Endocrine Journal
NOTE
A rare case of oncocytic adrenocortical carcinoma clinically presented as an incidentaloma
Ko Harada1), Miho Yasuda1), Yasuhiro Nakano1), Kazuhiro Yoshida2), Yuzo Umeda2), Takahito Yagi2), Yuto Yamazaki3), Hironobu Sasano3) and Fumio Otsuka1)
1) Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
2) Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
3) Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
Abstract. Adrenocortical carcinoma (ACC) is a rare aggressive tumor originating from adrenocortical parenchymal cells and its incidence is approximately 1 per million population per year. An oncocytic ACC is a recently identified entity among the several known histopathological variants of ACC, which is characterized by oncocytic cells, and only a few cases in the available literature have reported this tumor. In contrast to conventional ACCs, oncocytic ACCs usually manifest as solitary lesions presenting in adults without any sex predilection. We report a case of a 70-year-old Japanese man who presented with an incidentally discovered retroperitoneal mass without any evidence of excessive corticosteroid secretion. Laboratory and imaging studies, as well as transgastric endoscopic ultrasound-guided fine needle aspiration failed to establish a definitive diagnosis. Thus, the patient underwent surgical resection of the left-sided peritoneal tumor. Weiss score was positive in 6/9 points and the tumor met two major criteria of the Lin-Weiss-Bisceglia (LWB) system leading to a diagnosis of an oncocytic variant of ACC. Based on our findings in this patient, we conclude that a combination of the Weiss and LWB criteria is required to determine the malignant potential of oncocytic adrenal tumors because ACCs and oncocytomas could be frequently indistinguishable. Careful histopathological examination is pivotal in confirming the oncocytic component in the lesion and hence definitive diagnosis of ACCs.
Key words: Adrenocortical carcinoma, Oncocytic variant, Oncocytoma
ADRENOCORTICAL CARCINOMA (ACC) is a rare aggressive tumor originating from adrenocortical paren- chymal cells. The incidence of ACC is approximately 1 per million population per year and female is more fre- quently affected at any age [1]. Patients with ACC are usually associated with poor clinical outcome and its mean duration of overall survival was reported to be 14.5 months, with a 5-year mortality rate of 75%-90% [2, 3]. The classical ACC usually harbored heterogeneous histo- logical features and may present with several further rare
histopathological variants, including oncocytic, myxoid, and sarcomatoid subtypes [4, 5]. The oncocytic variant of ACC was recently identified among these subtypes and is histologically characterized by oncocytic cyto- plasm in which abundant mitochondria was identified by immunohistochemistry and/or electron microscopy. Approximately 30-40 cases of oncocytic ACC have been reported in English literature [6, 7]. In contrast to con- ventional ACCs, oncocytic ACCs usually manifest as solitary lesions presenting in adults without any sex predi- lection [8]. We herein report a rare case of oncocytic ACC.
Case Report
A 70-year-old Japanese man presented with an inci- dentally discovered retroperitoneal mass. Abdominal ultrasonography performed during regular medical checkup revealed a mass (5 cm) located at the splenic hilum. He had a past medical history of hypertension, dyslipidemia, and paroxysmal atrial fibrillation, which
Submitted Jan. 14, 2020; Accepted Mar. 11, 2020 as EJ20-0024 Released online in J-STAGE as advance publication Apr. 4, 2020 Correspondence to: Ko Harada, M.D., Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan. E-mail: me422084@s.okayama-u.ac.jp
Abbreviations: ACC, Adrenocortical carcinoma; CT, Computed tomography; MRI, Magnetic resonance imaging; SF-1, Steroido- genic factor; 3ßHSD, 3ß-hydroxysteroid dehydrogenase; P450c17, 17a-hydroxylase; CYP11B1, 11ß-hydroxylase; CYP11B2, Aldos- terone synthase; and DHEA-ST, Dehydroepiandrosterone sulfo- transferase
had been all well controlled with medication. He did not note any weight changes, loss of appetite, or fatigue prior to his visit. Physical examination revealed that his blood pressure was 142/92 mmHg and heart rate was 54 beats per min. His height, weight, and body mass index were 181.9 cm, 78.1 kg, and 23.6 kg/m2, respectively. He did not have any features suggestive of Cushing’s syndrome. His laboratory data were summarized in Table 1. Serum cortisol, testosterone, and dehydroepiandrosterone sul- fate (DHEAS), plasma aldosterone and catecholamine, as well as urinary free cortisol and aldosterone levels were within normal limits. However, the basal plasma ACTH level was low at 5.1 pg/mL (normal range 7.2-63.3 pg/ mL). Plain computed tomography (CT) revealed a left- sided retroperitoneal tumor measuring 62 mm in greatest diameter, and contrast-enhanced CT revealed a heteroge- neously enhancing tumor adjacent to the left adrenal gland (Fig. 1A-C). Chemical shift magnetic resonance imaging revealed a large irregular lesion that did not show signal loss between the in-phase and out-of-phase images, suggesting a lipid-poor tumor (Fig. 1D, E). T2- weighted imaging revealed that the tumor was heteroge- neous and hyperintense to the liver parenchyma (Fig. 1F). 123I-meta-iodobenzylguanidine (123I-MIBG) scintig- raphy revealed normal accumulation of the 123I-MIBG in the bilateral adrenal glands, and 131I-adosterol scintigra- phy revealed no significant uptake by the left peritoneal tumor, suggesting a neoplastic lesion and/or a tumor originating from extra-adrenocortical tissue. Transgastric endoscopic ultrasound-guided fine needle aspiration of the retroperitoneal mass was performed, and cytological analysis of the specimen revealed a class III lesion, although the histopathological diagnosis could not be conclusively established. Subsequently, he underwent open surgery for resection of the left peritoneal tumor and left adrenal gland. Before surgery, it was not clear whether the tumor was benign or malignant, or from which tissue the retroperitoneal tumor had originated. Preoperative radiological imaging revealed the possibil- ity of an un-differentiated tumor, such as adrenal gland cancer or retroperitoneal sarcoma, with invasion to the pancreatic body. Therefore, the surgical procedure was focused on obtaining a sufficient surgical margin, and a distal pancreatectomy, with extended dissection of the retroperitoneum, including the spleen, adrenal grand, and the crus adjacent to aorta, was performed. Cholecystec- tomy was concomitantly performed because of gallblad- der sludge which could lead to cholecystitis in the postoperative phase. Histopathological examination of the retroperitoneal tumor adjacent to the left adrenal gland revealed a solitary tumor harboring a relatively thin fibrous capsule (Fig. 2A) without invasion of the surrounding organs. Macroscopically, the color on cut-
section was brown/dark with necrosis, but there was no hemorrhage. Microscopically, the tumor cells contained abundant granular eosinophilic cytoplasm, and the Weiss score was 6 of 9 points including high mitotic rate, atypical mitoses, eosinophilic cytoplasm, coagulation necrosis, diffuse architecture and capsular invasion dem- onstrated by tumor cells (Fig. 2B, C). The Ki-67 labeling index was 14% at the hot spots (Fig. 2D). Immunohisto- chemical examination revealed tumor cells with immu- nopositivity for steroidogenic factor 1 and mitochondria (Fig. 2E, F). Tumor cells were also immunohistochemi- cally negative for 11ß-hydroxylase and aldosterone syn- thase and positive for 17a-hydroxylase and DHEA- sulfotransferase (DHEA-ST) (Fig. 2G-J). The adrenal cortex adjacent to the tumor demonstrated cortical atro- phy of the zonae fasciculata and reticularis atrophy and reduced DHEA-ST expression (Fig. 2K, L).
Based on these histopathological and immunohisto- chemical findings, we diagnosed this case as an onco- cytic variant of ACC. In addition, these results indicated that this tumor could have the capacity of producing bio- logically active corticosteroids including cortisol and the patient had been associated with chronic suppression of the hypothalamic-pituitary-adrenal (HPA) axis prior to surgery based on the findings in attached non-neoplastic adrenal gland. He was postoperatively administered with mitotane combined with replacement therapy using hydrocortisone because of rather high-grade nature of ACC. Serum cortisol, DHEAS, and plasma ACTH were 9.0 µg/dL, 16 µg/dL, and 61.8 pg/mL, respectively, which are within the normal ranges. The patient was followed-up for 5 months after surgery without any recurrence.
Discussion
Oncocytic ACCs constitute a rare histopathological variant of ACC. To the best of our knowledge, only a few cases have been reported in English literature but none in detailed histopathological evaluation including immunolocalization of steroidogenic enzymes. In 2017, the World Health Organization first recognized and clas- sified the oncocytic variant as a distinctive subtype of ACCs [9]. Therefore, accurate histopathological diagno- sis definitively warrants careful evaluation of the onco- cytic component in tissue specimens. Macroscopically, oncocytic ACCs are usually large, rounded, encapsu- lated, brown-yellow well-circumscribed masses with a mean diameter of 8 cm (range 2-20 cm) surrounded by a thin rim of non-neoplastic adrenal tissue [10]. Micro- scopically, these tumors are generally characterized by diffuse proliferation of polygonal cells with abundant granular eosinophilic cytoplasm in which abundant
| Complete blood count | ||
| White blood cell | 5,480 /uL | |
| Neutrophil | 63.3 | % |
| Lymphocyte | 24.9 | % |
| Eosinophil | 4.2 | % |
| Red blood cell | 432 × 104 | /uL |
| Hemoglobin | 14.9 | g/dL |
| Platelet | 22 × 104 | /μL |
| Tumor marker | ||
| Soluble interleukin-2 receptor | 400 | U/mL |
| Cytokeratin 19 fragment | 2 | ng/ml |
| Carcinoembryonic antigen | 1.13 | ng/ml |
| Neuron specific enolase | 12.9 | ng/ml |
| Carbohydrate antigen 19-9 | 4.5 | U/mL |
| Total protein | 6.8 | g/dL |
| Albumin | 4.3 | g/dL |
| Total bilirubin | 1.1 | mg/dL |
| Aspartate transaminase | 18 | U/L |
| Alanine transaminase | 12 | U/L |
| y-glutamyl transpeptidase | 21 | U/L |
| Lactate dehydrogenase | 213 | U/L |
| Sodium | 143 | mmol/L |
| Potassium | 4.8 | mmol/L |
| Chloride | 108 | mmol/L |
| Corrected calcium | 9.3 | mg/dL |
| Blood urea nitrogen | 16.5 | mg/dL |
| Creatinine | 0.99 | mg/dL |
| Fasting plasma glucose | 96 | mg/dL |
| Hemoglobin A1c | 5.6 | % |
| Endocrine | |||
| Testosterone | 363.5 | [242-972] | ng/dL |
| Adrenocorticotropin | 5.1 | [7.2-63.3] | pg/mL |
| Cortisol | 7.5 | [3.8-18.4] | µg/dL |
| Plasma renin activity | 0.4 | [0.2-2.7] | ng/mL/h |
| Aldosterone | 6.8 | [3.6-24.0] | ng/dL |
| Dehydroepiandrosterone sulfate | 157 | [15-240] | µg/dL |
| Adrenaline | 0.02 | [0-0.1] | ng/ml |
| Noradrenaline | 0.23 | [0.1-0.5] | ng/ml |
| Dopamine | 0.02 | [0-0.03] | ng/ml |
| Urine free cortisol | 41.6 | [26-187] | µg/day |
| Urine aldosterone | 1.2 | [0-7.5] | µg/day |
mitochondria were identified by immunohistochemistry and/or electron microscopy, large nuclei with prominent nucleoli, occasional mononuclear and binucleated giant cells, extracapsular extension with vascular invasion and necrosis, and variable atypia with mitotic figures [6].
Accurate assessment of the malignant potential of adrenal cortical neoplasms is often challenging. Applica- tion of the Weiss criteria (Table 2) is the most widely used system to predict the biological behavior of conven- tional adrenocortical tumors; occurrence of ≥3 of the 9 Weiss criteria distinguishes malignant from benign tumors [11]. In addition, the status of the Ki-67 protein expression, especially its labeling index, is significantly associated with tumor proliferation, and the Ki-67 label- ing index is not only useful in distinguishing between benign and malignant adrenocortical tumors but also in predicting postoperative clinical outcome of ACC patients. For instance, the European Network for the Study of Adrenal Tumors clinical guidelines recommend mitotane treatment in ACC patients who underwent radi- cal surgery and harbored a high risk nature of the disease defined by Ki-67 labeling index of >10% [12]. In our patient, the total Weiss score was 6 of 9 points with Ki-67 labeling index of 14%, indicating a high-risk group of ACC and therefore, adjuvant mitotane therapy was administered to this patient.
Oncocytic ACCs has been known to represent a dis- tinct subtype of adrenal neoplasms that differ from con- ventional ACCs with regard to clinical and prognostic features [8]. Previous reports showed that the prognosis of oncocytic ACCs may be more favorable than that of conventional ACCs [13, 14]. Both benign and malignant oncocytic adrenal neoplasms have diffuse architectures and high-grade nuclear features, which are markers of malignancy in the Weiss criteria. Therefore, it is sug- gested that the application of Weiss criteria alone to oncycitc ACCs can lead to misunderstanding of malig- nant potential. In 2004, Bisceglia et al. acknowledged the inaccuracy of the traditional Weiss criteria when applied to oncocytic ACCs and proposed the Lin-Weiss- Bisceglia (LWB) system (Table 3), for the classification of these neoplasms [14, 15]. The major criteria included in this LWB system included a mitotic rate of >5 mitoses/50 high-power field (HPF), any atypical mitoses, or venous invasion. The minor criteria include large- sized tumors (>10 cm and/or >200 g), necrosis, and cap- sular or sinusoidal invasion. Defining criteria include the cells with predominantly granular eosinophilic cyto- plasm, and a high nuclear grade with a diffuse architec- tural pattern. According to the proposed working rules, the presence of any one of the major criteria indicated malignancy or oncocytic ACC, and the presence of 1-4 minor criteria indicates uncertain malignant potential. In
A
B
C
D
E
F
Plain CT scan showing a left adrenal tumor measuring 62 mm in diameter (A, arrowhead), and a contrast-enhanced CT scan showing a heterogeneously enhancing adrenal tumor on an axial view (B, arrowhead) and a coronal view (C, arrowhead). Image showing the normal left adrenal gland adjacent to the tumor (C, arrow). Chemical shift MRI showing a large irregular left-sided lesion without signal loss between the in-phase (D, arrowhead) and out-of-phase (E, arrowhead) images. T2-weighted imaging showing a heterogeneous and hyperintense tumor to the liver parenchyma (F, arrowhead). CT, computed tomography; MRI; magnetic resonance imaging
A
B: HE (x40)
C: HE (x100)
D: Ki-67
E: SF-1
F: Mitochondria
G: CYP11B1
H: CYP11B2
I: P450c17
J: DHEA-ST
K: HE (x40)
L: DHEA-ST
Image demonstrating a solitary adrenal tumor with a thin fibrous capsule (A). Microscopic examination demonstrating tumor cells with abundant granular eosinophilic cytoplasm. The total Weiss score of the tumor was 6 of 9 points based on a high mitotic rate, atypical mitoses, eosinophilic cytoplasm, coagulation necrosis, diffuse architecture, and capsular invasion (B: ×40, C: ×100, hematoxylin and eosin staining). The Ki-67 labeling index is 14% at a hot spot (D). Immunohistochemical examination showing tumor cells immunopositive for (SF-1) (E) and mitochondria (F). Tumor cells showing negative expression of CYP11B1 (G) and CYP11B2 (H) but positive expression of P450c17 (I) and DHEA-ST (J). Adjacent adrenal cortex showing atrophic changes of the zona fasciculata and zona reticularis (K) and reduced DHEA-ST expression (L).
CYP11B1, 11ß-hydroxylase; CYP11B2, aldosterone synthase; DHEA-ST, dehydroepiandrosterone sulfotransferase; P450c17, 17a-hydroxylase; SF-1, steroidogenic factor 1
Table 2
Weiss system
High nuclear grade
>5 mitoses per 50 high-power field
Atypical mitotic figures
<25% of tumor cells are clear cells
Diffuse architecture (>33% of tumor)
Necrosis
Venous invasion (smooth muscle in wall)
Sinusoidal invasion (no smooth muscle in wall)
Capsular invasion
* The presence of three or more criteria highly correlates with malignant behavior.
Table 3
Lin-Weiss-Bisceglia system
Major criteria
Invasion of venous structures
Mitotic rate >5 mitoses per 50 high-power fields
Atypical mitoses
Minor criteria
Size >10 cm and/or weight >200 g
Tumor necrosis
Invasion of sinusoidal structures
Invasion through the capsule
* The presence of one major criterion indicates malignancy, one to four minor criteria present indicates uncertain malignant potential, and the absence of all major and minor criteria is indicative of benign biological behavior.
our present case, identification of 7 mitoses/50 HPFs and atypical mitoses definitively led to the diagnosis of onco- cytic ACC. Renaudin et al. reported 43 patients with oncocytic adrenocortical tumors in France and showed that both the Weiss criteria and the LWB criteria seemed to overestimate the potential malignancy of these tumors [16]. Further studies would be necessary to characterize the malignant potential of oncocytic tumors more accu- rately.
In this case, we did not perform the suppression test for endogenous steroids because hypersecretion of adre- nocortical hormones was not clinically detected prior to
surgery. However, histological findings of the tumor and non-neoplastic adrenal gland in this particular case did indicate the presence of cortisol excess based on the cortical atrophy of the zonae fasciculata and reticularis in the adrenal cortex adjacent to the tumor along with reduced DHEA-ST expression in the zona reticularis, suggesting the chronic suppression of his HPA axis. Moreover, it is supported by the fact that plasma ACTH level recovered after the surgery. Approximately 60% of ACC patients are known as hormone-secreting tumors, and the steroid profiles often demonstrated disorganized steroidogenesis [17]. Compared to the characteristic oncocytic ACC, adrenal oncocytic neoplasms are usually nonfunctional tumors; only 17% of them are functional [13, 18]. Results of immunohistochemical findings of steroidogenic enzymes detected in our patient were also consistent with those previously reported in patients with ACC. That is, excessive cortisol secretion by an adrenal tumor could suppress his HPA axis leading to atrophy of the adjacent adrenal cortex. Therefore, evaluation of the adrenal gland adjacent to the tumor could provide inert information as to preoperative glucocorticoid secretion [19].
In summary, we report a rare case of an oncocytic ACC, treated with surgical resection and adjuvant mitotane therapy. Our case report highlighted that a com- bination of the Weiss and LWB criteria is required to accurately determine the malignant potential of onco- cytic ACCs because these tumors are sometimes indistin- guishable from oncocytomas. Histopathological diagnosis of ACCs requires careful evaluation to confirm the oncocytic component of the tumor. Close and careful evaluation of the adrenal gland adjacent to the tumor is also pivotal in confirming preoperative status of HPA of the patient and to select an appropriate postoperative treatment strategy. Moreover, it is essential to distinguish oncocytic ACC from classical ACC using histopatholog- ical and immunohistochemical findings.
Acknowledgements
None.
Disclosure
None of the authors have any potential conflicts of interest associated with this research.
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