Accepted Manuscript
Title: Adrenocortical carcinoma in a 17th-century girl
Author: Tobias Else Richard J. Auchus Walter L. Miller
The Journal of Steroid Biochemistry & Molecular Biology
| PII: | S0960-0760(16)30054-1 |
| DOI: | http://dx.doi.org/doi:10.1016/j.jsbmb.2016.03.008 |
| Reference: | SBMB 4661 |
| To appear in: | Journal of Steroid Biochemistry & Molecular Biology |
| Received date: | 22-11-2015 |
| Revised date: | 11-2-2016 |
| Accepted date: | 3-3-2016 |
Please cite this article as: Tobias Else, Richard J.Auchus, Walter L.Miller, Adrenocortical carcinoma in a 17th-century girl, Journal of Steroid Biochemistry and Molecular Biology http://dx.doi.org/10.1016/j.jsbmb.2016.03.008
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Ms. Ref. No .: SBMB-D-15-00554 For Special Issue of J Steroid Biochem Mol Biol Revision of 2/8/16
Adrenocortical carcinoma in a 17th-century girl
Running title: Pediatric adrenal cancer
Tobias Else1, Richard J. Auchus1 and Walter L. Miller2
1Department of Medicine, University of Michigan (TE, RJA) and
2Department of Pediatrics and The Center for Reproductive Sciences, University of California, San Francisco (WLM)
Address correspondence to: Walter L. Miller, MD Distinguished Professor of Pediatrics, Emeritus Center for Reproductive Sciences, Room HSE-1634 University of California, San Francisco San Francisco, CA 94143-0556 wlmlab@ucsf.edu phone 415-476-2598
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Highlights
* We discuss a report published in 1697 describing the autopsy of a girl who died in 1688 with an adrenocortical carcinoma.
* The existence of the adrenal was controversial in the 17th century, and no adrenal tissue is described in the autopsy, but the signs of her profound combined glucocorticoid and androgen excess are unmistakable.
* The tumor invaded the left kidney and had metastasized to the lungs and possibly elsewhere.
* Pediatric adrenocortical carcinomas are most common in early childhood, are more common in girls, and are most frequently caused by mutations in the TP53 tumor suppressor gene.
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Abstract
Adrenocortical carcinoma (ACC) is a rare, often fatal disease, that may be seen sporadically or with hereditary predisposition syndromes. Patients with ACC are usually girls under the age of seven who present signs of excess production of adrenal glucocorticoids and androgens, with the diagnosis being confirmed by imaging. Here we reproduce and examine what we believe to be the first autopsy case report of a child with ACC, published by Dr. Henry Sampson in Philosophical Transactions, published by The Royal Society of London in 1697. The paper describes the autopsy of a girl with severe virilization and profound signs of Cushing syndrome who died at age six, strongly suggesting ACC. She apparently had extensive pulmonary metastases, and may have had liver involvement. The report indicates her disease arose from her left kidney and there is no indication of an adrenal origin, perhaps because the adrenal gland was not generally known as a separate organ at that time. This classic example of an early case report is particularly instructive in the context of medical knowledge and understanding in the 17th century compared to current knowledge.
KeyWords: Adrenal, autopsy, cancer, Cushing Syndrome, pediatrics
1. Introduction
The adrenal is a small, anatomically obscure organ. Ancient medical observers such as Galen of Pergamon (130-200 CE) failed to recognize the adrenal gland, which was first described as an identifiable structure in 1563 by Bartolomeo Eustachio in his anatomical tretise ‘Opuscula Anatomica’ [1]. However the beautifully detailed anatomic engravings by Pier Matteo Pini that were to accompany Eustachio’s text were not published at that time, but were sequestered in the Papal Library until 1714, when the Vatican finally permitted their publication by GM Lancisi as ‘Tabulae Anatomicae’. The adrenal remained no more than an anatomical curiosity until Thomas Addison described the
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clinical consequences of adrenal insufficiency in work published in 1849 and 1855, and Charles-Edouard Brown-Sequard demonstrated that adrenalectomy (but not a sham operation) was lethal to dogs in 1856 [1]. Thus clinial descriptions of adrenal disease before the mid-19th century are rare and veiled; for example, it is clear that Luigi De Crecchio described non-salt-wasting, virilizing congenital adrenal hyperplasia in 1865, but failed to appreciate the role of the autopsied patient’s massively enlarged adrenals [2].
Adrenocortical carcinoma (ACC) is a rare, often fatal disease; pediatric cases are usually seen in girls under the age of seven. Early reports of ACC are of interest as they illustrate the development of knowledge of the adrenal cortex and of the actions of its various secretions. A mid-20th century review of Cushing syndrome applied the eponym Cooke- Apert-Gallais syndrome to malignant adrenal tumors associated with adiposity and virilism [3]. Cooke’s report [4] in 1811 preceeded those of Apert [5] and Gallais [6] by a century, and is widely regarded as the first description of both adiposity and virilization associated with an adrenal tumor. Fox [7] reported a similar case in 1885, mentioning five other cases, and in 1905, Bulloch & Sequira reviewed the pathology literature on ACC, compiling 12 cases [8], including that of Adams [9]. These authors notably also reviewed early cases of congenital adrenal hyperplasia, clearly noting that the adrenal could profoundly influence the sexual phenotype. However, in reviewing the history of hyperandrogenic disorders in women, Azziz [10] pointed to a much earlier case of probable ACC, which had not been noted in earlier reviews, that includes a clear description of combined glucocorticoid excess and hyperandrogenism. That case [11], reported by Henry Sampson in 1697, is discussed here in detail.
In 1697 Henry Sampson, Fellow of the Royal College of Physicians, London, published a brief report entitled “A relation of one Hannah Taylor, a very extraordinary child of about six years of age, who in face, etc. was as large as a full grown woman; and of what appeared on the dissection of her body” [11]. Dr. Sampson (ca. 1629 - 1700), received his BA from Pembroke Hall, Cambridge in 1650, and was an unordained nonconformist (i.e. not Anglican) minister before pursuing medicine. He studied at the Univerity of Padua and at the University of Leyden, from which he received his MD in 1668, and
became an honorary fellow of the Royal College of Physicians in 1680 [12]. He published several reports in the Philsophical Transactions; the one under consideration is readily found at http://rstl.royalsocietypublishing.org/content/19/215-235.toc, and is reiterated here, with commentary in the following section.
2. Results
2.1 Sampson’s Report
Hannah Taylor was born in Crouched Fryars June 12, 1682. [comment A] She was till three Years old very sickly, lean and not able to go alone; but about Bartholomewtide [B], 1685 she began to grow strong and fat, which increased till the time of her Death: She was also a very foreward Child of Understanding, had her Pubes grown thick and long, as also Hair under her Arm-pits and a Downeyness upon her Chin, unusual with those of her Sex, except in some aged Persons. [C]
About half a Year before she dyed she began to complain of Pains, especially on her left side, and voided Gravel often by Urine, and with pain. Her Breath was straight [D], as is usual to fat People, especially when she went up a pair of Stairs: Yet on that very Evening before she dyed she walked abroad, was merry and lively, went to Bed, and slept as at other times; but after Midnight she awakened, cried out of a great pain in her side, and said, Mother, I want Breath, I shall dye; and in less than a quarter of an hour was quite dead. [E]
The Measures and Weight of her Body were as followeth. Round the Breast a Yard and 2 Inches, over the Hips at the Navel 1 Yard 5 Inches, over the Stomach a Yard, her height 1 Yard wanting an Inch, round the Thigh 1 Foot 9 Inches, Calf of the Leg 13 Inches, upper part of the Arm 14 Inches, the Wrist 7 inches, her weight 95 lb. [F] She had a Face as big and broad as any fat grown Woman of 20 Years [G]. Her Chin and Breast were so thick laid with fat, that she was forced to hold up her Head (or rather throw it backward) as she walked. These Measures were all taken before the Dissection. The thickness of the Fat upon the Muscles of the Abdomen was 2 inches, and not much less upon the Sternum: After the Fat was removed (which was as much as is usually in most fat and grown Persons) the Abdomen was very protuberant and round, and yet the Fat
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contained therein not extraordinary much, neither on the Omentum or Mesentery: yet it was more than is usual in well fed Persons, and so much, that with the bigness of the other Internal Parts (which were all of the largest size) it made her have so big and protuberant a Belly [H]. The Guts were all inflamed and thick, the Liver large, the left Kidney (where was the seat of her Misery) exceeding large, and double the bigness of that on the right side; upon the Dissection whereof there issued out a vast quantity of Blood, both from all the Vessels of it, and out of its Pelvis; and after several times Spunging of it, yet it came flowing in from the emulgent Artery: a certain Argument of a great Plentitude in the descending Trunk, which caused the Inflammation of the Mesentery and the Nephritis in the Kidney [I]: Here was also some small Gravel, which possibly had choaked up the Ureter, though that was not examined; but because there was no Blood in the Bladder I justly make this Conjecture. The Uterine Parts had nothing bigger, or more remarkable than in others her Age. The Testicles were large but smooth and white, without Protuberances or shew of Eggs [J]. The Bladder had a Purulent Matter in it [K]. When the Breast was denuded of its Fat, it shewed no bigger than of another Child of her Age [L]. The [pleural] Cavity was totally filled with the Lungs and Heart. The Heart was well and had very strong Fibres and no Polypus [thrombosis]. But the Lungs, besides that they were extended to fill up the whole Cavity, were annexed strongly to several parts of the Pleura, and had several Protuberances as big as Nutmegs filled with a Pulp like an Atheroma, and were in divers places rotten and corrupted [M]. Quaere, Why one with so bad Lungs was so Fat? Why had she not rather a Consumption? [N]
The evident cause of Death lay in the Inflammation of the lower Parts, but the suddenness thereof must be from some impression which that Inflammation made upon the Original of the Nerves moving to the Diaphragm, Bronchia and other Parts of Respiration, for her great and only Complaint was want of Breath [O]. Besides her very Face and Head were miserably coloured with redness of stagnant Blood. [P] The Head was not opened.
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2.2 Comments on Sampson’s Report
A. There is a Crouched Friars Residential Home for the elderly and infirm at 103-107 Crouch Street, Colchester CO3 3HA, United Kingdom. The term ‘crouched fryars’ derives from Fratres Cruciferi, a Roman Catholic order that came to Colchester, England in 1245 [13].
B. ‘Bartholomewtide’ is the festival of St. Bartholomew; August 24.
C. This is a clear description of hyperandrogenism, with increased muscle mass, pubic and axillary hair and early facial hair. Becoming ‘fat’ as described later, suggests increased glucocorticoid secretion. Hyperandrogenism plus hypercortisolemia in 3 year old female strongly suggests ACC. In children under 7 yo, Cushing syndrome is usually of adrenal, not pituitary origin [14], and ACC is an especially common cause. In general surveys that exclude syndromic causes of ACC, pediatric ACC is about 3 times more common in girls [15, 16], but in a large study of a Southern Brazilian genetic isolate of ACC caused by TP53 mutations the female predomonance was only 1.7:1 in patients less than 4 years old [17].
D. The term ‘straight breath’ indicates orthopnea; from Greek op0oo (orthos, ‘straight’) and Tvola (pnoia, ‘breath’). Breathing is easier when sitting or standing up straight.
E. Shortness of breath is not, in and of itself, a sign of Cushing syndrome, but as described in the autopsy, she had ‘bad lungs’ with apparent pulmonary metastases and also had enlarged abdominal organs, which may have impaired diaphragmatic excursion. The lung and liver are the principal targets for metastases from ACC.
F. These detailed measurements tell us much. Her height was only 35 inches (89 cm), which would be about -6.5 SD for height for a 20th century 6-year-old girl. European adults were about 4-5 cm shorter in the 17th century than today, so her growth impairment would be somewhat less than -6.5 SD. Profound glucocorticoid excess can lead to a total cessation of growth, even in the presence of hyperandrogenism, and she ‘was till three Years old very sickly’, which would also have impaired growth. Her obesity extended to her arms and legs and hence was generalized, not centripital; generalized rather than centripital obesity is typical of Cushing syndrome in children, as opposed to adults. Her weight of 95 lb (43.3 kg) is about +15 SD for weight for a 20th century 6-year-old girl.
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Obesity and arrested growth are the most common presenting symptoms in children with Cushing syndrome [18, 19].
G. Probably what we would call ‘moon facies’.
H. It is not clear why the abdomen was protuberant after removal of the fat; the autopsy does not describe ascites or any intraabdominal masses, although the abdominal organs were large. Unfortunately the liver was not sectioned, which we speculate would have revealed metastases and fatty infiltration.
I. Although the left kidney was ‘the seat of her misery’ and it was dissected, its contents are not described, other than the great amount of blood. Did it contain tumor tissue? We speculate that she had a primary left ACC that invaded the left kidney, accounting for its large size. The bleeding from the ‘emulgent’ (renal) vessels may suggest she had a renal vein thrombus; poor renal blood flow may have contributed to her nephrolithiasis (urinary gravel).
J. Apparently the term ‘testicles’ was used for ‘gonads’; the lack of visible ovarian follicles indicates she was prepubertal, and the uterine size being normal for age indicates she was not hyperestrogenic.
K. The presence of ‘Purulent Matter’ in the bladder indicates a urinary tract infection that resulted from her apparent ureteral obstruction; although fever is not mentioned, fever may be masked by hypercortisolism. Infection may have hastened her demise.
L. She had breast fat, but did not have gynecomastia, which is consistent with her pre- pubertal non-estrogenized uterus. ACCs may secrete estrogens, but this is rare.
M. This seems to be a description of multiple pulmonary metastases, some of which had become adherent to the pleural wall, and some of which were necrotic. Their ‘atheromatous’ appearance may reflect retention of cholesterol and cholesterol esters in steroidogenic ACC tissue.
N. Consumption (tuberculosis) was one of the most common diseases of this era, so it is not surprising that Sampson tried to understand his patient’s demise in that context. He could not have known that hypercortisolism would cause obesity despite poor lungs, but consumption would not cause her symptoms of hyperandrogenism and hypercortisolism, and Sampson’s clinical experience told him this case was different.
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O. Her massive obesity, distended abdominal contents and pulmonary metastases all contributed to her shortness of breath, but the ‘suddenness’ of her demise suggests a vascular event. Hemorrhage is often seen with large adrenal masses; alternatively, she may have had thrombosis of a large vessel compressed by the tumor and aggrevated by the hypercoagulable state seen with Cushing’s syndrome. Both are consistent with the vivid description of profuse bleeding at autopsy.
P. The ‘redness of stagnant blood’ appears to be more than the usual red cheeked appearance of Cushing syndrome, which is secondary to capillary fragility; her hyperandrogenism would have stimulated erythropoesis, and she was probably also dehydrated at death, exacerbating her plethoric appearance.
3. Discussion
3.1 Sampson’s Report
Endocrinologists today can easily identify Sampson’s description of the signs, symptoms and clinical course of Hannah Taylor as Cushing syndrome and virilization caused by excess glucocorticoids and androgens. However, when Sampson published his report, the existance of the adrenals was obscure, their function unknown, and the concept of hormones (first termed ‘internal secretions’) lay far in the future. Thus, while Sampson meticulously described his observations, he could not have known that there was a unifying diagnosis explaining Hannah Taylor’s clinical course and autopsy findings. Sampson does not mention adrenals, suggesting he was unaware of them or did not believe they existed. Many 17th century anatomists mentioned the adrenals [20], often ascribing fanciful functions to them, but none ascribed human disease to the adrenals until Thomas Addison in 1849. Sampson’s descriptions and discussion reflect the knowledge of his time, which influenced his expectations on what to find at autopsy. Thus Hannah’s multiple lung nodules suggested tuberculosis, which was then termed ‘consumption’ due to the associated weight loss and asthenia. Even today, in countries with a high prevalence of tuberculosis, an adrenal mass accompanied by a lung nodule or infiltrate suggests tuberculosis; however, tuberculosis of the adrenal is commonly infiltrative and bilateral. Hannah also lacked the usual clinical symptom of wasting; on
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the contrary, she was fat and appeared well nourished. This perplexed Sampson, who underscored his surprise with two questions: “Why one with so bad lungs was so fat? Why had she not rather a consumption?“. The lung nodules are described as ‘atheromatous,’ which probably reflect the abundant cholesterol esters in ACC metastases.
Sampson does not provide detailed discussion or speculation concerning the underlying pathophysiology, but in Sampson’s era most medical publications consisted of simple observation and phenomenology. Discussions appear in the medical literature of the late 19th and early 20th century, and Discussions explaining clinical findings in the context of the underlying science first appear in publications of the 1930’s and 40s. In the 17th century, almost all scientific communication was in books (e.g Galileo’s The Starry Messenger (Sidereus Nuncius) (1610), Boyle’s The Sceptical Chymist (1661), and Newton’s Principia Mathematica (1687)), and this persisted to the 19th century (e.g. Darwin’s On the Origin of Species (1859) and Maxwell’s A Dynamical Theory of the Electromagnetic Field (1865)); scientific writing of articles (and case reports) was a new venture at the time of Sampson’s report; the ‘Philosophical Transactions of the Royal Society’, the first scientific periodical in England, began publication in 1665, only 32 years earlier.
Sampson indicates that the kidney was the origin of Hannah’s tumor. While her tumor was clearly of adrenal rather than renal origin, the proximity of the adrenal and kidney and the resemblance of renal cell cancer cells to adrenocortical cancer cells has led to similar confusion in more recent history, as renal-cell cancers were once believed to originate from aberrant adrenal tissue. In 1883 Grawitz described renal-cell cancers and termed them “struma lipomatodes aberrata renis”[21]. His theory that these renal tumors arise from adrenal tissue led to the common term ‘hypernephroma’, and persisted until the late 1930s.
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3.2 Adrenocortical Carcinoma Today
The epidemiology, genetics, pathology and clinical management of ACC have been reviewed recently [22]. ACC affects patients of all ages with a predilection for females. Compared to other solid tumors, ACC is relatively more common in childhood than in adults, mainly because of its association with hereditary cancer syndromes. Ninety percent of childhood ACCs cause clinically apparent hormone-excess syndromes, typically hypercortisolism and/or hyperandrogenism [17]. Thus, Hannah Taylor’s case is typical of childhood ACC.
Li-Fraumeni syndrome, a genetic syndrome caused by TP53 mutations, accounts for about 50-70% of childhood ACCs (and many other tumors) [23]. We cannot know whether Hannah Taylor had Li-Fraumeni syndrome, as Sampson’s report lacks a family history that might suggest a hereditary predisposition. Moreover, the hereditary character of certain diseases was not appreciated until 19th century studies of Duchenne’s Muscular Dystrophy [24, 25] and Huntington’s Chorea [26], and the application of genetics to medicine began in the early 20th century [27]. In contemporary practice, genetic testing of TP53 should be considered even in the absence of a family history of tumors associated with Li-Fraumeni syndrome, as up to 25% of affected patients have de novo mutations [28]. ACC has also been described in the Beckwith-Wiedemann overgrowth syndrome, caused by alterations of the IGF2 locus, which predispose to Wilms tumor and other cancers during childhood but not in adults. ACC also occurrs in association with Lynch syndrome (hereditary nonpolyposis colorectal cancer), Multiple Endocrine Neoplasia Type 1 and familial adenomatous polyposis, but in these syndromes the ACC usually develops during adulthood [29-31].
ACC is potentially curable in its pre-metastatic stages 1-3, when the tumors are amenable to surgery, however, the prognosis of metastatic ACC is very poor. Mitotane and cytotoxic chemotherapy are used for advanced disease. However, all therapy of advanced ACC is palliative, and the limited success of chemotherapy should be weighed against quality of life for the patient. The hormone excesses in ACC are more readily controlled. The greatest morbidity is caused by hypercortisolism, leading to diabetes, hypertension,
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osteoporosis, opportunistic infections, poor healing, and neuropsychiatric disturbances. Mitotane alone has limited effects, but hypercortisolism can be controlled with metyrapone [32], a potent inhibitor of steroid 11ß-hydroxylase (CYP11B1), and glucocorticoid effects can also be antagonized at the receptor level by mifepristone [33]. Mifepristone usually requires additional therapy with spironolactone or eplerenone to mitigate the mineralocorticoid effects of cortisol and 11-deoxycorticosterone, which ACCs may produce in even greater amounts than cortisol. The hyperandrogenism is not life-threatening and can be treated with spironolactone, third-generation androgen receptor antagonists, or 5a-reductase inhibitors. In the future, inhibitors of 17- hydroxylase/17,20-lyase (CYP17A1) such as abiraterone [34] may be used to control androgen excess. However, blocking the 17-hydroxylase activity of CYP17A1 will increase seretion of 11-deoxycorticosterone (a potent mineralocorticoid), so that therapy aimed at CYP17A1 will probably have to await approval of agents that selectively target its 17,20 lyase activity.
Thus, if Hannah Taylor had received modern pediatric endocrine care when “she began to grow strong and fat” at age 3, she would have been diagnosed by hormonal assays and abdominal imaging and may have been cured by adrenalectomy. However, if she presented to a modern hospital at age 6 when she began to complain of pain, her metastatic disease might have been ameliorated by surgery and chemotherapy, but not cured. Genetic testing would determine whether she has an underlying genetic condition, and preventive surveillance for other tumors could be offered to her and family members who are carriers of the affected gene.
Disclosure statement: The authors have nothing to disclose
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