DISSEMINATED INVASIVE ASPERGILLOSIS IN A PATIENT WITH ADRENOCORTICAL CARCINOMA
Stanley M. Chen Cardenas, MD1,2; Kornelija Colovic, MD1; Theresa L. Nicol, MD3; Zahra Maleki, MD4; Esther Krug, MD5,6
ABSTRACT
Objective: To describe the course and anatomo-patho- logic findings in a patient with a cortisol-producing adre- nocortical carcinoma (ACC) who presented with dissemi- nated invasive aspergillosis (DIA). We also review the clinical characteristics of ACC and the pathogenesis of DIA in the setting of hypercortisolemia.
Methods: We describe the case of a 47-year-old man with a recent diagnosis of ACC associated with hypercor- tisolism, who presented with a large right basal ganglia hematoma and lesions on multiple organs thought to be metastatic. The patient deteriorated rapidly and unfortu- nately 6 days after presentation he died. An autopsy was performed which revealed DIA as the cause of death.
Results: DIA in ACC was reported for the first time in 1981. Since then, no other case has been reported in the literature associating these 2 conditions. The lesions this patient presented on images were difficult to differentiate from metastatic lesions. The lack of inflammatory features
Submitted for publication January 10, 2019
Accepted for publication February 1, 2019
From the 1Department of Medicine, Sinai Hospital of Baltimore, Baltimore, MD, 2Division of Endocrinology, Diabetes and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, MD, 3Department of Pathology, Sinai Hospital of Baltimore, Baltimore, MD, 4Division of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 5Department of Endocrinology, Sinai Hospital of Baltimore, Baltimore, MD, 6The Johns Hopkins University School of Medicine, Baltimore, MD.
Address correspondence to Dr. Stanley M. Chen Cardenas, The Johns Hopkins Hospital, Division of Endocrinology, Diabetes and Metabolism, 1830 East Monument Street, Suite 333, Baltimore, MD 21287. E-mail: schenca1@jhmi.edu.
DOI:10.4158/ACCR-2019-0016
To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright @ 2019 AACE.
due to hypercortisolemia accounted for this. Both ACC and DIA have very high mortality rates, even when DIA is treated appropriately.
Conclusion: Opportunistic fungal infections are common in hypercortisolemia, however disseminated and invasive forms are rare. Awareness of uncommon presen- tations of hypercortisolemia is important for early treat- ment of those patients with a chance of survival. (AACE Clinical Case Rep. 2019;5:e233-237)
Abbreviations:
ACC = adrenocortical carcinoma; CT = computed tomography; DIA = disseminated invasive aspergillosis
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare neoplasm, with an estimated incidence of 1 to 2 per million per year (1,2). ACC represents approximately 0.2% of all cancer deaths and is the second most aggressive endocrine malig- nancy after anaplastic thyroid carcinoma (2,3). About 50% of ACCs are hormone-producing tumors that cause clini- cal syndromes. Hypercortisolism is the most common of these syndromes accounting for 50 to 80% of functioning ACCs (1). These patients develop complications not only from tumor growth and invasion, but also from excessive hormone secretion.
Overall the prognosis is poor as most patients present with advanced, disseminated disease and large masses (2). However, a significant number of patients experience other complications related to hormone excess such as hyperten- sion, opportunistic infections, and hyperandrogenism that are potentially treatable to improve their quality of life. Here we present a clinical case and anatomo-pathologic findings in a patient with an expected, but rare and devas- tating complication of a glucocorticoid-producing ACC.
CASE REPORT
A previously healthy 47-year-old man presented to his primary care physician with left leg swelling and abdomi- nal distention. An abdominal ultrasound showed a large left adrenal mass measuring 11.3 cm in the largest diam- eter and numerous liver lesions (1 to 5 cm) suspicious for metastatic disease. They were confirmed with a computed tomography (CT) scan of the abdomen (Fig. 1 A). Biopsy of the adrenal mass revealed an ACC (Fig. 2 A through D). Around the same time, he was diagnosed with hyperten- sion and started on several antihypertensive medications. One month later, he presented to our emergency room with a few weeks’ history of shortness of breath, cough, and chest discomfort.
On physical examination, in addition to bilateral lower extremity edema, he was noted to have a new left facial droop and left hemiplegia. No cushingoid features were present on exam. CT of the head showed a large (3.8 x 2.3 × 3.0 cm) right basal ganglia hemorrhage and small addi- tional hemorrhagic focus in the left temporal lobe (Fig. 1 D). Chest CT revealed diffuse lung lesions and moderate right pleural effusion (Fig. 1 B and C). Laboratory results (Table 1) were significant for hyperglycemia, hypokale- mia, and metabolic alkalosis. Random cortisol level was markedly elevated at 4:00 PM (71.1 ug/dL) and at 1:00 AM (52.3 ug/dL). Adrenocorticotropic hormone level was low- normal at 7.7 pg/mL.
He was admitted to the intensive care unit where his illness was complicated by the new of onset seizures. He
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was treated with empiric antibiotics, levetiracetam for seizures, ketoconazole for hypercortisolemia, and whole brain radiation therapy for suspected brain metastatic disease. Hypercortisolemia, hypokalemia, and metabolic alkalosis improved with ketoconazole, spironolactone, and octreotide. However, he continued to clinically deterio- rate with worsening mental status, refractory seizures, and respiratory failure.
His hospital course was further complicated by the development of right lower extremity deep venous throm- bosis for which an inferior vena cava filter was placed. Magnetic resonance imaging (Fig. 1 E through H) of the brain revealed additional subtentorial hemorrhagic lesions. Due to the low likelihood of a favorable outcome in view of worsening intracerebral hemorrhages, goals of care were changed to comfort measures only. Sputum culture later the same day, 6 days after admission, came back posi- tive for Aspergillus fumigatus.
An autopsy was performed which revealed dissemi- nated invasive aspergillosis (DIA) involving both the right
and left lungs, left cerebral cortex, temporal and occipi- tal lobes, basal ganglia, cerebellum, left ventricle of the heart, left kidney, stomach, gastroesophageal junction, and thyroid (Fig. 2 E through L). The thyroid contained a 0.7-cm aspergilloma. The ACC measured 17 cm and was associated with hemorrhage and necrosis. Additionally, the autopsy confirmed hepatic and pulmonary metasta- ses. However, there were no signs of metastatic disease in the brain.
DISCUSSION
DIA is a rare systemic mycosis which most commonly affects immunosuppressed patients. The majority of these infections typically occur in bone marrow or solid organ transplant recipients (4). The first case reported in the literature of a patient with Cushing syndrome due to an ACC associated with DIA was published in 1981 by Walsh and Mendelsohn (5). The patient was a 64-year-old woman found to have DIA postmortem (5). Since then, there are no
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| Table 1 Laboratory Results | ||||
|---|---|---|---|---|
| Normal range | Day 1 | Day 3 | Day 6 | |
| Adrenocorticotropic hormone (pg/mL) | 5-46 | 7.7 | -- | -- |
| Aldosterone (ng/dL) | 0-30 | 2 | -- | -- |
| Bicarbonate (mmol/dL) | 21-32 | 47 | 45 | 36 |
| Cortisol (ug/dL) | 5-25 | 72 (4:00 PM) | 52 (1:00 AM) | 30 (12:30 AM) |
| Glucose (mg/dL) | 70-99 | 307 | 145 | 364 |
| Neutrophil count, absolute (per mm3) | 1,500-8,000 | 9,716 | -- | -- |
| Potassium (mmol/dL) | 3.5-5.1 | 2.1 | 3.4 | 3.6 |
| Renin (ng/mL/hour) | 0.3-3.0 | 13.5 | -- | -- |
| Sodium (mmol/dL) | 135-145 | 138 | 144 | 149 |
| White blood cells (103/uL) | 4.0-11.0 | 10.8 | 8.9 | 7.6 |
reports in the literature of ACC associated with DIA. Both conditions are very rare and perhaps underreported. Most of the associations of Cushing syndrome and DIA have been reported in patients with ectopic adrenocorticotropic hormone syndrome (6,7).
The case presented here combines both common and uncommon features of ACC. Our patient presented within the usual age range of presentation, between the fourth and the sixth decade (1,8). However, this cancer is more common in women with a ratio of 1.5 to 2.5:1 (1,8). He presented in stage IV as do 25 to 49% of patients (1,3), with lung and liver involvement being the most common sites, consistent with the patient’s presentation. The size of the tumor mass of 17 cm on autopsy was consistent with the median size reported of >11 cm from the literature (3). He had a hormone-secreting ACC as described in 40 to 60% of ACC cases (1,8), with cortisol being the most common hormone. The patient did not present any clinical finding suggestive of estrogen or adrenal androgen cosecretion, however these hormone levels were not obtained. The patient did not have a family history of ACC, or any asso- ciated syndromes (e.g. Li-Fraumeni syndrome, multiple endocrine neoplasia type 1, Lynch syndrome, Beckwith- Wiedemann syndrome, familial adenomatous polyposis coli, neurofibromatosis type 1, or Carney complex).
His markedly elevated cortisol level placed him at a very high risk for opportunistic infections. Because of his rapid deterioration in mental status, intubation, and low urine output we were not able to perform a formal screen- ing test for Cushing syndrome (which requires 24-hour urine free cortisol, late-night salivary cortisol, or 1-mg dexamethasone suppression test). His adrenocorticotropic hormone level was low normal, in the setting of critical illness, when it is expected to be markedly elevated. It was perhaps not completely suppressed due to the rapid onset of hypercortisolism, typically seen in ACC. Considering
all these, in a patient presenting with ACC, hypokalemia, metabolic alkalosis, normal ratio of plasma aldosterone concentration to plasma renin activity, and a markedly elevated 1:00 AM cortisol of 52.3 ug/dL when it should be very low, strongly supports the diagnosis of a cortisol- producing ACC.
The mechanisms that explain why hypercortisolemic patients are predisposed to develop Aspergillus infec- tions involve both the host and microorganism. Normally, when an immunocompetent host inhales molds such as Aspergillus, the pulmonary macrophages will phagocy- tose and eliminate the conidias. Some of the conidias will escape, germinate to hyphae, and initiate an invasive infec- tion. At this level polymorphonuclear cells such as neutro- phils can destroy the hyphae by cytotoxic mechanisms (7), in this way avoiding blood vessel invasion (angioinvasion) and dissemination.
In patients with hypercortisolemia, quantitative and qualitative defects occur in T-lymphocytes, polymor- phonuclear cells, monocytes, and macrophages. These defects allow Aspergillus to invade blood vessels and undergo hematogenous dissemination to other organs. The angio-invasiveness that characterizes Aspergillus explain the intraparenchymal brain hematomas that this patient developed. Glucocorticoids can also alter the biology of Aspergillus species. A study by Ng et al (9), found that in vitro A. fumigatus and A. flavus have a 30 to 40% increase in growth rate in the presence of pharmacological doses of hydrocortisone. Other studies attempting to establish a direct relationship between glucocorticoid use and the risk of invasive aspergillosis have been done, however many variables including the patient immune status, comorbidi- ties, and site of infection influence the risk.
The range of glucocorticoid dose shown to predispose to invasive aspergillosis is wide (10). Studies done in renal transplant patients and in allogeneic hematopoietic stem
cell transplantation recipients have reported that doses of prednisone between 0.5 to 1.25 mg/kg/day predict- ed an increased risk for Aspergillus infections (11,12). Additionally, methylprednisolone doses >1 mg/kg for over 21 days were associated with the development of invasive aspergillosis (10). Marr et al (13) reported that patients with hematopoietic stem cell transplants treated with doses of prednisone or methylprednisolone equivalents of <1.9 mg/kg/day had increased risk for invasive aspergillosis by approximately 5%; the risk doubles to 10% and almost triples to 15% when the doses were 1.9 to 3.0 mg/kg/day and >3 mg/kg/day, respectively.
In all of the cases of invasive aspergillosis in the setting of steroid use, the patients were using markedly high doses. Additionally, with high doses of methylpred- nisolone, prednisolone, and betamethasone, coinfection of invasive aspergillosis with Pneumocystis jirovecii has been described (14). Similarly, invasive aspergillosis infec- tion in the setting of steroid use has been reported in other scenarios including chronic obstructive pulmonary disease, asthma, collagen vascular disease, and human immunode- ficiency virus (10). In all these cases, supraphysiologic doses and prolonged duration seem to be the most impor- tant risk factors.
The case presented here illustrates the severity and fulminant course of an unrecognized Aspergillus infec- tion associated with a cortisol-producing ACC. DIA is a difficult diagnosis to make because hypercortisolemia significantly attenuates the inflammatory response and masks the signs of systemic infection (4,6). DIA can radiographically be confused with many other diagnoses including metastatic brain disease. Additionally, it is not uncommon to have difficulties establishing a diagnosis. A. fumigatus isolates may be atypical, growing slowly with poor sporulation, delaying diagnostic identification. In this case, positive sputum cultures were reported only after the patient’s death.
ACC and DIA both have very poor prognoses. According to the American Cancer Society, stage IV ACC has a 5-year relative survival rate of 7% and 17% based on the German registry (3). The risk factors predictive of death among patients with aspergillosis are disseminated disease, cerebral involvement, and administration of gluco- corticoids. Most of them were present in this patient. DIA has a mortality rate nearing 100%, even with appropriate therapy (4). Additionally, neutrophil impairment such as in hypercortisolemia has been associated with decreased anti- fungal response (7).
CONCLUSION
DIA in ACC is rare, and both carry extremely high mortality risk. Considering this, it is possible that earlier diagnostic workup performed immediately after discov-
ery of the adrenal mass and prior to presentation with brain hemorrhage could have prolonged this patient’s life. Therefore, clinicians should maintain a high index of suspicion for opportunistic infections in the setting of severe hypercortisolism, in order to treat early those with a chance of surviving.
ACKNOWLEDGMENT
We thank Dr. John Cmar, Chair of the Department of Infectious Diseases, Sinai Hospital of Baltimore, for review- ing the manuscript. We thank Dr. Konstatin Chernukha, Department of Radiology, Sinai Hospital of Baltimore, for reviewing the images. We also thank Dr. Roberto Salvatori, Professor of Medicine and Neurosurgery, The Johns Hopkins Hospital, for reviewing the manuscript.
DISCLOSURE
The authors have no multiplicity of interest to disclose.
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