Case report
Potassium losing, aldosterone producing adrenocortical carcinoma: a rare presentation
Zahir S Hussain, Smitha S Rao ®, Wajith Z Hussain, Shikhil Puzhakkal
Department of Endocrine and Breast Surgery, Madras Medical College and Research Institute, Chennai, Tamil Nadu, India
Correspondence to Professor Zahir S Hussain; zahirdr@gmail.com
Accepted 10 August 2020
SUMMARY
Adrenocortical carcinomas (ACCs) are rare malignancies with an incidence of one to two per million per year. Aldosterone-producing ACCs (APACs) are extremely rare with an incidence less than 1%. We describe a rare case of APAC, presenting with episodic lower-limb weakness and hypertension. Our patient was found to have serum aldosterone levels of 20.8 ng/dl (2.5-15.2) with persistent hypokalaemia and a 9.7×8.3×7.7 cm right adrenal mass, which was suspicious of malignancy on evaluation. He underwent a complete surgical resection which confirmed the diagnosis of ACC and normalised his aldosterone and potassium levels. He was then subjected to postoperative chemotherapy. Postoperative adjuvant chemotherapy with mitotane has a role in preventing recurrence.
BACKGROUND
Adrenocortical carcinomas (ACCs) are rare with an incidence of one to two per million per year. Most (60%) are functional, most of which are Cushing’s syndrome.2 ACCs are generally a post- operative diagnosis. Aldosterone-producing ACCs (APACs) are extremely rare with an incidence <1%. Preoperative complete evaluation is mandatory to establish diagnosis and plan treatment.3 Complete surgical resection would suffice in clearing the disease in most cases diagnosed early. Postoper- ative diagnosis is established by histology and modified Weiss criteria.4 We describe a rare case of APAC with clinical presentation of hyperaldo- steronism coexisting with endocrine hypertension and adrenal malignancy. A few anecdotal cases have been reported in the literature, most of them coexisting with Cushing’s syndrome. This case is reported to highlight the dilemma in diagnosis and management of such cases, bringing about a better management protocol.
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C BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
To cite: Hussain ZS, Rao SS, Hussain WZ, et al. BMJ Case Rep 2020;13:e235317. doi:10.1136/bcr-2020- 235317
CASE PRESENTATION
A 24-year-old sports man was referred to us with episodic lower-limb weakness (periodic paralysis) and headache for 3 months. He had no significant family history. His hypertension was controlled with amlodipine 5 mg/day. History had neither features suggestive of Cushing’s syndrome nor pheochromocytoma (PCC). On examination, he had a blood pressure of 146/90 mm Hg with no peripheral oedema. On palpation, he had a vague mass palpable in the right upper quadrant.
INVESTIGATIONS
Investigations revealed hypokalemia, which persisted despite serial corrections (table 1). Further evaluation revealed hyperaldosteronism with ratio of plasma aldosterone concentration to plasma renin activity 27.38. Twenty-four hours urine frac- tionated normetanephrines, metanephrines and cortisol were normal. Thyroid function tests, lipid profile, blood sugars and complete blood count were normal. The patient had normal cardiac eval- uation. Contrast-enhanced CT (CECT) of abdomen showed a right adrenal mass of 9.7x8.3×7.7 cm with irregular margins, lipid poor with decreased adrenal wash out, suspicious of adrenal malignancy. It had an average Hounsfield units (HU) of 24 in the unenhanced phase with 50 HU in the venous phase and 38 HU in the delayed phase with an absolute wash out of 46.15% and no liver metas- tasis (figure 1).
DIFFERENTIAL DIAGNOSIS
Hypokalaemia with hypertension suggested adrenal aetiology. This led us to a differential diagnosis of PCC, adrenal adenoma and ACC. PCC had to be considered due to presence of hypertension with heterogenous adrenal mass on imaging. Adrenal adenoma was considered due to the classical features of hyperaldosteronism and hypertension. Suspicious features on imaging led us to consider the possibility of malignancy as one of our differ- entials. In view of hypokalaemia and hypertension,
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| Table 1 Biochemical evaluation of our patient | ||
|---|---|---|
| Parameters | Result | Normal range |
| Serum potassium | 2.9-3.3 | 3.5-4.8 mEq/L |
| PAC | 20.8 | 2.5-15.2 ng/dL |
| PAC/PRA | 27.38 | <20 |
| 24 hours urine fractionated normetanephrines | 148.24 | <350 µg |
| 24 hours urine fractionated metanephrines | 191.76 | <600 µg |
| Serum 8:00AM cortisol | 110 | 170-500 nmol/L |
| 24 hours urinary free cortisol | 101 | 11-110 nmol/day |
PAC, plasma aldosterone concentration; PRA, plasma renin activity.
possibility of mineralocorticoid precursor as a cause for hyper- aldosteronism could be considered, though not evaluated in our case due to elevated aldosterone levels.
TREATMENT
Normokalaemia was achieved with oral and intravenous potas- sium before investigations. Surgery was performed by a skilled endocrine surgeon. Right open adrenalectomy revealed a large, well-encapsulated right adrenal tumour of 12×10×8cm with no surrounding invasion. There were no liver surface metas- tases or direct invasion. Ipsilateral kidney was free. There were no enlarged lymph nodes. Surrounding periadrenal fat, lymph nodes and hilar lymph nodes were excised in order to ensure R0 surgical clearance. Thorough wash was given before closure. No postoperative complications occurred and he recovered well. A postoperative diagnosis of stage II ACC was made.
OUTCOME AND FOLLOW-UP
Cut surface showed a grey brown colour with haemorrhage and calcified areas. Microscopy was suggestive of ACC with a modified Weiss score of 5/7, Ki67 60% and all surgical margins free. Adjacent fat that was received contained no positive lymph nodes (table 2 and figure 2). His blood pressure and potassium levels normalised over 10 days postoperatively. Though histo- pathology confirmed clear margins, the tumour was considered aggressive with a high modified Weiss score and Ki67. He was given six cycles of adjuvant chemotherapy with etoposide and cisplatin based on the multidisciplinary team (MDT) decision. Mitotane was not opted for in this case due to patient intoler- ance. He tolerated the above regimen with minimal side effects. It was decided against radiotherapy because of the R0 resection, free margins and negative lymph nodes on histology. He has completed 2 years of 3 monthly follow-up with no signs of recur- rence on clinical examination and imaging.
DISCUSSION
ACCs are hormonally active (60%), excessive cortisol accounting for most of them. Our case is an extremely rare entity of ACC with aldosterone excess, with a rarer presentation of endocrine hyperten- sion and severe hypokalaemia. He was a young man contrary to the common woman bimodal distribution.4
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Endocrine hypertension with hypokalaemia as presentations has been noted in other cases (table 2). Routine hormonal workup may incidentally reveal other hormones in excess. Hypercortisolism or virilising tumours suggest the presence of malignancy, needing evalu- ation. These hormones normalise postoperatively, as seen in our case. Most malignancies are non-functional. It is of utmost importance to simultaneously rule out a PCC by doing 24 hours fractionated meta- nephrines. PCC can be a great mimic, requiring a preoperative alpha blockade before planned surgery.4
A malignant lesion is usually >4cm, >10HU with less than 50% washout, while a benign lesion is generally <10HU on unenhanced image with high lipid density. However, 30% of adenomas can still turn out lipid poor. Comparison of imaging characteristics with other reported cases is detailed in table 2.
Presence of malignancy in the adrenal can be evaluated based on surrounding invasion, metastases on preoperative imaging, intraop- erative features and modified Weiss score on postoperative histology. Our patient had a score of 5/7 suggestive of malignancy. A case with no preoperative suspicion of malignancy will purely rely on the score for characterisation of malignancy and further staging, as seen in our case. Weiss score has been an independent prognostic factor for disease-free survival apart from tumour size and functional status as suggested by Beom et al. It has been modified to include major features, omitting the less important ones. A modified Weiss score has sensitivity of 96% for malignancy.45
Adjuvant mitotane may help to improve survival rates after complete resection. There is lack of robust evidence for the utility of mitotane in early resectable disease. Daga et al reported an APAC subsequently treated with mitotane.6
ACCs co-secreting aldosterone and cortisol have been reported. Those cases presenting with Cushing’s syndrome have poor blood
| Table 2 Comparison of our case with other reported cases highlighting the imaging and lab findings | ||||
|---|---|---|---|---|
| Comparison | Our case | Abma et al1 | Lazaro and Adorable-Wagan2 | Ohashi et al3 |
| Presentation | Hypertension, hypokalemic periodic paralysis | Hypokalemic hypertension | Hypokalemic hypertension, subclinical Cushing's syndrome | Hypokalemic hypertension, Cushing's syndrome |
| Hormone excess | Aldosterone | Aldosterone, cortisol | Aldosterone, cortisol, estradiol | Aldosterone, cortisol, DiHydroEpiAndroSterone |
| Imaging | Suspicious of malignancy | Malignancy | Lipid poor tumour, well defined | Malignant with liver metastasis |
| Stage | II | Recurrence, IV | II | IV |
pressure control when compared with the ones purely secreting aldosterone as evident in our case. A case report published in 2017 suggested that hypertension due to hyperaldosteronism is well controlled with medication.7
There is an alternate possibility of hypertension and hypokalaemia due to the production of mineralocorticoid precursors as suggested by Müssig et al. This particular report found 11-deoxycorticosterone as the primary cause of profound hypokalaemia since the aldosterone levels were within normal limits. In our case, since the aldosterone levels were elevated, further estimation of precursor steroids was not done. However, the possibility of co-secretion of aldosterone with the precursors could still be considered, though the hypokalaemia was mild and corrected with medication.8
The most recent guidelines by European Society of Endocrinology recommend evaluation of hormone excess in all adrenal tumours with hypertension along with CT as the basic imaging modality in all cases suspicious of carcinoma. Once the disease is staged appro- priately, subsequent management should be planned in an MDT. Open surgical complete resection with lymphadenectomy followed by chemotherapy based on prognostication is the best treatment. Follow-up is with regular imaging and hormone evaluation once in 3 months for 2 years followed by 6 monthly evaluation.9
It is imperative to remember that there is a high chance of recur- rence or metastases with recurrence of hyperaldosteronism in such cases. This makes frequent follow-ups mandatory, adding adjuvant systemic therapy prolongs disease-free and overall survival of these patients.9
CONCLUSION
Hypertensive patients with persistent hypokalaemia can create a dilemma between various functional adrenal tumours, leading to a laborious evaluation process.
CECT abdomen in our case highlighted ACC as one of the differential diagnoses.
Cushing’s syndrome is the most common presentation of adrenal carcinomas with a few co-secreting tumours reported in the past; APACs (<1%) are to be remembered as
Learning points
Most common hormone secreted with ACC remains corticol.
Imaging forms a main modality to diagnose this condition.
Long term follow up after RO resection and chemotherapy is mandatory
part of the differential diagnosis. Hyperaldosteronism could possibly be a less aggressive presentation of ACC.
Complete surgical excision significantly affects survival with long-term stringent follow-up, repeated imaging and biochemical workup.
Decision on adjuvant chemotherapy can be individualised and targeted for every patient.
Twitter Smitha S Rao @raosmits
Acknowledgements The authors thank the patient for his kind cooperation for the article and the images.
Contributors All authors were responsible for patient diagnosis and management. ZSH and SSR were responsible for the data collection, preparation of manuscript and literature review. WZH and SP took part in the review and revision of the article before submission.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
ORCID İD Smitha S Rao http://orcid.org/0000-0002-8350-5674
REFERENCES
1 Abma EM, Kluin PM, Dullaart RPF. Malignant aldosterone-producing adrenal tumour: reoccurrence with glucocorticoid excess without hyperaldosteronism. Neth J Med 2008;66:252-5.
2 Lazaro K, Adorable-Wagan P. Aldosterone-Producing adrenocortical carcinoma. JAFES 2018;33:57-62.
3 Ohashi K, Hayashi T, Sakamoto M, et al. Aldosterone-Producing adrenocortical carcinoma with prominent hepatic metastasis diagnosed by liver biopsy: a case report. BMC Endocr Disord 2016;16:1-5.
4 Seccia TM, Fassina A, Nussdorfer GG, et al. Aldosterone-producing adrenocortical carcinoma: an unusual cause of Conn’s syndrome with an ominous clinical course. Endocr Relat Cancer 2005; 12:149-59.
5 Beom SH, Lee K-W, Yang Y, et al. Metastatic adrenocortical carcinoma presenting simultaneously with Cushing’s and Conn’s syndromes: a case report. Jpn J Clin Oncol 2011;41:1287-91.
6 Daga G, Sharma S, Mittal V. Bilateral aldosterone-producing adrenocortical carcinoma: a rare entity. Indian J Surg Oncol 2017;8:88-90.
7 Veron Esquivel D, Batiz F, Farias Vega A, et al. Adrenocortical carcinoma, an unusual cause of secondary hypertension. BMJ Case Rep 2016;2016:bcr2016217918-4.
8 Müssig K, Wehrmann M, Horger M, et al. Adrenocortical carcinoma producing 11-deoxycorticosterone: a rare cause of mineralocorticoid hypertension. J Endocrinol Invest 2005;28:61-5.
9 Fassnacht M, Dekkers O, Else T, et al. European Society of endocrinology clinical practice guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol 2018;179:G1-46.
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