The Results of Surgical Treatment of Cushing Tumors in the Republic of Uzbekistan: Establishing Transsphenoidal Surgery in A Developing Nation

Background

Transsphenoidal surgery (TSS) was introduced into the Republic of Uzbekistan in 2005 and has been developing since then. The principal center for the management of all pituitary disease is a single site for a nation with a population of approximately 30 million. Results in surgery for Cushing disease are a marker of surgical technical skill in TSS. All previously published series come from the developed world, where sophisticated investigations and management are available. Many of these investigations are not available in Uzbekistan.

Methods

This mixed series of 154 patients from 2000 to 2013 presents the data from Uzbekistan. The management of Cushing disease before the introduction of TSS was with unilateral adrenalectomy, a procedure virtually unknown in the West. It reduces cortisol burden but is, in the long-term, only a temporary measure because it allows the tumor to continue to grow. The results of this procedure are presented and show that in the short-term, surprisingly reasonable remission is obtained.

Results

These results are contrasted with the experience with TSS, for which the impact of the input from an experienced team including an endocrinologist and neurosurgeon from the United Kingdom allowed a transformation in management and enabled outcomes to match what can be expected in the West.

Conclusions

TSS for Cushing's Disease achieved an early remission of 68.7% (early morning cortisol of <50 nmol/L), although 4 patients relapsed.

Introduction

The Republic of Uzbekistan emerged from the collapse of the Soviet Union in 1991. The country has a population nearing 30 million, of whom more than 3.5 million are in the capital, Tashkent. At the time of the first author's visit, transsphenoidal surgery (TSS) had never been carried out through lack of equipment and absence of any specialized training of any Uzbek neurosurgeon. Since this visit and subsequent training of 3 Uzbek neurosurgeons in the United Kingdom, as well as the employment of a Moscow-trained Uzbek endoscopic neurosurgeon, TSS has become firmly established with more than 500 cases overall, now spread between 3 units. The first author has continued his annual visits and now visits as a team with 2 others trained in endoscopic pituitary surgery from the United Kingdom.

Measuring the worth of the introduction of this procedure in Uzbekistan is generally compromised by tumor size at presentation, which is often substantial, as in many developing nations. However, pituitary Cushing tumors are usually microadenomas and surgical cure is potentially achievable, and the results, although dependent on case selection, reflect individual surgical skill, rather than being skewed by tumor size.

Measuring the results of Cushing surgery in the Republic is relatively straightforward, because there is only 1 endocrine service center in the capital, but with satellite clinics throughout the major cities. Cushing disease has been monitored since a neuroendocrine service was set up by the third author following her specialized training in the United Kingdom.

This audit initially studied all forms of Cushing syndrome in the Republic, from the initial period between 2000 and 2006 when TSS was not available to the end of the study in 2013, when these data were submitted in the second author's PhD thesis.

During the initial period of the study, the only form of surgical treatment available was adrenalectomy, which because of the difficulty of access to replacement corticosteroids was usually only unilateral, as suggested in a Turkish study.¹ This procedure reduces endogenous cortisol load and allows a form of remission, although recurrence is inevitable.

All these data are included in the audit because they show the difficulties that a developing nation encounters. Because almost half of the surgery has been carried out by Uzbek surgeons, all 3 authors believe that it shows the value of an experienced team from the developed world undertaking highly specialized and continuing training rather than just the results of an experienced Western neurosurgeon operating in a foreign country.

Cushing disease is a rare disorder, with an incidence of around 2 new cases per million population per year. Untreated, it has a poor 5-year survival.² The various causes must be differentiated: true pituitary Cushing disease, adrenocorticotropic hormone (ACTH)-ectopic syndromes, and ACTH-independent forms, such as both primary micronodular and macronodular dysplasia of the adrenal cortex and adrenal adenomas. The exogenous administration of corticosteroids (iatrogenic) is a further important and usually easily reversible cause.

Although various diagnostic tests used to differentiate between these causes have been established3, 4, 5, 6 and broadly agreed despite some remaining debate, aspects of optimal definitive therapy remain controversial.⁷ For adrenal causes that are ACTH independent, the indications for surgery are clear cut. In the developed world, this means endoscopic adrenalectomy, which is not available in Uzbekistan. Consequently, only open surgery is offered. The initial outcomes of all forms of surgery for Cushing disease (both TSS and adrenalectomy) are variable, as are the long-term remission and recurrence rates.8, 9 Nevertheless, it is broadly agreed that TSS offers the best results in true Cushing disease.

Although recognizing the importance of inferior petrosal sinus sampling in the investigation of pituitary Cushing disease, this cannot be carried out in Uzbekistan. Magnetic resonance imaging (MRI) contrast (until after the study period) and sophisticated high-field MRI are also not available. Sophisticated histopathologic studies of pituitary samples are not available; even classic trichrome stains and in particular immunocytochemistry are unavailable, although they are on a wish list for the future, so, at best, histology can only confirm or deny the presence of tumor.

Standard investigations of remission of Cushing disease in general usually includes 24-hour estimation of urinary free corticosteroids. By the end of the study period, this was being introduced as routine in the center. This test is a useful marker of the condition, although its use for confirmation of the condition and as confirmation of remission has some pitfalls.³ The cohort in whom this was used is small and results are not included, although they are commented on in the Conclusions section.