False-positive ¹²³I-metaiodobenzylguanidine scintigraphy in a patient with a gastrointestinal stromal tumor presenting as a left adrenal incidentaloma

Background

The frequency of detecting adrenal incidentalomas has increased with the increased use of diagnostic imaging (1). Although adrenal incidentalomas are derived from the adrenal cortex or medulla, non-adrenal tumors in the vicinity of adrenal glands are also rarely reported as pseudoadrenal tumors (2, 3). The strategy for treating adrenal incidentalomas is determined based on the hormonal activity, tumor size, tumor growth in a short period, and imaging phenotype (1); however, any test may show false-positive or -negative findings. Therefore, it is sometimes difficult to distinguish between primary non-functioning adrenal tumors and pseudoadrenal tumors. Herein, we report the first case of an extra-gastrointestinal stromal tumor (EGIST) mimicking a hormonally silent pheochromocytoma due to false-positive ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy findings.

Case presentation

A 47-year-old Japanese man with hypertension and dyslipidemia had been treated medically for 6 years. At 40 years of age, an abdominal computed tomography (CT) scan revealed a left adrenal incidentaloma 18 mm in maximal diameter. The adrenocortical and adrenomedullary hormone levels were within normal limits (Table 1). In the same year, he was admitted to the department of cardiology in our institute for the treatment of acute myocardial infarction. He was diagnosed with type 2 diabetes mellitus at 45 years of age and managed with dietary therapy. Because his glycemic control worsened over the next year, he was referred to the department of endocrinology to optimize treatment for diabetes mellitus. As part of that consultation, we reassessed the adrenal tumor.

Investigation

The patient had no abnormal findings other than general obesity; his body mass index was 31 kg/m². The blood pressure was 106/72 mmHg while taking an angiotensin receptor blocker and diuretic. The plasma corticotropin and cortisol concentrations were normal at 8:00 am and suppressed normally after a 1-mg overnight dexamethasone suppression test. The plasma aldosterone concentration and renin activity were increased and consistent with angiotensin receptor blocker and diuretic therapy. The 24-h urinary normetanephrine levels were mildly elevated above the upper limit of the reference range without any medications which affect his metanephrine level (Table 1). A review of the CT scan images from 5 and 2 years previously showed that the tumor had gradually increased in diameter over time and the shape had changed (Fig. 1). The latest CT scan showed that the left adrenal tumor had irregular margins, was 30 mm in maximum diameter, and had unenhanced CT attenuation of 40–50 Hounsfield units. On CT scan, the mass appeared to localize within the tip of the lateral limb of the left adrenal gland, and between the left adrenal gland and the posterior wall of the stomach (Fig. 1). The suspicious imaging phenotype (an enlarging, lipid-poor adrenal mass with irregular margins) was consistent with a hormonally silent adrenocortical carcinoma, ganglioneuroma, or pheochromocytoma. ¹²³I-MIBG scintigraphy, which was performed to distinguish pheochromocytoma based on his mild elevation of the 24-h urinary normetanephrine levels, showed accumulation in the left adrenal tumor (Fig. 2).

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Abdominal computed tomography (CT) showed a lipid-poor left adrenal tumor with irregular margins, which had been enlarging over time. (A) Maximal diameter was 21 mm at 42 years of age. (B) The size of the tumor increased to 28 mm in diameter at 45 years of age. (C): Subsequential plain CT slices from head to toes. When he was referred to our department at 47 years of age, the size of left adrenal tumor increased to 30 mm in diameter.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-22-0390

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Axial (A) and sagittal (B) images of ¹²³I-MIBG scintigraphy. ¹²³I-MIBG accumulated in the left, but not right adrenal tumor.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-22-0390

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Treatment

An attempt to resect the tumor laparoscopically with the left adrenal gland and a large amount of surrounding retroperitoneum fat was not successful; the tumor was not within the resected specimen. An abdominal CT scan postoperatively showed that the tumor was situated in the retroperitoneum or intraperitoneal space where the tumor appeared to connect to the posterior wall of the stomach. Esophagogastroduodenoscopy and endoscopic ultrasound showed no submucosal tumor in the stomach or tumor continuous with the gastric wall. A laparotomy was performed, and the tumor was isolated from the posterior wall of the stomach and removed.

Outcome and follow-up

The tumor measured 40 × 20 × 20 mm (Fig. 3). Microscopically, spindle-shaped tumor cells were noted with minimal nuclear atypia proliferating in a sheet-like manner. Immunohistochemical staining was positive for c-kit and CD34. The pathological diagnosis was an EGIST. Chromogranin A and synaptophysin staining were negative, and there were no findings suggestive of a pheochromocytoma.

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The resected tumor size was 40 × 20 × 20 mm. Histologic examination demonstrated a proliferation of spindle cells. Immunohistochemical staining was c-kit- and CD34-positive and consistent with a GIST. Mitotic figures were rare, and the Ki-67 index was a few percent. Chromogranin A and synaptophysin were negative, which indicated that the tumor was not a pheochromocytoma.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-22-0390

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Discussion

Approximately one-half of adrenal incidentalomas are non-functional cortical adenomas (4). Other primary adrenal tumors include cortisol- or aldosterone-secreting adenomas and adrenocortical carcinomas (ACC), non-functional ACCs, and pheochromocytomas. Pheochromocytoma and paraganglioma (PPGLs) are difficult to define as malignant or benign due to the absence of validated molecular or histologic markers of malignancy. All PPGLs are considered to have various metastatic potentials in the recent World Health Organization (WHO) classification of endocrine organ tumors. Therefore, ACC and pheochromocytomas need to be differentiated and removed even if the tumors are hormonally inactive. In addition to these tumors of adrenal origin, anatomic structures and tumors that develop in tissues neighboring the adrenal glands (pseudoadrenal tumors) may be confused with primary adrenal tumors. For example, retroperitoneal sarcomas, schwannomas, desmoid tumors, renal angiomyolipomas, and lymphomas have been reported as pseudo-adrenal tumors (3). The larger the tumor, the more difficult it is to determine continuity with the adrenal glands.

Gastrointestinal stromal tumors (GISTs) localized on the posterior wall of the stomach, as in our case, are rarely reported to be mistaken for hormonally inactive left adrenal incidentalomas (3). Although CT scans were obtained several times over the years in our case, the tumor appeared to be localized to the tip of the lateral limb of the left adrenal gland in all coronal and sagittal section images. A thin gap between the left adrenal gland and the mass was confirmed with careful observation. However, the finding was never mentioned by radiologists, physicians, and surgeons on all images during observation period. Consequently, it was difficult to determine that the tumor was not arising from the left adrenal gland.

Furthermore, the accumulation of ¹²³I-MIBG in the tumor in our case suggested that the tumor originated from the adrenal medulla. ¹²³I-MIBG scintigraphy is specific for diagnosing PPGLs. The sensitivity and specificity for diagnosing PPGLs are 77–90% and 95–100%, respectively (5). It has been reported that ¹²³I-MIBG may accumulate not only in neuroendocrine tumors but also in angiomyolipomas, renal cell carcinomas, hepatocellular carcinomas, adrenocortical adenomas, and adrenocortical carcinomas. Four GISTs with false-positive ¹²³I-MIBG scintigraphy findings have been previously described (6) (Table 2). There were no relationships between the patient age, sex, or symptoms. The serum catecholamine levels were within normal limits. The tumors were localized near the stomach. Mitotic figures were rare and the staining results were consistent with GISTs.

The following two theories are considered the mechanisms underlying MIBG accumulation in GISTs (6, 7). First, GISTs are believed to arise from interstitial cells of Cajal (ICCs). ICCs express receptors for neurotransmitters, hormones, and paracrine substances that take up ¹²³I-MIBG. Second, gastrointestinal autonomic nerve tumors (GANTs), which are a subtype of GISTs and exhibit electron microscopic findings similar to autonomic nerves, incorporate MIBG. Immunohistochemically, GANTs stain positive for vimentin, CD34, neuron-specific enolase, chromogranin, and synaptophysin (8). GANTs can only be diagnosed by ultrastructural examination in the absence of a specific discriminating antibody for GANTs (7). In our case, CD34 staining was positive, and chromogranin A and synaptophysin were negative; thus, the tumor exhibited no characteristics for GANTs. As in our case, the reported tumor was CD117- and CD34-positive, and chromogranin A- and synaptophysin-negative, and took up ¹²³I-MIBG (9). Additional cases need to be studied to clarify the mechanism underlying GIST uptake of MIBG.

Furthermore, the GIST in our case did not have continuity with the stomach wall and thus was classified as an EGIST. EGISTs represent 5–10% of GISTs; the tumorigenic mechanism has not been elucidated (10). Although genetic testing had not been performed in this patient, GISTs and EGISTs often have somatic mutations in c-kit gene and PDGFR-α gene. Those findings suggest that GISTs and EGISTs may be from the same origin (11). Because the tumor in our case was located in the abdominal cavity near the left adrenal gland and was ¹²³I-MIBG-positive, the possibility that the tumor was derived from the adrenal gland could not be excluded.

In summary, we report a patient with a GIST that mimicked an incidentally discovered left adrenal pheochromocytoma. Lessons learned from our case include the importance of clinician awareness of imaging study limitation and the uncertainty of an imaging-based preoperative diagnosis. Moreover, the final diagnosis of non-functioning adrenal incidentalomas necessitates tumor resection and a pathological evaluation. In addition, it is important to give patients sufficient informed consent when deciding on treatment strategies.

Declaration of interest

The authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study was conducted as a part of ACPA-J (Advancing Care and Pathogenesis of Intractable Adrenal Diseases in Japan) through a research grant from the National Center for Global Health and Medicine, Japan (grant number 20A1015) and a Grant-in-Aid from the Ministry of Health, Labour, and Welfare, Japan (Nanjiseisikkanseisakukenkyujigyo, 20FC1020).

Patient consent

Written informed consent for publication of their clinical details and clinical images was obtained from the patient.

Author contribution statement

E S, K M, A T, K N and N E were in charge of the medical care for the patient. E S and A T wrote the manuscript with important remarks from all authors. All authors read and approved the final manuscript.