre-operative imaging due to high quality MRI scans. The probability of cure with normal post-operative pituitary function is increased when imaging defines for the surgeon which part of the gland to remove and which part of the gland may be left undisturbed.
There are wide discrepancies between surgical cure rates for acromegaly on both a Regional and National scale, as highlighted in Table 3. Lissett et al.10 reported the outcome of surgical treatment of acromegaly in a series of 73 patients who were operated on by one of nine different surgeons. The cure rate in this study was 18%, and the authors proposed that the poor results were due to the dilution of experience occurring as a result of a large number of surgeons performing an infrequent surgical procedure. Two large European studies have looked at surgical outcome of acromegaly using a dedicated pituitary surgeon in each instance, and cure rates using this approach were 56%11 and 42%.12 A recent report from Ahmed et al.13 revealed that 67% of patients treated by a single surgeon 1974–1995 achieved a mean GH <5 mU/l. One study described the effect of a single surgeon taking on the workload of a group of several surgeons, which revealed an improvement in cure rate (defined as mean basal GH <6 mU/l) from 37% (during the period 1969–1986) to 81% (1987–1993).14 Clearly a number of variables (particularly imaging quality and surgical equipment) have changed between 1969 and 1993 that may explain the improved results, although the impact of a single surgeon may have contributed to the improved cure rate. Recently, two major centres in the US have published the results of an audit of outcome of surgery. In the first, 57% of 162 patients with acromegaly, operated on between 1978 and 1996, were cured following pituitary surgery alone.6 In the second, 76% of 254 patients operated on between 1974 and 1992 by a single surgeon achieved a GH of <10 mU/l.15
The implication of `surgical experience' being an important factor in outcome may be expected to be born out in an improvement in cure rates with time (the learning curve). We did look for such changes, although no statistically significant results were apparent, probably reflecting the relatively small numbers involved when these operations are subdivided into time periods. However, our data do suggest a possible trend towards improved biochemical cure in macroadenomas as a function of time/experience. Lissett et al.10 also noted a slight, non-significant trend to improved outcome with time. Recent work by Swearingen et al.6 did reveal a significant improvement in cure rate (irrespective of tumour size), from 45% during the period 1978–1987, to 73% between 1991 and 1996. Likewise, Ahmed et al.13 documented a cure rate of 48% following surgery performed prior 1981, rising to 73% during the period 1991–1995. However, during the time periods indicated, there have been significant improvements in imaging techniques and surgical equipment (e.g. operative microscopy) which are likely to have dramatic effects on ultimate surgical outcome, in addition to surgical `experience' per se. Our data, however, strongly support the view that adopting a dedicated pituitary surgeon results in a significant improvement in outcome for patients with acromegaly.
The controversies associated with the Bristol paediatric cardiac surgery cases16,17 have again highlighted the importance of clinical audit, and especially audit of surgical outcome. There is now intense pressure to standardize practices and treatments in all aspects of medicine, with the ultimate aim being to achieve nationally agreed standards. Our data show that surgical outcome for acromegaly is significantly enhanced if patients are operated on by a single experienced surgeon. Such findings should have important ramifications for the provision of surgical expertise to patients with pituitary tumours.
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References |
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Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab 1998; 83:2730–4.
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