JJCO Japanese Journal of Clinical Oncology
Metastatic Adrenocortical Carcinoma Presenting Simultaneously with Cushing’s and Conn’s Syndromes: A Case Report
Seung Hoon Beom1, Keun-Wook Lee1,4, Yaewon Yang1, Younak Choi1, Kyoung-Ho Song1, Yu Jung Kim1, Jee Hyun Kim1, Soo-Mee Bang1, Jin-Haeng Chung2 and Jong Seok Lee1
1Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, and 2Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
*For reprints and all correspondence: Keun-Wook Lee, Department of Internal Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeongi-do 463-707, Republic of Korea. E-mail: hmodoctor@hanmail.net
Received June 17, 2011; accepted September 5, 2011
We report the first case of adrenocortical carcinoma secreting cortisol (Cushing’s syndrome) and aldosterone (Conn’s syndrome) with extensive distant metastasis at the time of diagno- sis. A 72-year-old male with exertional dyspnea sought evaluation at our institution. The pattern of tumor spread (lung, pleura, bone and adrenal gland) and respiratory symptoms secondary to the tumor led clinicians to diagnose the primary tumor site as lung cancer and the adrenal mass as a metastatic site. However, endocrinologic studies and a biopsy revealed the primary site to be adrenocortical carcinoma. After histopathologic confirmation, the patient was treated with palliative chemotherapy, including mitotane, cisplatin, etoposide and doxoru- bicin. The patient died on the 14th day after chemotherapy of rapidly progressive and unex- pected pneumonia, which was thought to be an opportunistic infection secondary to Cushing’s syndrome. Our case suggests that a thorough endocrinologic investigation is important in patients with an adrenal mass and clinicians should be aware that patients with adrenocortical carcinoma and Cushing’s syndrome are susceptible to infections and need to be observed carefully for the possible development of unrecognized opportunistic infections.
Key words: adrenocortical carcinoma - cortisol - aldosterone - Cushing’s syndrome - Conn’s syndrome
INTRODUCTION
Adrenal cortical carcinoma (ACC) is a rare malignancy, with an incidence of 1-2 occurrences per 1.7 million population (1). ACC has a heterogeneous presentation and a variable, but generally poor prognosis (2,3). Adrenal cancers can be classified as functional or non-functional. Approximately 60% of ACCs are hormonally active and glucocorticoids and/or androgens are the steroids which are most frequently over-secreted. Rapidly progressive Cushing’s syndrome with or without virilization is the most frequent presentation; estrogen or mineralocorticoid excess occurs in <10% of cases (4,5). In contrast, hormonally inactive ACCs usually present with abdominal discomfort (nausea, vomiting and
abdominal fullness) or back pain caused by a mass effect of the large tumor.
We report the first case of a patient with metastatic ACC accompanied simultaneously by Cushing’s and Conn’s syn- dromes. Although this case was initially mistaken as disse- minated lung cancer, including adrenal gland metastasis, ACC was confirmed by hormonal and pathologic studies.
CASE REPORT
A 72-year-old male sought evaluation at a local clinic with a 1-week history of exertional dyspnea and poor oral intake with weight loss. He was referred to our institution for
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evaluation of lung masses with a large left pleural effusion and was suspected to have lung cancer with multiple metas- tases. The patient’s medical history revealed hypertension and atrial fibrillation. No other endocrine disorders were reported. He was mildly overweight [body mass index (BMI), 25.1 kg/m2), but did not have a cushingoid or andro- genic appearance. The blood pressure was normotensive (120/60 mmHg), and routine hematologic and biochemical findings were normal, except for marked hypokalemia [1.9 mmol/l (normal range, 3.5-5.5 mmol/1)].
A computed tomographic (CT) scan of the chest per- formed at the local clinic showed a 3 cm mass-like lesion between the left upper and lower lobar bronchi (Fig. 1A). The CT scan also revealed multiple well-defined nodules in both lungs, and a large left pleural effusion with pleural nodules (Fig. 1B). Although the mass-like lesion (Fig. 1A) was initially suspected to be the primary tumor site of a lung cancer, the nature of the tumor was not solid; the mass was finally identified as a localized pleural effusion after per- forming a follow-up CT scan. A CT scan of the abdomen showed a 79 × 69 mm adrenal mass with heterogenous
enhancement (Fig. 1C), multifocal, small, low-attenuated lesions in the liver and multiple osteolytic lesions in the sacral and axial bones. Whole-body positron emission tom- ography showed significant 18F-fluorodeoxyglucose uptake in the right adrenal gland and ill-defined, multiple lung par- enchymal lesions, including multiple mediastinal lymph nodes and bone lesions (Fig. 1D and E).
The endocrinologic investigation revealed suppressed renin and increased aldosterone levels with a markedly elev- ated aldosterone-to-renin ratio (>30), suggesting primary hyperaldosteronism. Primary aldosteronism was confirmed by the lack of suppression of plasma aldosterone after a saline infusion test. Although the basal plasma cortisol con- centration was within the normal range, analysis of a 24 h urine collection revealed abnormal steroidogenesis. Loss of suppressibility by dexamethasone suggested autonomous cor- tisol secretion. The laboratory results of hormonal studies are shown in Table 1.
A thoracentesis performed to relieve dyspnea showed indices consistent with an exudate; malignant cells were not found on the pleural cytologic examination. As pleural
| Hormone | Data | Reference range |
|---|---|---|
| Basal hormone | ||
| Serum cortisol (µg/dl) | 18.3 | 5-25 |
| Plasma ACTH (pg/ml) | 15 | 10-60 |
| Estradiol (pg/ml) | 52 | 15-47 |
| Testosterone (ng/ml) | 0.28 | 2.62-15.93 |
| Plasma renin activity (ng/ml/h) | 0.2 | 1-2.5 |
| Plasma aldosterone (ng/dl) | 4790 | 2-9 |
| Aldosterone-to-renin ratio | 23 950 | |
| Urinary free cortisol (µg/day) | 1121 | 19.5-115.6 |
| Urinary VMA (mg/day) | 2.9 | 2-7 |
| Urinary metanephrine (mg/day) | 0.3 | 0-0.8 |
| Saline infusion testa | ||
| Plasma aldosterone (ng/dl) | 3940 | |
| Low-dose dexamethasone testb | ||
| Serum cortisol (µg/dl) | 21.6 | |
| Urinary free cortisol (µg/day) | 1021 |
ACTH, adrenocorticotrophic hormone; VMA, vanillylmandelic acid. ªTwo liters of isotonic saline were intravenously infused over 4 h (from 8 AM to noon), while the patient was recumbent and the plasma aldosterone level was checked thereafter.
bDexamethasone (0.5 mg) was taken orally every 6 h at 9 AM, 3 PM, 9 PM and 3 AM for a total of eight doses. Blood was drawn 6 h after the last dose and 24 h urine was collected for measurement of the urine free cortisol level from 9 AM on the second day to 9 AM on the third day of dexamethasone administration.
nodules were the easiest sites from which to acquire tissue specimens, a CT-guided core biopsy was performed. The his- tologic examination of the pleural specimen revealed a meta- static endocrine neoplasm (Fig. 2). Immunohistochemical examination showed positive labeling of neoplastic cells for synaptophysin, cytokeratin, CD56, neuron-specific enolase and neurofilament, while tumor cells did not express S-100 protein. The adrenal mass was thought to be the primary site, thus the histopathologic diagnosis was finally reported as an ACC.
After the diagnosis of metastatic ACC, the patient received palliative chemotherapy, including mitotane, cispla- tin, etoposide and doxorubicin The planned schedule of che- motherapy was as follows: cisplatin, 40 mg/m2 intravenously on days 2 and 9; etoposide, 100 mg/m2 intravenously on days 5-7; doxorubicin, 20 mg/m2 intravenously on days 1 and 8; and mitotane, orally administered with the dosage of 2 g/day (every 4 weeks). For control of fluid retention and hypokalemia, the patient was treated with spironolactone and supplemented with potassium. On the fifth day after che- motherapy was initiated, a dry cough and worsening dyspnea developed. On the sixth day after chemotherapy was initiated, the dyspnea was progressively aggravated and he was transferred to the intensive care unit for mechanical
ventilation with discontinuation of chemotherapy. A fever and tachycardia developed. A chest CT scan showed a fine reticular pattern superimposed on areas of ground-glass opacity (i.e. ‘crazy-paving’ appearance), especially in the right upper and middle lobes (Fig. 3A), and bronchocentric consolidation in both lower lung fields (Fig. 3B). The radiol- ogists reported that bronchopneumonia or Pneumocystis infection should be considered. An echocardiogram showed normal cardiac function and the cardiac enzymes were normal. To exclude the possibility of mitotane-induced adrenal insufficiency as the cause of rapid clinical deterio- ration, follow-up 24 h urine free cortisol was tested twice and both levels were above the normal range (1178 and 905 µg/day on the 7th and 10th days, respectively). With the presumptive diagnosis of an opportunistic pulmonary infec- tion, broad-spectrum antibiotics were used empirically [van- comycin, carbapenem and trimethoprim-sulfamethoxazole (TMP-SMX)]. Although extensive laboratory tests (cultures and polymerase chain reaction tests for microbial pathogens) were performed using sputum, blood and bronchoalveolar lavage specimens, all tests were negative for viral, bacterial and fungal pathogens, including Pneumocystis jirovecii. Despite the use of antibiotics, the hypoxemia worsened and the patient died of respiratory failure caused by uncontrolled opportunistic pulmonary infection of unknown etiology on the 33rd day after admission (14th day after the initiation of chemotherapy).
DISCUSSION
Although there have been some reports on ACC with cortisol and aldosterone secretion, our case had three notable clinical features. First, this is the first case of metastatic ACC with Cushing’s and Conn’s syndromes simultaneously at the time of initial presentation. Most functional ACCs produce corti- sol, but aldosterone production is quite rare. Through a lit- erature search, we identified five additional cases of ACC simultaneously secreting cortisol and aldosterone at the time of initial diagnosis (6-9). All of the patients except one had localized and operable cases when initially diagnosed with ACC, and consequently, curative surgical resections were performed; in another case, the tumor extent and applied treatment was not described (7). However, there have been no reports on ACC cases with distant metastasis and simul- taneously secreting cortisol and aldosterone as the initial presentation.
Second, the pattern of tumor spread (lung, pleura, bone, and adrenal gland) and respiratory symptoms caused by tumors led clinicians to mistake the primary tumor site as lung cancer and the adrenal mass as the metastatic site. The mass-like lesion represented by the localized pleural effusion (Fig. 1A) was initially considered as the main mass of the primary lung cancer. However, the right adrenal mass was confirmed as the primary site by pathologic and hormonal studies. This case serves to remind clinicians that the
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possibility of an adrenal mass being the primary cancer site should always be considered when evaluating patients with an adrenal mass with other metastatic sites, although the incidence of ACC is extremely rare. In our case, marked hypokalemia and hormone studies indicating primary hyper- aldosteronism was the initial clue to the diagnosis of a func- tioning adrenal tumor rather than a metastatic lesion. Although the patient had no classical feature of Cushing’s syndrome, the existence of Cushing’s syndrome was con- firmed based on a dexamethasone suppression test. This case reflects the importance of a thorough endocrinologic investi- gation in patients presenting with an adrenal mass, as the pattern of hormone secretion may be a clue to ACC (10).
Third, our patient developed pneumonia abruptly during the first cycle of chemotherapy. The clinical features strongly suggested the development of severe respiratory infection and he died of rapidly progressive respiratory insufficiency even though undergoing intensive treatment with broad-spectrum antibiotics, including intravenous TMP-SMX. As no
microbial pathogen was identified by laboratory tests or culture studies and an autopsy was not performed, we were not able to identify the pathogen which caused the pneumo- nia. The patient was not neutropenic at the onset of pneumo- nia. The chest CT scan revealed a ‘crazy-paving’ appearance, which is a non-specific finding associated with a variety of interstitial and airspace lung diseases, including pneumonia caused by P. jirovecii (11). Although opportunistic infections after external glucocorticoids are well known, opportunistic infections in patients with endogenous cortisol overproduc- tion have been less commonly recognized. Graham and Tucker (12) showed that patients with Cushing’s syndrome have the same spectrum of infections as patients treated with pharmacologic doses of corticosteroids. The risk of an oppor- tunistic infection in Cushing’s syndrome is known to be related to the cortisol level (13). Our case strongly suggests that a fatal opportunistic infection developed under immuno- suppressive conditions caused by the endogenous release of excess cortisol secondary to Cushing’s syndrome.
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In conclusion, we report the first case of metastatic ACC in a patient with concurrent Cushing’s and Conn’s syn- dromes at the time of initial presentation. Our case empha- sizes the importance of a thorough endocrinologic investigation in patients with an adrenal mass, even though the clinical presentation may be more suggestive of solid tumors other than ACC. Clinicians should be aware that a patient with ACC and Cushing’s syndrome is susceptible to infections and needs to be observed carefully for the possible development of unrecognized opportunistic infections.
Conflict of interest statement
None declared.
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