contents
1.1 Introduction . . . 1
1.2 Milestones in the Surgical Treatment of Adrenal Disease . . . 2
1.3 The Development of the Surgical Technique of Adrenalectomy . . . 4
References . . . 5
1.1 Introduction
The adrenal glands were first depicted by Bartholo- maeus Eustachius in 1552. They were drawn onto copper plates, Eustachius being the first anatomist to use this method, and reproduced in print in 1563 [1].
The early anatomists such as da Vinci,Galen and Vesal- ius had overlooked the glands, first named “glandulae renibus incumbents” (glands lying on the kidneys) by Eustachius. Successive names include “glandulae renales”, coined by Thomas Wharton, physician to St. Thomas’ Hospital, London, in 1656 [2], and
“capsulae suprarenales”, used by Jean Riolan of Paris in 1629 [3]. The terms cortex and medulla, to describe the two component parts of the adrenal,were first used by Emil Huschke, anatomist and embryologist at Jena, in 1845.
The function of the adrenals was the subject of much speculation in the 19th century with the sugges- tion that they might release “a peculiar matter into the blood,”or conversely “absorb humid exudates from the large vessels nearby”. The fundamental, but contro- versial, proposal that the adrenal glands produced
‘internal secretions’ (‘secretion interne’) was made by the Parisian physiologist Claude Bernard in 1855 [4].
Remarkably, in the same year, Thomas Addison de- scribed 11 patients showing clinical features attribut- able to adrenal insufficiency, namely anemia, debility, feebleness of the heart, irritability of the stomach, and a change in skin color. The autopsy findings were
adrenal destruction by unilateral or bilateral tubercu- losis, metastatic carcinoma, or simple atrophy. These observations were presented to the South London Medical Society in 1849, focusing on the anemia com- ponent of the syndrome, but the classical description of Addison’s disease (the eponym being ascribed by Armand Trousseau [5]) was published 6 years later as a monograph, On the Constitutional and Local Effects
of Disease of the Suprarenal Capsules [6]. Althoughthe publication stimulated much interest, some con- troversy, and important experimental work, the syn- drome of Addison’s disease was not universally accepted for many years.
Charles Édouard Brown-Séquard concluded that the adrenals were essential for life (essentials à la vie) after carrying out a series of experiments on dogs,cats, hares and guinea pigs in which bilateral adrenalecto- my always resulted in death in a few hours and even unilateral adrenalectomy was often fatal [7].
William Osler was the first to attempt treatment of adrenal insufficiency in 1896, using an extract of pig’s adrenal [8]. The isolation of epinephrine by Abel in 1897 [9], following Oliver and Schäefer’s work with adrenal extract in 1894 [10], had attracted great inter- est, and the absence of this chemical was thought to be responsible for the weakness and low blood pressure of Addison’s disease and the fatal consequences of adrenalectomy. Epinephrine was used at the Mayo Clinic in 1920 to treat a patient with symptoms of Addison’s disease following nephrectomy [11].
Although administration of epinephrine resulted in temporary relief of the patient’s weakness, he later succumbed. Others reported the lack of efficacy of this medullary hormone,and it soon became clear that Addison’s disease affected the adrenal cortex only.
In 1926, cortical extracts were used successfully in
adrenalectomized animals, but it was not until the
1940s that cortisone was isolated and synthesized,
work led by Edward Kendall of the Mayo Clinic[12],
and Tadeus Reichstein of Basle [13], later to be award-
Dean A. Harris, Malcolm H. Wheeler
ed the Nobel Prize for their remarkable achievements.
It was realized that the adrenal cortex produced sever- al steroids, with deoxycorticosterone being the first to be synthesized. Aldosterone, initially called electro- cortin, was discovered later by James Tait and Sylvia Simpson in London [14], and was found to exert influ- ence over electrolyte fluxes.
Development of techniques to measure urinary and plasma steroids subsequently facilitated the assess- ment of adrenal gland function and paved the way for the precise identification and investigation of a whole range of pathological conditions of the adrenals, in- cluding Cushing’s syndrome, Addison’s disease and Conn’s syndrome.
In common with the investigation of most dis- orders of the endocrine glands, once the hormonal dysfunction has been confirmed it became necessary to localize the site of the pathological lesion. With re- gards to the adrenals there was an initial dependence upon the insensitive method of plain abdominal radi- ography. The first attempt of specific adrenal imaging was by retroperitoneal gas insufflation [15]. This tech- nique was not reliable and many preferred pyelogra- phy. Caval venous sampling, first performed in 1955 to assay catecholamines, was a significant breakthrough [16]. The refinement of selective adrenal venous sam- pling subsequently aided localization of adrenal pathology, and indeed remains a most valuable diag- nostic tool today [17]. Phlebography, whilst being a sensitive technique,was associated with complications such as adrenal rupture or gland infarction [18], and never really gained favor. Scintigraphy, developed by Beierwaltes and colleagues at Ann Arbor, Michigan [19], employed radiolabeled cholesterol and was use- ful to diagnose hyperplasia and functioning tumors of the adrenal cortex.
Cross-sectional imaging with computed tomog- raphy (CT) was first used in 1975 [20], and along with magnetic resonance imaging (MRI) [21] remains the mainstay of localization investigation today.
1.2 Milestones in the Surgical Treatment of Adrenal Disease
Despite a growing understanding of adrenal anatomy and physiology and several reports of surgical removal of pathologically enlarged adrenal glands it is believed that no adrenal tumor was precisely diagnosed preop- eratively before 1905 [22].
Knowsley Thornton is thought to have performed the first successful adrenalectomy for suprarenal
tumor in London in 1889, reported in 1890 [23]. The patient, a 36-year-old woman with hirsutism second- ary to the tumor, survived 2 years, until the disease re- curred. The tumor weighed in excess of 20 lbs, neces- sitating concomitant nephrectomy.
Although Harvey Cushing (Fig. 1) had defined the fundamental role of the pituitary basophil cell in Cushing’s disease [24], others soon recognized that the development of Cushing’s syndrome required the presence of the adrenal cortex [25]. Therefore explo- ration of the therapeutic avenue of surgical adrenal- ectomy for this disorder was the next logical step.
Results of ten adrenalectomies for Cushing’s syn- drome, performed by Walters and Priestley, were pub- lished in 1934 [26]. They found four carcinomas, one adenoma, three cases of hyperplasia, and two normal glands. Even when subtotal adrenalectomy was per- formed there was 30% mortality [27]. The outlook for patients undergoing adrenalectomy for Cushing’s syn- drome was dramatically transformed once cortisone became available for therapeutic replacement. The first recorded perioperative use of cortisone in adrenal- ectomy for Cushing’s syndrome was in 1949 at the Mayo Clinic and the mortality rate fell to zero for the subsequent 18 reported cases [27]. Replacement corti- sone therapy was then continued postoperatively, a procedure which of course today is routine practice.
This development had a major impact on endocrine surgery, not only making adrenalectomy a safe proce- dure but also facilitating the operation of total hy- pophysectomy.
Two years after the discovery of aldosterone the syndrome of primary aldosteronism,characterized by hypertension and hypokalemia, was reported by Jerome Conn in 1955 [28] (Fig. 2). His patient was a 34-year-old woman suffering from tetany, periodic paralysis, paresthesia, polyuria, polydipsia and hyper- tension. She was thought to have bilateral adrenal hyperplasia, but at exploration of the right adrenal, a 4-cm cortical adenoma was discovered, removal of which cured the patient of her hypertension and meta- bolic abnormalities. Conn subsequently published details of 108 collected patients with aldosterone pro- ducing adenomas [29]. Seventy-nine of these under- went surgery, and hypertension was cured in 66%, im- proved in 20% but remained unchanged in 14%.
With the initial enthusiasm for diagnosing Conn’s
syndrome it was thought that the condition might
account for a significant proportion of hypertensives,
but by 1980 it was apparent that less than 1% of the hy-
pertensive population suffered from this surgically
treatable disorder.
Adrenaline was the first adrenal hormone to be dis- covered, but its crucial role in the clinical syndrome caused by pheochromocytoma was not defined until many years later when the hormone was extracted from adrenal tumors [30]. Fränkel provided the first report of a patient with a probable pheochromocy- toma, an 18-year-old female suffering from intermit- tent palpitations, tachycardia and anxiety attacks [31].
She died after a severe episode of chest pain and dys-
pnea, and at autopsy was noted to have highly vascu- lar bilateral adrenal tumors.The term pheochromocy- toma was coined by Pick [32] in 1912 and the first suc- cessful removal of a pheochromocytoma was by Cesar Roux in Lausanne in 1926 [33] followed by Dr. Charles Mayo in Rochester,Minnesota,the following year [34].
It soon became apparent that surgery for this con- dition was extremely hazardous with a high mortality related to the uncontrolled preoperative hypertension, severe hypertensive surges during intraoperative tumor manipulation and postoperative hypotension. With improving anesthetic techniques and a greater under- standing of the pathophysiology of the disease, allied to the use of agents such as phentolamine and nora- drenaline to control blood pressure, Priestley was able by 1956 to report a remarkable series of 51 patients un- dergoing surgery without any mortality [35].
Further advances in diagnosis with HPLC (high pressure liquid chromatography) methods for cate- cholamine assay, localization with CT, MRI or MIBG ([
131I]meta-iodobenzylguanidine),improved pharma- cological control of blood pressure, evolving surgical methods and a multidisciplinary approach have now rendered the surgical treatment of pheochromocy-
Fig. 1. aHenry Cushing as depicted in a portrait at the PeterBent Brigham Hospital. b Cushing’s surgical notes on a pa- tient with the syndrome that bears his name, pituitary tumor.
Taken from Endocrine Surgery (Linos 1984). c Minnie G., the first patient seen by Dr. Cushing, with the obvious signs of the disease that carries his name
Fig. 2.Dr. Jerome Conn, Professor of Medicine at the Univer- sity of Michigan. (From Endocrine Surgery, Linos 1984)
toma a relatively safe event with a low morbidity and virtually zero mortality.
In the 1960s it had become apparent that pheochro- mocytoma could also occur in association with other endocrine tumors, including medullary thyroid carci- noma, within a familial setting as part of the MEN IIa and IIb syndromes [36, 37, 38]. The search for the underlying genetic defect coincided with spectacular advances in molecular biology and culminated in the identification of the RET proto-oncogene mutations on chromosome 10 [39]. These dramatic develop- ments paved the way for genetic screening of family members predisposed to the hereditary forms of the disease.
The increasing application of abdominal cross-sec- tional imaging with CT and MRI resulted in adrenal lesions being discovered when investigations were performed for unrelated reasons. The vast majority of these so-called incidentalomas are non-secreting adrenocortical adenomas.The precise management of these lesions still remains somewhat controversial,but it is agreed that the key issues to be considered before making a decision to perform surgery are biochemical evaluation of possible hormonal secretory excess and assessment of malignant potential [40]. The advent of minimally invasive techniques for adrenalectomy,with their attendant minimal morbidity and mortality, has introduced the risk of changing the indications for performing adrenalectomy in these circumstances.
1.3 The Development of the Surgical Technique of Adrenalectomy
The first adrenalectomy was performed through a T-shaped subcostal incision similar to that previously described in 1882 by Carl von Langenbüch for chole- cystectomy [41]. Most of these early operations on the adrenal were for the removal of large tumors, but be- cause the incisions employed, whether anterior trans- peritoneal, lateral or retroperitoneal, were essentially similar to those used for renal surgery it was found that these approaches were frequently too low to permit adequate access.Therefore surgeons began to site their incisions at a progressively higher level usually resect- ing the 11th or 12th ribs. In 1932 Lennox Broster of London devised an operation which provided almost ultimate access to the adrenal, utilizing a transpleural, trans-diaphragmatic approach through a long, poste- rior intercostal incision [42]. In 1927, Charles Mayo used a flank incision when performing the first adrenalectomy in the United States for pheochromo-
cytoma [34]. Various anterior, lateral and retroperi- toneal incisions became established each with their own merits and problems.
Anterior incisions, roof-top (bilateral subcostal) or midline permitted a full exploration of the abdominal cavity,especially important when operating for lesions such as pheochromocytoma which might be multiple or ectopic, before the development of accurate local- ization studies. The anterior approach still has special utility when operating for large tumors such as adrenocortical carcinoma. It is possible to gain excel- lent access by subcostal extension and on rare occa- sions even converting to a thoraco-abdominal expo- sure.
Lateral incisions with 11th rib removal gave excellent access, but bilateral pathology such as Cush- ing’s syndrome due to hyperplasia required the pa- tient to be turned to allow access to the contralateral side.
Hugh Young designed a posterior approach, re- moving the 12th rib, which would also permit bilater- al simultaneous exposure of both adrenals [43].
Although an excellent method for removal of smaller tumors such as Conn’s adenomas, access could often be difficult and totally inadequate for dealing with larger lesions over 5 cm in diameter.
Open removal of the adrenal was unchallenged un- til 1992, when Gagner [44] described a transperitoneal laparoscopic approach to the gland. This exciting new method was enthusiastically embraced by the endo- crine surgical community and others described a posterior retroperitoneal endoscopic approach [45].
These methods have a wide range of application espe- cially for Conn’s tumors, Cushing’s syndrome and pheochromocytoma, offering the patient very real benefits with respect to postoperative pain, speed of recovery and ultimately cosmesis. Laparoscopic tech- niques, however, are not generally appropriate for the removal of larger tumors >8 cm in diameter,malignant and potentially malignant tumors. However, it must be appreciated that this question of size and malignancy remains something of a gray area with divided opinion.
The international body of evidence in favor of mini-
mally invasive adrenalectomy for small, benign, func-
tioning adrenal lesions suggests that this method is
now the new surgical ‘gold standard’.
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