Neurosurg Rev (2014) 37:269–277 DOI 10.1007/s10143-013-0509-3

ORIGINAL ARTICLE

Transsphenoidal surgical treatment of pituitary adenomas in patients aged 80 years or older Shunji Yunoue & Hiroshi Tokimura & Atsushi Tominaga & Shingo Fujio & Prasanna Karki & Satoshi Usui & Yasuyuki Kinoshita & Mika Habu & FM Moinuddin & Hirofumi Hirano & Kazunori Arita

Received: 3 September 2012 / Revised: 27 May 2013 / Accepted: 27 July 2013 / Published online: 15 November 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract To know the clinical characteristics of pituitary adenomas in the elderly patients aged 80 years or older who were surgically treated. From 1995 through 2012, 907 patients underwent surgery for the pituitary adenomas at Kagoshimaand Hiroshima University hospitals in Japan. Ten (1.1 %) patients were aged 80 years or older. We retrospectively assessed the clinical characteristics including preoperative comorbidities, manifestations, neuroimaging findings, and endocrinologic features of these ten patients. The subjects included eight males and two females. Their ages ranged from 80 to 86 with mean of 83.1 years. Of these, besides one case of growth hormone-producing adenoma, others were clinically nonfunctioning adenoma. Six patients had modest comorbidities such as hypertension, cardiovascular diseases, diabetes mellitus, or chronic kidney dysfunction, and all patients were classified into grade 2–3 on American Society of Anesthesiologists’ Physical Status grading. Transsphenoidal surgery was performed in all due to visual disturbance in eight, diabetes mellitus as an intercurrent illness of acromegaly in one, and for the purpose of preventing visual disturbance in one patient who had an adenoma impinging optic chiasm but still had normal visual field. The surgeries provided sufficient decompression of the optic pathways and improved visual disorder in all. In an acromegalic male, his comorbidities considerably improved. No permanent surgical morbidity ensued. More than three axes of anterior pituitary hormones S. Yunoue : H. Tokimura (*) : S. Fujio : P. Karki : M. Habu : F. Moinuddin : H. Hirano : K. Arita Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8520, Japan e-mail: [email protected] A. Tominaga : S. Usui : Y. Kinoshita Department of Neurosurgery, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan

were preoperatively impaired in all, which were rarely recovered. Transsphenoidal surgery is safe and efficient treatment way for patients aged 80 years or older with pituitary adenomas with chiasmatic symptoms when the patients’ general condition is well preserved and pituitary hormonal deficiency is adequately replaced. Keywords Elderly . Eighty years old or over . Pituitary adenoma . Transsphenoidal surgery

Introduction As general population is rapidly aging, proportions of elderly in total patients with pituitary adenomas are increasing [2, 9, 12, 17, 19, 26, 29]. According to brain tumor registry of Japan, patients over 70 years old comprise 6.6 % of total patients with pituitary adenomas registered between 1984 and 1996 [24]. Recent survey in Japan showed that the proportion of elderly people aged over 80 years has most rapidly increased among all age groups, from 1.1 % in 1975 to 5.9 % in 2008 [23]. Hasegawa et al. presented pituitary apoplexy in three elderly patients over the age of 80. But the clinical features of pituitary adenoma of this age group have yet to be systematically surveyed [11]. We here conducted retrospective survey to elucidate the clinical characteristics of the patients 80 years old or older with pituitary adenomas.

Subjects and methods From 1995 through 2012, 907 patients with pituitary adenomas were surgically treated by two senior authors (K.A. and A.T.) or under their supervision at Kagoshima University and Hiroshima University hospitals. Ten (1.1 %), eight males and two females, among these 907 patients were 80 years of age or

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older (Fig. 1). Nine patients had clinically nonfunctioning adenoma and one had growth hormone-producing adenoma. All of these underwent transsphenoidal surgery. Follow-up period ranged from 5.3 to 99.3 months with mean of 37.9 months±29.6 (SD). All patients underwent imaging study using magnetic resonance imaging (MRI), ophthalmologic study, and assessment of pituitary functions pre- and postoperatively. Anterior pituitary provocation tests and measurements of target hormones were performed in eight patients preoperatively and seven patients postoperatively from 3 to 6 months after operation. For growth hormone (GH) secretion, 100 μg of growth hormone-releasing peptide 2 (GHRP2) or 0.5 g/kg of L -arginine hydrochloride was used. In the GHRP2 test, blood samples were taken before and 15, 30, 45, and 60 min after GHRP2 injection. GH response with peak value >15 μg/dL after GHRP2 injection was judged to be normal according to Chihara et al. [5]. For the assessment of adrenocorticotropic hormone (ACTH)–cortisol axis, serum cortisol level was measured before and after administration of 100 μg corticotrophin-releasing hormone. For thyroid-stimulating hormone (TSH) secretory function, serum TSH level was measured before and after loading of 500 μg thyrotropinreleasing hormone in addition to the measuring of basal free T4 level. For gonadotropin secretory function, serum luteinizing hormone (LH)/follicle-stimulating hormone (FSH) was measured before and after injection of 100 μg luteinizing hormone-releasing hormone in addition to the measurement of testosterone or estradiol level. In this study, the criteria for intact secretory functions of pituitary hormones were determined as follows. For GH, peak GH value in arginine infusion test was >3.0 μg/L [16] or peak GH value in GHRP2 test was 15 μg/dL. For TSH, free T4 level was above the lower

250

Number of patients

200

150

100

50

10 0 0-10

10-20 20-30 30-40 40-50 50-60 60-70 70-80 80-90

90-

age Fig. 1 The age distribution of patients who underwent transsphenoidal surgery for pituitary adenomas from 1995 to 2012. Each bar indicates the number of patients of every 10-year age groups

normal limit (1.1 ng/dL) and peak value of TSH was >2.5fold basal level. For gonadotropin, peak value of LH was >3fold basal level and peak value of FSH was >2-fold basal level in addition to normal estradiol or testosterone level [16].

Results Preoperative clinical characteristics The maximum tumor diameter on MRI ranged from 20 to 39.3 mm with mean of 28.5 mm±5.79 (SD). The degree of lateral expansion of tumor on its prominent side according to Knosp grading system [14] was as follows: grade 0 in one, grade I in four, grade II in one, grade III in three, and grade IV in one of all the ten patients. Six (60.0 %) of all the ten patients had comorbidities including hypertension in four, cardiovascular diseases in three (angina pectoris, thoracic aortic aneurysm, abdominal aortic aneurysm), diabetes mellitus in two, chronic kidney dysfunction in one, and hyperlipidemia in one (Table 1). As all of these illnesses were not so serious, patients’ physical conditions were categorized into grade 2 (patients with mild systemic disease) in five patients and grade 3 (patients with severe systemic disease) in five patients according to American Society of Anesthesiologists’ Physical Status (ASA-PS) grading [22]. The reasons of the surgical treatment were visual disturbance in eight, diabetes mellitus as an intercurrent illness of acromegaly in one, and for preventing future visual disturbance in a patient who had an adenoma impinging optic chiasm but still had normal visual function. Surgery All the patients underwent transsphenoidal surgery under surgical microscope with aid of endoscopic observation. Endonasal route was employed in seven and sublabial route was employed in three patients to reach the sphenoid sinus (Table 2). Mean operation time was 152.5 min±30.5 (SD). There were no major problems hindering surgical procedure. Intraoperatively, cerebrospinal fluid leakage was seen in three cases, which was successfully treated by insertion of adipose tissue soaked with fibrin glue in the tumor removal cavity. No one needed prolonged use of desmopressin except during early postoperative period, usually 5 days. Visual improvement was reported in all the patients with preoperative visual field defect (Fig. 2). Patient case 9, an 83-year-old acromegalic male, with 29.4 ng/mL of GH and 1,113.7 ng/mL of IGF-1 had been suffering from intercurrent illness including diabetes mellitus, sleep apnea syndrome, abdominal aortic aneurysm, and hypertension [3]. The transsphenoidal surgery was chosen because of these active acromegalic symptoms in spite of no

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Table 1 Preoperative clinical characteristics side Case no.

Age

Gender

Comorbidity on admission

Subtype

Tumor size (mm)

Knosp grade

ASA-PS

Cause of operation

1 2 3

83 84 84

M M M

NF NF NF

37.4 23.4 26.0

I III II

2 2 3

Visual disturbance Visual disturbance Visual disturbance

4

83

F

HT None HT TAA None

NF

28.0

I

2

Visual disturbance

5 6 7 8 9 10

87 86 80 81 83 80

F M M M M M

None AP Hyperlipidemia, DM CKD HT, CKD DM, HT AAA None

NF NF NF NF GH NF

27.0 30.0 39.3 28.4 20.0 23.0

0 I IV I III III

2 3 3 3 3 2

Visual disturbance Prophylactic Surgery Visual deterioration Visual disturbance DM visual disturbance

HT hypertension, TAA thoracic aortic aneurysm, CI cerebral infarction, CA cerebral aneurysm, AP angina pectoris, CKD chronic kidney dysfunction, DM diabetes mellitus, AAA abdominal aortic aneurysm, NF clinically nonfunctioning adenoma, GH growth hormone-producing adenoma, ASA-PS American Society of Anesthesiologists’ Physical Status, Knosp grade the degree of lateral extension in the more prominent

ophthalmic symptoms. Due to grade III lateral extension of the tumor, surgical cure was not achieved. But postoperatively, both blood GH and IGF-1 considerably decreased to 1.8 and 522.8 ng/mL, respectively. Along with these changes, his abnormal glucose tolerance and sleep apnea syndrome well improved and he was alive as of the latest visit at the age of 91, 99.3 months after the surgery.

recurrence (Fig. 3). At the latest follow-up, all the patients excluding case no. 8, who died of pneumonia 31.3 months after the surgery, were alive. The recurrence or regrowth of the residual tumor was not detected during the mean of 37.9 months long follow-up (Table 3).

Anterior pituitary function Follow-up results Preoperative Karnofsky performance status (KPS) was 80–90 in all and postoperative deterioration of KPS was not reported in any. The postoperative hospital stay in our series ranged from 7 to 15 days with mean of 11.5±3.6 (SD). Only one patient (case 1) received an adjuvant therapy, stereotactic gamma knife radiotherapy for residue of the tumor because preoperative rapid growth suggested a possibility of early

Table 2 Intraoperative assessments

op. time operation time, TS transsphenoidal surgery, minimum 70-year olds with pituitary adenomas [6, 9, 10, 17]. Nonfunctioning adenomas comprised 73 to 100 % of the series. The safety and efficacy of surgery were also acceptable in these series as well as ours. Therefore, there seems no age limit as a surgical contraindication. Murad et al.

statistically established safety of transsphenoidal surgery for nonfunctioning adenoma in comparison to transcranial approach by a meta-analysis of 58 previous reports [20]. But the mortality and morbidity are yet negligible, 1 and 5 % [20]. And it may be likely to encounter intra- and perioperative complications more frequently in elderly patients than the younger ones because of compromised immunity, function of wound healing, homeostasis of water balance, and hormonal reaction. So the pituitary surgeon should be prudent enough when surgical indication is considered for these most aged patients. Patients without tumor-related symptoms can be followed with regular MRI and perimetry. Considering slow growing nature of pituitary adenomas especially in elderly and their limited life expectancy, our “not seeking radicality” policy may be justified, in which total removal was not always sought. Subtotal and partial removal provided sufficient decompression of optic chiasm and prolonged progression-free status. The recent progression of stereotactic radiation therapy and its dissemination facilitate its use for the pituitary adenoma which reportedly provides relatively long-term control of the tumor [27]. In one case of our series (Fig. 3), stereotactic radiation was given to residual tumor due to the fear of early recurrence, which was

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Table 3 Follow-up result Case no

Age/sex

Additional treatment

Survival

Follow-up period (months)

Regrowth at latest follow-up

KPS preop./ latest follow-up

1 2 3 4

83/M 84/M 84/M 83/F

γKnife None None None

Alive Alive Alive Alive

56.8 14.2 15.4 70.0

None None None None

80/90 90/90 80/90 90/90

5 6 7 8 9 10

87/F 86/M 80/M 81/M 83/M 80/M

None None None None None None

Alive Alive Alive Dead (pneumonia) Alive Alive

19.5 57.6 11.9 31.3 99.3 5.3

None None None None None None

80/90 90/90 90//90 90/90 90/90 90/90

M male, F female, preop. before surgery, KPS Karnofsky performance status

suggested by preoperative rapid growth of the tumor. This treatment modality will lessen the requirement of total resection of the pituitary tumors in the elderly. But the longitudinal endocrinologic follow-up is still mandated [27]. Fortunately, there was no grade 4 patient on ASA-PS grading system, patient with constantly life-threatening severe systemic disease in our series. Physiologic conditions of all patients were classified into grade 2—patients with mild systemic disease, or grade 3—patients with severe systemic disease. So, we could recommend transsphenoidal surgery for patients of 80 years old or older with symptomatic pituitary adenoma when the patient’s physical condition is ASA-PS (%)

(8/8) (7/7)

; preoperative ; postoperative

100 (6/7)

90 80

(6/8)

70 (4/7)

(4/7)

60 (4/8)

50 (3/8)

40 30 20 10 0

GnD

GHD

TSHD

ACTHD

Fig. 4 The change of deficient ratios of anterior pituitary hormones between preoperative (black bar) and postoperative test (white bar). No postoperative improvement was recorded in any hormonal axis. GnD gonadotropin deficiency, GHD growth hormone deficiency, TSHD thyroid-stimulating hormone deficiency, ACTHD adrenocorticotropic hormone deficiency

grading 2 or 3. While, patients with tumor-related symptoms and ASA-PS grade >3 may be candidates for stereotactic radiation. In case 8, an 83-year-old acromegalic male with ASA-PS 3 underwent transsphenoidal surgery due to active acromegalic symptoms, which improved postoperatively along with decreases of GH and IGF-1. This patient was described in our previous report as an 82year-old male according to the age at his first visit to our hospital [3]. Activity of intercurrent illness of acromegaly could be a good reason of transsphenoidal surgery in elderly acromegalics with relatively maintained physical status [3]. During the same period of this study, there was another referral of acromegalic patient over 80 years not included in this series, whose general condition was too sick to undergo general anesthesia and surgery, ASA-PS grade 4. The patient had multiple intercurrent illnesses including valvular diseases, severe diabetes mellitus, and renal failure and stayed in a care home. Because our institutes are third tier referral centers for pituitary surgery, only possible candidates for surgery with relatively maintained general condition have been referred and too sick patients might have been omitted from referral. Thus, to know the actual incidence and clinical status of this highest age group with pituitary adenoma, community-based study is needed because this sort of hospital-based study will be biased according to patients’ general condition. Since the end of 1990s, we have introduced endoscopy into the transsphenoidal surgery. Our good result in this series might have reflected the employment of endoscopic assistance in all and endonasal route in seven patients. Now, we are changing from endoscopyassisted pituitary surgery to pure endoscopic endonasal

M male, F female, NF clinically nonfunctioning adenoma, GH growth hormone, PRL prolactin, ACTH adrenocorticotropic hormone, TS transsphenoidal surgery, CSF cerebrospinal fluid

Improvement of visual function, 8/8 (100 %) None All TS NF, 9 (80 %) GH-secreting, 1 (10 %) 10 (M/F; 8/2) More than 80 years (83.1±2.3 years) Presenting study

All TS ACTH-secreting, 1 (9 %)

All NF 32 (M/F; 17/15)

PRL secreting, 1 (9 %)

NF, 8 (73 %) GH-secreting, 1 (9 %) Over 70 years of age (72.8±2.0 years) 11 (M/F; 5/6 Fraioli et al. [9]

Kurosaki et al. [16] Older than 70 years (73.9±3.4 years)

Meningitis, 1 (2.6 %)

None

Improvement of visual function, 8/11 (73 %)

CSF leaks, 5 (15.3 %) Improvement of visual function, 19/23 (83 %) Transient oculomotor nerve palsy, 1 (3.1 %)

275

All TS

CSF leaks, 6 (15.3 %)

Improvement of visual function, 19/27 (70 %)

Improvement of pituitary function, 2/39 (5 %) Worsening of pituitary function, 2 (10.2 %) Diabetes insipidus, 10 (25.6 %) GH-secreting, 5 (12.8 %) PRL-secreting, 3 (7.7 %)

Improvement of visual function, 7/12 (58.3 %) Deterioration of visual function, 1 (8.3 %)

Deterioration of visual function, 1 (2.6 %) All TS

All TS All NF 12 After the age of 70 years

Older than 70 years (74.1±2.9 years)

Cohen et al. [5]

Ferrante et al. [8]

39 (M/F; 21/18) NF, 31 (79.5 %)

Surgical results (%) Approach Surgical complication (%) Subtype (%) Patient number Age Author (year)

Table 4 Reports of surgically treated patients aged 70 years or older with pituitary adenoma

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surgery. Considering the patients’ compromised health and recuperative ability of this highest age group, endonasal endoscopic surgery seems ideal surgical modality. Widening of accessibility to the various types and sizes of suprasellar lesions through advancing surgical techniques and instruments for endoscopic surgery [7, 21] will further limit the indication of the transcranial surgery for pituitary adenomas especially in the elderly. The rate of preoperative GnD, GHD, TSHD, and ACTHD was 100, 75, 50, and 37.5 %, respectively in our series. Hong et al. previously reported the clinical data on 103 elderly patients older than 65 years (mean 72.3 ± 2.9 years) with pituitary adenoma. In their report, GnD, TSHD, and ACTHD in preoperative evaluation were observed in 34, 23.3, and 7.8 %, respectively. Patients over 80 years old with pituitary adenoma in our series seem to have higher rates of pituitary dysfunction compared to 10 years younger patients. We especially should pay attention to TSHD and ACTHD, often life-threatening condition, which was seen to be 50 and 37.5 % of patients in our series. Postoperatively, we did not see improvement of impairment ratio of pituitary function. The result was concordant with the view that recovery of pituitary function in elderly is less frequent than in younger patients [1, 9]. The recovery potential of pituitary function might be largely compromised in this most elderly group. Therefore, adequate postoperative assessment of pituitary function is mandatory for this age group.

Conclusion We here first reported clinical and endocrinologic characteristics of elderly patients aged 80 years or older with pituitary adenomas, in which nonfunctioning adenomas comprised overwhelming majority. Even though the patients had mild to moderate physical morbidity and impaired pituitary function, transsphenoidal surgery with sufficient postoperative care including replacement for the pituitary dysfunction provided long-term advantages for the patients. So, transsphenoidal surgery is a useful treatment for patients aged 80 years or older with pituitary adenomas with chiasmatic symptoms when the patients’ general condition is well preserved and pituitary hormonal deficiency is adequately replaced.

Acknowledgments This work was supported (in part) by Grants-in-Aid for Scientific Research (Research on Hypothalamo-Pituitary Dysfunction) from the Ministry of Health, Labor and Welfare, Japan.

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Comments Shang-Hang Shen, Xiamen, China The authors discussed an interesting topic about the transsphenoidal surgical treatment of pituitary adenomas in most elderly people—80 years or older. The transsphenoidal approach has been accepted as a safe approach for pituitary adenomas by most neurosurgeons in the world. Although age alone is not a contraindication for active treatment with this approach, there are still few reports about pituitary adenomas in patients aged 80 or more. As general population is rapidly aging, the importance of the topics about highest age patients will be even more important. The study is a retrospectively research of a group of 10 cases of elderly pituitary adenomas patients (age 80 to 86 years, mean 83.1 years) and physical condition of ASA-PS grading 2 or 3. The follow-up period ranged from 5.3 to 99.3 months with mean of 37.9 months. The average age of the patients in this study is higher than in other papers on the topic. All the patients underwent transsphenoidal surgery under surgical microscope with aid of endoscopic observation and received sufficient decompression of optic pathways and improved visual disorder. The authors conclude that transsphenoidal surgery is safe and efficient treatment for patients aged 80 years of older with pituitary adenomas with chiasmatic symptoms provided the patients’ general condition is well preserved and pituitary hormonal deficiency is adequately replaced.

Neurosurg Rev (2014) 37:269–277 Usually, pituitary adenomas can be resected successfully with both transcranial and transsphenoidal approaches. The transcranial approach allows for a significant achievement in optic pathway decompression, but sometimes, it also causes disturbance to the nerves, vessels, and brain around the tumor or on the operational way. As a newer and welldeveloped surgery, transsphenoidal surgery under surgical microscope, with the aid of both microscope and endoscopic observation, or only with the aid of endoscopy, has been indicated a safer and also efficient way in the surgical treatment of pituitary adenomas, even the aged patient can well survive the surgery (see references 1–4 at the end of this comment). The question of whether older patients with pituitary adenomas should be operated is still a matter of debate. The important issue of course is the safety and efficiency of the particular operative technique. In patients without tumor-related symptoms, follow-up with regular MRI and perimetry may be the better choice. If, however, the tumor causes significant symptoms, the surgery will become necessary. In this study, the

277 authors give us a clear demonstration that older patients with pituitary adenomas whose general condition is well can also tolerate transsphenoidal surgery and have good outcome after operation. References 1. Hasegawa Y, Yano S, Sakurama T (2011) Endoscopic surgical treatment for pituitary apoplexy in three elderly patients over the age of 80. Acta Neurochir Suppl 111:429–433 2. Locatelli M, Bertani G, Carrabba G, Mantovani G, Lania A, et al. (2013) The trans-sphenoidal resection of pituitary adenomas in elderly patients and surgical risk. Pituitary 16(2):146–151 3. Hong J, Ding X, Lu Y (2008) Clinical analysis of 103 elderly patients with pituitary adenomas: transsphenoidal surgery and follow-up. J Clin Neurosci 15(10):1091–1095 4. Sheehan JM, Douds GL, Hill K, et al. (2008) Transsphenoidal surgery for pituitary adenoma in elderly patients. Acta Neurochir (Wien) 150(6):571–574; discussion 574