Internal Medicine The Japanese Society of Internal Medicine
A Rare Case of Interleukin-6-producing Adrenocortical Carcinoma Presenting with a Persistent Fever
Kohei Oguni12, Yukiko Goshima’, Keita Tatsushima’, Michikata Hayashida3, Shinji Urakami3, Shinji Ito4, Yuto Yamazaki5, Hironobu Sasano5, Yasuhiro Takeuchi 1,6 and Akira Takeshita 1,6
Abstract:
A 16-year-old girl presented with a high fever that had persisted for more than 4 weeks. Computed to- mography revealed a 4-cm mass in the left adrenal gland. Clinically, there were no obvious symptoms of ad- renal hormone excess; however, serum interleukin-6 (IL-6) and C-reactive protein levels were significantly elevated. After laparoscopic left adrenalectomy, the fever subsided, and her IL-6 level normalized. The tumor was pathologically diagnosed as adrenocortical carcinoma (ACC), with a Weiss score of 5/9. The tumor cells were immunoreactive for IL-6. To our knowledge, this is the first case report of symptomatic IL-6-producing ACC that initially presented with a persistent fever.
Key words: adrenocortical carcinoma, interleukin-6, fever of unknown origin
(Intern Med 64: 2350-2355, 2025) (DOI: 10.2169/internalmedicine.4599-24)
Introduction
Adrenocortical carcinoma is a very rare tumor, with an in- cidence of 0.7 to 2 per million people per year. Clinically evident adrenal hormone production occurs in 50-60% of cases. Therefore, Cushing’s and virilization are the two most common clinical manifestations. A fever was also reported as a rare symptom of adrenocortical carcinoma in one case (1). A detailed histopathological examination of tumor cells reveals overexpression of the inflammatory cytokine C- X-C motif chemokine 5 (CXCL5), implying the pathogene- sis of the fever (1).
Interleukin-6 (IL-6) is a pleiotropic cytokine that plays pivotal roles in immune and inflammatory responses. The excessive production of IL-6 induces inflammation and stimulates the release of acute phase proteins, such as C- reactive protein. More than 40 cases of pheochromocy- toma (2) and two of adrenal oncocytoma (3) have been re-
ported as IL-6-producing adrenal parenchymal neoplasms. Most of these cases are clinically characterized by a fever and strong inflammatory responses (2, 3). To our knowl- edge, however, IL-6-producing adrenocortical carcinomas as- sociated with symptomatic systemic inflammatory features have not yet been reported.
We herein report the first case of IL-6-producing adreno- cortical carcinoma that clinically manifested as a persistent fever of unknown origin.
Case Report
A 16-year-old Japanese girl presented to her physician with a fever that had persisted for over 4 weeks. No obvious signs of infection were clinically noted, and subsequent computed tomography (CT) revealed a 4-cm left adrenal mass with CT attenuation of 28 Hounsfield units (Fig. 1A). She was then referred to our hospital for an evaluation of the adrenal mass. There were no comorbidities or family
1Department of Endocrinology and Metabolism, Toranomon Hospital, Japan, 2Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan, 3Department of Urology, Toranomon Hospital, Japan, 4Department of Pathol- ogy, Toranomon Hospital, Japan, 5Department of Pathology, Tohoku University Graduate School of Medicine, Japan and 6Okinaka Memorial In- stitute for Medical Research, Japan
Correspondence to Dr. Akira Takeshita, coactivator@mac.com
A
B
C
adrenalectomy
Naploxen
BT[°C]
40
38
36
WBC[/uL]
10000
5000
0
CRP[mg/dL]
30
10
0
IL-6[ng/L]
200
100
0
SS
2
4
6
8
10
12 26
28
30
32
day
history suggestive of Li-Fraumeni syndrome or Lynch syn- drome.
The vital signs at the time of admission were as follows: temperature, 39.0°C; blood pressure, 131/54 mmHg; and si- nus tachycardia, with a heart rate of 133 beats/min. A physi- cal examination revealed no clinical symptoms of Cushing’s syndrome, hirsutism, or virilization. A laboratory analysis revealed mild anemia (hemoglobin, 10.9 g/dL), thrombocy- tosis (platelet count, 504,000/uL), and hypoalbuminemia (al- bumin, 2.5 g/dL). A markedly elevated C-reactive protein level (24.6 mg/dL) and an increased erythrocyte sedimenta- tion rate (>110 mm/h) were also noted. Her blood IL-6 level was markedly elevated at 120.0 ng/L (normal <7 ng/L). No abnormalities were detected on coagulation tests [activated partial thromboplastin time (APTT) and prothrombin time (PT)].
Regarding adrenal magnetic resonance imaging, the left adrenal mass demonstrated hyperintensity on T2-weighted images (Fig. 1B), which initially led us to suspect a pheo- chromocytoma. However, blood catecholamine, metaneph-
rine, and normetanephrine levels were all within normal lev- els, with no significant Iodine-123 metaiodobenzylguanidine (123I-MIBG) uptake in the mass (Fig. 1C), ruling out a catecholamine-producing pheochromocytoma. Her morning cortisol level was high (31.6 ug/dL), whereas her adrenocor- ticotropic hormone (ACTH) level was not suppressed (22.1 pg/mL), ruling out an autonomous cortisol-producing tumor. Nocturnal cortisol measurements, 24-h urinary free cortisol sampling, and dexamethasone suppression tests were not performed. Regarding the renin-aldosterone-angiotensin sys- tem, an elevated plasma concentration of aldosterone (15.4 ng/dL) and high plasma renin activity (5.4 ng/ml/h) were detected. Androgens were slightly elevated with a total tes- tosterone level of 66.3 ng/dL (reference 10.8-56.9 ng/dL); however, there were no signs of gonadotropin suppression or menstrual irregularities.
The patient’s clinical course after admission is shown in Fig. 2. Acetaminophen did not attenuate the fever, whereas naproxen reduced it to 37°℃ before surgery. The patient un- derwent laparoscopic left adrenalectomy under a pre-
| Value before surgery | Value after surgery | Reference range | |
|---|---|---|---|
| WBC (/uL) | 9,800 | 4,100 | 3,300-8,600 |
| Hb (g/dL) | 10.9 | 14.1 | 11.6-14.8 |
| PLT (×104/uL) | 50.4 | 20.9 | 15.8-34.8 |
| Albumin (g/dL) | 2.5 | 4.8 | 4.1-5.1 |
| CRP (mg/dL) | 24.62 | 0.01 | <0.30 |
| IL-6 (ng/L) | 120 | <1.5 | <7.0 |
| ACTH (pg/mL) | 22.1 | 39.9 | 7.2-63.3 |
| Cortisol (ug/dL) | 31.6 | 13.9 | 7.1-19.3 |
| PAC (ng/dL) | 15.4 | 2.1 | 0.4-8.2 |
| PRA (ng/mL/h) | 5.3 | 1.1 | 0.2-2.3 |
| DHEA-S (ng/ml) | 2365 | 2447 | 510-3210 |
| Testosterone (ng/dL) | 66.3 | 40.4 | 10.8-56.9 |
WBC: white blood cell count, Hb: hemoglobin, PLT: platelet count, CRP: C-reactive protein, IL-6: interleukin-6, ACTH: adrenocorticotropic hormone, PAC: plasma aldosterone concentration, PRA: plasma renin activity, DHEA-S: dehydroepiandrosterone sulfate
A
HE
B
SF1
C
Ki-67
200um
200μm
200um
D
HSD3B
E
CYP17
F
CYP21
G
HSD17B5
200um
200um
200um
200um
operative diagnosis of an IL-6-producing adrenal tumor. The patient became afebrile after the surgery, and the IL-6 de- creased to 7.0 ng/L at 1 h postoperatively. Anemia, throm- bocytosis, hypoalbuminemia, and elevated C-reactive protein levels due to the hyperinflammatory state subsequently nor- malized. The preoperative hypercortisolemia and slightly elevated total testosterone levels also normalized postopera- tively. There was no recurrence during an approximately 24- month follow-up period, and her serum IL-6 level remained within the normal range (Table).
The tumor measured 5.5x3.5x2.5 cm and weighed 39 g. Histologically, it was composed of proliferative atypical cells with an eosinophilic cytoplasm (Fig. 3A). Steroido- genic factor 1 (SF-1), a transcription factor of steroidogene- sis, was diffusely expressed in the nuclei of tumor cells (Fig. 3B), indicating that the tumor was of an adrenocortical origin. A high nuclear grade, high mitotic rate (6/50 high-
power fields) with a Ki-67 labeling index of 8% at hot spots (Fig. 3C), eosinophilic tumor cell cytoplasm, architectural abnormality, and capsular invasion were detected. The Weiss score (4) was 5/9, and the tumor was subsequently diag- nosed as an adrenocortical carcinoma.
Oncocytoma was ruled out based on the histopathological findings of a low percentage of oncocytic cells and diffuse positive immunoreactivity of SF-1 in tumor cells. The tumor was stage II according to the European Network for the Study of Adrenal Tumors (ENSAT) classification (5). Since R0 resection was successfully performed and the Ki-67 in- dex was <10%, postoperative adjuvant therapy was not ad- ministered according to the European Society of Endocrinol- ogy clinical practice guidelines (5).
3ß-Hydroxysteroid dehydrogenase (HSD3B), 17a- hydroxylase/C17-20 lyase (CYP17), 21-hydroxylase (CYP 21), and 17ß-hydroxysteroid dehydrogenase (HSD17B5)
A
IL-6
B
CD68
C
CD3
D
CD4
200um
200um
200um
200μm
E
CD8
F
CD20
G
CD79a
H
PD-L1
200μm
200um
200µm
200µ₥
(Fig. 3D-G) were immunohistochemically positive, whereas 11ß-hydroxylase (CYP11B1), aldosterone synthase (CYP11 B2), and dehydroepiandrosterone sulfotransferase (DHEA- ST) were negative. The absence of CYP11B1 and CYP11B2 immunoreactivity indicated that the tumor did not produce biologically active corticosteroids including cortisol and al- dosterone. Atrophy was not detected in the zona fasciculata of the attached non-neoplastic adrenal gland, which was consistent with the intact long-term preoperative hypothalamic-pituitary-adrenal (HPA) axis prior to surgery. The slightly elevated total testosterone levels before surgery may be explained by the positive immunoreactivity of HSD 17B5 in tumor cells. An immunohistochemical analysis of IL-6 revealed sparse but clearly positive findings in tumor cells (Fig. 4A). IL-6 immunoreactivity was mainly detected in tumor cells and partially detected in cluster of differentia- tion (CD) 68-positive macrophages in the tumor tissue. These results led to the final diagnosis of IL-6-producing adrenocortical carcinoma with androgen production. In addi- tion, a large number of tumor-infiltrating CD68+ macro- phages were detected in tumor tissues (Fig. 4B). Regarding tumor-infiltrating CD3+ T lymphocytes (TILs), cytotoxic T cells (CD8+) rather than helper T cells (CD4+) were rela- tively prominent, without relevant necrosis (Fig. 4C-E). CD 20 and CD79a, markers of B cell lymphocytes, were not de- tected (Fig. 4F, G). An immunohistochemical analysis of programmed cell death ligand 1 (PD-L1) revealed im- munopositivity in the plasma membrane of tumor cells and in the cytoplasm of mononuclear inflammatory cells; the tu- mor proportion score and combined positive score were both >1% (Fig. 4H).
Discussion
We encountered a unique case of symptomatic IL-6- producing adrenocortical carcinoma initially presenting with
a fever of unknown origin, which, to our knowledge, has not yet been reported in the literature.
IL-6 is produced by a number of cells, including immune cells, such as lymphoid cells and monocytes, as well as fi- broblasts, endothelial cells, mesangial cells, and skeletal and myocardial cells. In humans, IL-6 and its receptor, IL-6R, are predominantly expressed in the medial adrenal cortex and are considered to act in both autocrine and paracrine manners to regulate adrenocortical hormone secretion, inde- pendent of the HPA axis (6).
In the present case, the adrenal tumor was diagnosed as adrenocortical carcinoma according to the Weiss criteria (4). The Weiss criteria are based on an analysis of tumors in adult patients between 20 and 70 years old. The Wieneke criteria (4) are currently considered more suitable for diag- nosing adrenocortical carcinoma in children, particularly in- fants, than the Weiss criteria. The Wieneke criteria were de- rived from a cohort of 83 patients between 4 months and 19 years old, with a mean age of 7.6 years old and a median age of 4 years old; only 37% were older than 10 years old. Since the present case involved a 16-year-old adolescent, we considered the Weiss criteria to be more appropriate than the Wieneke criteria for the diagnostic evaluation of the resected specimen.
A previous study investigated serum IL-6 levels in pa- tients with various adrenal tumors. Although the reference value for IL-6 differs from that in the present study, serum IL-6 levels were significantly higher in tumors of adrenocor- tical and medullary origin, particularly non-functioning adrenocortical carcinomas, than in healthy controls, despite the absence of a clinically manifesting fever (7).
In the present case, the serum cortisol level was elevated, whereas the ACTH level was not suppressed. Negative im- munostaining for CYP11B1 and CYP11B2, as well as the absence of atrophy of the accompanying adrenocortical zona fasciculata and zona reticularis of normal tissues, suggested
that the tumor was unlikely to autonomously produce gluco- corticoids. IL-6 stimulates the HPA axis (8, 9) and directly stimulates the production of adrenocortical steroids, such as cortisol, aldosterone, and DHEA-S (6). Furthermore, ele- vated IL-6 levels have been associated with enhanced corti- sol response to ACTH stimulation (10). Previous studies re- ported that daily administration of IL-6 increased both ACTH and cortisol levels, and although cortisol levels re- mained elevated over time, ACTH responses were attenu- ated (8, 9). These mechanisms may account for the normal ACTH and elevated cortisol levels observed before surgery in the present case.
IL-6 is generally secreted from tumor cells as well as macrophages, dendritic cells, and myeloid-derived suppres- sor cells in an autocrine and paracrine manner (11). Consis- tent with these findings, IL-6 immunoreactivity was mainly detected in tumor cells in our case but was also partially present in macrophages.
However, the percentage of IL-6-positive cells was lower than that expected from clinical presentation. There are two possible reasons for this finding. IL-6 is a secreted protein; thus, intracellular stores of IL-6 may have been low. In ad- dition, IL-6 production may have been heterogeneous within the tumor. Few studies have compared serum IL-6 levels with IL-6 immunoreactivity in tumor cells, and one study reported no correlation in patients with breast cancer (12). In addition to immunohistochemistry, it may be useful to as- sess IL-6 production in tumor cells by measuring the con- centration of IL-6 in the culture medium of primary cultures and/ or examining mRNA expression by reverse transcription-polymerase chain reaction or in situ hybridiza- tion. However, these tests were not performed in this case.
Elevated IL-6 levels are generally regarded as poor prog- nostic factors for cancer (13, 14). Several drugs targeting the IL-6/janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways have already been ap- proved by the Food and Drug Administration (FDA) for the treatment of inflammatory diseases and myeloproliferative neoplasms. Despite their therapeutic potential, inhibitors of the IL-6/JAK/STAT3 pathways in solid tumors have not yet demonstrated consistent antitumor effects in clinical tri- als (13, 14). Within the tumor microenvironment, IL-6 exerts a number of deleterious effects, such as promotion of tumor growth, metastasis, angiogenesis, and immune evasion. IL-6 also promotes the differentiation of M1 macrophages into M 2 macrophages, contributing to their immunosuppressive ef- fects (11). Therefore, the tumor-infiltrating macrophages in the present case may have been associated with tumor IL-6 secretion. In contrast, IL-6 was recently shown to exert anti- tumor effects, such as via an increased T-cell proliferation and survival and CD8+ T-cell trafficking to tumors (15). Therefore, TILs may also have been associated with IL-6 production in the tumors in the present case.
The infiltration of CD3+ T-cell is generally a favorable prognostic factor for adrenocortical carcinoma, regardless of the presence of CD3+CD4+ helper T cells or CD3+CD8+ cy-
totoxic T cells (16). Glucocorticoid overproduction in adrenocortical carcinoma negatively correlates with the num- ber of CD3+CD4+ helper T cells and is associated with a poor prognosis (16). In the present case, CD3+CD8+ cyto- toxic T cells rather than CD3+CD4+ helper T cells were pre- dominant; however, the tumor did not produce glucocorti- coids. Although whether or not the TILs in the present case were associated with its prognosis remains unclear, there was no recurrence on imaging, and the serum level of IL-6 remained undetectable approximately two years after sur- gery.
Significant PD-L1 expression was detected in the plasma membrane of the tumor cells in this patient. Since IL-6 has been reported to induce the expression of PD-L1 (13), PD-L 1 expression in this case may have been associated with tu- mor IL-6 production. In previous studies on PD-L1 expres- sion in adrenocortical carcinoma, a high expression of PD-L 1, assessed immunohistochemically, was detected in only 3- 11% of tumors (17). A recent meta-analysis showed that im- mune checkpoint inhibitors did not improve outcomes com- pared to chemotherapy with etoposide, doxorubicin, and cis- platin plus mitotane in the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) trial, and no clear effi- cacy was demonstrated, even in PD-L1-expressing pa- tients (17).
In conclusion, we reported a rare case of symptomatic IL- 6-producing adrenocortical carcinoma. Although rare, we need to consider the possibility of adrenocortical carcinoma, pheochromocytoma, and oncocytomas in patients presenting with adrenal tumors and a persistent fever.
Written informed consent for publication of clinical details and/or clinical images was obtained from the patient and her mother.
The authors state that they have no Conflict of Interest (COI).
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2025 The Japanese Society of Internal Medicine Intern Med 64: 2350-2355, 2025