ORIGINAL ARTICLE
Predictors of malignancy in primary aldosteronism
Ayman Agha . Matthias Hornung . Igors Iesalnieks · Andreas Schreyer . Ernst Michael Jung . Assad Haneya . Hans J. Schlitt
Received: 28 January 2013 / Accepted: 8 September 2013 /Published online: 19 September 2013 C Springer-Verlag Berlin Heidelberg 2013
Abstract
Introduction Primary aldosteronism (PA, also Conn syndrome) is a benign disease in majority of cases. However, malignant transformation has been described. Present study reports on three cases of aldosterone producing adrenocortical carcinoma (APAC) in comparison to patients with benign PA. Patients and methods Data of patients undergoing adrenalec- tomy for benign PA were compared to patients with APAC. Retrospective chart analysis was performed. All patients re- ceived spironolactone for 6-8 weeks preoperatively.
Results Seventy-four patients underwent adrenalectomy for PA between 1994 and 2011. Three of them revealed an APAC. Patients with APAC presented with a significantly lower serum potassium level (1.7 mmol/l vs. 3.4 mmol/l, p=0.001) and significant larger tumors (5.2 vs. 1.8 cm, p=0.002). In addition, aldosterone/renin (A/R) ratio 675 in patients with APAC as compared to 74 in patients with benign PA (p=0.0001). Sixty-eight of 71 patients with benign PA underwent minimal invasive surgery, whereas all three patients with APAC were
Ayman Agha and Matthias Hornung contributed equally.
A. Agha . M. Hornung () . H. J. Schlitt Department of Surgery, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany e-mail: matthias.hornung@klinik.uni-regensburg.de
A. Schreyer · E. M. Jung Department of Radiology, University Hospital Regensburg, Regensburg, Germany
A. Haneya Department of Cardio-thoracic Surgery, University Hospital Regensburg, Regensburg, Germany
I. Iesalnieks Department of Surgery, Marienhospital Gelsenkirchen, Gelsenkirchen, Germany
operated conventionally. All patients with APAC developed disease recurrence 6-18 months postoperatively.
Conclusion Tumor size >4 cm and a very high A/R ratio seems to predictors of malignancy in patients with PA. If these criteria are present, open adrenalectomy should be performed instead of endoscopic procedure.
Keywords Conn syndrome . Aldosterone producing adrenocortical carcinoma · Adrenalectomy
Introduction
The prevalence of primary aldosteronism (PA) in patients with essential hypertension lies between 0.5 and 1 %; however, it might be as high as 5-13 % if all hypertensive patients would undergo a hormonal screening [1-5]. Aldosterone producing adenoma (APA) is one of the most common causes of PA [6, 7] and is the leading cause of secondary hypertension. The biochemical triad described by Conn 1955 included arte- rial hypertension, low serum potassium level, and a high serum aldosterone/renin ratio [8]. However, about 50 % of patients with Conn’s syndrome are normokalemic at presen- tation [9].
Malignant transformation of a Conn adenoma to an aldo- sterone producing adrenocortical carcinoma (APAC) is very rare. First description of APAC was published by Foye and Feichtmeier [10]. The incidence of APAC between patients with PA is 1-2.5 % [11, 12]; however, there have been only single cases reported and a systematic review is still missing in literature due to the rarity of the disease [7, 13-24] (Table 1). Some publications do not mention aldosterone level and aldosterone/renin (A/R) ratio [25-27].
Here, we report three cases of APAC and compare them to patients with benign PA.
| Author | Year | No. of patients (n) | Hypokalemia (mmol/l) | Tumor size (cm) | PAC/PRA (ng/dl:ng/ml/h) | |
|---|---|---|---|---|---|---|
| Taylor | 1982 | 1 52 J/w | 3.0 | 9 | 1,050 | |
| Ludvik | 1988 | 1 | 48 J/m | Severe hypokalemia | 3 | 438.8 |
| Deckers | 1999 | 1 74 J/m | 2.9 | 2.7 | 35.1b | |
| Sweeney | 2002 | 1 52 J/w | 2.7 | 6 | 52 | |
| Honda | 2004 | 1 44 J/w | 3.1 | 3 | 290 | |
| Abma | 2008 | 1 | 52 J/w | 3.0 | 4 | 164.5b |
| Zinnamosca | 2010 | 1 | 55 J/m | 2.42 | 5ª | 778 |
a Adrenal gland measured 5x3 x 1.5 cm, adrenal nodule 2 cm
b Translation from nanomoles per liter to nanogram per deciliter
Patients and methods
Seventy-two patients underwent surgery for symptomatic PA at the University Hospital of Regensburg between January 1994 and December 2011. Two more patients with APAC were admitted to our department after surgery at external hospitals. Demographic, clinical, and surgical data of all patients were analyzed retrospectively with special attention paid to APAC patients. Biochemical diagnosis of PA was assessed by hor- mone analysis preoperatively in all patients. The plasma aldo- sterone concentration to plasma renin activity ratio (PAC/PRA ratio) was considered to be diagnostic at the level of more than 30 (ng/dl)/(ng/ml/h).
Orthostatic tolerance test and sodium chlorine infusion test were performed to confirm the diagnosis. Imaging procedures were used to localize adrenal adenoma. Adrenal venous sam- pling (AVS) was performed in case of bilateral tumors. All patients received preoperatively 200 mg spironolactone daily for 6-8 weeks. Normal serum aldosterone level, postoperative A/R ratio of <15, and a normal potassium serum level 3 months after surgery were considered as successful treatment of PA. Furthermore, three patients with APAC were classified with cases from literature into one group (group I) and compared to our 71 benign cases with PA (group II) regarding potassium level, tumor size, and A/R ratio.
Statistics
For statistic evaluation, SPSS (version 16.0 SPSS for win- dows, LEAD technologies) was used. The Chi2 test and the Wilcoxon signed-rank test was used for the evaluation of the distribution patterns. Using the t test, p value of <0.05 was regarded as statistically significant.
Results
In total, 74 patients with symptomatic PA undergoing adrenal- ectomy were analyzed retrospectively. Sixty-one patients presented with arterial hypertension, and 57 patients were
hypokalemic. AVS was used in four patients with bilateral adrenal tumor, and the correct side of the APA could be iden- tified in all these cases. Three patients with APAC were identi- fied (incidence, 4 %). Patients with APAC showed signifi- cantly lower serum potassium level than patients with be- nign PA (mean: 1.7 mmol/l vs. 3.4 mmol/l; p=0.001); tumors were significantly larger (5.2 vs. 1.8 cm, p=0.002) and the A/R ratio was significantly higher [675 vs. 74 (ng/dl)/(ng/ml/h), p=0.0001, Table 2].
Comparing all APAC (three own cases + literature) with our benign PA, one can find significant differences regarding tumor size and A/R ratio (p=0.001 and 0.014) (Table 3). Sixty-eight of 71 patients with benign PA underwent laparoscopic trans- or retroperitoneal surgery; the remaining three patients were op- erated conventionally because of high BMI and previous ab- dominal surgeries. All three patients with APAC received open adrenalectomy. In the first case, surgical approach started laparoscopically but it was converted to open approach because of suspected infiltrative growth followed by right adrenalecto- my with interaortocaval lymph node dissection. The remaining two patients underwent surgery which included left adrenalec- tomy and para-aortic lymphadenectomy. In all three cases, postoperative pathology revealed highly differentiated carcino- ma of the adrenal cortex with capsule and venous infiltration but without infiltration of surrounding tissue.
Intraoperative blood loss and operation time were signifi- cant lower in patients with benign tumors (p=0.005, p=0.006) (Table 4). Surgical and oncological data of the three patients with APAC are shown in Table 5.
Follow-up
At 13 months after surgery, patient no.1 developed a new- onset tumor of 2.5×1.5 cm between the right kidney and the spinal column and with multiple lung metastases. A palliative chemotherapy + spironolactone were initiated. Patient died 19 months after the first operation.
Patient no. 2 received adjuvant postoperative chemotherapy with mitotane. However, he developed a local recurrence in the left upper abdomen 18 months after surgery. It was resected.
| Variable | Benign PA (n=71) | Malignant PA (n=3) | p value |
|---|---|---|---|
| Age (year) | |||
| Median/range | 31.8 (48-55.6) | 55 (58-69) | 0.006 |
| Gender | |||
| Male/female | 23/48 | 2/1 | n.s |
| Art. hypertension | |||
| Yes/no | 61/10 | 3/0 | n.s |
| Hypo/normokalemia | 67/4 | 3/0 | n.s |
| Potassium | |||
| (mmol/l) | 3.4 (1.8-4.2) | 1.7 (1.5-1.8) | 0.001 |
| Mean body mass index kg/m2 | 27.3(23.7-38.8) | 32.5 (31.2-35.7) | 0.721 |
| Localization of the tumor | |||
| Left/right | 45/26 | 2/1 | n.s |
| Mean tumor size | |||
| (cm) | 1.8 (1.6-2.7) | 5.2 (4.4-6.1) | 0.002 |
| A/R Q | 74 (45.5-281.5) | 675 (495-1.298) | 0.0001 (ng/ml/h:ng/dl) |
Thirty months after first surgery and 12 months after the second, patient is disease-free.
Patient no. 3 developed a local recurrence 1 year after surgery. Second surgery was performed; it included resection of the recurrent lesion, splenectomy, and pancreas tail resec- tion. Postoperatively, patient was treated with mitotane. He is disease-free 24 months after primary and 12 months after the second surgery.
Discussion
Our results as a largest series in the literature confirm the three criteria, which have been described to be suggestive for APAC in the literature (Table 1): Severe hypokalemia, very high aldosterone/renin ratio, and large (over >4 cm) Conn tumors.
Preoperative diagnostic provides no significant evidence to differentiate between benign and malignant PA. In the present
| Criteria | Benign aldosteronism (PA) | Malignant aldosteronism (APAC) | p value |
|---|---|---|---|
| Potassium (mean) mmol/l | 2.85 | 2.45 | 0.222 |
| Tumor size (mean) cm | 1.9 | 4.5 | 0.001 |
| PAC/PRA (mean) ng/dl:ng/ml/h | 220.8 | 527.6 | 0.014 |
Potassium (six cases in literature + three own cases), tumor size, and PAC/PRA ratio (seven cases in literature + three own cases)
study, the rare disease of APAC is analyzed considering own cases and literature. According to the classical triad of PA [8] until today, it is still unclear which clinical and biochemical parameters could be helpful to distinguish APAC in order to conclude potential therapeutic consequences. In literature, three criteria seem to be helpful in the diagnosis of malignancy (Table 1).
1. Severe hypokalemia
2. Very high aldosterone/renin ratio
3. Big conn tumors over 4 cm
Hypokalemia
One of the leading symptoms of PA is hypokalemia. Severe hypokalemia and consecutive metabolic alkalosis can be explained by high aldosterone secretion and chronic diarrhea [7]. In patients with APAC, a significant lower potassium level compared to PA group was evident (p=0.001), which is compatible to published data (Table 2). However, potassium level was lower by trend in cases of APAC than PA but reached no significance (p=0.222) (Table 3). Ludvik et al. even postulate that serum potassium level of 2.5 mmol/l should be considered as a sign for malignant aldosteronism [16]. Classical symptoms of severe hypokalemia in PA are neurological discomfort and muscular weakness to the point of tetany and paresthesia [28]. The three patients in this study suffered from severe headache and neck muscle paresis. One of them showed during tumor recurrence weakness and pain with neurological deficit at both upper extremities.
| Table 4 Intra- and postoperative results of the two groups | Variable | Benign PA (n=71) | malignant PA (n=3) | p value |
|---|---|---|---|---|
| Surgical procedure | ||||
| Laparoscopic/open | 68/3 | 0/3 | – | |
| Laparoscopic technique | ||||
| Lateral position, transperitoneal | 24 | 0 | – | |
| Retroperitoneoscopic | 44 | 0 | – | |
| Hospital stay (days) | ||||
| Median/range | 7.5 (5.5-10) | 16 (12-20) | 0.012 | |
| Loss of blood | ||||
| (ml+/-SD) | 50+/-15 | 220 (150-300) | 0.005 | |
| a Reasons for conversion: n=2, | Operating time (min) | |||
| conversion from retroperitoneal | Median/range | 76.5 (43.7-95.4) | 185(165-215) | 0.006 |
| to open technique due to high | Conversation rate | |||
| BMI >35 kg/m2; n=1, conver- sion from transperitoneal to open | n (%) | 3ª | – | – |
| technique due to intraoperative | Complications, n (%) | |||
| bleeding | Intraoperative bleeding | 1 | 0 | n.s |
| b Two patients after retroperitone- | Pancreatitis | 0 | 1 | n.s |
| al adrenalectomy due to close tro- car positioning near the 12th rib | Irritation of subcostal nerves | 2b | 0 | n.s |
A/R ratio
Biochemical diagnosis of PA plasma aldosterone concentra- tion and plasma renin activity over 30 (ng/dl)/(ng/ml/h) are required [28-31]. A/R ratio >20 and plasma aldosterone con- centration (PAC) of 15 ng/dl are also used for the diagnosis, and a link has been stated between the severity of hyperten- sion with the presence or absence of hypokalemia [12, 32]. In benign, PA A/R ratio is only slightly elevated whereas very high A/R ratio is considered as sign for malignancy. Patients
of our study revealed significant differences between both groups, which can be confirmed by publications listed in Tables 2 and 4.
Tumor size
Diagnosis of malignant adrenal cortex tumors is extremely difficult due to the clinical and radiological symptoms. Tumor size represents an important sign for malignancy, but is not an
| 1 | 2 | 3 | |
|---|---|---|---|
| Age (year) | 69 | 58 | 55 |
| Gender (male/female) | Male | Male | Female |
| Localization of the tumor | Right | Left | Left |
| Tumor size (cm) | 6.1 | 5.2 | 4.4 |
| OP procedure first operation | AD+LND | AD+LND | AD+LND |
| OP time (min) | 215 | 185 | 165 |
| Time of recurrence (months) | |||
| Local | 13 | 18 | 12 |
| Distant | 13 (lung) | – | – |
| OP procedure recurrence | No tumor resection due to multiple lung metastases | Tumor resection left upper abdomen | Tumor resection with splenectomy and pancreas tail resection |
| Disease-free survival | 13 months | 30 months after initial surgery | 24 months after initial surgery |
| Survival (months) | 19 | Alive | Alive |
AD adrenalectomy, LND lymph node dissection interaortocaval for right tumor and para-aortal for left tumors
absolute predictor [33, 34]. For several authors, operation is indicated from a tumor size of 4 cm [35, 36]. Usually, in case of APA, tumor are smaller than 2 cm and mostly there are benign [37, 38], but bigger tumors can potentially be malig- nant. Carcinomas of the adrenal cortex can reach a size be- tween 11 and 14 cm [39], which means that APAC can be smaller than adrenocortical carcinomas and bigger than APA [24]. In our study, mean tumor size in case of APA was 1.7 cm compared to 5.2 cm in APAC (p=0.002). Almost all published carcinomas of the adrenal cortex reveal tumor size >4.5 cm (Table 3).
Age and gender
Significant difference was found in the age of patients with APAC compared to the group with APA (55 vs. 32 years, p=0.006). Wu et al. reported 145 patients with APA and the mean age of 37.9 years [40]. However, several studies of APA patients showed a mean age of about 50 years [41-45]. Distribution of gender revealed more female patients with APA, but no significance could be detected. In literature also, different data could be found concerning this matter. Proportion of gender was similar in the study of Wu et al. (male/female: 46.2 vs. 53.7 %) [40], whereas data of Japan showed a male/female ratio of 24/11 (68.6 vs. 31.4 %) [45]. In summary, data regarding age and gender are not consistent, and therefore, a clear statement could not be made.
Prognosis
Adrenocortical carcinomas are characterized by a high risk of recurrence up to 80 % [46] and a bad prognosis. Presented patients in this study developed almost after 12, 18, and 24 months local recurrence in spite of initial curative resection. Five-year survival between 23 and 60 % has been reported [47, 48]. Prognosis of malignant PA is comparable to AC according to published data [16, 18]. Seccia et al. reported in a cohort of 58 cases a mean survival time approximately 1.5 years [38].
Limitations
Our systematic comparison between the usual benign and the very uncommon malignant PA is limited by the inhomogene- ity of both groups, which is caused by the rare incidence of malignancy. Furthermore, patients were analyzed retrospec- tively. But, nevertheless, this study lets recognize important preoperative predictors for malignancy in case of PA.
Conclusion
Summarizing our data with published cases a relation between malignant degeneration of PA and the typical criteria (tumor size >4.5 cm and very high A/R ratio) can be distinguished. The presence of these two criteria should help to differentiate malignant tumor, which requires, in our opinion, open surgery.
Conflicts of interest None.
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