Case Report
Horm Res 1999;52:97-100
Received: May 17, 1999 Accepted after revision: September 6, 1999
Peritoneal Carcinomatosis following Laparoscopic Resection of an Adrenocortical Tumor Causing Primary Hyperaldosteronism
S. Deckersa L. Derdelinckxa V. Colb J. Hamelsc D. Maiterb
ªDivision of Endocrinology, St Luc Hospitals of Bouge, bUniversité Catholique de Louvain, Brussels, and cInstitute of Pathology and Genetics, Loverval, Belgium
Key Words
Carcinoma, adrenocortical · Hyperaldosteronism · Metastases, peritoneal · Adrenalectomy, laparoscopic
Abstract
A clinical syndrome combining hypertension and hypo- kalemic alkalosis led to the diagnosis of primary hyperal- dosteronism, caused by a right-sided, 2 cm large, appar- ently benign aldosterone-producing adenoma. The adre- nal tumor was completely resected by laparoscopic ad- renalectomy. Six months after surgery, the patient exhib- ited a severe relapse of hyperaldosteronism. Extensive peritoneal metastases of a mixed aldosterone- and corti- sol-secreting adrenocortical carcinoma were found at abdominal laparotomy. In the light of this case report, we discuss the possibility that laparoscopic resection of adrenocortical tumors might contribute to their subse- quent peritoneal dissemination.
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Nonsuppressible primary hyperaldosteronism or Conn’s syndrome is caused in approximately 65% of cases by a unilateral adrenal tumor which is usually a benign adenoma and rarely a carcinoma. Other causes include bilateral diffuse or nodular adrenal hyperplasia, and a rare familial form, described as glucocorticoid-suppressi- ble or remediable hyperaldosteronism [1]. Clinical fea-
tures consist of hypertension with muscle weakness, poly- uria and polydipsia, and laboratory findings include hy- pokalemic alkalosis, inappropriate kaliuria and elevated plasma and urinary aldosterone levels with low plasma renin activity. We describe a case of classical primary hyperaldosteronism caused by an apparently benign adre- nal tumor which relapsed 6 months after laparoscopic adrenalectomy as a malignant carcinoma with peritoneal metastases.
Case Report
A 74-year-old man was admitted to our department for severe hypokalemia at 2.9 mEq/1 (normal: 3.5-5 mEq/1). His familial and medical history was uneventful except for a recently discovered hypertension. Physical examination was normal except for a high blood pressure at 170/90 mm Hg. Initial laboratory tests disclosed high plasma aldosterone levels (1.22 nmol/l; normal: < 0.4 nmol/l) and low but detectable plasma renin activity in the supine position (0.9 ng/ml/h; normal: 2-5 ng/ml/h). Abdominal CT scan was per- formed and revealed a right-sided, homogeneous and well delimited adrenal mass of 27 × 23 mm consistent with a benign adenoma (fig. 1).
The patient underwent laparoscopic transperitoneal partial right adrenalectomy under CO2 insufflation which allowed entire dissec- tion of the tumor and its retrieval with a protective bag. Macroscopic examination showed a 2 cm large tumor with ischemic necrosis and an hemorrhagic area of 0.7 cm. Histologic analysis of the tumor led to the diagnosis of a nonencapsulated, polymorphic adrenocortical ade- noma, associated with cortical hyperplasia surrounding the adeno- matous area. Nuclear abnormalities were reported as mild to moder-
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Fig. 1. Initial abdominal CT imaging showing a right-sided adrenal mass of 27 x 23 mm. The small size, round shape, well-defined mar- gins and homogeneous density are consistent with the diagnosis of a benign adrenocortical adenoma. Fig. 2. Histologic findings in the primary adrenal tumor: microscop- ic view of the tumoral tissue demarcated by normal adrenal cortex on the left side: The tumor is not encapsulated and consists of round or polygonal cells with regular nuclei and few mitoses or nuclear abnor- malities. HE. ×130. Fig. 3. Abdominal CT imaging performed 10 months after initial laparoscopic surgery and showing the appearance of multiple perito- neal masses, indicated by an asterisk.
3
1
2
ate and no typical sign of malignancy such as high mitotic activity, vascular or capsular invasion was seen (fig. 2).
After this surgical procedure, the patient remained normotensive and normokalemic during a 6-month period. At this time, he was readmitted for relapse of severe hypertension (180/110 mm Hg) and hypokalemia (2.5 mmol/l). Further biological analysis showed severe metabolic alcalosis (CO2 42 mmol/l; normal: 24-32 mmol/l), very high plasma (4.72 nmol/l) and urinary aldosterone concentrations (86.3 µg/24 h; normal: < 15 µg/24 h), undetectable plasma renin activity (<0.2 ng/ml/h; normal: 0.9-2 ng/ml/h), normal plasma corti- sol concentration at 8 a.m. (13.8 ug/dl; normal: 9-20 µg/dl) and nor- mal cortisoluria (39 µg/24 h; normal: 10-80 µg/24 h).
Several dynamic tests were performed (table 1). No change in aldosterone levels was observed after upright posture and ambula- tion, after captopril suppression, sodium load and furosemide intake, while plasma renin activity remained persistently low. An abdominal CT scan was performed and did not reveal any abnormality. To local- ize the source of this recurrent primary hyperaldosteronism, bilateral
adrenal venous sampling was planned but could only be performed 3 months later. It revealed a markedly high secretion of aldosterone (10.0-17.4 nmol/l) with slightly high cortisol levels (9.6-15.4 ug/dl) and diminished DHEA levels (1.8-3.7 nmol/l). No gradient was found in this hypersecretion of aldosterone and cortisol. Hormonal analysis also disclosed at that time the absence of circadian rhythm in plasma cortisol (8 h: 13.4 ug/dl; 20 h: 11.8 µg/dl), low ACTH levels (8 h: 7 pg/ml, 20 h: 2 pg/ml) and elevated cortisoluria (152 µg/24 h). 131I-iodocholesterol scintigraphy was negative. Thoracic CT scan was normal but the lower sections showed abdominal abnormalities. Abdominal scan was repeated and showed multiple epiploic masses (10 months after initial surgery) (fig. 3).
These tumors were resected by laparotomy, and histological anal- ysis showed cytologic features similar to those of the initially resected adrenal tumor with only minor differences, such as a slightly higher cellular density, a more extensive area of necrosis and a greater degree of nuclear pleomorphism (data not illustrated). Thus, those tumors were considered to be epiploic metastases of an adrenocorti-
| Test | Time 0 | Post-test |
|---|---|---|
| Posture1 | ||
| Potassium, mmol/l | 2.3 | 2.7 |
| Aldosterone, nmol/l | 3.45 | 3.54 |
| PRA, ng/ml/h | <0.1 | <0.1 |
| Sodium load2 | ||
| Potassium, mmol/l | 2.4 | 2.2 |
| Aldosterone, nmol/l | 4.3 | 3.5 |
| PRA, ng/ml/h | <0.1 | <0.1 |
| Furosemide3 | ||
| Potassium, mmol/l | 3 | 2.3 |
| Aldosterone, nmol/l | 4.3 | 4.63 |
| PRA, ng/ml/h | <0.1 | <0.1 |
| Captopril suppression4 | ||
| Potassium, mmol/l | 2.1 | 2.2 |
| Aldosterone, nmol/l | 3.7 | 4.25 |
| PRA, ng/ml/h | <0.1 | <0.1 |
PRA = Plasma renin activity.
Time of sampling for post-test measurements was 3 h after ambu- lating in the posture test and after captopril and furosemide adminis- tration, and 4 h after the start of saline infusion
1
12 h supine position followed by 3 h ambulating.
2 4 h perfusion of 2 liters 0.9% sodium chloride.
3 Oral intake of 40 mg furosemide.
4 Oral intake of 1 mg/kg captopril.
cal carcinoma secreting mostly aldosterone and accessorily cortisol. A medical adjuvant treatment with mitotane was started but not tolerat- ed and the patient was treated symptomatically. He died 2 years after diagnosis from extensive peritoneal dissemination of the tumor.
Discussion
Adrenocortical carcinoma (ACC) is a rare tumor that accounts for 0.023% of all malignancies [2]. The annual incidence is estimated at 0.5-2 cases per million. It occurs more frequently in women, the sex ratio being 1:2.5 [3], and mean age at diagnosis is around 35, men tending to be 5-10 years older at the age of diagnosis [2]. Malignant aldosteronomas account for only 2.5% of these cancers, corresponding to a very rare annual incidence of 0.12-0.5 cases per ten million people, according to a French study of 1992 [3]. More frequently, malignant functioning tu- mors are associated with Cushing’s syndrome, virilisation or both. Clinical symptoms may however be lacking in patients with an overproduction of active steroids since androgen-secreting tumors are asymptomatic in adult
males [4] and are revealed, like non-functioning tumors, by abdominal pain or mass, fever, or symptoms of metastatic diffusion. According to an Italian study, 63% of the pa- tients with ACC present with metastases, usually located in the lung, liver and distant lymph nodes [4]. More recent studies report only 22 or 30% of initial metastases, a lower incidence likely reflecting earlier diagnosis [3, 5, 6].
It is not always easy to differentiate between benign and malignant tumors on a histological basis as the only absolute criterion of malignancy is the extension of tumo- ral cells outside the adrenal glands, i.e. locoregional inva- sion or metastases [3]. Other relative criteria are a tumor size over 5 cm, a tumor weight of more than 100 g, archi- tectural disorders, tumor cell necrosis, hemorrhage, calci- fications, high mitotic activity, nuclear pleomorphism and vascular or capsular invasion [3, 4]. In the present case, histological analysis of the primary tumor showed a few of these characteristics, such as focal necrosis, calcifi- cations and mild nuclear abnormalities. However, most of the major criteria were lacking and the final pathologi- cal diagnosis of a benign adrenal adenoma was made.
After an initial presentation as a small, apparently benign aldosterone-producing adenoma, the tumor recur- red a few months after initial laparoscopic surgery as a malignant adenocarcinoma with peritoneal metastases. The possible contribution of laparoscopic surgery to the dissemination of the tumor, although not proven, needs to be discussed. Metastases of an adrenocortical tumor oc- curring soon after laparoscopic surgery have rarely been reported up to now, but serious concern has recently been raised among surgeons regarding the suitability of lapa- roscopy for resection of malignant tumors [7, 8], even though laparoscopic surgery induces less trauma and im- munosuppression than open surgery [9, 10]. Large tumors are usually not removed by laparoscopy because of their potential malignancy but the cut-off size is usually consid- ered to be around 5 cm [11]. The above-described 2 cm large tumor was thus still considered as an indication for laparoscopic surgery.
In animal models, evidence exists that tumoral im- plantation throughout the peritoneal cavity may occur after laparoscopy with CO2 insufflation. Indeed, Mathew et al. [7] observed a more widespread tumoral dissemina- tion under CO2 gas insufflation during laparoscopy than after gasless laparoscopy or laparotomy. The origin of this phenomenon seems not well clarified yet and may involve physical, metabolic and/or environmental effects of CO2 gas. Possible mechanisms to explain tumoral dissemina- tion are aerosolization of tumor cells, hematogenic and/or lymphatic spread, adhesion of tumor cells to instruments
or to the port itself, and some particular aspects of the surgical technique as e.g. specimen retrieval through a small incision [8]. Another hypothesis suggests changes in tumor biology in a CO2 environment [12]. Of course, we cannot exclude that the tumor had already seeded micro- scopically at the time of first surgery, or that disease was multifocal straightaway, involving both adrenal glands at diagnosis. However, several facts argue for the contribu- tion of laparoscopy to the tumoral dissemination: the short disease-free interval between apparently complete resection of the initial tumor and extensive relapse; the widespread peritoneal extension, a rather uncommon mode of dissemination of ACC, without any evidence for involvement of the contralateral adrenal gland or other metastatic locations, and similarities in histological char- acteristics between the apparently benign initial primary tumor and epiploic metastases, suggesting a ‘mechanical’ spread rather than a biological transformation of the tumor. No port site metastases, which are typical for tumor spillage due to laparoscopic surgery, were however observed in our patient. Interestingly enough, another similar case was reported recently, describing a peritoneal carcinomatosis occurring early after laparoscopic resec- tion of a small, apparently benign adrenal tumor with pre- clinical Cushing’s syndrome [13].
In most cases of ACC with hyperaldosteronism, hyper- secretion of cortisol and/or androgens is also found [1, 2] but they do generally not cause Cushing’s syndrome or virilisation [1]. In this case, there was no evidence for ini-
tial hypersecretion of cortisol by the small adrenal tumor but metastatic spread produced, in addition to the marked hyperaldosteronism, a slightly excessive and au- tonomous cortisol secretion without clinical signs of Cushing’s syndrome.
Adrenal malignancies bear a poor prognosis: the over- all 5-year mortality ranges between 75 and 90% in most series [2]. A 5-year actuarial survival rate of 53% was noted in local disease, but was reduced to 24% in locore- gional disease, while the mean survival time was only 1 year in patients with metastases [3, 4]. The mainstay of treatment for ACC is complete resection, and even in the presence of metastases, reduction of the tumor load appears useful to attenuate functional symptoms and facilitate subsequent chemotherapy [4]. The overall effi- ciency of mitotane therapy remains controversial [14]. Our patient was operated on a second time for debulking of the peritoneal metastatic masses and mitotane therapy was initiated but rapidly discontinued because of intoler- ance.
In conclusion, we describe a rare clinical case of an aldosterone-producing tumor evolving after laparoscopic surgery as a metastatic carcinoma with overproduction of aldosterone and cortisol. The attention of the reader is brought to the rare frequency of malignant aldosterono- ma, to the occasional cosecretion of aldosterone and corti- sol by such tumors and to the possible contribution of the laparoscopic procedure to the peritoneal spread of tumors with initial malignant potential.
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Copyright: S. Karger AG, Basel 1999. 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 1999. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.