Abstract
Adrenocortical adenoma is a benign neoplasm derived from cells of the adrenal cortex. The myxoid variant of this tumor is extremely rare. To our knowledge, only 23 cases of myxoid adrenocortical adenoma have been reported so far and 19 of them mentioned the pseudoglandular pattern. We reported a new case of 56-year-old Chinese female patient whose left adrenal gland was shown a neoplastic lesion by computed tomography (CT) and magnetic resonance (MR) imaging. Histopathological study showed that the mass was a myxoid adrenocortical adenoma with a pseudoglandular pattern. Then, we performed immunohistochemistry with 28 biomarkers to make differential diagnosis and found that tumor cells were diffusely positive for vimentin, melan-A, CD56, NSE and USP10, and focally positive for cytokeratin pan, cytokeratin 8/18 and VEGF. The labeling index of Ki-67 and Cyclin D1 were about 1% and 50%, respectively. No immunoreactivity was found for EMA, cytokeratin 7, HMB45, S-100, alpha-inhibin, calretinin, synaptophysin, chromogranin A, P53, EGFR, MMP2, DNA topo II alpha, CA125, E-cadherin, P63, P16 and Her-2. The patient has been followed up for 37 months after tumor resection and no evidence was found to suggest any local recurrence or any metastatic disease. Myxoid adrenocortical adenoma with a pseudoglandular pattern is extremely rare. The accurate diagnosis should be based on combined consideration of clinical characteristics, CT, MR imaging and pathological features, and should be distinguished from other retroperitoneal myxoid tumors.
Keywords: Adrenocortical adenoma, myxoid variant, pseudoglandular pattern
Introduction
Myxoid variant is a rather rare change in adrenocortical adenomas and carcinomas. Up to present, 56 cases (23 cases of myxoid adrenocortical adenomas, 2 cases of borderline myxoid adrenocortical neoplasms and 31 cases of myxoid adrenocortical carcinomas) have been reported [1]. Among them, 23 cases of these tumors were pseudoglandular pattern [1-13]. We here present another case of myxoid adrenal cortical neoplasm with a pseudoglandular pattern. Histologically, it was alike those reported benign-looking tumor cells arranged in pseudoglandular pattern with myxoid stroma. We made a definite diagnosis combining the common pathological results with CT, MRI, angiographic results and immunohistochemistry.
Case presentation
Clinical history
A 56-year-old female presented a repeating limb weakness in the past six months with a historical hypertension for 8 years, which was controlled by taking Nifedipine and Hydrochlorothiazide. Laboratory tests showed abnormality of FT3 (12.42 pg/ml), FT4 (4.04 ng/dl), TSH (0.007 μIU/ml), potassium (3.1 mmol/L), which presented the syndrome of hyperthyroidism with limb weakness and hypertension. Endocrine evaluation showed the levels of cortisol, aldosterone, angiotensin I, norepinephrine, epinephrine, adrenocorticotropic hormone and total catecholamine were within the normal limits, except higher rennin (29.60 pg/mL) and lower angiotensin II (6.40 pg/mL).
Unenhanced CT showed an abnormality on the left adrenal gland (Figure 1A). MRI also revealed a mass shadow whose maximum cross-sectional area was about 33.3×39.3 mm in the coronal plane and 35.5×30.3 mm in the transverse plane, which was consistent with the CT result (Figure 1B). All these results led to a neoplastic lesion that was most likely to be an adrenal pheochromocytoma, but did not rule out the possibility of an adenoma. Digital subtraction angiography (DSA) displayed the tumor was located on the upper pole of the left kidney and blood-supplied by branches of the abdominal aorta (Figure 1C).
Figure 1.
CT and MR imaging findings of a pseudoglandular myxoid adrenocortical adenoma. A. CT scan showed a rounded low-density mass in the left adrenal gland (coronal plane). B. CT scan presented a mass shadow whose maximum cross-sectional area was about 35.5×30.3 mm in the transverse plane. C. DSA indicated the tumor was located on the upper pole of left kidney and got its blood supply from abdominal aorta.
Materials and methods
The tumor cells were fixed in 10% formaldehyde and embedded in paraffin for pathological study. Sections (4 µm) were cut from each paraffin block for histopathological examination and special stains (periodic acid-Schiff and Alcian blue).
Immunohistochemistry analysis was performed as previously described [14]. A large panel of primary antibodies were used (source and solutions): Vimentin (RMA-0547, SP20), HMB45 (MAB-0098, HMB45), S-100 (MAB-0585, 4C4.9), Melan-A (MAB-0275, A103), Cytokeratin 8/18 (CK8/18, MAB-0650, 5D3), Cytokeratin 7 (CK7, MAB-0166, OV-TL 12/30 + 72.2), Synaptophysin (RMA-0537, SP11), Chromogranin A (RMA-0548, SP12), CD56 (MAB-0256, 56C04), Calretinin (RMA-0524, SP13), VEGF (MAB-0243, VG1), CD34 (MAB-0034, QBEnd/10), EGFR (RMA-0554, SP9), Cyclin D1 (RMA-0541, SP4), Actin (Smooth Muscle) (SMA, Kit-0006-2, 1A4), E-cadherin (MAB-0589, A42C7), P53 (MAB-0142, DO-7), P63 (MAB-0365, 4A4), P16 (INK4A) (MAB-0673, MX007), Bcl-2 (MAB-0014, 8C8), CD45 (LCA, MAB-0037, PD7/26 + 2B11), C-erbB-2 (Her-2, RMA-0555, SP3), Ready-to-use; Maixin Bio, Fujian, China; Cytokeratin pan (ZM-0069, AE1/AE3), Epithelial Membrane Antigen (EMA, ZM-0095, E29), Neuron Specific Enolase (NSE, ZM-0203, E27), CD31 (ZM-0044, JC70A), CA125 (ZM-0019, TA347), Ki-67 (ZM-0166, K2), Ready-to-use; ZSGB-Bio, Beijing, China; alpha-inhibin (GM360902, R1), Ready-to-use; Gene Tech (Shanghai) Company Limited, Shanghai, China. Ubiquitin-specific protease 10 (USP10, ab109219), 1:250; Abcam, Cambridge, MA, USA.
Sections were lightly counterstained with hematoxylin. Appropriate positive and negative controls were performed concurrently for all the applied antisera.
Pathological findings
Grossly, the mass was roundish with clear boundaries, measured 3.5×3.3×3.0 cm with partial capsule, surrounded by less well-formed fat, and had a grayish-white color. A small amount of atrophic brown-colored adrenal tissue could be seen on one side of the mass and had a clear demarcation with the margin of tumor (Figure 2A).
Figure 2.
Pathologic findings of a pseudoglandular myxoid adrenocortical adenoma. A. Macroscopic appearance of the resected adrenal tumor. The mass was roundish with clear boundaries, measured 3.5×3.3×3.0 cm with partial capsule, surrounded by less well-formed fat, and had a grayish-white color. The outermost adrenal cortex (arrowheads) was compressed and bordered by a fibrous capsule. B. Tumor cells were loosely anastomosing and had a clear demarcation from the compressed adrenal gland (HE, ×40). C. The tumor was encapsulated (HE, ×100). D. Focal capsular penetration (HE, ×100). E. The tumor had a clear demarcation from the compressed adrenal gland (HE, ×100). F. The tumor had a clear demarcation from the adipose tissue (HE, ×100). G. Focal lipomatous metaplasia within the tumor (HE, ×100). H. Tumor cells were showing distinct pseudoglandular pattern with myxoid material inside (HE, ×200). I. The tumor contained large amounts of extracellular acidic mucous material (Alcian blue staining, ×200).
At light microscopy, most of the tumor was demarcated by a fibrous capsule (Figure 2B, 2C). Focal capsular penetration was observed (Figure 2D). Atrophic adrenal gland tissue was found at the periphery of the tumor (Figure 2B) and had a clear demarcation from the solid (Figure 2E). Adipose tissue was around the tumor cells (Figure 2F), while focal lipomatous metaplasia was found within the tumor (Figure 2G). Some of the tumor cells arranged in compact cords and tubules, while other cells were anastomosing irregularly, or formed the so called pseudoglandular characteristics, floating loosely in the myxoid background. The medium-sized polygonal cells with clear boundaries had abundant of eosinophilic cytoplasm. The deep-dyed caryons were roundish or oval, karyotheca and nucleolus were clear (Figure 2H). The lesion showed limited dysplasia or cell pleomorphism, rare mitoses and no evidence of necrosis or vascular invasion. Diffuse histochemical staining for Alcian blue highlighted the abundant eosinophilic myxoid material in the glandular cavity and interstitial (Figure 2I).
Immunohistochemistry
The immunohistochemical data displayed that tumor cells were diffusely positive for vimentin, melan-A, CD56, NSE and USP10, focally positive for cytokeratin pan, cytokeratin 8/18 and VEGF. The labeling index of Ki-67 and Cyclin D1 was about 1% and 50%, respectively (Figure 3). Other markers, including EMA, CK7, HMB45, S-100, alpha-inhibin, calretinin, synaptophysin, chromogranin A, P53, EGFR, MMP2, DNA topo II alpha, CA125, E-cadherin, P63, P16 (INK4A), CD31, CD34, SMA and Her-2, were all negative.
Figure 3.
Immunohistochemical staining of a pseudoglandular myxoid adrenocortical adenoma. A. Strong and diffuse immunoreactivity for Vimentin (×200). B. Focal CK 8/18 positivity (×200). C. Strong and diffuse immunoreactivity for melan-A (×200). D. Strong and diffuse immunoreactivity for CD56 (×200). E. Diffuse immunoreactivity for USP10 (×200). F. Ki-67 labeling index showed a fraction of 1% of positive tumor cells (arrowhead represented a positive tumor cell, ×400).
Based on the above findings, this tumor was diagnosed as myxoid adrenocortical adenoma with a pseudoglandular pattern.
Here, 23 cases of myxoid adrenocortical adenoma were summarized (Table 1). We also analysed all the immunohistochemical results that have been evaluated in this case (Table 2). In addition to basic immunohistochemistry test, indicators for differential diagnosis among myxoid adrenocortical adenoma, pheochromocytoma, adenocarcinoma metastatic, melanoma, PEComa and chordoma were detected (Table 3). Six markers for differential diagnosis between adrenocortical adenoma and carcinoma were examined (Table 4). Moreover, we presented the negative data of the immunohistochemical markers which could be referenced for other researchers.
Table 1.
Review of the English literature of the last 16 years
| No. | Information Literatures | Age | Sex | Clinical record | Pathology | |||
|---|---|---|---|---|---|---|---|---|
|
|
|
|||||||
| Diameter/size(cm) | Side | Symptom | Myxoid area | Pseudoglandular pattern | ||||
| 1 | Brown et al., 2000 | 21 | F | 7.5 | Slightly elevated cortisol | 95% | 4/6 + | |
| 2 | 35 | F | 3.5 | 40% | ||||
| 3 | 31 | F | 6.0 | Normal lab values | 70% | |||
| 4 | 73 | M | 4.0 | 50% | ||||
| 5 | 16 | F | 7.0 | Conn’s syndrome | 80% | |||
| 6 | 62 | F | 6.0 | Normal lab values | 40% | |||
| 7 | Honda et al., 2001 | 56 | M | 3.2×2.0×3.0 | R | Slightly elevated cortisol and aldosterone | 2/3 | + |
| 8 | Dundr et al., 2003 | 45 | M | 5.0 | R | Arterial hypertension | 90% | + |
| 9 | Bollito et al., 2004 | 58 | M | 5.0×4.0 | R | Hypertension | >75% | + |
| 10 | Fine et al., 2005 | 64 | M | 8.8×7.0×4.0 | L | Normal lab values | Multiple | + |
| 11 | du et al., 2005 | 41 | M | 3.3×2.8×2.7 | R | Hypertension | Showed | + |
| 12 | Zhang et al., 2006 | 45 | M | 3.3×2.8×2.7 | R | Mild hypertension | Nearly all | + |
| 13 | Wang et al., 2007 | 66 | M | 6.0×4.5×4.0 | R | Normal lab values | 90% | + |
| 14 | Lu et al., 2008 | 32 | F | 5.0×4.5×2.0 | L | Hypertension | Most | + |
| 15 | Zhang et al., 2011 | 43 | F | 5.5 | Elevated aldosterone | 90% | + | |
| 16 | 37 | M | 3.0 | Hypertension | 30% | - | ||
| 17 | 45 | M | 6.5 | Hypertension | 30% | + | ||
| 18 | 53 | M | 3.5 | Hypertension | 70% | + | ||
| 19 | 45 | F | 3.0 | Elevated aldosterone | 90% | + | ||
| 20 | 51 | M | 4.0 | Hypertension | 70% | + | ||
| 21 | De Padua et al., 2014 | 67 | F | 8.0×7.0×5.5 | L | Hypertension | 20% | + |
| 22 | Kim et al., 2014 | 74 | F | 6.0×4.7×1.6 | R | Hypertension | >90% | - |
| 23 | Wang et al., 2014 | 34 | F | 3.0×3.0×2.5 | L | Normal lab values | Showed | + |
| Present case | 56 | F | 3.5×3.3×3.0 | L | Conn’s syndrome | Showed | + | |
F, female; M, male; L, left; R, right.
Table 2.
Antibodies used and results in this case
| Antibodies | Result | Antibodies | Result |
|---|---|---|---|
| Vimentin | (Diffuse) + | CgA | - |
| Melan-A | (Diffuse) + | HMB45 | - |
| CD56 | (Diffuse) + | S-100 | - |
| NSE | (Diffuse) + | EMA | - |
| USP10 | (Diffuse) + | CK 7 | - |
| pan-CK | (Focal) + | Syn | - |
| CK 8/18 | (Focal) + | α-inhibin | - |
| VEGF | (Focal) + | Calretinin | - |
| Cyclin D1 | (50%) + | CA125 | - |
| Ki-67 | (1%) + | EGFR | - |
| LCA | (Lymphocytes) + | E-cadherin | - |
| CD34 | (Vascular) + | P53 | - |
| CD31 | (Vascular) + | P63 | - |
| SMA | (Basement membrane) + | P16 (INK4A) | - |
| Her-2 | - |
CK, cytokeratin.
Table 3.
Differential diagnosis of myxoid adrenocortical adenoma with a pseudoglandular pattern
| Myxoid adrenocortical adenoma | Pheochromocytoma | Adenocarcinoma metastatic | Melanoma/PEComa | Chordoma | |
|---|---|---|---|---|---|
| Vimentin | + | + | - | + | + |
| Cytokeratins | (Focal) +/- | - | + | - | + |
| EMA | - | - | + | - | + |
| Melan A | + | - | - | + | - |
| CgA | - | + | - | - | - |
| HMB45 | - | - | - | + | - |
| S-100 | - | - | - | + | + |
Table 4.
Immunohistochemical markers in adrenal cortical adenoma, carcinoma and this case
| Immunohistochemical markers | LI or Positive rate (%) | This case | ||
|---|---|---|---|---|
|
| ||||
| Adenoma | Carcinoma | Reference | ||
| Ki-67 (LI) | LI<4.0% | LI≥4.0% | Aubert S et al. | LI = 1% |
| p53 (LI>20%) | 6.6% | 73.0% | Gupta D et al. | Negative |
| MMP2 | 2.0% | 74.0% | Volante M et al. | Negative |
| DNA topo II alpha | 0.0% | 64.7% | Iino K et al. | Negative |
| EGFR | 27.3% | 63.6% | Zhang J et al. | Negative |
| VEGF | 30.0% | 71.4% | Wang CP et al. | Focal positive |
LI, labeling index.
Clinical follow-up
The patient has been followed up for 37 months after laparoscopic adrenalectomy. The levels of potassium recurred to the normal ranges and BP was within normal limits by treated with medicine for hyperthyroidism. And there was no evidence to suggest any palindromia.
Discussion
Myxoid adrenocortical adenoma, reported by Brown et al. for the first time in 2000 [4], is a rare adenoma originated from adrenal cortex. We referred to 23 cases and summarized them (see Table 1 for details and references). The age of these patients ranged from 16 to 74 years old (mean 47.5) with a male-to-female ratio of 1:1. Tumor diameter ranged from 3 to 8.8 cm. A characteristic feature of these tumors is that cords and nests of tumor cells were floating loosely in a myxoid background, some of which exhibited lumens imparting a pseudoglandular appearance [1,4-6,8,9,11-13]. All cases noted myxoid change and the range of myxoid area was 40%-95%. Pseudoglandular pattern was showed in 19 cases and revealed a strong connection between pseudoglandular pattern and myxoid change [1,3-9,11,12]. Since the pseudoglandular pattern has been seldom observed in conventional adrenal tumor, the possible reason may due to the myxoid change which induces the formation of pseudoglandular structure. The tumor cells in most cases were polygonal with clear cell boundaries and finely granular eosinophilic cytoplasm [1,4-6,8,9,11-13]. Necrosis and vascular invasion were absent in adenomas [1,4-6,8,9,11-13]. In current reporting case, we could hardly observe significant gelatinous areas in gross as other reports mentioned. However, under the microscope, pseudoglandular areas were found and characterized with small tubulars containing mucintype material. The tumor cells were medium-sized and polygonal with clear boundaries and eosinophilic cytoplasm. Roundish or oval caryons were deep-dyed with clear karyotheca and nucleolus. The lesion showed limited dysplasia or cell pleomorphism, rare mitoses and no evidence of vascular invasion or necrosis. All the above evidences supported our diagnosis.
A serial of markers were detected in our case for differential diagnosis with pheochromocytoma, adenocarcinoma metastatic, melanoma, PEComa and chordoma. Vimentin was diffusely positive while EMA was negative, and cytokeratin pan was focally positive. These markers excluded the possibility of epithelial origined tumor and suggested that the glandular structures were pseudoglandular pattern but not adenocarcinoma. Melan-A was diffusely positive while S-100 and HMB45 were negative, and this suggested that the tumor might be originated from the adrenal cortex, rather than malignant melanoma or a metastatic one. Our previous study showed that the expression of USP10 was found in 100% of adrenocortical adenomas, 88.89% of adrenocortical carcinomas, and 10% of pheochromocytomas; the difference between adrenocortical adenoma/carcinoma and pheochromocytoma was statistically significant. Thus, a positive USP10 immunoreaction can be useful in distinguishing adrenal cortical tumors from pheochromocytoma [15]. In this article, Melan-A and USP10 were positive and chromogranin A was negative, which excluded pheochromocytoma and supported the diagnosis that the tumor was originated from the adrenal cortex rather than adrenal medulla [15]. EMA was negative and cytokeratin pan was focally positive, which ruled out the possibility of chordoma. Alcian blue staining highlighted the extracellular acidic mucosubstances in all reported myxoid adrenal tumors and so did in this case. The observed staining of the myxoid material existing outside rather than inside the cells indicated that its origin was probably related to degenerative changes, instead of mucosubstances produced by tumor cells [11].
Several multiparametric systems have been published in differential diagnosis between benign and malignant adrenocortical tumors. The Weiss scoring system and its modified version appear to be most utilized due to its simplicity and reliability [16]. According to the modified Weiss system, our case fitted the criteria of a conventional adenoma for having only partial capsular infiltration. Moreover, Aubert et al. reported that Ki-67 was a reliable marker in the differential diagnosis of adrenocortical tumors [16]. A 4% Ki-67 labeling index threshold for malignancy achieved 95.7% sensitivity and 91.7% specificity. In our case, Ki-67 labeling index showed a fraction of 1% of positive tumor cells. Recently, several additional markers have been described to identify adrenocortical tumors, such as P53 [17], MMP2 [18], DNA topo II alpha [19], EGFR [20] and VEGF [21]. P53 plays a role in apoptosis, genomic stability, and inhibition of angiogenesis. Gupta et al. evaluated a set of molecular markers including p53, and correlated their expression with histological diagnosis and clinical outcome [17]. The authors found higher p53 labeling index was present in 73% of malignant adrenal cortical tumors but was found in only 6.6% of benign adrenal cortical tumors, the difference was statistically significant. Metalloproteinases were demonstrated to be implicated in malignant progression and metastatization of solid tumors, including endocrine ones. Volante et al. reported the expression of MMP2 was detected in neoplastic cells in 74% of adrenocortical carcinomas and 2% of adrenocortical adenomas, which gave the most significant results [18]. As a cell cycle-related intranuclear protein, DNA topo II alpha did help to differentiate carcinoma from adenoma in resected adrenocortical neoplasms [19]. EGFR had strong regulatory effects on cell differentiation, proliferation, survival, and migration. And, VEGF was an important signaling protein involved in both vasculogenesis and angiogenesis [21,22]. It was reported that the expression of EGFR and VEGF was higher in adrenocortical carcinoma than in adrenocortical adenomas [20,21]. Integrated above information, these markers could be allegedly stained in most of carcinomas but a few of adenomas. In present case, no immunoreactivity was found for these markers, supporting the diagnosis of adrenocortical adenoma. Furthermore, the clinical outcome of this case being uneventful in the following 37 months also confirmed the diagnosis.
Conclusions
In conclusion, the immunohistochemical profiles including vimentin, cytokeratin pan, melan-A, USP10, chromogranin A, etc. differentiated adrenocortical adenoma from other retroperitoneal myxoid tumors. The negative expressions of Ki-67, MMP2, EGFR, etc. supported the tumor as benign. The histological features of pseudoglandular myxoid pattern differentiated this tumor from a conventional adrenocortical tumor. Moreover, CT and MRI results were of great help in showing the size and the location of the tumor.
Acknowledgements
This work was supported by grants from National Natural Science Foundation of China (Grant No. 81602535 to Zhi Zeng and No. 81301019 to Li-Juan Gu), Hangzhou science and technology development project (Grant No. 20140633B33). We thank the patient, who requested anonymity, for agreeing to our report and for providing a detailed medical history. We also thank Mr Furkan Dogan for polishing the language to improve the readability. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Disclosure of conflict of interest
None.
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