Hormone Research
Case Report
Received: May 8, 1998 Accepted after revision: July 31, 1998
G. Höflea R.W. Gasserª K. Lhottaa G. Janetschekb A. Kreczyc G. Finkenstedta
Departments of a Internal Medicine and
b Urology, and
c Institute of Pathology, University of Innsbruck, Austria
Adrenocortical Carcinoma Evolving after Diagnosis of Preclinical Cushing’s Syndrome in an Adrenal Incidentaloma
A Case Report
Key Words
Adrenocortical carcinoma Preclinical Cushing’s syndrome Incidentaloma Laparoscopic adrenalectomy o,p’-Dichlorodiphenyldichloroethane
Abstract
A 43-year-old female patient underwent abdominal ultrasonography and CT scan because of uncharacteristic abdominal pain. A 3-cm homogeneous adre- nal tumor was diagnosed. The endocrine tests revealed an adrenal preclinical Cushing’s syndrome (PCS). Due to the latent hormone excess we decided to operate on the adrenal tumor. Since the tumor was small, laparoscopic adre- nalectomy was performed. Histological evaluation showed an adrenocortical tumor of undetermined nature. Four months later the patient presented with a metastasizing cortisol- and androgen-producing adrenocortical carcinoma (ACC). After pretreatment with ketoconazole to suppress the biosynthesis of adrenal steroids under substitution with hydrocortisone, we reduced the tumor load by surgery. Postoperatively we continued ketoconazole and started o,p’-dichlorodiphenyldichloroethane as well as chemotherapy with doxorubi- cin and suramin. However, the patient died from ACC 7 months after adrenal- ectomy. It is known from several reports that PCS may persist clinically silent- ly or may progress to full-blown Cushing’s syndrome. This is the first time a malignant course of PCS is described. Independent of the initial therapeutic strategy of PCS, i.e. surgery or regular follow-up visits, we must be aware that also relatively small adrenal tumors can harbor malignancy.
Introduction
Careful endocrine work-up of adrenal incidentalomas reveals increasing numbers of preclinical endocrine disor- ders. Preclinical Cushing’s syndrome (PCS) was first de- scribed in the early 1980s [1-3]. Yet there is controversy about the risk of progression from a preclinical disorder to full-blown hypercortisolism [4, 5]. Therefore it is contro-
versial whether all patients with PCS should be operated on to prevent the possible negative effects of autonomous cortisol secretion.
The wider application of CT scans and ultrasonogra- phy reveals an increasing number of adrenal masses (inci- dentalomas). In autopsy studies adrenal incidentalomas were seen in 1.9-8.7% [6, 7]. It is estimated that they are discovered in about 2% of abdominal CT scans [8]. 7% of
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Günter Höfle, MD Department of Internal Medicine, University of Innsbruck Anichstrasse 35 A-6020 Innsbruck (Austria) Tel. +43 512 504 3255, Fax +43 512 504 4105, E-Mail Guenter.Hoefle@uibk.ac.at
these adrenal masses produce aldosterone, 0.035% gluco- corticosteroids, and 6.5% are pheochromocytomas or 0.058% adrenal carcinomas [8]. Androgen or estrogen production is rarely reported.
The term preclinical Cushing’s syndrome (PCS) is applied to adrenal tumors with preclinical autonomous cortisol production. 5-12% of all adrenal incidentalomas are PCS [9-11]. The biochemical findings in PCS vary. The circadian rhythm of ACTH and cortisol secretion is altered, cortisol is not suppressed in the overnight dexa- methasone suppression test (low or high dose) and the morning ACTH levels may be suppressed. 24-Hour uri- nary cortisol excretion is (high) normal or slightly ele- vated. Furthermore the response to CRF administration is blunted [12]. Little is known about the natural course of PCS. It has been reported in the literature that the endo- crine disorder either remains preclinical [2] or develops into full-blown Cushing’s syndrome [11]. A malignant PCS has never been reported.
Adrenocortical carcinoma (ACC) is a very rare tumor with an annual incidence of 0.5-2/1 million people [13]. The prevalence is estimated to be lower than 1:250,000. An adrenal mass of <6 cm bears a low probability (<1:10,000) of being malignant [8]. Tumors of >6 cm have a higher malignancy potential [14]. In the study of Copeland [14] 92% of all ACCs reached or exceeded 6 cm. An ACC may be functional or nonfunctional. Hormone production is reported in 24-79% of ACCs [15, 16]. There are, however, more authors who found a frequency of hor- mone production exceeding 50% [16-19]. The frequency of ACC may be different in age and gender subgroups [18]. ACCs often have glucocorticoid, androgen or com- bined hormone production [16]. Synthesis of cortisol pre- cursors, androgen precursors, aldosterone or estrogen is rare. Hypoglycemia and hypercalcemia are also reported to be associated with ACC.
Therapy of ACC is based on radical resection of the tumor and metastases, if present. An incompletely excised tumor or an inoperable recurrent tumor mass makes o,p’-dichlorodiphenyldichloroethane (o,p’DDD) therapy mandatory [20, 21]. o,p’DDD is also used in patients who are operated on curatively to prevent recurrent disease. The benefit of this therapeutic approach remains contro- versial until more information has been gathered [17, 22, 23]. Doxorubicin, suramin and cisplatin-containing poly- chemotherapeutic regimens are used as second-line thera- py [20]. The 5-year survival rate for all stages of ACC is 22-34% [16, 21]. This reflects the poor prognosis of patients with ACC regardless of the therapeutic strategy, i.e. surgery, chemotherapy and/or radiotherapy.
Case Report
E.W., a 43-year-old female patient, underwent abdominal ultra- sonography because of uncharacteristic abdominal pain. An adrenal mass was suspected and confirmed by abdominal CT. A 3 x 2.5 x 2.5 cm adrenal tumor was diagnosed (fig. 1). The tumor had regular borders and a homogeneous appearance on CT scan. The unen- hanced CT attenuation value of 45-50 Hounsfield units were high but lower than that of liver tissue. The small tumor size, the regular borders and the homogeneity of the tumor suggested an adrenal ade- noma in spite of the high CT attenuation values which are often seen in malignancy or hemorrhage of the adrenal gland [24] but also in a considerable number of benign adrenal adenomas [25-27]. The patient did not have any signs of Cushing’s syndrome; she was nor- motensive and normoglycemic and she had regular menses, stable body weight (body mass index 24) and no Cushing’s stigmata.
The endocrine evaluation repeatedly showed suppressed ACTH levels and normal plasma cortisol as well as 24-hour urinary cortisol in the upper normal range (table 1). Overnight 1-mg dexamethasone suppression test was performed twice and plasma cortisol was not suppressible. Plasma renin activity, aldosterone, testosterone, 24- hour urinary catecholamines, DHEAS and 11-deoxycortisol were normal. Therefore we diagnosed PCS originating from a left-sided adrenal adenoma. We decided to operate on the adrenal tumor because of the latent hormone excess. Because the tumor was rela- tively small, adrenalectomy was performed laparoscopically. The patient was given substitution therapy with hydrocortisone to pre- vent possible peri-/postoperative adrenal insufficiency by the sup- pressed contralateral adrenal gland.
Endocrine evaluation 1 month postoperatively (table 1) showed that the ACTH level had increased to the normal range, and values for cortisol and ACTH-stimulated cortisol were also normal. We interpreted the normalization of plasma ACTH mainly as an effect of the decreasing suppression due to the removal of the adrenal mass. The normal ACTH-stimulated cortisol level and the slightly de- creased 24-hour urinary cortisol reflect and almost normal function of the contralateral adrenal gland.
Initial histological evaluation showed an adrenocortical tumor of undetermined malignant potential. The operation specimen was not definitely classified as an ACC mainly because of the destruction of the specimen by fragmentation. This is done during laparoscopic adrenalectomy in order to remove the tumor in an entrapment sack.
We planned regular follow-up visits at our Endocrinology Outpa- tient Department. The patient remained well for some weeks. Then, symptoms similar to those occurring preoperatively developed and they continuously increased in intensity. At a consultation 4 months after surgery she presented with a full-blown Cushing’s syndrome, but only moderate virilization (table 1). A CT scan showed a large recurrent tumor mass in the left upper quadrant of the abdomen, local (celiac) lymph nodes were grossly enlarged and there was evi- dence of peritoneal carcinomatosis (fig. 2). The tumor load could be reduced by surgery and histological evaluation of the removed tumor then proved to be ACC. We started o,p’DDD (Lysodren®, Anabolic Inc., Irvine, Calif., USA) and increased the dose until 9 g daily was reached. We continued ketoconazole (Nizoral®, Janssen & Cilag Pharma, Vienna, Austria) 200 mg p.o. 3 times daily which was begun preoperatively. o,p’DDD had to be reduced to 4 g daily because of gastrointestinal intolerance. Adrenal insufficiency was prevented by hydrocortisone (Hydrocortone®, Merck, Sharp & Dohme, Haarlem, The Netherlands) 30 mg daily. Postoperatively cytotoxic chemother-
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ANTERIOR
| Hormone parameter | Reference range | Preoperative | 1 month postoperative | Recurrent disease |
|---|---|---|---|---|
| ACTH basal (8 a.m.), pg/ml | 9-60 | 5.1 | 29 | 2.2 |
| Cortisol basal (8 a.m.), µg/dl | 5-18 | 16 | 9 | 24.6 |
| Cortisol overnight dexamethasone suppression test (1 mg), ug/dl | <5 | 24.3 | n.d. | 22.9 |
| ACTH-stimulated cortisol | ||||
| (0.25 mg Synacthen i.v.) | n.d. | n.d. | 23.3 | n.d. |
| 24-Hour urinary cortisol, ug/24 h | 26-135 | 127.2 | 22.5 | 467.3 |
| 24-Hour urinary noradrenaline, ug/24 h | <100 | 56 | n.d. | n.d. |
| 24-Hour urinary adrenaline, ug/24 h | <25 | 14 | n.d. | n.d. |
| Aldosterone, ng/dl | 1-16 | 16 | n.d. | <2.5 |
| 11-Deoxycortisol, ug/1 | 1-5 | 3 | n.d. | 8.1 |
| Plasma renin activity | 150-2,200 | 1,121 | n.d. | 659 |
| Testosterone, ug/l | 0.1-1 | 0.9 | n.d. | 3.8 |
| DHEAS, µg/1 | 500-3,000 | 1,280 | n.d. | 3,390 |
n.d. = Not determined.
apy with doxorubicin (Adriblastin®, Farmitalia Carlo Erba, Zug, Switzerland) 60 mg/m2 i.v. was administered. The planned schedule of chemotherapy every 3 weeks could not be adhered to because of a malignant pleural effusion on the left side, which had to be drained repeatedly. Finally, we performed thoracoscopic instillation of talc; the pleural effusions, however, decreased only moderately. Suramin
therapy (Germanin®, Bayer 205, Bayer, Leverkusen, Germany) 1 g i.v. weekly, which we planned to combine with doxorubicin, had to be postponed until the pleural effusions were under control. The patient, however, received only one infusion of suramin and three cycles of doxorubicin before she died from ACC 7 months after adre- nalectomy. Autopsy confirmed diffuse peritoneal tumor spread.
| Histopathological characteristics | |
| Nuclear atypia, cellular pleomorphism | yes (considerable) |
| Prominent nucleoli | yes |
| Rate of mitosis | 21/50 HPF |
| Atypical mitosis | sparse |
| Lipoid cells | borderline (normal >25%) |
| Architecture | not interpretable (specimen morcellated) |
| Vascular invasion (venous, sinusoidal structures) | sinusoidal invasion |
| Capsular invasion | no (specimen morcellated) |
| Necrosis, regressive alterations, fibrous bands | no |
Scoring [26]: 4 (malignancy ≥4); scoring [27]: 18.5 = (malignancy ≥8); scoring [28]: 2 (malignancy 2.91 ± 0.9).
Table 3. Immunohistochemistry of the tumor removed by laparoscopic adrenalectomy
| Immunohistochemistry | Result | Interpretation [25] |
|---|---|---|
| p53 protein | 1-2% | malignancy >1% |
| Ki 67 molecule (MiB-1 AK) | 5%, segmentally 20% | malignancy ≥8% |
Discussion
The nature of adrenal incidentalomas is assessed ac- cording to characteristics from imaging procedures, such as (change of) tumor size, the shape and homogeneity of the tumor, regularity of the borders of the tumor, CT attenuation values or MRI signal intensity ratios and the presence of distant metastases. If surgery is necessary, his- topathological examination may clarify the nature of the adrenal mass. There are, however, a considerable number of patients in whom histopathological examination of the adrenal mass does not result in a definite classification of the nature. It may be helpful to use various histological scores [28] to improve the accuracy of diagnosis. Immu- nohistochemical proliferation markers, such as Ki 67 molecule and p53 protein, probably give additional infor- mation on the nature of the tumor [29].
The interpretation of the histological findings were dif- ficult because of the fragmentation of the specimen. In spite of cellular pleomorphism and a high mitotic rate, a definite classification of ‘malignant’ did not seem to be justified because of the lack of necrosis and fibrous areas. Furthermore, capsule penetration and pericapsular vessel infiltration by the tumor could not be assessed. In addi-
tion an area within the tumor mass exhibited invasion of a sinusoidal structure. Primarily, this finding was not classi- fied as being diagnostic for malignancy because it was not a venous structure and it was located within the tumor borders. Therefore the initial histopathological diagnosis was adrenocortical tumor of undetermined malignant po- tential. The retrospective analysis (table 2) of the histolog- ical data using the criteria of Weiss [30] and van Slooten et al. [31] indicated malignancy, the criteria of Hough et al. [32] and Lack [15] were borderline. Later on, immuno- histochemical staining for Ki 67 molecule, a human nuclear proliferation associated antigen, and p53 protein, a product of tumor suppressor gene p53, was performed, both giving positive staining in an increased number of tumor cells, indicating malignancy (table 3).
As demonstrated in this case report laparoscopic adre- nalectomy may generate additional problems in discrimi- nating benign from malignant tumors. This surgical pro- cedure requires fragmentation of the tumor in an entrap- ment sack before removal through the incision of the tro- car. In particular, penetration of the tumor capsule and possible infiltration of periadrenal adipose tissue cannot be assessed adequately. At that time we assumed a poten- tially curative surgical procedure. Therefore, and because
malignancy was not clearly demonstrable, we did not start adjuvant o,p’DDD. In addition, adjuvant o,p’DDD re- mains controversial for apparently successful surgery in ACC [16, 19, 22, 23, 33].
Since there was a large recurrent tumor mass with metastases all over the peritoneal cavity the question arises whether the initial surgical procedure, i.e. laparos- copic adrenalectomy, induced or accelerated the local and peritoneal tumor spread. Most frequently, metastases oc- cur primarily at the port site, but this was not seen in our case. Mechanical tumor cell spillage is certainly a risk which is known in open surgery as well as laparoscopic surgery. So far only port site metastases have been de- scribed after laparoscopic surgery but not widespread metastases in the peritoneal cavity as in our case. It has been speculated that aerosolization of tumor cells due to the CO2-pneumoperitoneum may occur, thereby explain- ing diffuse metastases. A recent survey of the literature in this context shows that this mechanism of spillage ob- viously only plays a minor role [34]. Therefore we do not
believe that open surgery instead of laparoscopic surgery would have changed the course of the disease in our patient. This interpretation is underlined by the fact that in our case no port site metastases, which are typical for tumor spillage due to laparoscopic surgery, were ob- served.
In summary, laparoscopic adrenalectomy is an elegant, minimally invasive technique for treatment of adrenal tumors. If there is suspicion of malignancy preopera- tively, open abdominal surgery should possibly be pre- ferred, mainly because a more radical operation can be performed. In treating adrenal incidentalomas we have to take care to observe signs of malignancy in imaging proce- dures. This is also true for the PCS for which we describe a malignant course of the first time. Although it seems obvious to correct an autonomous hormone secretion as present in PCS, first of all we have to await long-term fol- low-up studies elucidating the natural course of PCS. Pos- sibly only certain subgroups with PCS require adrenal- ectomy?
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Höfle/Gasser/Lhotta/Janetschek/Kreczy/ Finkenstedt
Copyright: S. Karger AG, Basel 1998. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Copyright: S. Karger AG, Basel 1998. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.