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Myxoid Adrenocortical Carcinoma
A Clinicopathologic and Immunohistochemical Study of 7 Cases, Including 1 Case With Lipomatous Metaplasia

Annikka Weissferdt MD, FRCPath, Alexandria Phan MD, Saul Suster MD, Cesar A. Moran MD
DOI: http://dx.doi.org/10.1309/AJCPCDZLC13RSXRZ 780-786 First published online: 1 June 2013


Adrenocortical carcinomas (ACCs) with myxoid features are rare neoplasms. We identified 7 cases of myxoid ACC and studied the clinicopathologic and immunohistochemical features of these neoplasms. The patients were 5 men and 2 women with a mean age of 45 years. Histologically, the tumors contained alcian blue–positive myxoid areas ranging from 10% to 50% of the tissue examined. One case showed lipomatous metaplasia. Areas of conventional ACC were present in all cases. Immunohistochemically, the tumors were positive for steroid receptor cofactor 1, inhibin, melan A, calretinin, and synaptophysin but negative for high-molecular-weight cytokeratin, CAM5.2, and Pax8. Clinical follow-up information for 4 patients demonstrated that all patients had died of their disease 11 to 69 months after diagnosis. Myxoid ACCs are rare tumors that expand the differential diagnosis of myxoid neoplasms involving the retroperitoneum. Contrary to previous reports proposing that the biologic behavior is similar to conventional ACC, our series seems to indicate that myxoid morphology is associated with more aggressive behavior.

Key Words:
  • Adrenocortical carcinoma
  • Myxoid change
  • Immunohistochemistry
  • Endocrine tumor

Adrenocortical carcinomas (ACCs) are rare malignant neoplasms of the adrenal cortex with an incidence of 0.7 to 2 cases per million population.1 These tumors most often affect patients during the fifth decade of life but are also not uncommon in children. Females are more commonly affected than males. In addition to different architectural patterns in conventional ACC, including diffuse, trabecular, nested, or alveolar patterns, several distinct tumor subtypes have been described, including oncocytic, sarcomatoid, and myxoid variants. To date, fewer than 35 myxoid ACCs have been described in the English literature.211 This variant is characterized by tumor cells arranged in cords, clusters, or pseudoglandular structures embedded in a prominent myxoid stromal background. These myxoid areas may be focal or involve the entire tumor tissue. The clinical, immunohistochemical, and ultrastructural findings are thought to be similar to those of conventional ACC.7,8 Another unusual feature described in a single case of myxoid ACC is the presence of lipomatous metaplasia,5 a process previously thought to be associated only with benign adrenocortical lesions. In this study, we report the clinicopathologic and immunohistochemical characteristics of 7 myxoid ACCs and detail the spectrum of morphologic features that these tumors may show.

Materials and Methods

During a review of 77 cases of ACC, 7 cases (9%) with myxoid features were identified from the surgical pathology files of the MD Anderson Cancer Center (Houston, TX) and the Medical College of Wisconsin, Milwaukee. H&E-stained sections from adrenalectomy specimens were available for review in each case. All tumors were confirmed as ACC according to the Weiss criteria.12 Representative paraffin blocks were available for histochemical and immunohistochemical studies. Paraffin-embedded tissue sections of 2 cases were stained with alcian blue (pH 2.5), periodic acid-Schiff (PAS), and mucicarmine stains. Deparaffinized tissue sections of 3 cases were incubated with antibodies directed against high-molecular-weight cytokeratin (1:50; Dako, Carpinteria, CA), CAM5.2 (1:50; BD Biosciences, San Jose, CA), inhibin (1:50; AbD Serotec, Raleigh, NC), melan A (1:25; Novocastra, Buffalo Grove, IL), chromogranin (1:100; Dako), synaptophysin (1:200; Dako), calretinin (1:40; Invitrogen, Carlsbad, CA), steroid receptor cofactor 1 (1:100; Cell Signaling, Danvers, MA), Pax8 (1:100; Protein Tech, Chicago, IL), and Ki67 (1:200; Dako) using the polymeric biotin-free horseradish peroxidase method. Appropriate negative and positive controls were run for all antibodies tested. Clinical and follow-up information were obtained from the patients’ medical records or from referral information where available.


Clinical Features

The main clinical features are summarized in Table 1. The patients were 5 men and 2 women aged 19 to 66 years (mean, 45 years). Two patients presented with symptoms related to hormone secretion, more specifically Cushing syndrome. Abdominal pain led the other patients to seek medical attention. The right adrenal gland was affected in 5 cases and the left adrenal gland in 2. None of the patients had a prior history of malignancy. Preoperative pathologic staging according to the seventh edition of the American Joint Committee on Cancer staging manual13 showed that 1 patient had T2 disease (tumor >5 cm, no extra-adrenal invasion) and 2 patients had T3 disease (tumor of any size with local invasion, not invading adjacent organs); for the rest of the patients, no staging information was available. Treatment consisted of adrenalectomy in all cases. Adjuvant chemotherapy with mitotane was administered in at least 2 cases (Table 1).

Gross Features

The lesions were described as variably encapsulated tumors with a lobulated architecture and a variably gelatinous translucent or fleshy tan-yellow cut surface. The tumors ranged in size from 6 to 14.5 cm. Weight information was recorded for only 1 case (516 g). Areas of necrosis and hemorrhage were a frequent finding. Yellow-golden strips of normal adrenal gland tissue were identified macroscopically in 3 cases.

Histologic Features

The histologic features were similar in all cases. At low magnification, all tumors exhibited either diffuse or lobulated growth patterns Image 1A and Image 1B. At higher magnification, the tumor cells were arranged in trabeculae, clusters, or cords floating in a prominent myxoid stromal background Image 1C, Image 1D, and Image 1E. In several cases, a pseudoglandular or microcystic pattern was apparent Image 1F. Two cases showed a nodular or club-shaped arrangement of cells with hypocellular centers and tumor cells radiating outward, forming more cellular peripheral outlines Image 2A. The individual tumor cells were either small with angulated and hyperchromatic nuclei and small or inconspicuous nucleoli or large and pleomorphic with polygonal shape, eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli Image 2B and Image 2C. The myxoid stroma was characterized by pools, lakes, or microcysts of loose mucoid material. In 2 cases, this stroma adopted a more dense appearance reminiscent of chondroid matrix material Image 2D. This myxoid change represented 10% to 50% of the tumor volume submitted in each case. The mitotic count ranged from 2 to more than 20 mitoses per 10 high-power fields. Atypical mitotic forms were not identified in any case. Tumor necrosis was present in 3 cases, ranging from 10% to 30%. Areas of more conventional ACC characterized by eosinophilic or lipid-rich clear cells arranged in diffuse, trabecular, or nested growth patterns were present in all cases Image 2E. A small rim of normal adrenal gland was present in 3 cases. Another distinct morphologic change observed in a single case were areas of mature adipocytes intimately admixed with the tumor cells Image 2F. The tumor cells surrounding the adipocytic component had prominent clear vesicular cytoplasm mimicking immature adipocytes or lipoblasts. The pathologic characteristics are summarized in Table 2.

View this table:
Table 1
Image 1

A, Low-power magnification of a myxoid adrenocortical carcinoma (ACC) with a lobulated growth pattern (H&E, ×4). B, Large lobules or club-shaped structures characterize this myxoid ACC (H&E, ×4). C, Trabecular pattern of growth in a myxoid ACC. The tumor cells are set in a myxoid background (H&E, ×10). D, Myxoid ACC composed of interanastomosing cords of tumor cells separated by a myxoid matrix (H&E, ×10). E, Clusters of tumor cells floating in myxoid material (H&E, ×10). F, Lakes and pools of myxoid material imparting a pseudoglandular appearance (H&E, ×10).

Image 2

A, Intermediate-power view of myxoid adrenocortical carcinoma (ACC) with club-shaped growth, hypocellular myxoid centers, and cellular periphery (H&E, ×10). B, Myxoid ACC composed of small monomorphic-appearing tumor cells with little cytoplasm and inconspicuous nucleoli (H&E, ×20). C, Other cases contained tumor cells with abundant eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli (H&E, ×10). D, Dense myxoid background reminiscent of chondroid change (H&E, ×10). E, Areas of myxoid change alternating with conventional-type ACC (H&E, ×4). F, Lipomatous metaplasia interspersed with tumor in an ACC with myxoid change (H&E, ×10).

Immunohistochemical Features

Histochemical studies were performed in 2 cases and showed the myxoid material to be positive for alcian blue and negative for PAS and mucicarmine stains Image 3A and Image 3B. Immunohistochemical studies were performed in 3 cases. The tumor cells of all 3 cases were diffusely positive for steroid receptor cofactor 1, inhibin, calretinin, melan A, and synaptophysin Image 3C, Image 3D, Image 3E, and Image 3F. Negative markers included high-molecular- weight cytokeratin, CAM5.2, chromogranin, and Pax8. The Ki67 proliferative index ranged from less than 5% to 10%.

Clinical Follow-up

Follow-up information available for 4 patients demonstrated that all patients succumbed to their disease 11 to 69 months after diagnosis; in 3 patients, local tumor recurrence or distant metastasis was recorded. Three patients were lost to follow-up (Table 1).


Myxoid ACCs are rare tumors of the adrenal cortex, and to date fewer than 35 myxoid ACCs have been described in the English literature.211 In summary, all these reports state similar clinical characteristics as for conventional ACC. Patients are usually in the fifth decade of life at presentation, but sex distribution in myxoid tumors is nearly equal. Presenting symptoms may be hormone related and most often represented by evidence of glucocorticoid excess. Tumor size and weight are also comparable to conventional ACC. The characteristic morphologic appearance is a variable proportion of myxoid stroma, which can range from 10% to 60% of the total tumor volume. This myxoid material is typically alcian blue positive and negative for PAS or mucicarmine stains. Tumor cells are arranged in cords, trabeculae, clusters, or pseudoglandular structures, often floating in pools or lakes of myxoid material. The nonmyxoid areas are often composed of conventional ACC. The immunohistochemical phenotype is identical to conventional ACC, which is typically positive for inhibin, melan A, synaptophysin, and vimentin and variably reactive for cytokeratin. Ultrastructurally, the tumor cells contain rough endoplasmic reticulum, mitochondria with tubulovesicular cristae, and lipid droplets in the absence of neurosecretory granules. More recently, a Chinese study investigated a series of myxoid adrenocortical neoplasms on a molecular level and concluded that epidermal growth factor receptor (EGFR) protein expression was a common finding in these tumors, but EGFR gene mutation was universally absent.10 The biologic behavior of myxoid ACC is thought to be similarly aggressive as for conventional ACC.7,8

In the cases described herein, some features in terms of clinical presentation and morphologic and immunohistochemical findings strongly resemble those described previously. However, one important issue to highlight is that all patients for whom follow-up information was available died of their disease 11 to 69 months after diagnosis, once again emphasizing the aggressive nature of these tumors. Our findings seem to suggest that myxoid morphology may be associated with an even worse prognosis than conventional ACC. It is important to prospectively analyze these tumors in a large cohort to fully determine their clinical behavior.

The etiology and significance of myxoid change in adrenocortical tumors have long been a matter of debate. In one of the earliest reports on myxoid ACC, Forsthoefel3 in 1994 speculated that myxoid change was a degenerative phenomenon or the result of production by stromal fibroblasts and was negatively correlated with functional status. Other proposals included the belief that the myxoid matrix was produced by the cells of the adrenal cortex, but no intracellular myxoid material could be demonstrated.14 Although we believe that a degenerative process is the most likely explanation, to date the significance of myxoid change or its mechanism of production remains speculative, necessitating further studies into this phenomenon.

View this table:
Table 2
Image 3

A, The myxoid material shows a positive reaction with alcian blue histochemical stain (×4). B, Periodic acid-Schiff is negative in the myxoid areas of a myxoid adrenocortical carcinoma (ACC) (×10). C, Immunostaining for inhibin showing a strong positive reaction in the tumor cells of myxoid ACC (×10). D, Steroid receptor cofactor 1 is expressed in the tumor cells of myxoid ACC (×10). E, Positive reaction for melan A in a myxoid ACC (×20). F, Myxoid ACC with strong reactivity for calretinin (×20).

One additional morphologic change that we were able to appreciate in 1 of our cases was the presence of lipomatous metaplasia. Lipomatous change in the adrenal gland mostly has been associated with benign disorders or tumoral conditions1517 and only once before has been described in a myxoid ACC.5 In our case, areas of mature adipocytes were found dispersed throughout the tumor in a similar pattern to that reported in the previous case. Various hypotheses have been put forward to explain such an occurrence, including the possibility that this represents a reactive process in response to degeneration or a metaplastic process of the neoplastic cells. The latter possibility was favored by Izumi et al5 in their description of lipomatous metaplasia in a myxoid ACC. The authors argued that their case contained cells at various stages of metaplasia with increasing lipid accumulation in tumor cells, leading to a prominent vesicular or vacuolated cytoplasm and eventually resembling mature adipocytes. The fact that a spectrum of such cells was also seen in one of our cases seems to support the idea of a metaplastic process.

The importance of recognizing myxoid change in ACC is that it expands the spectrum of tumors that can contain myxoid material in the retroperitoneum. The differential diagnosis of tumors that can display myxoid change in this location is already wide and includes myxoma, liposarcoma, malignant fibrous histiocytoma, nerve sheath tumors, smooth muscle tumors, carcinomas, chordoma, extraskeletal myxoid chondrosarcoma, and gastrointestinal stromal tumor. A combination of the clinical parameters, thorough radiologic correlation to determine the exact location of the tumor, careful histologic assessment of the tumor morphology, and an immunohistochemical panel to include markers associated with adrenocortical differentiation should help to establish the diagnosis.

In summary, we have presented 7 cases of myxoid ACC and have discussed their clinicopathologic and immunohistochemical characteristics. Myxoid ACCs are rare tumors that need to be included in the differential diagnosis of myxoid neoplasms that may arise in the retroperitoneal area. As with other benign conditions of the adrenocortical cortex, lipomatous change can also be associated with malignant adrenocortical tumors. The early mortality in our cases appears to suggest that myxoid ACCs have an even more aggressive biologic behavior than conventional ACCs.


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