Clinical Endocrinology (1 987), 26, 707-7 12

THE DEFINITION OF TRUE RECURRENCE OF

AFTER TRANSSPHENOIDAL OPERATION PITUITARY-DEPENDENT CUSHING’S SYNDROME

S. W. J . LAMBERTS, J . G. M . KLIJN AND F. H. DE JONG

Department of Medicine and Clinical Endocrinology, Erasmus University, Rotterdam, The Netherlands

(Received 3 September 1986; returned for revision 24 September 1986;finalty revised 16 December 1986; accepted 20 January 1987)

SUMMARY

Two patients are described with pituitary-dependent Cushing’s syndrome who had successful transsphenoidal selective removal of basophil microadenomas. After a period of adrenal insufficiency the clinical signs and the cortisol secretion rate became normal after 12-1 8 months, together with the return of a normal feedback response to glucocorticoids (dexcamethasone suppression), a normal diurnal rhythm of plasma cortisol, and a normal response to stress (increase of plasma cortisol to insulin-induced hypoglycaemia). However, pituitary-depen- dent Cushing’s syndrome recurred 38 and 56 months after operation. This was preceded by gradual changes of the results of the dexamethasone tests, disappearance of the diurnal rhythm of cortisol, and of the responses of plasma cortisol to hypoglycaemia. ‘True recurrence’ should be defined as the return of the clinical and biochemical characteristics of Cushing’s syndrome after a successful transsphenoidal operation, with a normal hypothalamic-pituitary- adrenal axis as evidenced by a normal response to dexamethasone, a normal diurnal rhythm of cortisol and a normal increase of plasma cortisol with insulin- induced hypoglycaemia.

Cushing’s observation (1932) that most patients with the disease named after him harbour small basophil pituitary adenomas was confirmed by transsphenoidal microsurgery, which became the first choice of therapy (Lagerquist et al., 1974; Salassa et al., 1978; Tyrrell et al., 1978; Bigos et al., 1980).

We present the clinical and biochemical data of two patients with pituitary-dependent Cushing’s syndrome who had transsphenoidal surgery in our hospital. Following surgery, complete remission and disappearance of all clinical and biochemical signs of Cushing’s syndrome, and normal hypothalamic regulation of ACTH secretion were observed, but

Correspondence: Steven W. J. Lamberts, M.D., Department of Medicine 111, University Hospital Dijkzigt, 40, Dr Molewaterplein, 3015 GD Rotterdam, The Netherlands.

707

708 S. W. J . Lamberts et al.

the disease recurred, respectively, 3 and 4 years later. We have tried to define ‘true’ recurrence of pituitary-dependent Cushing’s syndrome, and to give an estimate from the literature of the incidence of true recurrences after transsphenoidal operations.

MATERIALS A N D METHODS

The 1 mg overnight dexamethasone suppression test, the measurement of the diurnal rhythm of cortisol, the insuiin-tolerance test, the lysine vasopressin (LVP) test (10 pressure units LVP intramuscularly) and the metyrapone test (6 x 750 mg) were carried out according to standard procedures (Lamberts et al., 1977). The normal values are shown in Table 1.

Cortisol secretory rate (CSR) was measured by an isotope dilution technique and plasma cortisol and G H were measured by radioimmunoassay (Lamberts et al., 1977).

CASE HISTORIES A N D RESULTS

Both patients were female, aged 50 and 32 years, and showed the classical clinical signs of Cushing’s syndrome. The diagnosis was confirmed by an increased CSR, an abnormal response to dexamethasone, an absent diurnal rhythm of plasma cortisol and an absent response of cortisol to hypoglycaemia (Table 1). The diagnosis of pituitary-dependent Cushing’s syndrome was made after demonstration of a normal or excessive response of the pituitary-adrenal axis to LVP and metyrapone (Table 1) and an adequate suppression in response to a high dose of dexamethasone intravenously (data not shown). No abnormalities were seen in the pituitary fossa on skull X-ray and tomography of the sella turcica. Both patients were operated upon by the transsphenoidal route. In both a macroscopically clearly visible microadenoma was removed, and turned out to be a basophil adenoma. On the day of operation a steroid cover of 300 mg hydrocortisone was given and this was gradually reduced to 25 mg/d by the 7th postoperative day, For postoperative studies all steroid replacement therapy was discontinued on day 14, and the tests were carried out between days 18 and 25. Other anterior pituitary functions were normal as shown by a normal free T4 index, a normal reaction of TSH and PRL to 200 pg TRH and a normal reaction of LH and FSH to 100 pg GnRH.

In both patients basal plasma cortisol levels and CSR had become subnormal after operation (Table 1). No reactions of plasma cortisol and 1 1-desoxycortisol to hypogly- caemia, LVP and metyrapone were observed. Both patients were maintained on 25 mg/d of hydrocortisone for 3 months. Despite this therapy they complained of anorexia, postural hypotension, weight loss, myalgia and arthralgia. The signs and symptoms of Cushing’s syndrome subsided within 3 months.

In patient 1 (Table I) basal plasma cortisol remained low 3 months after operation, but CSR had returned to normal. The response of plasma cortisol to LVP had become normal, and the responses of G H to hypoglycaemia and of ll-desoxycortisol to metyrapone were borderline. In patient 2 a comparable course was noted. Substitution therapy with hydrocortisone was stopped after 10 months in patient 1 and after 8 months in patient 2. The abnormal biochemical pattern improved after 12 and 10 months, respectively. In patient 1 CSR was normal, while there was also a normal diurnal rhythm of plasma cortisol and a normal suppression to dexamethasone. In addition, there was a normal increment of plasma cortisol and GH to hypoglycaemia, suggesting a complete

Tab

le 1

, The

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dif

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sts

of t

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and

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in tw

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ith

Cus

hing

's di

seas

e

Insu

lin-to

lera

nce

test

Dex

amet

haso

ne

Diu

rnal

rhy

thm

of

Max

imum

M

axim

um

LV

P- te

st

3 R 2 Pa

tient

I

5 B

efor

e op

erat

ion

99

389

493

608

560

+O

+

o

+291

18

90

2 ?

Aft

er 2

2 m

onth

s 35

11

5 35

0 22

7 23

5 + I

48

+ I6

-

-

0

supp

ress

ion

plas

ma

corti

sol (

nmol

il)

rise

of

rise

of

max

imum

rise

of

1 I-d

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tisol

C

SR

plas

ma

corti

sol

plas

ma

corti

sol

plas

ma

GH

pl

asm

a co

rtiso

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ter

met

yrap

one

(pm

o1/2

4 h)

(nm

olil)

09

00 h

17

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2200

h

(nm

ol/l)

(P

SiU

(n

mol

il)

(nm

olil)

n m

Aft

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pera

tion

16

109

28

28

134

+ 39

+

I

+ 70

14

A

fter

3 m

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s 29

-

42

I12

28

+ 120

+

8

+ 372

36

7 A

fter

12

mon

ths

45

78

370

148

196

+ 227

+ 1

8 + 4

76

580

Aft

er 3

8 m

onth

s 85

17

1 29

4 26

3 24

1

+o

+

o

+378

I0

94

5- 3 A

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15

mon

ths

32

90

258

95

160

+ I60

+ I

4 + 2

94

338

E

Patie

nt 2

3'

09

h-

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oper

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n 19

5 40

0 58

2 40

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0 +

36

+I

+ 4

93

1361

14

A

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3 m

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-

28

28

20

+ 90

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3 + 2

52

62

Afte

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32

14

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20

20

+ 146

+ 1

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39

470

-

+316

+ I

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mon

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32

Aft

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3 m

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s 53

-

227

196

185

+210

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6 A

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52 m

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s 53

17

1 22

4 21

3 17

9 + 2

27

+3

+ 5

35

713

Afte

r 56

mon

ths

85

342

227

518

323

+ 53

+

o

t83

7

818

Nor

mal

val

ues

26-8

0 <

140

V

alue

s at

1700

han

d 22

00 h

+ >

195

-395

+ >

10

+ > 1

9542

0 >

4 1 2

-640

-

Afte

r op

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ion

21

36

62

28

143

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7

m

-

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% o

f val

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t 090

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0

W

710 S. W. J . Lamberts et al.

restoration of the hypothalamic regulation of CRF secretion. Similarly, in patient 2 all tests were normal 15-18 months after operation.

In patient 1 the clinical course showed no abnormalities for nearly 3 years. Twenty-two months after operation the increase of plasma cortisol in response to hypoglycaemia had become subnormal, however. After 38 months she was readmitted with acute pulmonary embolism and a clinical and biochemical recurrence of Cushing’s disease. Because of her clinical condition and the thrombolytic therapy, it was decided to treat this patient with external pituitary irradiation of 4500 rads. Four months later (42 months after operation) CSR was back within the normal range (68 pmo1/24 h). Patient 2 was readmitted without complaints after 52 months. A diminished sensitivity to dexamethasone, an absent diurnal rhythm of cortisol and a diminished response of GH to hypoglycaemia were found. Four months later (56 months after operation) she returned with clinical and biochemical proof of Cushing’s disease. This patient also had external pituitary irradiation and CSR became normal after 6 months (65 pmo1/24 h). At the time of recurrence, no abnormalities were seen at tomography of the pituitary fossa to suggest the presence of a microadenoma in either patient.

DISCUSSION

Even in the presence of a completely normal pituitary fossa on neuroradiological examination, Wilson et al. (1980) found pituitary adenoma tissue in virtually all patients with pituitary-dependent Cushing’s syndrome. It became evident that ACTH secretion by the normal pituitary cells surrounding these microadenomas was suppressed in most cases, and that this suppression persists for months after the selective removal of ACTH- secreting microadenomas, before a gradual return to normal occurs (Fitzgerald et al., 1982). This was accompanied by clinically detectable hypoadrenalism to a degree seldom achieved more thoroughly after operation in other types of pituitary tumours. A gradual return to normal of hypoadrenalism, the sensitivity to dexamethasone, the diurnal rhythm of ACTH and cortisol, and the responses of ACTH and cortisol to insulin- induced hypoglycaemia has been observed to occur simultaneously in most patients (Lagerquist et al., 1974; Tyrrell et al., 1978; Lamberts et al., 1981; Fitzgerald et al., 1982). There seems therefore to be no evidence for a persisting hypothalamic defect in the regulation of CRF-secretion after complete selective removal of an ACTH-secreting pituitary microadenoma, suggesting that the primary cause in most patients with pituitary-dependent Cushing’s syndrome must be sought at the pituitary level and that these patients are completely cured after adenomectomy.

The two patients described in the present paper show a true recurrence of pituitary- dependent Cushing’s syndrome after an initially successful cure by transsphenoidal selective adenomectomy. True recurrence should be defined as the return of the clinical and biochemical characteristics of pituitary-dependent Cushing’s syndrome after a period of adrenal insufficiency, followed by a period during which the hypothalamo-pituitary- adrenal axis was completely normal as shown by a normal sensitivity to dexamethasone, a normal diurnal rhythm of cortisol and a normal increase of plasma cortisol in response to insulin-induced hypoglycaemia. Recurrences have been reported in one patient out of a group of 20 patients who had surgery from 1-5 years before (Aron et al., 1982), in two out of 12 patients with microadenomas reported by Bigos et al. (1980), in three out of 61 patients by Miiller et al. (1 984) and in one solitary case (Pont & Hartman, 1979). It should

True recurrence of Cushing ’s disease 71 1

be stressed, however, that not all criteria of a true recurrence have been met in these patients. In none of these patients were postoperative cortisol levels found to be virtually undetectable, as was observed in some patients by Tyrrell et al. (1978). Most current studies on the effect of transsphenoidal surgery in patients with pituitary-dependent Cushing’s syndrome have a relatively short follow-up. More important, however, seems the fact that long-term follow-up studies involving extensive biochemical evaluation has not been reported so far in studies involving a considerable number of patients. In a survey of patients said to be ‘cured’ (although the criteria were not rigorously defined) Krieger (1983) counted 13 recurrences after transsphenoidal operations in 123 patients over a postoperative period of 2 4 8 months.

There seem to be two possible explanations for the recurrence of pituitary-dependent Cushing’s syndrome in our patients. Firstly, it is possible that a few ACTH-secreting pituitary tumour cells had been left in situ during the transsphenoidal operation. These tumour cells could have grown over a period of 3-4 years, and so caused a recurrence. Secondly, a primary pituitary or hypothalamic defect might remain to cause hypersecre- tion of ACTH, hyperplasia of ACTH-secreting cells, and eventually adenoma formation. Our data do not distinguish between these possibilities in our patients. However, the high sensitivity to additional external pituitary irradiation in both patients might support the second hypothesis.

Our observations probably mean that even those patients who seem to be ‘completely’ cured after operation, including a period of adrenal insufficiency and the return of all normal characteristics of ACTH secretion (feedback, diurnal rhythm and stress- response), should still be checked regularly for the appearance of recurrence. External pituitary irradiation should probably not be considered in the period immediately after selective adenomectomy when normal regulation of ACTH secretion has not returned. Three of our previous patients who had a successful complete selective adenomectomy after external pituitary irradiation had adrenal insufficiency up to 4 years after operation.

In comparison with the considerable problems involved in diagnosing recurrences and following patients after ‘selective’ transsphenoidal adenomectomy in Cushing’s disease as summarized by Burch (1983), several centres in the United Kingdom have adopted a more radical approach in which a virtual complete hypophysectomy is carried out. No reports of recurrences have been published as yet following initially successful treatment of patients by this procedure (Thomas & Richards, 1983; Brand et al., 1985).

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BIGOS, S.T., SOMMA, M., RASIO, E., EASTMAN, R.C., LANTHIER, A,, JOHNSTON, H.H. & HARDY, J . (1980) Cushing’s disease: management by transsphenoidal pituitary microsurgery. Journal of Clinical Endocrino- logy and Metabolism, 50, 348-354.

BRAND, I.R., DALTON, G.A. & FLETCHER, R.F. (1985) Long-term follow up of transsphenoidal hypophysec- tomy for Cushing’s disease. Journal of the Royal Society of Medicine, 78,291-293.

BURCH, (1983) A survey of results with transsphenoidal surgery in Cushing’s disease. New England Journal of Medicine, 308, 103-104.

CUSHING, H. (1932) The besophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bulletin of the Johns Hopkins Hospital, 50, 137-158.

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KRIEGER, D.T. (1983) Physiopathology of Cushing’s disease. Endocrine Reviews, 4, 2243. LAGERQUIST, L.G., MEIKLE, A.W., WEST, C.D. &TYLER, F.H. (1974) Cushing’s disease with cure by resection of

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LAMBERTS, S.W.J., KLIIN, J.G.M., DE JONG, F.H. & BIRKENHAGER, J.C. (1981) The recovery of the hypothalamo-pituitary-adrenal axis after transsphenoidal operation in three patients with Cushingl disease. The effect of prior external pituitary irradiation. Acta Endocrinologica, 98, 580-584.

LAMBERTS, S.W.J., DE JONG, F.H. & BIRKENHAGER, J.C. (1977) Evaluation of diagnostic and differential tests in Cushing’s syndrome. Netherlands Journal of Medicine, 20, 261-274.

MULLER, O.A., FAHLBUSCH, R. & VON WERDER, K. (1984) Real recurrences after transsphenoidal operation of ACTH-secreting pituitary adenomas? In Trends in Diugnosis and Treutment uf Pituitary Adenomas. (eds S.W.J. Lamberts, F.J.H.T. Tilders, E.A. van der Veen & J. Assies), pp. 339-344. Free University Press, Amsterdam.

PONT, A. & GUTIERREZ-HARTMAN, A. (1979) Cushing’s disease. Recurrence after a surgical induced remission. Archives of lniernal Medicine, 139, 938-942.

SALASSA, R.M., LAWS JR, E.R., CARPENTER, P.C. & NORTHCUTT, R.C. (1978) Transsphenoidal removal of pituitary microadenomas in Cushing’s disease. Mayo Clinic Proceedings, 53, 24-28.

THOMAS, J.P. & RICHARDS, S.H. (1983) Long term results of radical hypophysectomy for Cushing’s disease. Clinical Endocrinology, 19, 629-636.

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