Abstract
123I-metaiodobenzylguanidine (MIBG) scintigraphy is highly accurate for diagnosing pheochromocytoma and paraganglioma (PPGL), and positive uptake in non-PPGL adrenal lesions is rare. We report a 56-year-old woman with an adrenal endothelial cyst (vascular type) showing localized 123I-MIBG uptake, initially suspected to be pheochromocytoma. After mild growth during observation, robot-assisted adrenalectomy was performed. Histopathology confirmed an endothelial cyst positive for CD31 and D2-40. Among 601 adrenalectomies, eight adrenal endothelial cysts (1.3 %) were identified, three showing MIBG uptake. Adrenal endothelial cysts may rarely show MIBG uptake, complicating preoperative differentiation from PPGL.
Keywords: Adrenal cyst, Endothelial cyst, Vascular type, MIBG, Pheochromocytoma differential diagnosis
1. Introduction
123I-MIBG scintigraphy is widely used in PPGL diagnosis, with high sensitivity and specificity.1,2 However, physiological adrenal uptake exists, and false positives have been reported in non-PPGL adrenal lesions such as adrenocortical adenoma, schwannoma, and adrenocortical carcinoma.3, 4, 5 Proposed mechanisms include norepinephrine transporter (NET)-mediated uptake, vesicular monoamine transporter (VMAT)-mediated sequestration into neurosecretory granules, and passive diffusion related to increased tumor vascularity.6, 7, 8
According to the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors (5th Edition), adrenal cysts are classified into four subtypes: pseudocyst, endothelial cyst (vascular/lymphatic type), epithelial cyst, and parasitic cyst.9 Endothelial cysts (vascular type) are benign, fluid-filled lesions lined by endothelial cells, usually arising from blood or lymphatic vessels. Clinically and radiologically, they may simulate cystic adrenal neoplasms, including pheochromocytoma or adrenocortical carcinoma, making accurate preoperative diagnosis challenging.9, 10, 11 We present the first reported adrenal endothelial cyst (vascular type) with positive 123I-MIBG uptake, together with review of three cases at our institution.
2. Case presentation
A 56-year-old woman was referred to our department after abdominal ultrasound revealed a left adrenal cyst during evaluation for hypertension detected at a health checkup. She had no remarkable past medical or family history. On presentation, her blood pressure was 144/88 mmHg and pulse rate was 68 bpm; other physical findings were unremarkable.
Laboratory findings: Plasma and urinary metanephrines and catecholamines were within normal ranges. Specifically, plasma adrenaline 20 pg/mL, plasma noradrenaline 14 pg/mL, plasma dopamine ≤20 pg/mL, urinary adrenaline 8 μg/day, urinary noradrenaline 89.1 μg/day, urinary dopamine 1100 μg/day, urinary metanephrine 0.09 mg/day, urinary normetanephrine 0.16 mg/day.
Imaging (Fig. 1): CT showed a 48-mm multilocular cystic lesion with calcification in the left adrenal gland. MRI revealed a multilocular cyst with low signal on T1-weighted and high signal on T2-weighted images. 123I-MIBG SPECT/CT demonstrated significant uptake at the lesion site.
Fig. 1.
a Contrast-enhanced CT revealed a lobulated cystic lesion with calcification in the left adrenal gland. b 123I-MIBG scintigraphy showed intense uptake corresponding to the left adrenal cyst. c The lesion showed low signal intensity on T1-weighted MRI. d T2-weighted MRI demonstrated a 53-mm multilocular cystic lesion with septations and high signal intensity.
Clinical course: Although pheochromocytoma was suspected, endocrine evaluations were inconclusive. The patient initially opted for observation, but gradual growth (5 mm over 2 years) led to surgical intervention. After preoperative α-blockade (doxazosin 16 mg/day), robot-assisted left adrenalectomy was performed. No intraoperative hemodynamic instability was observed. Postoperatively, no significant change in blood pressure was observed, and the pre-existing calcium-channel blocker was continued.
Pathology: Grossly, the cyst had septations with hemorrhagic content (Fig. 2a). Histologically, the cyst wall consisted of vascular structures with smooth muscle (Fig. 2b). Endothelial cells lining the cyst wall stained positive for CD31 and D2-40 (Fig. 2c and d). The final diagnosis was adrenal endothelial cyst (vascular type).
Fig. 2.
a Gross appearance of the resected specimen revealed old hemorrhagic contents within the cyst. b Histological examination showed vascular structures containing smooth muscle within the cyst wall (H&E staining, × 10). c CD31-positive endothelial cells were observed (×100). d D2-40-positive endothelial cells were also detected (×100).
2.1. Review at our institution
Among 601 adrenalectomies performed from January 2015 to January 2025, adrenal endothelial cysts (vascular type) were observed in 8 cases (1.3 %). Of these, 5 underwent 123I-MIBG imaging, and 3 cases (including the present case) showed positive uptake. None of the 8 cases were preoperatively diagnosed as adrenal endothelial cysts (vascular type). Surgery was performed due to suspicion of pheochromocytoma, adrenocortical carcinoma, or progressive enlargement. Clinical details of each case are summarized in Table 1.
Table 1.
Clinical characteristics of 8 cases of adrenal endothelial cysts (vascular type).
| Age | Sex | Side | Tumor size (mm) | Preoperative diagnosis | Indication for surgery | MIBG | Plasma/urinary metanephrines | Surgical approach | Immunohistochemistry |
|---|---|---|---|---|---|---|---|---|---|
| 56 | F | L | 73 × 48 | Pheochromocytoma | Suspected PPGL | Positive | Normal | Robot-assisted | CD31+, D2-40+ |
| 73 | M | L | 16 × 12 | Pheochromocytoma | Suspected PPGL | Positive | Normal | Laparoscopic | N/A |
| 77 | F | L | 45 × 30 | Pheochromocytoma | Suspected PPGL | Positive | Abnormal | Laparoscopic | CD31+ |
| 30 | M | L | 60 × 40 | Nonfunctioning adrenal tumor | Tumor size ≥40 mm | Not performed | Normal | Laparoscopic | CD31−, D2-40+ |
| 61 | F | R | 48 × 33 | Nonfunctioning adrenal tumor | Tumor growth | Not performed | Normal | Laparoscopic | N/A |
| 75 | M | L | 139 × 109 | Nonfunctioning adrenal tumor | Tumor growth | Negative | Normal | Open | N/A |
| 75 | F | L | 50 × 40 | Nonfunctioning adrenal tumor | ACC not excluded | Not performed | Normal | Robot-assisted | CD31+ |
| 71 | F | R | 50 × 48 | Subclinical Cushing syndrome | Tumor size ≥40 mm | Negative | Normal | Robot-assisted | CD31+ |
PPGL: pheochromocytoma and paraganglioma, ACC: adrenocortical carcinoma.
3. Discussion
This case highlights an adrenal endothelial cyst (vascular type) presenting with hypertension and positive 123I-MIBG uptake, preoperatively indistinguishable from pheochromocytoma. To our knowledge, no prior reports have described MIBG-positive adrenal endothelial cysts (vascular type). Our institutional review identified 2 additional cases, suggesting that this phenomenon should be recognized as a possible pitfall in differential diagnosis.
Endothelial cysts (vascular type) are defined histologically by the presence of endothelial lining cells within the cyst wall. Immunohistochemical positivity for CD31, CD34, and D2-40 confirms endothelial origin and distinguishes them from hematomas or mesotheliomas.9, 10, 11 Reported peak incidence is in the fifth to sixth decades, with a female-to-male ratio of 3:1.9,10 They are classified as endothelial (24–45 %), pseudocyst (39–56 %), epithelial (6–9 %), and parasitic (2–7 %).11 Most cases are nonfunctional and discovered incidentally. Surgical indications include suspicion of malignancy, tumor size >5 cm, hemorrhage, or symptomatic presentation. Preoperative diagnosis remains challenging, as in the present case.10,12
123I-MIBG demonstrates high sensitivity and specificity for PPGL, but physiological adrenal uptake and false positives are known. Reported non-PPGL adrenal lesions with uptake include cortical adenomas, schwannomas, and adrenocortical carcinomas. Semi-quantitative analyses (lesion-to-liver or lesion-to-mediastinum ratios) may improve diagnostic accuracy but are not definitive.7
Proposed mechanisms of false-positive uptake include (1) passive diffusion due to increased tumor vascularity, (2) vesicular monoamine transporter (VMAT)-mediated storage in neurosecretory granules, and (3) uptake via NET.6,7 In this case, passive diffusion due to vascular nature and high blood flow of the cyst was considered the most likely mechanism.
Clinical implications: Previous reports have described pheochromocytomas with normal biochemical findings, as well as cystic pheochromocytomas.1,13 Therefore, when surgery is considered for an MIBG-positive adrenal mass with non-typical biochemical results, adrenal endothelial cysts should also be included in the differential diagnosis. When PPGL cannot be excluded in adrenal tumors, pathological confirmation is necessary, and surgery may be unavoidable. Although biochemical findings were normal, α-blockade was administered as a precautionary measure for possible PPGL, in order to prevent perioperative blood pressure fluctuations. Preoperative α-blockade therefore remains a useful safety measure. MIBG positivity alone should not be considered diagnostic for PPGL; discrepancies with biochemical or imaging findings require careful evaluation and appropriate patient counseling.
3.1. Limitations
This is a single-institution, retrospective review. MIBG scintigraphy was not performed for all adrenalectomy cases, and the mechanism of false-positive uptake remains speculative.
4. Conclusion
Adrenal endothelial cysts (vascular type) may rarely demonstrate 123I-MIBG uptake, complicating differentiation from PPGL. Comprehensive diagnosis should integrate imaging, biochemical, and pathological findings.
CRediT authorship contribution statement
Riona Asai: Writing – original draft, Data curation. Tomonori Sato: Writing – original draft, Data curation. Yuto Yamazaki: Writing – original draft, Investigation. Yuta Tezuka: Writing – original draft. Yoshikiyo Ono: Writing – original draft. Hiromichi Katayama: Data curation. Yohei Satake: Data curation. Takuma Sato: Data curation. Yoshihide Kawasaki: Data curation. Naoki Kawamorita: Data curation. Hideki Katagiri: Writing – review & editing, Supervision, Conceptualization. Akihiro Ito: Writing – review & editing, Supervision, Conceptualization.
Funding
The publication fee of this article was supported by JSPS KAKENHI Grant Number JP24K19644.
References
- 1.Lenders J.W., Duh Q.Y., Eisenhofer G., et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915–1942. doi: 10.1210/jc.2014-1498. PMID: 24893135. [DOI] [PubMed] [Google Scholar]
- 2.Wiseman G.A., Pacak K., O'Dorisio M.S., et al. Usefulness of 123I-MIBG scintigraphy in patients with suspected pheochromocytoma or paraganglioma: Results from a rrospective multicenter trial. J Nucl Med. 2009;50(9):1448–1454. doi: 10.2967/jnumed.108.058701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Jung H.S., Moon S.J., Kim Y.M., et al. False positive 123I-MIBG uptake in undifferentiated adrenal malignant tumor. Case Rep Oncol Med. 2015;2015 doi: 10.1155/2015/164280. PMID: 26257977. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Shapiro B., Copp J.E., Sisson J.C., et al. Iodine-131 metaiodobenzylguanidine for localization of suspected pheochromocytoma: experience in 400 cases. J Nucl Med. 1985;26(6):576–585. PMID: 3888818. [PubMed] [Google Scholar]
- 5.Izawa S., Matsuzawa K., Sumiya K., et al. Clinical characteristics of 123I-MIBG–positive adrenal tumors requiring differential diagnosis from pheochromocytoma. Folia Endocrinol Jpn. 2014;90:45–48. [Google Scholar]
- 6.Kolby L., Bernhardt P., Levin-Jakobsen A.M., et al. Uptake of meta-iodobenzylguanidine in neuroendocrine tumours is mediated by vesicular monoamine transporters. Br J Cancer. 2003;89(7):1383–1388. doi: 10.1038/sj.bjc.6601276. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Endo K., Inoue Y., Koyama K., et al. False positive uptake of metaiodobenzylguanidine in hepatocellular carcinoma. Br J Radiol. 2002;75(894):548–551. doi: 10.1259/bjr.75.894.750548. [DOI] [PubMed] [Google Scholar]
- 8.Bozic Antic I., Vujic G., Zivaljevic V., et al. Clinicopathologic features and outcome of surgically treated adrenal cysts: a single-center experience and literature review. J Clin Med. 2024;13(3):846. doi: 10.3390/jcm13030846. PMID: 38366443. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.WHO Classification of Tumours Editorial Board . fifth ed. International Agency for Research on Cancer; Lyon: 2022. Endocrine and Neuroendocrine Tumours. [Google Scholar]
- 10.Carvounis E., Marinis A., Arkadopoulos N., et al. Adrenal endothelial cyst: diagnosis and management. Arch Pathol Lab Med. 2006;130(11):1722–1724. doi: 10.5858/2006-130-1722-VACABR. PMID: 17090196. [DOI] [PubMed] [Google Scholar]
- 11.Tagawa H., Kasai T., Sato T., et al. Adrenal endothelial cyst: a case report and review of the literature. Radiol Case Rep. 2021;16(6):1294–1299. doi: 10.1016/j.radcr.2021.03.016. [DOI] [Google Scholar]
- 12.Okada K., Shimamoto T., Shimizu T., et al. A case of adrenal hemangioendothelial cyst. J Jpn Surg Assoc. 2021;82(10):1912–1918. [Google Scholar]
- 13.Suzuki T., Fujita K., Kimura T., et al. Cystic pheochromocytoma: a diagnostic challenge. Radiol Case Rep. 2020;15(5):603–607. doi: 10.1016/j.radcr.2019.12.025. [DOI] [Google Scholar]