Primary adrenocortical carcinoma: a case report

Introduction:

Adrenal tumors are very common, affecting 3–10% of the human population, and most are small, benign, nonfunctional adrenocortical adenomas. Adrenocortical carcinoma (ACC), in contrast, is a very rare disease. The median age of diagnosis is in the fifth to sixth decade. There is a predilection for the female gender (the ratio of female to male ranges from 1.5 to 2.5 : 1) the adult.

Case presentation:

A 28-year-old man who had no prior history of systemic hypertension or diabetes mellitus presented with bilateral limb swelling for 2 months and facial puffiness for 1 month. He had an episode of hypertensive emergencies. A radiological and hormonal work-up established the diagnosis of primary ACC. One cycle of chemotherapy was given until he lost follow-up and succumbed to death due to financial constraints.

Conclusions:

Adrenocortical carcinoma is an extremely uncommon tumor of the adrenal gland, and it is even more uncommon when it manifests without any symptoms. If patients exhibit signs of rapid and multiple adrenocortical hormone excess, such as weakness, hypokalaemia, or hypertension, ACC may be suspected. Recently developed gynecomastia in men may be brought on by an ACC producing too much sex hormone. To accurately diagnose the condition and give the patient a fair prognosis, a multidisciplinary approach involving endocrine surgeons, oncologists, radiologists, and internists is advised. Proper genetic counseling is recommended. It is critical to know whether the adrenal mass is malignant or not, and to get this ascertained by a computed tomography finding and biopsy.

Introduction

Highlights

• Primary adrenocortical carcinoma is a rare entity.

• To accurately diagnose the condition and give the patient a fair prognosis, a multidisciplinary approach involving endocrine surgeons, oncologists, radiologists, and internists is advised.

• Proper genetic counseling is recommended.

• It is critical to know whether the adrenal mass is malignant or not which can be ascertained by computed tomography findings and biopsy.

• Metastasis and a large tumor size confer a poor prognosis.

Adrenal tumors, affecting 3–10% of the human population, are very common, and most are small, benign, nonfunctional adrenocortical adenomas1. Adrenocortical carcinoma (ACC), however, is a very rare disease. The National Institutes of Health Office of Rare Diseases Research defines rare diseases as having a prevalence of fewer than 200 000 patients in the United States2. In accordance with the aforementioned definition, ACC might be regarded as an ultrarare disease. The incidence is believed to be 1–2 per million per year; however, valid data are lacking3. The Surveillance, Epidemiology, and End Results database provides an estimation of incidence of ~0.72 per million cases per year, which results in 0.2% of all cancer deaths in the United States4. The median age of diagnosis is in the fifth to sixth decade, with the German ACC Registry recommending a median age of 46 years at diagnosis5. There is a predilection for the female gender (the ratio of female to male ranges from 1.5 to 2.5 : 1) in adults6,7. Despite the high probability of recurrence, complete surgical resection of the tumor can provide the best chance for cure8. Due to the limited size of the clinical trials and the lack of data from prospective randomized trials, the chemotherapeutic regimen for recurred or metastatic ACC has not been standardized yet9.

Herein, we present a case of advanced ACC presenting with edema and cytotoxic chemotherapy-induced partial response. This case report is reported according to SCARE guideline10.

Case report

A 28-year-old man who had no prior history of systemic hypertension or diabetes mellitus presented with bilateral limb swelling for 2 months and facial puffiness for 1 month. The swelling was of the pitting type, which started from the feet and eventually spread up to the knee, aggravating on standing and relieved on lying down. On examination, patient was alert with a sitting blood pressure of 190/120 mm Hg. The patient was treated in the line of hypertensive urgency with tablets of amlodipine 5 mg and losartan 50 mg. Adequate blood pressure control was not obtained and thus patient was admitted in ward and screening for secondary cause of systemic hypertension was carried out . On admission, blood pressure readings were 170/100 mm Hg when supine and 180/100 mm Hg while seated.

On investigation, hypokalaemia was found and treated with oral potassium replacement. A computed tomography (CT) scan of the abdomen and pelvis showed a 7.4×7×6.9 cm mass in the left adrenal gland with increased heterogeneity (Fig. 1). There was evidence of hepatic metastasis as shown in Figures 2A and B. Figure 3 showed long segment circumferential symmetrical enhancing thickening (7 mm) of wall of jejunum – likely inflammatory/ischemic pathology with positive fecal sign with mild dilatation (2.6 cm) – suggestive of small bowel obstruction. To rule out phaeochromocytoma, 24-h urine collection of vanillylmandelic acid and metanephrine levels was done which were negative. He had facial puffiness and plethora along with central obesity which was of recent suggestive of cortisol excess along with increased libido and gynecomastia (Fig. 4). Figure 5A–C) shows the histopathological findings. On hormonal work-up, basal cortisol was raised and overnight dexamethasone suppression test was not suppressed along with suppressed morning adrenocorticotropic hormone level suggestive of adrenal cushing. Dehydroepiandrosterone sulphate (DHEAS>1500), was also raised. As urinary metanephrines were negative and with strong clinical suspicion of ACC, we did Fine needle aspiration cytology of hepatic space occupying lesion which proved to be metastasis from an adrenocortical tumor. On slit lamp examination, no evidence of hypertensive retinopathy was seen. Since an adrenal tumor along with distant metastasis was present, it was attributed to stage IV according to McFarlane staging. Anatomopathological diagnosis was made by percutaneous biopsy of the liver metastasis and histopathology.

Figure 1.

Computed tomography scan showing large left adrenal tumor with increasing heterogeneity abutting pancreas with liver metastasis and displacing spleen suggesting adrenal carcinoma.

Figure 2.

(A and B) Contrast-enhanced computed tomography scan showing well-defined heterogeneously enhancing soft tissue density lesion with nonenhancing areas within with exophytic component noted in segment Iva of left lobe suggesting hepatic metastasis.

Figure 3.

Computed tomography scan showing circumferential symmetrical enhancing thickening (7 mm) of wall of jejunum suggesting – small bowel inflammatory/ischemic pathology.

Figure 4.

Gynecomastia and reddish pigmentation over the chest.

Figure 5.

Showing tumor composed of variably sized nests, large sheets and trabeculae (A), large pleomorphic cells with compact eosinophilic cytoplasm (B), and intranuclear inclusions and atypical mitosis (C).

The patient was started on chemotherapy with Mitotane (tablet, 500 µg). After 2 days, the patient started deteriorating, and he was started on injectable chemotherapy (injection Doxorubicin 40 mg, Etoposide 100 mg, Cisplatin 40 mg, and tablet Mitiotane 500 mg) which was well tolerated by the patient. The patient’s situation further deteriorated, and he was contacted for the rest of the cycles of chemotherapy until he succumbed to death due to financial constraints.

Discussion

Adrenocortical carcinoma is apparently more common in children11. In the adult population, the proportion of secondary malignancies is about 10–20%11. However, no association or specific tumor pattern has been mentioned in previous studies. patients, A contralateral tumor is present, presenting either as a synchronous or a metachronous ACC in roughly 2–10% of ACC11. Similar to findings in a review by Else and colleagues, our patient had unilateral involvement with the normal contralateral adrenal gland. Moreover, female predilection was reported in previous studies, but in our case, the patient was a male5,6.

Three main clinical scenarios have been described for ACC patients who present. For 40–60% of patients, the major presenting complaints are symptoms and signs of hormone excess3,12. Other third present with nonspecific symptoms such as abdominal or flank pain, abdominal fullness, or early satiety due to local tumor growth11. Roughly, 20–30% of ACCs are incidental diagnoses by imaging procedures11. Only a few patients with ACC present with classical tumor symptoms, such as cachexia or night sweats3,11. Paraneoplastic syndromes are rare12. The patient presented with symptoms and signs of hormone excess, like worsened hypertension. There were no compressive symptoms due to local tumors and no paraneoplastic symptoms were present.

Although earlier studies found 49% of patients with metastatic disease at presentation, at present, it is reported that only 25–30% of patients present with metastatic disease11. The patient presented with metastatic disease in spite of increased use of abdominal imaging procedures. It may be attributed to the lower availability of imaging procedures in remote areas of Nepal.

On clinical presentation, ACCs are typically large tumors, often measuring more than 6 cm in diameter13. Due to the presence of internal hemorrhage, necrosis, and calcifications, these tumors tend to differ in appearance with frequent heterogeneous enhancement. They are bilateral in 2–10% of cases12. Metastases to the liver, lungs, or lymph nodes can be seen. Invasion of adjacent organs or venous extension into the renal vein and/or inferior vena cava may be evident. Contrast-enhanced CT or MRI is the diagnostic imaging modality of choice and is also useful for initial imaging and staging as well as for follow-up. Both modalities are appropriate for detecting local recurrence and metastatic disease14. The patient presented with a unilateral tumor of large size (7.4×7×7.9 cm) with hepatic metastases as evident in contrast-enhanced CT.

The diagnosis of ACC is often clear in the setting of a large adrenal mass with concomitant hormone excess. However, if an incidental large adrenal mass is discovered or hormone excess is established, differential diagnosis should be considered if imaging has not been conducted. The main differential diagnoses for ACC are Adrenocorticotropic hormone-independent macronodular hyperplasia and cortisol-producing adenomas, which are differentiated by imaging11. The main differential diagnoses for an adrenal lesion greater than 4 cm include a large ACA, myelolipoma, adrenal metastasis of another cancer, pheochromocytoma, adrenal cyst, ganglioneuroma, or other rare tumors of the adrenal gland, such as sarcomas or lymphomas11. In our patient, ACC was diagnosed owing to the CT findings (large adrenal mass, increased heterogeneity, irregular borders) with concomitant secondary hypertension and hyperandrogenism.

At present, the only curative approach to ACC is complete tumor resection. Adjuvant therapies are targeted to decrease the chance of recurrence. All therapy for unresectable or metastatic ACC must be considered palliative. This needs to be discussed with the patient so that reasonable expectations are set11. Our patient presented in stage IV with hepatic metastasis, so even though, adrenalectomy was initially planned, it was not performed owing to its large size, distant metastasis, and uncontrolled hypertension.

The outcomes have remained suboptimal after surgical resection alone11. Evidence suggests that patients with ACC remain at high risk for tumor recurrence despite complete surgical tumor excision, which has warranted the search for adjuvant therapies. Adjuvant treatment is routinely started within 3 months after surgery. A recent large retrospective study indicates a benefit of adjuvant mitotane therapy11. Cytotoxic chemotherapy is currently the standard treatment for advanced and metastasized ACC. Initial studies in the 1970s and 1980s evaluated single-compound regimens with minor success, showing response rates ranging from 10 to 20%11. A recent phase 3 trial (FIRM-ACT, First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment) compared the most promising regimens [etoposide, doxorubicin, cislatin, and mitotane (EDPM) vs. streptozotocin, mitotane] to establish a gold standard of cytotoxic chemotherapy for ACC. This study supported the efficacy of chemotherapy and proved the superiority of EDPM11. Thus, we opted to provide an EDPM regimen to our patient, but it only showed a partial response.

Naturally, age at diagnosis is correlated with decreased overall survival in patients with ACC15. Tumor characteristics of malignancy and the velocity of tumor growth are usually related to a poor prognosis. Tumor extent (e.g. stage), specifically the presence of distant metastasis and the number of organs involved in metastatic disease, is a bad prognostic factor16. High tumor grade (>20 mitoses per high-power field), on the other hand, is also an unfavorable prognostic factor11. Since ACC was diagnosed at a later stage, the velocity of growth could not be ascertained. The presence of distant metastases and their large size proved to be unfavorable prognostic factors.

Conclusions

Adrenocortical carcinoma is an extremely uncommon tumor of the adrenal gland, and it is even more uncommon when it manifests without any symptoms. If patients exhibit signs of rapid and multiple adrenocortical hormone excess, such as weakness, hypokalaemia, or hypertension, ACC may be suspected. Recently developed gynecomastia in men may be brought on by an ACC producing too much sex hormone. To accurately diagnose the condition and give the patient a fair prognosis, a multidisciplinary approach involving endocrine surgeons, oncologists, radiologists, and internists is advised. Proper genetic counseling is recommended. It is critical to know whether the adrenal mass is malignant or not and to get this ascertained by a CT finding and biopsy.

Ethical approval

Not required.

Consent

Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Sources of funding

None.

Author contribution

D.N., S.K., P.U., S.K.S., U.K.S.: study concept, data collection, and surgical therapy for the patient. D.N., S.K., S.P.S., S.K.S., U.K.S.: writing – original draft preparation. D.N., S.K., S.D., S.K.S., U.K.S.: editing and writing. D.N., S.K., S.K.S.: senior author and manuscript reviewer. All the authors read and approved the final manuscript.

Conflicts of interest disclosure

None.

Research registration unique identifying number (UIN)

None.

Guarantor

Sarada Khadka.

Provenance and peer review

Not commissioned, externally peer-reviewed.