MEDICINE
☐ CASE REPORT ☐
Endothelial Cyst of the Adrenal Gland Associated with Adrenocortical Adenoma: Preoperative Images Simulate Carcinoma
Takeshi Nigawara1, Satoru Sakihara’, Kazunori Kageyama’, Ken Terui’, Shinobu Takayasu’, Shingo Hatakeyama2, Chikara Ohyama2, Hironobu Sasano3 and Toshihiro Suda1
Abstract
A 68-year-old woman was referred for characterization of a left adrenal incidentaloma. Endocrinological examinations indicated subclinical Cushing’s syndrome, whereas the large volume (10 cm in diameter) and heterogeneous configuration of the tumor raised a strong suspicion of adrenal carcinoma. Hence, left adrenalectomy was performed. Histopathologically, this lesion was a thick hyaline-walled endothelial cyst, flanked with a compressed adrenocortical adenoma. The puzzling image resemblance of a variation of adre- nal cyst to carcinoma necessitated histological examination for confirmative diagnosis. This is the first re- ported case of adrenal endothelial cyst associated with adrenocortical adenoma, the former of which alone is a rarity.
Key words: adrenal cyst, endothelial cyst, CD34, adrenocortical adenoma, adrenal carcinoma
(Inter Med 48: 235-240, 2009) (DOI: 10.2169/internalmedicine.48.1506)
Introduction
With the increasing number of adrenal incidentalomas be- ing identified in everyday practice, the frequency of occa- sions when clinicians encounter tumors of ambiguous nature is also increasing. We herein report an extraordinarily rare case with a large benign adrenal tumor whose image pheno- type (1) was almost indistinguishable from that of adrenal carcinoma (AC). We also comment on the unusual histopa- thological findings of this lesion.
Case Report
A 68-year-old woman was referred to our endocrine de- partment in June 2005 for characterization of a large left ad- renal mass. She had been treated medically for gastric ulcer and hypertension for approximately ten years at a nearby clinic, where abdominal ultrasonography and gastric endo- scopy were performed once a year. The results of these
clinical examinations were unremarkable until six months previously when a large left perirenal mass was identified. Subsequent computed tomogram (CT) scan demonstrated the presence of a left adrenal mass with a maximum diameter of 7 cm. Follow-up CT scan after six months revealed that the mass had become enlarged to 10 cm in the greatest dimen- sion. The patient did not complain of weight loss, episodic palpitation or diaphoresis. Her hypertension was well con- trolled with the same dose of nifedipine (20 mg/day) as she had been taking. Her past history and family history were not contributory.
On physical examination, she did not show any Cushin- goid features such as moon face or skin atrophy. Despite her apparent obesity (body mass index 32.9 kg/m2), the pattern of fat deposition was generalized rather than centripetal. Her blood pressure was 124/80 mmHg.
In laboratory examinations, her serum potassium level was normal, and her LDL-cholesterol level and hemoglobin A1c percentage were mildly elevated (Table 1). Results of 75 g oral glucose tolerance test (OGTT) fell within the cri-
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, 2Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki and 3Department of Pathology, Tohoku University Graduate School of Medicine, Sendai Received for publication July 14, 2008; Accepted for publication October 21, 2008
Correspondence to Dr. Takeshi Nigawara, nigawara@cc.hirosaki-u.ac.jp
| ACTH (pg/mL) | 26 | (10-60) | |||
| cortisol (ug/dL) | 16.3 | (4-17) | |||
| DHEA-S (µg/dL) | 25 | (13-154) | |||
| u-free cortisol (µg/day) | 64.9-35.7-42.1 | (10-80) | |||
| 17-OHCS (mg/day) | 7.7-7.8-8.5 | (2.0-8.0) | |||
| 17-KS (mg/day) | 3.4-3.5-3.1 | (2.0-9.0) | |||
| plasma renin activity (ng/mL/h) | 0.3 | ||||
| aldosterone (ng/dL) | 6.2 | ||||
| u-aldosterone (ug/day) | 2.2-3.6-2.4 | (<10) | |||
| u-metanephrine (mg/day) | 0.06-0.06-0.07 | (0.50-0.20) | |||
| u-normetanephrine (mg/day) | 0.21-0.20-0.22 | (0.10-0.28) | |||
| 75gOGTT | |||||
| time (min) | 0 | 30 60 | 90 | 120 | |
| plasma glucose (mg/dL) | 98 | 171 | 194 | 171 | 161 |
| immunoreactive insulin (uU/mL) | 11 | 145 162 | 407 | 185 | |
CRH test
| time (min) | 0 | 30 | 60 | 90 |
| ACTH (pg/mL) | 79 | 108 | 61 | 30 |
| cortisol (ug/dL) | 14.0 | 31.4 | 29.1 | 27.7 |
| midnight | Dex 1 mg | Dex 8 mg | |
|---|---|---|---|
| ACTH (pg/mL) | 20 | <5 | <5 |
| cortisol (µg/dL) | 7.4 | 3.4 | 1.8 |
Reference ranges are shown in parentheses. In urine examination, values of three different days are shown to view day-to-day variations. ACTH, adreno- corticotropic hormone; CRH, corticotropin releasing hormone; Dex, overnight dexamethasone suppression test; DHEA-S, dehydroepiandrosterone sulfate; 17- KS, 17-ketosteroid; OGTT, oral glucose tolerance test; 17-OHCS, 17- hydroxycorticosteroid.
teria of impaired glucose tolerance. Robust hypersecretion of insulin was also demonstrated, indicating severe insulin re- sistance. Basal plasma levels of adrenocorticotropic hormone (ACTH), cortisol, aldosterone and dehydroepiandrosterone sulfate (DHEA-S) were within normal limits. Urine17- ketosteroid measurements were also normal. Plasma ACTH rose properly (>1.5 times the basal value) in human cortico- tropin releasing hormone (CRH) test, while serum cortisol was insufficiently suppressed in overnight 1 mg dexametha- sone test (3.4 ug/dL; reference range <3 ug/dL). The latter was consistent with the Japanese criteria of adrenal subclini- cal Cushing’s syndrome (subCS) (2). The values of 24-hour urine metanephrines were within normal limits.
CT scan (Fig. 1) demonstrated a huge (9x7 cm) left adre- nal tumor with highly heterogeneous configuration, includ- ing foci of calcification. Contrast media stained only the rim of the tumor. No normal adrenal cortex was identifiable. Magnetic resonance imaging (MRI; Fig. 2) demonstrated that the tumor consisted of a thick wall and encapsulated fluid. The irregular tumor wall was approximately isointense as the liver on both T1- and T2-weighted images, suggesting
R
very little fat component. The protein-rich fluid was inter- preted as degenerated blood or exudates from necrotic tis- sue. 131I-Adosterol scintigram (Fig. 3) exhibited approxi- mately even density on both sides of the adrenal gland, which could imply that the left adrenal mass was not as overtly hyperfunctioning as to suppress normal adrenal cor- tex.
The enormous volume and the bizarre image phenotype of the tumor were strongly suggestive of AC, while the mild autonomy in steroid production and less invasive nature of the tumor (possibly sparing normal cortex) were not. Al- though not all these findings were consistent with the typi- cal features of AC, the possibility was not excluded that this tumor may be a mildly functioning adrenal carcinoma (3, 4) as yet replacing the normal cortex. Left adrenalectomy was therefore performed by an open surgery, during which no in- vasion to the surrounding tissues was identified. Impaired cortisol suppressibility to dexamethasone was resolved after the operation, suggesting remission of subCS (Table 2). Her postoperative course was uneventful without glucocorticoid replacement.
| DHEA-S (ug/dL) | 24 | (13-154) | |
| u-free cortisol (µg/day) | 62.5-34.0-35.9 | (10-80) | |
CRH test
| time (min) | 0 | 30 | 60 | 90 |
| ACTH (pg/mL) | 19 | 106 | 75 | 50 |
| cortisol (ug/dL) | 6.2 | 13.9 | 11.9 | 13.1 |
Dex 1 mg Dex 8 mg
| ACTH (pg/mL) | <5 <5 | |
| cortisol (µg/dL) | 1.1 0.5 | |
For abbreviations, see Table 1.
Pathological Findings
The resected tumor measured 10 cm in diameter, and weighed 270 g (Fig. 4). The core was mostly composed of both old and new blood clots, randomly compartmentalized by fibrous tissue. The surface consisted of fibrous capsule, flanked with an atrophic normal adrenal cortex.
Histopathological evaluation demonstrated that the speci- men mainly consisted of a multilocular cyst associated with endopapillary proliferation of endothelial cells, on the outer surface of which a clear cell-dominant adrenocortical ade- noma was seen (Fig. 5a). The cyst, containing massive hya- line degeneration, was considered to be of angiomatous ori- gin rather than lymphangiomatous origin, because the mono- layer lining cells were CD34-positive (Fig. 5b) and D2-40- negative (Fig. 5c). The cystic lesion was therefore diagnosed
a
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b
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as an angiomatous endothelial cyst. Weiss’s criteria (5) sup- ported the diagnosis of adrenocortical adenoma in the por- tion of the lesion that demonstrated the proliferation of clear cortical cells. Ki67 or MIB1 labeling index was less than 1%, also ruling out the possibility of adrenocortical malig- nancy. Immunohistochemical analysis of steroidogenic en- zymes (6) showed the expression of P450scc, 3฿- hydroxysteroid dehydrogenase (3ßHSD), P450c17 and P450- c21 in the adenoma (Fig. 6a-d), corroborating the cortisol- producing potential of this lesion. Although DHEA- sulfotransferase (DHEA-ST) expression was not apparently suppressed in the zona reticularis of the attached normal ad- renal cortex (Fig. 6e), the atrophy of zona fasciculata was consistent with the autonomous hyperfunctioning of the adrenocortical adenoma, i.e. subCS.
Discussion
Adrenal cysts are infrequent among adrenal incidentalo- mas, comprising approximately 6% (7). They are classified into (i) hemorrhagic cysts, (ii) endothelial cysts, (iii) epithe- lial cysts, and (iv) parasitic cysts (8). Hemorrhagic cysts or pseudocysts are those whose walls lack the lining endothe-
a
b
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d
*2
e
lial or epithelial cells. They can occur in association with adrenocortical adenoma, adrenal carcinoma and pheochro- mocytoma. Endothelial cysts are classified into angiomatous and lymphangiomatous cysts. Cysts that are lined by epithe- lial cells are extremely rare variants of adrenal cysts, and are divided into true glandular and embryonal cysts. Parasitic cysts are usually associated with echinococcosis. In a series of 41 cases in Mayo Clinic, the numbers of the above four variants were 32, 6, 1 and zero, respectively (8). The term vascular cyst refers to the consortium of hemorrhagic and endothelial cysts.
The cystic lesion of the present case was diagnosed as en- dothelial cyst, and further determined to be of angiomatous origin, according to the immunopositivity of CD34 (an- giomatous marker) and negativity of D2-40 (lymphangioma- tous marker). The occurrence of endothelial cyst per se is very rare, and its association with other adrenal neoplasm is even more rare; the review by Erickson et al included only one case of endothelial cyst associated with pheochromocy- toma (8). To the best of our knowledge, this is the first re- ported case of adrenocortical tumors associated with an en- dothelial cyst.
The pathogenesis of an endothelial cyst within an adreno-
cortical adenoma is an interesting conundrum. Vascular cysts of the adrenal gland often occur in the context of local cir- culatory failure, repeating cycles of thrombus formation and recanalization. In the present case, the presence of an adre- nal central vein adjacent to the cystic lesion may suggest prior communication of the blood flow with a preexisting hemangioma. Massive hyalinization beneath the endothelial lining also supports the history of local circulatory failure. However, modification of the histological findings by repeti- tive hemorrhagic changes makes it difficult to predicate.
In the preoperative radiological examination, the image resemblance of endothelial cyst to AC was a puzzling prob- lem. The previously reported images of adrenal endothelial cysts are extremely variable; the most simple endothelial cysts are unilocular and have thin walls (9); more deformed ones are lobulated, have calcifications within the fluid, or have a few mural nodules (10-12); some can grow huge, re- taining similar features (13); the most heavily organized ones, including our present case, have thick solid walls (14), which are almost indistinguishable from the CT appearance of AC (15). Thus, it seems to be almost impossible for these imaging studies to discriminate between thick-walled endo- thelial cyst and AC. Alternatively, the present case appears
similar to an adrenal hemangioma both in CT and MRI as reported by Otal et al (10).
Functionality of the tumor may be a lead to suspect AC, but a certain unknown percentage of AC are nonfunctioning or hypofunctioning (3, 4). Overall, the size of the tumor (whether or not it exceeds 5-6 cm in diameter (16, 17)) may be the most reasonable measure to judge whether or not to operate on the patient.
Preoperative MRI in this case demonstrated that the mass had a substantial parenchymatous component, whereas CT did not depict it; the contrast media stained only the rim of the mass, giving the impression that it was comprised of a thin capsule filled with heterogeneous fluid. Comparing the images with the cut surface of the resected specimen, the enhanced rim may correspond to a part of the cyst wall where blood flow was retained. The rest of the cyst wall was mostly hyalinized, whose density on CT was almost equal to that of the fluid component, obscuring the bound- ary between the two components.
131I-Adosterol scintigram did not present a typical uptake pattern seen in subCS. Our explanation for this issue is that autonomous cortisol secretion from the adenoma was so mild that plasma ACTH responded normally to CRH load and that plasma cortisol value after 1 mg dexamethasone in- gestion was only 0.4 ug/dL above the cut-off value (2). Also, the flattened adrenocortical adenoma by compression of the large adrenal cyst most likely resulted in an extremely weak uptake image, making it almost indiscernible. The relatively dense uptake in the upper pole of the left adrenal gland may reflect a preserved uptake in the remaining nor- mal cortex, due to the mild negative feedback to ACTH. In spite of the atypical scintigram for subCS, its diagnosis we think is confirmative, because suppressed tracer uptake in the normal cortex is a supportive finding of subCS, and not a requisite (2). Also, persistent expression of DHEA-ST in zona reticularis of the normal cortex is reported in mild subCS (18). The result of the dexamethasone suppression test, together with atrophy of zona fasciculata of the normal cortex in postoperative pathology were the determining fac- tors in the diagnosis of subCS in the present case.
18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was not available in our hospital at that time. Recent reports show fairly good accuracy of FDG-PET in
differentiating adrenal malignancy (19, 20), although there are some false positive cases (21). It seems prudent to take multimodal data into account, in discussing the indication of surgery especially in those who harbor large tumor with cys- tic components such as in the present case.
The adrenal tumor consisting of a solid wall and cystic component has to be managed with great caution, because there is a potential risk of pheochromocytoma (1). Needle biopsy is contraindicated for pheochromocytoma (22). Even if pheochromocytoma is ruled out by biochemical evalu- ation, it has little diagnostic value in differentiating adrenal malignancy, because such tumors usually contain a consider- able amount of hemorrhagic and necrotic tissue, and even an image-guided needle may not hit the diagnostic portion (23). We advocate the basic policy of considering adrenalectomy if the tumor is functioning, is large (>5 cm), or has a suspi- cious image phenotype (16). The present case applied to the latter two terms, and was warranted for adrenalectomy, rather than being subjected to needle biopsy. Some cystic adrenal lesions consist of multiple histological components, ranging from myelolipoma to carcinoma (24), again warrant- ing the whole-specimen exploration following total unilateral adrenalectomy.
In summary, we encountered a case of adrenal endothelial cyst formed within an adrenocortical adenoma, which could not be clearly discriminated from adrenocortical carcinoma in preoperative imaging studies. Although it was diagnosed as benign in our particular case, suspicious large nodules should always be closely characterized and considered for resection, because there is a potential risk of malignancy that requires detailed histological exploration. As far as we know, this is the first reported case of adrenal endothelial cyst associated with adrenocortical adenoma.
Acknowledgement
T.S. is supported by the Japanese Ministry of Health, Labor and Welfare as a member of the Research Workgroup for Hypothalamicuitary Disorders, and also by Japan Society for the Promotion of Science with Grant-in-Aid for Scientific Re- search #18591014. H.S. is supported by the Japanese Ministry of Health, Labor and Welfare as a member of the Research Work- group for Intractable Adrenal Diseases.
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