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Journal of Infection and Chemotherapy
journal homepage: http://www.elsevier.com/locate/jic
Journal of Infection and Chemotherapy
Case Report
Disseminated cryptococcosis in a patient with adrenocortical carcinoma and Cushing’s syndrome
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Hirohisa Fujikawa a, b, *, Makoto Araki b
ª Department of Medical Education Studies, International Research Center for Medical Education, Graduate School of Medicine, The University of Tokyo, 7-3-
1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
b Department of Internal Medicine, Suwa Central Hospital, 4300 Tamagawa, Chino, Nagano, 391-8503, Japan
ARTICLE INFO
Article history: Received 16 January 2020 Received in revised form 8 June 2020
Accepted 17 July 2020 Available online 31 July 2020
Keywords:
Adrenocortical carcinoma Adrenal tumor Cushing’s syndrome Opportunistic infection Cryptococcosis Cryptococcus
ABSTRACT
Corticosteroids have been used for the treatment of a great variety of diseases. Therefore, the relationship between high doses of cortisol and infections has been widely known and prophylactic therapy has been established. Adrenocortical carcinoma is a rare malignancy with poor prognosis, so little is known about how to deal with the complications resulting from hormone excess such as Cushing’s syndrome. Here we report a case of an 82-year-old woman who presented with a 1-day history of dyspnea and was finally diagnosed as disseminated cryptococcosis at autopsy. The patient had received a diagnosis of metastatic adrenocortical carcinoma and Cushing’s syndrome three months earlier. The findings of this study indicate the relation between severe hypercortisolemia due to adrenocortical carcinoma and opportu- nistic infections. In the setting of adrenocortical carcinoma with Cushing’s syndrome, clinicians should maintain a high index of suspicion for opportunistic infections including cryptococcosis, which are potentially treatable by early detection and prompt intervention.
@ 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
1. Introduction
Since their introduction to clinical practice, corticosteroids have been widely used in the treatment of numerous medical conditions for approximately 70 years [1]. Therefore, the relation between high-dosage cortisol therapy and infections has been commonly recognized and prophylactic treatment has been established [2]. On the other hand, adrenocortical carcinoma is a rare endocrine tumor with poor prognosis, so little is known about how to deal with the complications resulting from hormone excess such as Cushing’s syndrome. In this report, we describe a case of disseminated cryptococcosis in a patient with adrenocortical carcinoma and Cushing’s syndrome.
2. Case presentation
An 82-year-old woman presented to the hospital with a 1-day history of dyspnea. The patient had been well until five months before the presentation, when moon face, central obesity and bilateral pitting leg edema developed. Three months before the presentation, computed tomography (CT) demonstrated right ad- renal tumor with multiple lung masses, which led to the clinical diagnosis of metastatic adrenocortical carcinoma (ACC) (Fig. 1A and B). The patient was also diagnosed with non-adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (CS). Serial ex- aminations showed morning cortisol level of 23.1 (normal 7.1-19.6) ug/dL, ACTH level of 2.7 (normal 7.2-63.3) pg/mL, and urinary free- cortisol level of 340 (normal 11.2-80.3) ug/day. Cortisol was not shown to be suppressed in the low-dose dexamethasone sup- pression test (24.3 ug/dL, normal <1.8 ug/dL). The patient’s other previous medical diagnoses included secondary hypertension and diabetes due to CS. Mitotane, amlodipine besilate, sitagliptin phosphate hydrate, furosemide, and potassium gluconate were administered.
On examination, she had tachycardia (116 beats/minute), increased respiratory rate (25 breaths/minute), and oxygen
* Corresponding author. Department of Medical Education Studies, International Research Center for Medical Education, Graduate School of Medicine, The Univer- sity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
E-mail addresses: hirohisa.fujikawa@gmail.com (H. Fujikawa), makoto.araki@ gmail.com (M. Araki).
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saturation of 91% while breathing ambient air. The body tempera- ture was within the normal range. Chest auscultation revealed bilateral crackles. Laboratory tests demonstrated white cell count of 8.7 (normal 3.5-9.1) × 109/L and C-reactive protein level of 28.64 (normal 0-0.3) mg/dL (Table 1). Tests for human immunodefi- ciency virus (HIV) antigen and antibody were negative. Chest- abdomen-pelvis CT showed enlarged adrenal tumor, growing metastatic lung masses, and diffuse ground-glass opacities with newly appearing multiple tiny nodules distributed throughout both lungs (Fig. 1C and D).
Our initial differential diagnosis included pulmonary lym- phangitic carcinomatosis, drug-induced interstitial lung disease, bacterial pneumonia, and congestive heart failure. We adminis- tered intravenous pulse methylprednisolone (1 g/day), piperacillin/ tazobactam (9 g/day), minocycline (200 mg/day), and furosemide (20 mg/day). However, despite these treatments, her respiration gradually deteriorated. On the sixth day of hospitalization, blood
cultures were found to be positive for Cryptococcus neoformans. She died 7 days after admission.
An autopsy was performed. The right adrenal mass was adhered to the liver and the right diaphragm. Microscopically, direct invasion into the liver and the right diaphragm was observed. Histological examination of the right adrenal gland showed a malignant tumor composed of adrenocortical cells (Fig. 2). The neoplastic cells were arranged in an alveolar pattern. Ki-67 protein was positive in approximately 40-50% of the tumor cells. The metastatic sites, including both lungs, small-bowel mesentery, serosa of ascending colon, and para-aortic lymph nodes, demonstrated the same histological findings. On the other hand, microscopic examination revealed disseminated crypto- coccal infection with organisms isolated from the pulmonary alveoli, bilateral kidneys, thyroid gland, and cerebrospinal fluid (Fig. 3). Thus, the autopsy led to the diagnosis of stage IV ACC and disseminated cryptococcosis.
| Three months before | On admission | Unit | Three months | before On admission | Unit | ||
|---|---|---|---|---|---|---|---|
| WBC | 4480 | 8730 | /HL | BUN | 22.0 | 14.0 | mg/dL |
| Hb | 12.9 | 14.0 | g/dL | Cr | 0.79 | 0.80 | mg/dL |
| Plt | 10.7 | 14.5 | 104/dL | Na | 145.1 | 138.2 | mEq/L |
| TP | 6.8 | g/dL | K | 3.1 | 2.8 | mEq/L | |
| Alb | 3.5 | g/dL | Cl | 104 | 96 | mEq/L | |
| AST | 24 | 84 | IU/L | CRP | 28.64 | mg/dL | |
| ALT | 32 | 72 | IU/L | 1,3-beta-D-glucan | 30.5 | pg/mL | |
| LDH | 431 | 1065 | IU/L | Cortisol | 23.1 | ug/dL | |
| T-bil | 0.87 | 1.05 | mg/dL | ACTH | 2.7 | pg/mL | |
| ALP | 123 | 177 | IU/L | Urinary free-cortisol | 340 | ug/day | |
| Y-GTP | 79 | 254 | IU/L | Renin | 0.6 | ng/ml/hour | |
| Glu | 114 | 91 | mg/dL | Aldosterone | 5.9 | ng/dL | |
| HbA1c | 6.8 | % | Cortisol in the low-dose dexamethasone suppression test | 24.3 | ug/dL |
quantitative and qualitative defects in T-lymphocytes, poly- morphonuclear cells, monocytes, and macrophages, it predisposes patients to a variety of opportunistic infections caused by micro- organisms such as Cryptococcus, Nocardia, Pneumocystis jirovecii, Aspergillus, Candida, Toxoplasma, Cryptosporidium, the herpes vi- ruses, Mycobacterium tuberculosis, M. avium-intracellulare, and Lis- teria monocytogenes [5,6]. The symptoms and signs of opportunistic infections are masked in hypercortisolism [5,7], which can result in delayed diagnosis and poor prognosis.
Several cases of cryptococcosis with ACC have been identified in the English literature [8]. Cryptococcosis, a systemic mycosis with worldwide distribution, is caused by pathogenic encapsu- lated yeasts from the genus Cryptococcus. Currently, two species of Cryptococcus commonly cause diseases in humans: C. neoformans and C. gattii. C. neoformans inhabits natural envi- ronments such as soil and grows in bird droppings. The primary infection commonly occurs in the lungs following inhalation
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3. Discussion
ACC is a rare neoplasm, and very little knowledge is available about the management of complications relevant to hormone excess. The present case is significant, as it indicated the relation- ship between severe hypercortisolemia and opportunistic infections.
The incidence of cancer is increasing dramatically with age. Therefore, ACC can never be ignored despite its current rare inci- dence of approximately 1-2/100,000 person-years [3]. Although most cases of ACC are sporadic, it can be a part of hereditary cancer syndromes such as Li-Fraumeni syndrome, Lynch syndrome, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia type 1, and familial adenomatous polyposis coli. ACC may be pre- sent with pain or may be incidentally discovered on imaging studies performed for another indication (20-30%). The most frequent clinical presentation is signs/symptoms of excessive ad- renal hormone production (40-60%) [3].
The overall prognosis is poor, as ACC is usually identified at an advanced stage [4]. However, the condition is remarkable for complications related to excessive hormone secretion, including opportunistic infections, hypertension, and hyperandrogenism, that are possibly treatable. Therefore, appropriate intervention for these complications may improve the prognosis and quality of life of patients.
The most commonly produced hormone in patients with ACC is cortisol (50-80% of the hormone-secreting ACCs), while hyper- androgenism is the second most common presentation in patients with excessive hormone secretion (40-60% of the hormone- secreting ACCs) [3]. Because hypercortisolemia causes
through the respiratory tract. The organism occasionally dis- seminates via the bloodstream and has a propensity to be located in the central nervous system. C. neoformans infection usually occurs in immunocompromised hosts, especially in those with HIV infection. Glucocorticosteroid therapy, solid-organ trans- plantation, chronic organ failure, rheumatologic diseases, and hematologic malignancy may also predispose individuals to cryptococcosis [9]. Disseminated form of cryptococcosis is more common in immunosuppressed hosts [10].
The efficacy of antifungal prophylaxis for the primary preven- tion of cryptococcosis is not evident in patients with ACC and CS. In HIV-infected individuals, preventive therapy for cryptococcosis is not generally recommended, because the best way to prevent cryptococcal infection is through the early initiation of antiretro- viral therapy. However, in patients with ACC and CS, it is doubtful whether cryptococcosis can be prevented just by treating ACC and CS, because ACC is frequently diagnosed late in its course and is difficult to treat. Besides, risk stratification for opportunistic in- fections should be considered in patients with ACC and CS. In HIV- infected patients with a low CD4 count, a strategy involving serum cryptococcal antigen screening and antifungal therapy in addition to antiretroviral therapy can further diminish the risk of crypto- coccal meningitis [11]. One paper reports that primary prophylaxis for pneumocystis jirovecii infection should be initiated when cortisol levels exceed 2500 nmol/L [12]. Because the degree of cortisol excess correlates with the degree of immunological impairment, risk of infection, and type of infection [5], preventive therapy for cryptococcosis may be considered according to the level of cortisol thresholds, possibly improving the prognosis and quality of life of patients with ACC and CS.
Funding statement
The authors have no funding to report.
Authorship statement
All authors meet the ICMJE authorship criteria.
HF contributed to the acquisition, analysis and interpretation of the patient data and the drafting of the manuscript. He approves of the final version to be published. He agrees to be accountable for all aspects of the work in ensuring that questions related to any part of the work are appropriately investigated and resolved.
MA contributed to the acquisition, analysis and interpretation of the patient data and the drafting of the manuscript. He approves of the final version to be published. He agrees to be accountable for all aspects of the work in ensuring that questions related to any part of the work are appropriately investigated and resolved.
Declaration of Competing Interest
None declared.
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