Objective: To assess the surgical outcome of hypophysectomy in acromegalic patients, differences in response to surgery in micro and macroadenoma and the development of associated hormonal deficiency after surgery.
Methods: Retrospective analysis of charts of acromegalic patients who were operated upon at Aga Khan University Hospital, Karachi, was done. Information regarding presentation, laboratory data, radiological assessment, details of surgery and postoperative outcome was recorded. Surgical outcome was classified depending on the degree of disease control after surgery as biochemical cure, remission and treatment failure.
Results: Out of 30 patients, eighteen (60%) were males and 12 (40%) females with mean age at the time of diagnosis 35.6+/-10.4 years. The mean duration of symptoms was 3.2+/-2.4 years. Twenty-five patients had macroadenoma and five had microadenoma. Preoperative mean GH level was 42.4 ng/ml with range of 2.5 to 534 ng/ml. Following surgery, 13 had biochemical cure, 4 were in remission and 13 failed to respond. The outcome in microadenoma was better than in macroadenoma i.e. 100% vs. 32%. Preoperatively four patients had panhypopituitarism with additional six patients (20%) developing hypopituitarism postoperatively.
Conclusion: Our study showed that acromegaly was seen at a much earlier age, outcome of surgery was comparable to other international studies and postoperative panhypopituitarism was seen in significant number of patients. The outcome in microadenoma was better than in macroadenoma but the number of patients seen with microadenoma was small

Chandna, A

Haque, N

Islam, N

Jabbar, A

Zuberi, L

English

eCommons@AKU

eCommons@AKUSection of Diabetes, Endocrinology andMetabolism Department of MedicineJune 2004Clinical features and outcome of surgery in 30patients with acromegalyA ChandnaAga Khan UniversityN IslamAga Khan University, najmul.islam@aku.eduA JabbarAga Khan UniversityL ZuberiAga Khan UniversityN HaqueAga Khan University, naeem.haque@aku.eduFollow this and additional works at: https://ecommons.aku.edu/pakistan_fhs_mc_med_diabet_endocrinol_metabPart of the Endocrinology, Diabetes, and Metabolism CommonsRecommended CitationChandna, A., Islam, N., Jabbar, A., Zuberi, L., Haque, N. (2004). Clinical features and outcome of surgery in 30 patients withacromegaly. Journal of Pakistan Medical Association, 54(6), 315-319.Available at: https://ecommons.aku.edu/pakistan_fhs_mc_med_diabet_endocrinol_metab/36Clinical Features and Outcome of Surgery in 30 Patients with AcromegalyA. Chandna, N. Islam, A. Jabbar, L. Zuberi, N. HaqueEndocrinology Section, Department of Medicine, Aga Khan University Hospital, Karachi.AbstractObjective: To assess the surgical outcome of hypophysectomy in acromegalic patients, differences in responseto surgery in micro and macroadenoma and the development of associated hormonal deficiency after surgery.Methods: Retrospective analysis of charts of acromegalic patients who were operated upon at Aga KhanUniversity Hospital, Karachi, was done. Information regarding presentation, laboratory data, radiological assess-ment, details of surgery and postoperative outcome was recorded. Surgical outcome was classified dependingon the degree of disease control after surgery as biochemical cure, remission and treatment failure. Results: Out of 30 patients, eighteen (60%) were males and 12 (40%) females with mean age at the time ofdiagnosis 35.6± 10.4 years. The mean duration of symptoms was 3.2± 2.4 years. Twenty-five patients hadmacroadenoma and five had microadenoma. Preoperative mean GH level was 42.4ng/ml with range of 2.5 to534 ng/ml. Following surgery, 13 had biochemical cure, 4 were in remission and 13 failed to respond. The out-come in microadenoma was better than in macroadenoma i.e. 100% vs. 32%. Preoperatively four patients hadpanhypopituitarism with additional six patients(20%) developing hypopituitarism  postoperatively.Conclusion: Our study showed that acromegaly was seen at a much earlier age, outcome of surgery was com-parable to other international studies and postoperative panhypopituitarism was seen in significant number ofpatients. The outcome in microadenoma was better than in macroadenoma but the number of patients seen withmicroadenoma was small (JPMA 54:315;2004). IntroductionAcromegaly is an uncommon disease with an annu-al incidence of 3/million and an estimated prevalence of40/million population.1 In the majority of patients it iscaused by a pituitary adenoma and is associated with signif-icantly shortened life span that is not due to direct effectfrom the tumour but results from cardiovascular, respirato-ry and cerebrovascular complications.2 In addition there isan increased risk of malignancy.3 Acral growth, coarsenedfacial features and soft tissue swelling are the most commonsymptoms of acromegaly4 which develop slowly over timeso the diagnosis is delayed for years.5Optimal therapy should be aimed at alleviatingsymptoms, reducing tumour bulk, preventing regrowth andreducing mortality without the development of hypopitu-itarism.6 Surgery remains the treatment of choice as thisoffers a rapid permanent reduction of Growth hormone(GH) level and relief from the mass effect of the tumour. Inthose patients in whom operative cure is not achieved,radiotherapy and/or medical therapy are useful treatmentmodalities. Biochemical cure is considered as GH level<2.5ng/ml, normal IGF level and post Oral Glucose ToleranceTest(OGTT), GH level<1 ng/ml.7,8 Using strict criteria forcure, rate as high as 67% have been reported for surgeryalone.9 Outcome of surgery is inversely correlated to preop-erative GH level10, tumour size11 and tumour stage.12 We retrospectively analyzed the medical records ofpatients with acromegaly who were operated upon, to assesthe  surgical  outcome  of  hypophysectomy,  the difference in outcome of microadenoma and macroadenoma anddevelopment of postoperative hormonal deficiencies.Patients and MethodsA retrospective review of medical records was per-formed on 45 patients with the diagnosis of Acromegalywho presented at Aga Khan University Hospital between1989-2002.  Ten patients who had had previous pituitary surgeryor irradiation were excluded. Five patients who did notundergo surgery were also excluded.Information regardingpresentation, investigations like hormonal and radiologicalassessment, details of surgery and postoperative outcomewere recorded.All patients exhibited signs and symptoms ofacromegaly with confirmation of diagnosis by elevatedbaseline GH levels and OGTT suppression test. An OralGlucose Tolerance Test was performed by fasting the patientovernight and then taking a 0900 h basal blood sample. Thepatient was then given an oral dose of 75 g of glucose.Blood samples were collected every 30 min for 120 min andwere analyzed for GH and glucose levels.Preoperative MRI/CT scan were done and tumourswere classified into macro (>10 mm) or microadenomas(<10 mm). The postoperative cure was assessed by measuringrandom GH levels in most of the patients and postoperativeOGTT suppression test was done in five patients. The hor-monal assessment was done within two weeks of surgery.Biochemical cure was considered to be achieved when therewas suppression of random GH level of <2.5 ng/ml orserum GH <1 ng/ml after OGTT, remission when GH levelwas between 2.5 and 5.0 ng/ml and failure to surgical treat-ment when persistently elevated random GH levels or fail-ure to suppress/paradoxical rise of GH on OGTT.7,13Postoperative workup also included repeat MRI scanof pituitary and hormonal assessment for pituitary insuffi-ciency. GH measurement was done using Immulite® 2000analyzer(Diagnostic Product Corp. Ltd.) with chemilummi-nescence assay. The normal adult range for this kit  was0.06-5.0 ng/ml.Statistical MethodResults were expressed as mean + standard devia-tion, median with range for all continuous variables (e.g,age, duration of symptoms etc.) and number (percentage)for categorical data (e.g, gender, surgical outcome etc.).Univariate analysis was performed by using the PearsonChi-square test, Fisher Exact test, and Mann Whitney U-testwhenever appropriate. A p-value <0.05 was considered asstatistically significant. All p-value were two sided. TheStatistical package for social science SPSS (Release 10.0.5,standard version, copyright © SPSS; 1989-99) was used fordata analysis.ResultsPatient populationOut of 30 patients, eighteen were males (60%) and12 were females (40%). The mean age of patients at the timeof diagnosis was 35.6 ± 10.4 years (range, 16-52) (Figure1). The mean duration of symptoms reported by the patientat the time of diagnosis was 3.2 ± 2.4 years.  The majority of tumours were macroadenoma, i.e.25 patients (83%) but 5 had microadenoma (17%). Out of25 macroadenamas, 19 had suprasellar extension and 12were with optic chiasmal compression. Cavernous sinusinvolvement was present in 3 patients and sellar floordestruction with sphenoid sinus involvement in 3 patients. Preoperative mean GH level was 42.4ng/ml withrange of 2.5 to 534 ng/ml. In patients with microadenomaGH level was between 4.5 - 17.5ng/ml whereas higher lev-els were seen with macroadenoma. Preoperative OGTT sup-pression was done in 10 patients and was found to be abnor-mal in all.Figure 1. Age distribution.Table 1. Summary of characteristics of adenomas.Characteristics MRI size of adenoma p-valueMacro Micro(n=25) (n=5)Pre-op GH level 30.4 (5.8-534) 12.5 (5.3-19) 0.015Post-op GH level 5.7 (0.5-213) 0.9 (0.4-1.9) 0.021Age (years) 31 (16-52) 45 (37-51) 0.016Duration ofsymptoms (years) 2 (0.5-10) 5 (0.3-9) 0.552abnormal in all.Out of 30 patients who underwent surgery, thirteenpatients had serum GH level of <2.5 ng/ml, four had levelsbetween 2.5-5 whereas 13 had elevated levels.Postoperative OGT was done in 5 patients and no suppres-sion of GH was there in four cases. Thus 13 had biochemi-cal cure, 4 patients were in remission and 13 failed torespond to surgical treatment( Table 2). The outcome inmicroadenoma was better than in macroadenoma i.e., 100%vs. 32%.Preoperatively four patients had panhypopituitarism,who did not recover from suppression after surgery.Postoperatively, additional six patients (20%) had panhy-popituitarism.DiscussionAcromegaly is a slowly progressive disease charac-terized by disfigurement and disability.14 Mortality inuntreated acromegalics is probably two to three times that ofhealthy people.1,15 The observation that this increased mor-tality is decreased to normal in a population of curedacromegalics16 highlights the importance of achieving abiochemical cure. Treatment by surgery not only offers theadvantage of an immediate decline of GH levels17 but alsorelieves the local pressure effects, reducing the systemicmorbidity and normalizing the mortality. Surgery thusremains the first line treatment modality with adjuvent ther-apy consisting of radiotherapy and/or medical treatment. We retrospectively analyzed the clinical features andoutcome of transsphenoidal hypophysectomy, in patientswith acromegaly. There was male preponderance i.e. 60%whereas other studies suggested nearly equal sex distribu-tion.18,19 We found that the mean age was lower than thatreported in other studies i.e., 35.6 years as compared to46.320 and 5018 years. The changes in appearance occur insidiously, so thatvery often the disorder is diagnosed only when a new physi-cian replaces the usual doctor and sees the patient for thefirst time or when photographs of the patient taken over anumber of years are collected together.5 Hence there can bea delay of 5-8 years18,19 in the diagnosis. From the chartsreviewed it was noted that the mean duration of symptomsreported by the patients, was 3.3 ± 2.4 years (Table 1). Thiscomparatively short duration can either be because of moreaggressive disease but more likely this can be due to delayon part of the patient in observing the subtle changes in theFigure 2. GH levels in microadenoma. Figure 3. GH levels in macroadenoma.Table 2. Surgical outcome.Outcome of surgeryCure Remission Failure TotalPre-op MRI Macro 8 (32%) 4 (16%) 13 (52%) 25 (100%)size of adenoma Micro 5 (100%) 5 (100%)Total 13 (43.3%) 4 (13.3%) 13 (43.3%) 30 (100%)on part of the patient in observing the subtle changesin the features until they become very obvious.Majority of patients had macroadenoma which is inaccordance with literature.16,18 It has been suggested thatyoung patients with acromegaly generally have larger andmore rapidly growing tumours at the time of diagnosis thanolder patients.21 Our data also showed that macroadenomawas seen in younger age group i.e. between 16-52 yearswith median of 31 years, whereas in case of microadenomamedian age was 45 (Table 1). The definition of cure of acromegaly has been a mat-ter of controversy. Till 1980s, a post therapeutic GH level<5 ng/ml was considered to be consistent with diseasecure22-24 but in the beginning of mid 1990s, a more stringentdefinition of cure has been used because analyses of longterm outcomes have shown that mortality rates among treat-ed acromegalics do not reach those of the normal populationuntil GH levels drop below 2.5 ng/ml.25 It was seen thatwith levels less than 5 ng/ml, there was recurrence of thedisease in most of patients but with levels less than2.5ng/ml, the long term cure rate went upto 97%.26Accordingly using the older criteria, many patients willexperience remission of their disease rather than a cure.13According to the consensus statement issued in19997,  the cure is said to be achieved when circulating IGF-I is reduced to an age-adjusted normal range and nadir GHafter an oral glucose load is less than 1 µg/L.In our study, 13 patients had GH level of <2.5 ng/mland only 5 of them underwent dynamic study with OGTTwith one patient having suppression of GH level. So therewas a biochemical cure rate of 43.3% (Table 2) which is thesame as reported by Sheaves et al26 using the strict criteria.IGF 1 level measurement is not available in our country.Thus random GH levels and OGTT suppression test areonly available tests to asses treatment outcome.The study had a number of limitations. It was a retro-spective analysis of the charts, most of the patients followedup with neurosurgeons rather than endocrinologists, unavail-ability of IGF 1 level measurement and only few of them haddynamic testing done to asses the cure.The surgical outcome in microadenoma was betterthan with macroadenoma i.e., 100% vs. 32%  but there werelimited number of cases with microadenoma (n=5).Generally, the microadenomas do well postoperatively thanmacroadenomas.26During selective adenomectomy, pituitary functionis generally well preserved27 and preoperative suppressionalso improves as a result of surgical removal of the tumour.Ross and Wilson showed that only nine (5.2%) of 172patients had postoperative deterioration of pituitary func-tion.22 We observed that preoperatively four patients hadhypopituitarism which persisted postoperatively. In thepresent study postoperative hypopituitarism was seen in sig-nificant number of cases (20%).In conclusion, the data reviewed showed thatacromegaly was seen at a much earlier age, more aggressivedisease was seen in younger age group, the outcome of sur-gery was comparable to other studies and postoperativepanhypopituitarism was seen in significant number ofpatients. The outcome in microadenoma was better than inmacroadenoma but the number of patients seen withmicroadenoma was small. AcknowledgementWe wish to thank Mr Muhammad Islam, PGD (statis-tics), Research Coordinator, Department of Medicine, AgaKhan University Hospital for his help in statistical analysis.References1. Bates AS, Van't Hoff W, Jones JM, et al. An audit of outcome of treatment inacromegaly. Q J Med1993;86:293-9.2. Melmed S, Ho K, Klibanski A, et al. Clinical review. 75:Recent advances inpathogenesis, diagnosis and management of acromegaly. J Clin EndocrinolMetab 1995;80:3395-402.3. Tharper K, Kovacs K, Stefaneanu L, et al. Overexpression of the growth hor-mone releasing hormone gene in acromegaly associated pituitary tumors: anevent associated with neoplastic progression and aggressive behavior. Am JPathol 1997;151:769-84.4. Ezzat S, Forster MJ, Berchtold P, et al. Acromegaly. Clinical and biochemicalfeatures in 500 patients. Medicine (Baltimore), 1994;73:233-40.5. Molitch ME. Clinical manifestations of acromegaly. Endocrinol Metab ClinNorth Am 1992;21:597-614. 6. Lamberts SWJ. Acromegaly and its treatment. J Endocrinol 1997;155 (Suppl-1): S49-51.7. Giustina A, Barkan A, Casaneuva FF, et al. Criteria for cure of acromegaly: aconsensus statement. J Clin Endocrin Metab 2000;85:526-9.8. Sheaves R, Jenkins P, Blackburn P, et al. Outcome of transsphenoidal surgeryfor acromegaly using strict criteria for surgical cure. Clin Endocrinol 1996;45:407-13.9. Ahmed S, Elsheikh M, Stratton IM, et al. Outcome of transsphenoidal surgeryfor acromegaly and its relationship to surgical experience. Clin Endocrinol1999;50:561-7.10. Melmed S. Acromegaly. Metabolism 1996;45(suppl 1):51-52.11. Fredu PU, Wardlaw SL, Post KD. Long term endocrinological follow-up eval-uation in 115 patients who underwent transsphenoidal surgery for acromegaly.J Neurosurg 1998;89:353-8.12. Tindal GT, Oyesiku NM, Watts NB, et al. Transsphenoidal adenomectomy forgrowth hormone - secreting pituitary adenomas in acromegaly: outcomeanalysis and determinants of failure. J Neurosurg 1993;78:205-15.13. Melmed S, Jackson I, Kleinberg D, et al. Current treatment guidelines foracromegaly. J Clin Endocrin Metab 1998;83 2646-2652.14. Melmed S. Acromegaly. N Engl J Med, 1990; 322:966-77.15. Alexander L, Appleton D, Hall R, et al. Epidemiology of acromegaly in theNewcastle region. Clin Endocrinol 1980;12 71-9.16. Swearingen B, Backer FG, Katznelson L, et al. Longterm mortality aftertranssphenoidal surgery and adjunctive therapy for acromegaly. J ClinEndocrinol Metab,1998;83 3419-26.17. Hardy J, Somma M. vfb Acromegaly: Surgical treatment by transsphenoidalmicrosurgical removal of the pituitary adenoma. In: Tindall GT, Collins WF(eds). Clinical Management of Pituitary Disorders. NewYork, Raven Press;1979; p. 209.18. Fakuda I, Hizuka N, Murakami Y, et al. Clinical features and therapeutic out-comes of 65 patients with acromegaly at Tokyo Women's Medical University.Intern Med 2001;40:987-92.19. Ezzat S, Forester MJ, Berchtold P, et al. Acromegaly. Clinical  and biochemi-19. Ezzat S, Forester MJ, Berchtold P, et al. Acromegaly. Clinical  and biochemi-cal features in 500 patients. Medicine 1994;73:233-40.20. Kreutzer J, Vance ML, Lopes BS, et al. Surgical management of GH secretingpituitary adenomas: an outcome study using modern remission criteria. J ClinEndocrin Metab 2001;86:4072-77.21. Serri O, Robert F, Comtois R, et al. Distinctive features of prolactin secretionin acromegalic patients with hyperprolactinemia, 1987;17:429-36.22. Ross DA, Wilson CB. Results of transsphenoidal surgery for GH-secretingpituitary adenoma in a series of 214 patients. J Neurosurg 1988;68:854-67.23. Laws ER, Piepgras DG, Randall RV, et al. Neurosurgical management ofacromegaly. Results in 82 patients treated between 1972 & 1977. J Neurosurg,1979;50:454-61.24. Lindholm J, Giwercman B,  Giwercman A, et al. Investigation criteria forassessing the outcome of treatment in acromegaly. Clin Endocrinol1987;27:553-62. 25. Bates AS, Van't Hoff, Jones JM, et al. Does treatment of acromegaly affect lifeexpectancy? Metabolism, 1995; 44( suppl 1): 1-5.26. Sheaves R, Jenkin P, Blackburn P, et al. Outcome of transsphenoidal  surgeryfor acromegaly using strict criteria for surgical cure. Clin Endocrinol1996;45:407-13.  27. Giovanelli MA, Fahlbusch R, Giani SM, et al . Surgical treatment of growthhormone secreting microadenoma. In: Faglia G, Giovanelli MA, Macleod RM(eds): Pituitary Microadenomas. London, Academic Press; 1980, p. 427.

Clinical features and outcome of surgery in 30 patients with acromegaly

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Clinical features and outcome of surgery in 30 patients with acromegaly

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