Virilising adrenocortical carcinoma
Diogo Nunes Correia, Inês Redondo de Carvalho, Jeenal Assuani Mangi
Universidade Nova de Lisboa Faculdade de Ciências Médicas, Lisboa, Portugal
Correspondence to Jeenal Assuani Mangi; a2015250@nms.unl.pt
Accepted 5 May 2021
SUMMARY
Adrenocortical carcinoma (ACC) is a rare malignancy, with an estimated annual incidence of 0.7-2 cases per million and a median overall survival of 3-4 years. Hormone-secreting ACCs represent most cases; of these, only a small minority presents with virilisation alone. Early diagnosis is key to increase the chances of a better outcome. Here, we report a case of a 41-year-old woman who presented with menstrual irregularities, hirsutism and virilising symptoms, associated with abdominal discomfort and constitutional symptoms. On physical examination, there was a palpable mass in the right upper quadrant. Laboratory workup revealed elevated serum androgens. The imaging study showed a 163×110×122 cm right adrenal mass with features consistent with ACC and suggested potential hepatic invasion. Our patient underwent surgical resection, and the histopathological findings confirmed the diagnosis. She was referred to a specialised centre for follow-up and adjuvant therapy.
BACKGROUND
Adrenocortical carcinoma (ACC) is a rare malig- nancy, with an estimated annual incidence of 0.7-2 cases per million.1 It has higher prevalence in females and has a bimodal age distribution, with peaks of incidence at the first and the fourth to fifth decades.2 ACC is also one of the most aggressive endocrine tumours with a median overall survival of 3-4 years.3 Clinical findings may include adrenal hormone excess syndromes, local mass effect and
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To cite: Correia DN, Carvalho IR, Mangi JA. BMJ Case Rep 2021;14:e242895. doi:10.1136/bcr-2021- 242895
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constitutional symptoms.3 Hormone-secreting ACCs represent approximately 60% of the tumours.1 3 Most frequently, the patients present either hypercortisolism alone or mixed with viril- isation. In adults, isolated hyperandrogenism is reported in only 3%-5% of cases.4 Local mass effect symptoms include abdominal pain, early satiety, nausea and vomiting. Constitutional symptoms are seldom present and include fatigue, anorexia and weight loss.3
The multitude of possible clinical presentations poses a challenge, delaying the diagnosis and thereby the treatment. Due to the rarity of the disease, the evidence is still weak,3 emphasising the importance of a multidisciplinary and individualised approach.
Here, we present a case which illustrates this challenge. It is a rare case of an androgen-secreting ACC with a significant size, presenting with virilisa- tion, mass effect and constitutional symptoms.
CASE PRESENTATION
A 41-year-old woman was referred to general surgery due to a 10-month history of hirsutism, virilising symptoms, including deepening of the voice and clitoris hypertrophy, and menstrual irregularities. Additionally, for the last 3 months, she presented worsening abdominal and right lumbar pain, abdom- inal fullness, asthenia and anorexia. Her past and family history was unremarkable. On physical exam- ination, a hard, poorly defined abdominal mass was palpated on the right upper quadrant. The patient was normotensive and had no history of hypertension, paroxysmal headaches, palpitations or diaphoresis.
INVESTIGATIONS
A hormonal study was conducted, which revealed a marked elevation of serum androgen levels, with
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Case report
dihydroepiandrosterone-sulfate (DHEA-S) of 5.37 (N: 0.25- 2.2µg/mL), total testosterone of >2160 (N: 5.71-77.0 ng/dL) and free testosterone of 79 (N: 0.8-2.3 pg/mL). The 24-hour urine-free cortisol was 41 (N: 28.5-213.7 mcg/24 hours). Metanephrines were normal.
The abdominal MRI (figure 1) showed a large 163×110×122 cm heterogeneous right adrenal mass, compressing the surrounding structures. It presented lobulated contours and areas of necrosis and haemorrhage. These findings were highly suggestive of an ACC. Additionally, intraparenchymal nodular areas were described on the VIII liver segment, raising the possibility of direct hepatic invasion.
For staging purposes, a thoraco-abdomino-pelvic CT scan was performed, which showed no suspicious distant lesions or adenopathy. A positron emisson tomography (PET) scan was also conducted, revealing possible diffuse osteomedular metastasis.
DIFFERENTIAL DIAGNOSIS
Our patient presented with manifestations of hyperandrogenism (hirsutism, virilisation and menstrual irregularities), confirmed by the laboratory results. Her age, rapid development of severe hyperandrogenism and abdominal mass raised the suspicion of an androgen-secreting ACC or an ovarian tumour, two rare and serious causes of androgen excess. The elevated levels of DHEA-S associated with an upper abdominal mass were more suggestive of an adrenocortical rather than ovarian tumour. The cortisol levels were within normal range, which correlates with the absence of Cushing syndrome features in our patient. Although no clinical manifestations of pheochromocytoma were present, to exclude this diagnosis urinary metanephrines were also measured, which were normal. These results highly suggested an isolated androgen- secreting ACC, which was further supported by the abdominal MRI.
TREATMENT
Following a multidisciplinary discussion, a surgical approach with curative intent was proposed. The surgery comprised a laparotomic en bloc right adrenalectomy, right hepatectomy and cholecystec- tomy. Intraoperatively, a big and hypervascular mass, compressing the liver, was found (figure 2). An isolated lesion was also identi- fied on the IVb hepatic segment, leading to the extension of the hepatectomy to this segment. No complications were encountered intraoperatively.
Gross examination of the surgical specimen (figure 3) revealed a multinodular tumour with 210x120×100mm and 650g, which had entirely replaced the adrenal gland. Two hepatic nodules were
also identified, most probably metastatic, since continuous invasion of the hepatic tissue was absent.
The histopathological examination characterised the mass as a high-grade, oncocytic tumour, with extensive necrosis, invading the lymphovascular and peripheral tissues. The neoplastic tissue exhib- ited strongly positive and diffuse synaptophysin with only focally positive inhibin and melan-A. Additionally, the tumour displayed a high proliferative index, with Ki-67 of 40% and mitotic activity of more than 20 per 50 high power fields (HPF). The modified Weiss criteria supported the diagnosis of ACC.
According to the eighth edition of the TNM (tumour, node, metastases) system, the tumour was staged as pT3NxM1 (stage IV) with R1 resection status.
The patient remained stable during the hospital stay. On the eighth postoperative day, a CT scan was obtained, which showed a new nodule in the II hepatic segment, possibly a secondary lesion. The patient was discharged after 11 days of hospitalisation.
OUTCOME AND FOLLOW-UP
Within 1 month, in the follow-up appointment, a partial regres- sion of the virilisation symptoms was noted. A thermoablation was initially planned for the single hepatic nodule found on the CT scan. However, in a follow-up MRI conducted 3 months after surgery, multiple hepatic metastases were observed (figure 4), and therefore, the thermoablation was not performed.
The patient was referred to a specialised centre for subse- quent treatments. She underwent adjuvant therapy with mitotane combined with chemotherapy. However, due to hepatic toxicity, mitotane was suspended within less than a month. Despite multiple cycles of chemotherapy, the disease is progressing, and the prognosis is poor.
DISCUSSION
Our patient fits in the demographic profile of a patient with ACC, as a woman in her 40s. She presented hyperandrogenism manifesta- tions, local mass effect and constitutional symptoms.
ACC poses a diagnostic challenge as a result of its rareness and the broad spectrum of possible clinical presentations. To investi- gate a suspected ACC, biochemical and imaging studies must be conducted. Hormonal workup should include 24-hour free urine cortisol, sex steroids and its precursors, and eventually aldoste- rone/renin ratio.3 Additionally, plasma or urinary metanephrines should be determined in order to rule out pheochromocytoma.3 Our patient presented with rapid development of virilisation and a total testosterone level above 200ng/dl, which usually indicates an androgen-secreting tumour.5 She also presented an elevated DHEA-S, a hormone mainly produced in the adrenal cortex.6 These findings suggested ACC.
Imaging has a valuable role in the presumable diagnosis of ACC, preoperatively. Through abdomino-pelvic section imaging (CT or MRI), apart from identifying the adrenal mass, it is possible to draw information regarding its benign or malignant nature. A large (usually >4cm), heterogeneous, ill-defined mass, with low-fat content (thus, high density) and areas of necrosis and haemorrhage, as presented by our patient, are malignancy-defining characteris- tics.13 Adrenal biopsy is usually not recommended due to the risk of haemorrhage and tumour dissemination.3
Most ACCs are diagnosed at an advanced stage.7 Lungs are the most common site of metastasis, followed by liver, lymph nodes and bone.3 Thus, for staging purposes, a chest and abdominal CT is indicated in all patients. Additionally, an MRI may assist in better evaluating hepatic, nodal and vascular involvement.3 Due to our patient’s advanced stage of ACC on encounter, indicated by hepatic
2
2
cm
A
B
invasion, she was also submitted to an 18F-fluorodeoxyglucose (FDG)-PET, which could not rule out bone involvement. FDG-PET has shown promising results in detecting malignant adrenal tumours and distant metastasis, but its actual role in the workup of ACC remains to be defined.3
All cases of ACC should be discussed in a multidisciplinary expert team meeting.13 Surgery is the only potentially curative treatment1 3 and should be performed by surgeons experienced in adrenal and oncological surgery.3 The standard procedure is a complete en bloc adrenal tumour resection and open surgery is usually preferred. In advanced cases, even if complete resection is less likely, surgery is still considered and may involve adjacent organ resection and metas- tasectomy. However, it is not recommended in patients with wide- spread metastatic disease.3 Considering that there was no concrete evidence of metastases, in the multidisciplinary meeting it was decided that the treatment would have curative intent. Moreover, due to the considerable size of the mass, the surgical resection would provide symptomatic relief.
The histopathological analysis of the resected mass is mandatory for definitive diagnosis.3 The modified Weiss criteria combine five histological features, distinguishing benign from malignant adrenal tumours. Our patient scored at least three points, fulfilling the criteria for ACC diagnosis.8
In advanced ACCs, adjuvant therapy comprising mitotane, an adrenolytic drug, and cytotoxic chemotherapy is the best available treatment.1 3 The need for local therapy, such as radiotherapy or radiofrequency ablation, should be individualised.3
The stage at the diagnosis represents the most relevant prog- nostic factor,3 emphasising the importance of early diagnosis. Unfortunately, in our case, the patient only reported the symptoms months after their onset, delaying the diagnosis. She presented
with metastatic disease (stage IV), in which the documented 5-year survival ranges from 0% to 28%.3 The high tumour grade (>20 mitoses per HPF) and elevated Ki-67 index (40%) are also indica- tors of an unfavourable prognosis.27
Learning points
Severe features of hyperandrogenism should raise the suspicion of an androgen-secreting tumour and prompt laboratory and imaging evaluation. Early diagnosis is key to increase the chances of a better outcome.
Imaging studies may suggest malignant nature of the adrenocortical tumour and guide treatment. However, the definitive diagnosis of adrenocortical carcinoma is histopathological.
Surgery is the only potentially curative treatment.
Treatment options should be discussed in multidisciplinary meetings and tailored to the patient.
Acknowledgements The authors thank the patient for her kind cooperation. The authors express their sincere appreciation to Dr Pedro Amado for his time and guidance. They also thank Dr Valeriano Leite and Dra Rita Roque, who provided relevant information on the case.
Contributors DC, IRdC and JM conceived and designed the manuscript, acquired and interpreted the data, drafted the article and critically revised it. DC, IRdC and JM approved the final version of the manuscript to be published.
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.
REFERENCES
1 Jasim S, Habra MA. Management of adrenocortical carcinoma. Curr Oncol Rep 2019;21:20.
2 Paragliola RM, Corsello A, Locantore P, et al. Medical approaches in adrenocortical carcinoma. Biomedicines 2020;8:551.
3 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.
4 Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol 2003; 169:5-11.
5 Macut D, Ilić D, Mitrović Jovanović A, Jovanovic AM, et al. Androgen-Secreting ovarian tumors. Front Horm Res 2019;53:100-7.
6 Klinge CM, Clark BJ, Prough RA. Dehydroepiandrosterone research: past, current, and future. Vitam Horm 2018;108:1-28.
7 Else T, Kim AC, Sabolch A, et al. Adrenocortical carcinoma. Endocr Rev 2014;35:282-326.
8 Lau SK, Weiss LM. The Weiss system for evaluating adrenocortical neoplasms: 25 years later. Hum Pathol 2009;40:757-68.
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