Natural History and Management Options for Cushing’s Disease

8 Natural History and Management Options for Cushing’s Disease

Benjamin H.M. Hunn and James A.J. King

Abstract

Cushing’s disease is caused by excess secretion of adrenocorticotropic hormone from a pituitary adenoma, which causes high serum cortisol. Excess serum cortisol causes a variety of metabolic and psychiatric disturbances, including hypertension, type 2 diabetes mellitus, obesity, depression, and insomnia. Rarely, Cushing’s disease may first come to attention due to local mass effect of the pituitary adenoma causing visual disturbance or hyrocephalus. Historically, survival of untreated Cushing’s disease is less than 5 years. Mortality in Cushing’s disease is chiefly due to cardiovascular disease and systemic malignancy. Surgical resection of the causative pituitary adenoma is the primary therapy for Cushing’s disease and reduces the rate of mortality. Resection of the pituitary adenoma can be performed by microscopic or endoscopic approaches, and outcomes are similar. For pituitary macroadenomas, the endoscopic approach is associated with a higher rate of remission than the microscopic approach. Radiotherapy and medications have also been used to treat Cushing’s disease; however, remission rates are lower than those demonstrated by surgery. In general, recurrence of Cushing’s disease following transsphenoidal surgery should prompt repeat transsphenoidal surgery. When transsphenoidal surgery fails twice, is declined, or is contraindicated, radiotherapy, bilateral adrenalectomy, or medical therapy should be considered.

Keywords: pituitary adenoma Cushing’s disease surgery transsphenoidal

8.1 Introduction

Cushing’s disease is caused by a pituitary adenoma that secretes excess adrenocorticotropic hormone (ACTH; sometimes known as corticotropin; see Fig. 8.1). ACTH stimulates the production of cortisol from the zona fasciculata of the adrenal gland. The manifestations of Cushing’s disease arise from supraphysiological serum cortisol levels caused by excess ACTH. Cushing’s disease is rare, with an estimated incidence of 1 to 2 cases per million people per year.¹^, ² Females are affected at least three times more frequently.¹^, ² The incidence of Cushing’s disease peaks at approximately 40 years of age (Table 8.1).¹^, ²

Table 8.1 Characteristics of Cushing’s disease patients in published studies

Study	Period	n	Female (%)	Age, mean (y)	Initial TSS (%)	Remission (%)	Follow-up (y)	SMR if cured	SMR not cured
Swearingen et al²⁰	1978–1996	161	80	38	100	93	5.7	NA	NA
Lindholm et al¹	1985–1995	73	68	41^a	54	62	8.1	0.3	5.1
Hammer et al¹⁹	1975–1998	289	83	36^b	100	82	11.1	1.2	2.8
Dekkers et al²²	1977–2005	74	76	39^b	100	80	12.8	1.8	4.4
Bolland et al⁴ (macroadenoma)	1960–2005	30	73	45	NA	93	6.9	2.3	5.7
Bolland et al⁴ (microadenoma)	1960–2005	158	77	36	NA	91	7.5	3.1	2.4
Clayton et al¹⁸	1958–2010	60	85	NA	58	90	1.3	3.3	16
Hassan-Smith et al¹⁷	1988–2009	72	79	40	100	72	4.6	2.5	4.1
Ntali et al¹⁵	1967–2009	182	75	40^a	87	62^c	12	10	NA
Yaneva et al¹⁶	1965–2010	240	82	38	66	55^d	7.1	1.7	4.6
Weighted SMR (95% CI)								2.5 (1.4–4.2)	4.6 (2.9–77.3)
Abbreviations: CI, confidence interval; SMR, standardized mortality ratio; TSS, transsphenoidal surgery. Source: Adapted from van Haalen et al.³ The study by Bolland et al⁴ separated patients based on tumor size with no pooled data. ^aMedian. ^bAge at operation, not diagnosis. ^cOf 159 undergoing initial transsphenoidal surgery. ^dOf 154 undergoing initial transsphenoidal surgery.

Fig. 8.1 Radiological and histological features of Cushing’s disease. (a) Preoperative and (b) postoperative contrast-enhanced T1-weighted coronal magnetic resonance imaging (MRI) of a patient with a corticotroph cell pituitary macroadenoma causing Cushing’s disease. (c) Preoperative and (d) postoperative contrast-enhanced T1-weighted sagittal MRI of a patient with a corticotroph cell pituitary macroadenoma causing Cushing’s disease. (e) Hematoxylin and eosin staining demonstrating a moderately cellular pituitary adenoma with Crooke’s hyaline change in several cells (× 600). (f) ACTH immunostaining demonstrating moderate positive staining in tumor cells consistent with granulated corticotroph cell adenoma (× 400). (g) T-pit transcription factor immunostaining demonstrating strong positive staining in tumor cell nuclei confirming corticotroph cell lineage (× 400). (h) Section immunostained for low-molecular-weight cytokeratin CAM5.2 highlighting perinuclear Crooke’s hyaline change (× 400). (The photomicrographs are provided courtesy of Michael Gonzales, Associate Professor, Royal Melbourne Hospital.)

Harvey Cushing first described the constellation of signs caused by elevated serum cortisol and attributed them to a basophil pituitary adenoma in his patient Minnie G.⁵^, ⁶ Typically, Cushing’s disease is used to refer to hypercortisolism caused by a corticotroph pituitary adenoma, whereas Cushing’s syndrome refers to signs and symptoms resulting from any other cause of increased serum cortisol. Overproduction of cortisol causes multiple deleterious effects in patients, with the typical features as follows⁷:

●Symptoms: Depression, fatigue, menstrual abnormalities, and insomnia.

●Signs: Hirsutism, facial fullness and plethora, obesity, dorsocervical fat pad, abdominal striae, bruising tendency, and proximal myopathy.

●Associated diseases: Hypertension, type 2 diabetes mellitus, and osteoporosis.

●In pediatric patients: Short stature and precocious or delayed puberty.

Pituitary adenomas, including those causing Cushing’s disease, are often separated based on size. Pituitary adenomas less than 10 mm in size are referred to as microadenomas and those greater than 10 mm in size are referred to as macroadenomas (Fig. 8.1). Rarely, Cushing’s disease presents due to a macroadenoma causing local mass effect. Symptoms of mass effect include the following⁸:

●Compression of the optic chiasm: Classically produces bitemporal hemianopia but can produce unilateral visual deficits or reductions in visual acuity.

●Compression of the third ventricle: Can cause obstructive hydrocephalus.

●Compression of the cavernous sinus: Can cause diplopia (cranial nerves III, IV and VI), facial pain (cranial nerves V₁, V₂), or proptosis (occlusion of the cavernous sinus).

Genetic abnormalities may underlie the development of ACTH-secreting pituitary adenomas. Cushing’s disease is a rare feature of multiple endocrine neoplasia type 1 (MEN1), which is caused by mutations in menin.⁹ Somatic mutations in the genes encoding or regulating the growth hormone receptor, the epidermal growth factor receptor, and P53 may also be associated with the development of corticotroph pituitary adenomas.¹⁰^, ¹¹

Diagnosis of Cushing’s disease can be complex, and should involve a multidisciplinary team including a neurosurgeon, endocrinologist, neuroradiologist, and neuropathologist. In most instances, when Cushing’s disease is suspected based on signs and symptoms, an assay that assesses serum cortisol is performed. This may be a 24-hour urinary cortisol study, a low-dose dexamethasone-suppression test, or late-night salivary cortisol.⁷ Following the demonstration of pathologically heightened cortisol, further investigations should be performed to investigate the cause of cortisol hypersecretion. A key distinction is between ACTH-dependent and ACTH-independent causes, and this can be examined by measuring serum ACTH levels, or performing a high-dose dexamethasone-suppression test or a corticotrophin-releasing hormone test. Once ACTH-dependent hypercortisolism is established, a magnetic resonance imaging (MRI) to examine for the presence of a corticotroph pituitary adenoma is indicated. Thin-cut coronal and axial sequences are necessary to examine for microadenomas. If no adenoma is detectable on MRI, some centers use inferior petrosal sinus sampling (IPSS) to determine if there is a central to peripheral ACTH gradient, indicating a likely pituitary source of ACTH. IPSS can also be used to determine whether the right or left pituitary is producing excess ACTH and, therefore, provide a target for surgery when an adenoma is not radiologically identifiable. It should be noted, however, that IPSS correctly predicts tumor laterality in only 70% of cases.¹²

The mainstay of Cushing’s disease treatment is surgical resection of the causative pituitary adenoma, as this achieves key goals of treatment: biochemical normalization of cortisol levels with acceptable morbidity, reversal of clinical signs and symptoms, and long-term remission.13 However, several other treatment options are available or under investigation, most notably pituitary irradiation, bilateral adrenalectomy, and drug therapies.

8.2 Selected Papers on the Natural History of Cushing’s Disease

●Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 1932;50:137–195

●Lindholm J, Juul S, Jørgensen JO, et al. Incidence and late prognosis of cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 2001;86(1):117–123

●van Haalen FM, Broersen LHA, Jorgensen JO, Pereira AM, Dekkers OM. Management of endocrine disease: mortality remains increased in Cushing’s disease despite biochemical remission—a systematic review and meta-analysis. Eur J Endocrinol 2015;172(4):R143–R149

8.3 The Natural History of Cushing’s Disease

Cushing’s disease is associated with significant mortality and morbidity. In Cushing’s original series, the median survival of untreated Cushing’s disease was 4.6 years.⁵ A summary of contemporary studies that examine mortality in Cushing’s disease is provided in Table 8.1.¹^, ¹⁴^, ¹⁵^, ¹⁶^, ¹⁷^, ¹⁸^, ¹⁹^, ²⁰ The data from these studies examine patients with treated Cushing’s disease, with the data pertaining to patients with relapsed Cushing’s disease perhaps the best proxy for the natural history of the disease. A well-designed and conducted meta-analysis by van Haalen et al of a pooled group of 776 Cushing’s disease patients showed that patients who were not cured had a standardized mortality ratio (SMR) of 4.6 (95% confidence interval [CI]: 2.9–7.3) compared to an age- and sex-matched population, indicating patients with Cushing’s disease were 4.6 times more likely to die compared to patients without Cushing’s disease.³ Successful treatment lowered the SMR to 2.5 (95% CI: 1.4–4.2).

Mortality in Cushing’s disease is predominantly secondary to cardiovascular disease (30–62.7%, depending on series), manifesting mainly as ischemic heart disease or stroke. Other common causes of death in Cushing’s disease are systemic malignancy (7.7–25%) and infection (3.9–21.4%). Older age at diagnosis and male sex both predict mortality.⁴^, ¹⁵^, ¹⁶^, ¹⁸^, ¹⁹^, ²⁰

Common comorbid diseases are those caused by cortisol excess, and are listed in Table 8.2.²¹ When compared to patients with nonfunctioning pituitary adenomas, patients with Cushing’s disease have poorer outcomes, suggesting that there are factors intrinsic to the disease that cause increased morbidity and mortality.²²

Table 8.2 Common comorbidities in Cushing’s disease at the time of diagnosis

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