Clinical Endocrinology (1983) 19, 629-636

LONG TERM RESULTS OF RADICAL HYPOPHYSECTOMY FOR CUSHING’S DISEASE

J. P. THOMAS AND S . H. RICHARDS

Departments of Medicine and Otolaryngology, University Hospital of Wales, Heath Park, CardiSfCF4 4XW. Wales, UK

(Received 17 January 1983; revised 25 April 1983; accepted 28 April 1983)

SUMMARY

Sixteen consecutive cases of Cushing’s disease were treated by radical trans- sphenoidal hypophysectomy. Surgical removal was not possible in two cases. Of the other 14, there was total clinical and biochemical remission of the disease in 13 and partial remission in one. Some form of replacement therapy has been necessary in 1 1 out of the 14 cases. During a long period of postoperative clinical and biochemical assessment extending over 5-14 years (average 8 years) there have been no recurrences.

During recent years many reports have appeared which advocate trans-sphenoidal selective adenomectomy for the treatment of Cushing’s disease. The trans-sphenoidal route has been used by us for the removal of pituitary tumours since 1964 and has proved to be an excellent surgical approach (Richards et al., 1974).

There are reservations however as to whether selective adenomectomy gives sufficiently good sustained results in such a serious disease to justify its general adoption in preference to more radical removal.

In this paper we present long term ( 5 to 14 years) results in 16 cases of Cushing’s disease treated by radical trans-sphenoidal hypophysectomy.

Preoperative selection and assessment

A total of 28 cases of Cushing’s syndrome were seen during the years 1968 to 1977. Of these, nine had an adrenal tumour, three had ectopic ACTH syndrome and 16 had pituitary-dependent Cushing’s disease. This paper deals exclusively with these 16 consecutive pituitary-dependent cases who were treated by trans-sphenoidal hypophysec- tomy.

The main presenting clinical features are shown in Table 1. All 16 patients had the classical clinical features of Cushing’s syndrome, 15 had hypertension (with a diastolic pressure of 100 mmHg or above) and six had diabetes. All but one of the premenopausal females had amenorrhoea for six months or more.

Cardiff CF4 4XW. Correspondence: Dr J. P. Thomas, Department of Medicine, University Hospital of Wales, Heath Park,

629

630 J . P . Thomas h S . H . Richards

Table 1. Principal clinical features in 16 cases of pituitary Cushing’s syndrome (Cardiff

1968-1977)

Sex 15 Females Age l(t20 years

2&30 years 3 W O years 4&50 years 5&60 years

Hypertension Present in 15

Diabetes Present in 6

1 Male 1 case 4 cases 4 cases 3 cases 4 cases

Absent in 1

Absent in 10

The diagnosis was confirmed by measurement of the diurnal variation of plasma 17-hydroxycorticosteroids (170HCS) using the method of Hatfield & Shuster (1959) and of basal urinary 170HCS by the method of Liddle et a/ . (1955). Both methods measure Porter-Silber chromogens. Cortisol secretion was measured by the method of Cope & Black (1958). The dexamethasone test was performed by administration of 2 mg of the steroid 6 hourly for 2 d. In eight patients the plasma ACTH and the response of urinary

1400

I120

c 2 \ -J 0

5 840 c

v) 0 I 0 P-

g 560 0 P -

2 80

0 0900 0300

Time ( h )

Fig. I . The level of plasma 170HCS at 0900 h and 0300 h in 16 patients with Cushing’s disease before surgery.

Total hypophysectomy for Cushing ’s disease 63 I

T

Fig. 2. Response of urinary I70HCS to dexamethasone (2 mg 6 hourly for 2 d) in 16 preoperative patients with cushing’s disease.

170HCS to metyrapone, 250 mg 2 hourly for 3 d, were measured. Plasma 170HCS was normal in the majority at 0900 h but invariably raised at night (Fig. 1). Basal urinary I70HCS (Fig. 2) and cortisol secretion (Fig. 3) were raised in all cases. Suppression of urinary steroid excretion (by more than 50% of basal value) with dexamethasone was witnessed in all except one patient (SC). Pituitary Cushing’s disease in this one patient was nevertheless established by finding that the plasma ACTH was 81 ng/l at 0900 h and 347 ng/l at midnight (normal less than 80 ng/l) and that the urinary 170HCS rose from 38 to 1 15 pmol/l per day on the third day of metyrapone administration. Adrenal tumour and an ectopic ACTH syndrome were thereby excluded.

Lateral radiographs of the skull showed expansion of the pituitary fossa in 5 of the 16 patients. Air encephalography was carried out on these five cases but only one showed a suprasellar extension and this was of minimal size. The incidence of fossa enlargement is thus similar to that reported by other authors (Salassa et af., 1959; Rovit & Berry, 1965; MacErlean & Doyle, 1976).

Operation

All 16 patients were subjected to trans-sphenoid sellotomy using the technique described by Richards & Thomas (1 980). The gland was removed by microdissection and division of the stalk under direct vision x 16 magnification through an operating microscope. In two patients removal was not possible owing to the presence of a large venous sinus occupying

632 J. P. Thomas & S . H . Richards

D c? I \ L 0 a J

J -. 0 E 3. I

- 0 ._ c L 0 0

Pre Post

Fig. 3 . Pre and post hypophysectomy cortisol secretion rate in 16 patients with Cushing’sdisease

the whole of the floor and anterior walls of the sella. Severe bleeding rendered the procedure too hazardous and the attempted hypophysectomy was abandoned. Both operations were performed before the use of profound hypotension during surgery which in subsequent cases has rendered the bleeding so slight that visibility is not significantly hampered.

The main operative findings are described in Table 2. We would emphasise that in 11 out of the 14 cases in which hypophysectomy was performed the gland was of normal

Table 2. Operative findings in 14 cases* of trans- sphenoidal sellotomy for Cushing’s disease (Cardiff

1968-1977)

Finding No. of Cases

Evidence of bone erosion 2 Estimated size of gland in 14 cases Normal 11

Enlarged 3 Supraseilar extension 1

* 2 of original 16 patients inoperable

Total hypophysectomy for Cushing ’s disease 633

appearance and size with no visible tumour on the surface. In the other three cases the hypophysis was obviously enlarged and tumour (of a creamy consistency) was seen on its surface. A minimal suprasellar extension was seen in one of these three.

After removal of the gland the sella was packed with muscle graft taken from the thigh and this was retained in position by a dural suture. The only serious complication was postoperative meningitis in two patients. Both occurred before the introduction of the dural suture technique. Both responded rapidly to antibiotic therapy.

Histology

Histological material was available for examination in 15 cases. A definite tumour was detected in only five of these but serial sections were not performed routinely and a few specimens were incomplete because part of the specimen was used to investigate corticotrophin metabolism in Cushing’s disease.

Postoperative assessment and results

The clinical response in each patient is summarised in Table 3. Two cases in whom hypophysectomy was not surgically possible naturally failed to respond and have subsequently undergone successful bilateral adrenalectomy. The remaining 14 cases had a dramatic improvement in their physical status with loss of weight, reversal of skin changes and a return to normal appearance. The response was considered to be complete in 13 and partial in one (KD, Case 15). Normal menstruation was restored in five women, one of whom (GC, Case 10) has had two normal pregnancies. One patient (FJ, Case 5 ) whose

Table 3. Cushing’s disease. Clinical data before and after pituitary surgery

Preoperative Postoperative

Age at Weight B.P. Diabetes Interval Weight B.P. Diabetes Case operation (kg) (mmHg) (GTT) (years) (kg) (mmHg) (GTT)

1 2 3 4 5 6 7 8 9

10 11 12 13 14 15 16

CF GE EB MP FJ JS sw BF sc GC NH MR ED JL KD MW

58 74 38 68 42 84 37 85 52 58 26 101 35 86.5 31 108 16 53 21 100 56 79 26 73.5 54 99 47 64 26 65 43 65

160/100 175/115

180/110

190/ I40

lSO/llO 120/70 lSO/llO 180/110 180/110 lSOjl10 210/130 160/110 160/ 120

lSO/llO

200/ 120

1 so/ 100

- 14 61 + 12 55 + 12 57 + 11 69 - 9 46 - 9* 71 - 9 59 - 9 104 - 8 51 - 7 73.5 - 7 64 - 7 48.1 + 6* 78 - 6 56 + 5 58 + 5 52

140/90 1 10190 120/70 160/90 160/100 145/95 125/80 140/90 100/70 lOSj80 135175 100/70 140/85 120/80 130/90 145/85

* Hypophysectomy unsuccessful; results recorded after adrenalectomy.

634 J . P. Thomas & S. H . Richards

blood pressure did not return to normal after operation died nine years later of a cerebral haemorrhage and the one patient (MP, Case 4) in whom diabetes persisted after surgery died of a myocardial infarction after 1 1 years. The surviving patients have remained under continued observation up to the present time and there have been no cases of clinical recurrence.

All patients were readmitted between 6 and 12 months after operation for biochemical assessment and again after a minimum of 5 years had elapsed. Cortisol production fell to normal or sub-normal levels in 13 of the 14 patients in whom hypophysectomy had been performed (Fig. 3). The response was partial only in one woman (KD) where cortisol production fell from 140 to 87 pmol/l per day, a value just above our normal range of 17 to 78 pmol/l daily. This is the patient mentioned in the previous paragraph whose clinical response was also partial. These results remained unchanged when the patients were reassessed after a minimum of 5 years.

Postoperative pituitary reserve was assessed by methods previously described (Richards & Thomas, 1980). This involved simultaneous injection of insulin 0.10 units/kg, TRH 200 p g and LHRH 100 pg with measurement of plasma GH, TSH, LH and plasma 170HCS. We found that all but three patients required some form of hormone replacement (Table 4). The requirements of any individual patient did not change significantly after the first postoperative year.

Table 4. Replacement therapy in 14 cases* of Cushing’s disease treated by hypophysectomy. (Cardiff 1968-1 977)

Replacement therapy No. of cases

Cortisone, thyroxine and desmopressin 2 Cortisone and thyroxine I Thyroxine only 2 No therapy 3

* 2 of original 16 cases inoperable.

DISCUSSION

Pituitary surgery by trans-ethmoidal seliotomy is now accepted as the treatment of choice for Cushing’s disease but the precise form of surgical intervention is not yet agreed. There appear to be three alternatives, namely selective adenomectomy, partial hypophysectomy or radical hypophysectomy.

Selective removal of a microadenoma resulted in clinical remission of Cushing’s disease in 48 of a combined total of 62 patients included in the three largest studies reported from North America (Tyrell et al., 1978; Salassa et al., 1978; Bigos et al., 1980). Figures concerning long term cure and replacement therapy for hypopituitarism are lacking.

The true incidence of discrete microadenomas in Cushing’s disease is difficult to determine. Tyrell et al. (1978) operated on consecutive cases when tumours were found in 15 of 20 patients (75%); an incidence similar to that found a t post-mortem (Plotz et al., 1952). At operation, tumours measuring 3-10 mm diameter were readily distinguishable from normal pituitary tissue in most patients but were visible on the glandular surface in

Total hypophysectomy for Cushing 's disease 635

only a few so that multiple incisions were necessary in the remainder to reveal the adenoma. These findings are in sharp contrast with the experience of European surgeons, notably Ludecke et al. (1976) and Carmalt et al. (1977), who found clear distinction between normal and pathological tissue in a minority only and therefore performed total hypophysectomy in all their patients. Single tumours were seen in only 7 of 13 patients reported by Carmalt et ai. (1977) and both groups found evidence of hyperplasia of basophil cells in the remaining pituitary tissue.

A recent immunocytochemical study by McNicol (1981) of the distribution of ACTH secreting cells emphasises the diversity of pathology in pituitary Cushing's disease. She found a normal distribution of cells in some, an adenoma with either reduction or hyperplasia of ACTH cells in others and diffuse hyperplasia with no adenoma in the remainder.

There is reason then to examine more closely the outcome following selective removal of a single tumour. As stated, in the short term at least this is usually good but there are exceptions. Salassa et al. (1978) and Lamberts et al. (1980) each reported a patient in whom there was no remission after excision of a single tumour. In the case reported by Lamberts and his associates, numerous small nests of adenomatous basophil cells were found in pituitary tissue surrounding the adenoma. Over a long period, Bigos et ai. (1980) reported recurrence in two patients after apparent cures lasting 10-30 months, whilst Pont & Gutierrez-Hartman (1979) and Kuwayama et al. (1981) each reported one patient who had recurrence of symptoms after a year in remission.

CONCLUSIONS

The following criticisms of selective adenomectomy seem justified. Detailed dissection of the pituitary reveals that an adenoma is not present in all cases (McNicol, 1981). When an adenoma is present its boundaries are indistinct, making it difficult to ensure total removal (Wrighton, 1978). Though good initial results have been reported, many patients need replacement therapy, recurrences have arisen and the length of follow up has been inadequate.

Until such criticisms are resolved, we feel that a more radical surgical excision is obligatory and favour total hypophysectomy; a policy supported by the results of this present study. Hypophysectomy was not possible in two, yet all but one of the other 14 patients had a complete remission and this is maintained over 5 to 14 years (mean 8 years). Eleven of the 14 patients have hypopituitarism and are obliged to take substitution therapy but this is acceptable in exchange for more certain cure of an otherwise lethal disease (Rovit & Duane, 1969).

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