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Annals of Diagnostic Pathology 12 (2008) 344-348
Myxoid adrenal cortical neoplasms
Kirtee Raparia, MD, Alberto G. Ayala, MD, Anna Sienko, MD, Qihui J. Zhai, MD, Jae Y. Ro, MD, PhD*
Department of Pathology, The Methodist Hospital, Weill Medical College of Cornell University, Houston, TX 77030, USA
Abstract
Myxoid adrenal cortical neoplasms are rare, and to our knowledge, only about 23 cases have been reported in the literature, including 13 carcinomas and 10 adenomas. We recently experienced 4 cases of myxoid adrenal cortical neoplasms (3 benign and 1 borderline malignancy) and studied the clinical, histopathological, and immunohistochemical features of these neoplasms. There were 2 male and 2 female patients (age range, 37-61 years, mean, 48 years). All but 1 patient had hormone-related symptoms. The tumors weighed from 24.1 to 94 g (size, 4.1-9.8 cm). They were variably encapsulated with areas of hemorrhage. Histologically, the tumor cells were arranged in delicate arborizing cords or trabecula with myxoid areas varying from 30% to 70%. Three tumors were benign and 1 was of borderline morphology with mitoses of 3/10 high-power fields and mild to moderate nuclear pleomorphism. Two cases contained areas of myelolipomatous component. The tumor cells were positive for vimentin, synaptophysin, and inhibin but negative for cytokeratin. All patients are alive with no recurrence of their tumors or evidence of metastasis (follow-up of 14-20 months). Myxoid changes in adrenal cortical neoplasms are rare but can be seen in both an adenoma and a tumor of uncertain malignant potential. Because of prominent myxoid changes, other myxoid tumors occurring in the retroperitoneum should be excluded. The usual clinical and histological features can be applied to classify the lesions as benign, borderline tumor, or malignant. In our series, there was no case with frank malignant tumor. @ 2008 Elsevier Inc. All rights reserved.
Keywords: Myxoid neoplasms; Adrenal cortex; Immunohistochemical study
1. Introduction
Adrenal cortical adenoma (ACA) is a benign neoplastic proliferation of adrenal cortical tissue that may be function- ally active (hormone producing) or may be nonfunctional. Adrenocortical carcinomas (ACCs) are rare malignant neoplasms of the adrenal cortex that are sometimes hormonally active [1]. The estimated frequency of ACC in the United States is about 1 case per a million population [2]. A variety of different architectural patterns can be found in ACAs and ACCs, ranging from diffuse to alveolar, with a trabecular pattern being most common, and are sometimes admixed in the same neoplasm [2]. A rare histological type is the myxoid type.
Since Tang et al first reported a case of myxoid ACC in 1979, relatively few cases have been reported. Thus, including adenomas and carcinomas, a total of 23 cases (13 carcinomas and 10 adenomas) have been reported in the literature [3-10]. Because of the awareness of myxoid change in ACC, the presence of myxoid changes in any adrenal cortical neoplasms often raises the possibility of malignancy.
In this study, we report the clinicopathological and immunohistochemical features of 4 patients with myxoid adrenal cortical neoplasms (3 benign and 1 borderline malignancy). We also reviewed the literature for these unusual neoplasms.
2. Materials and methods
The cases were retrieved from the pathology files of the Methodist Hospital from 2005 to 2006 and from the
* Corresponding author. Tel .: +1 713 441 2263; fax: +1 713 793 1603. E-mail address: jaero@tmhs.org (J.Y. Ro).
consultation files of the authors (A.A., J.Y.R.). A total of 4 adrenocortical neoplasms exhibiting 30% or more myxoid areas were included in the study. The pathology reports, hematoxylin-eosin-stained slides, and paraffin- embedded blocks or unstained slides were available for all patients. The charts of these patients were reviewed in accordance with institutional review board guidelines to determine patient age, sex, functionality (hormone produc- tion), and clinical outcome.
Immunohistochemical staining for keratin (CAM5.2; 1:800; Dako, Carpinteria, Calif), a-inhibin (1:50; Serotec, Toronto, Canada), synaptophysin (1:40; ICN, Los Angeles, Calif), and vimentin (1:500; Dako) was performed with the avidin-biotin-peroxidase complex method with appropriate positive and negative controls.
3. Results
The clinical findings of the 4 cases of myxoid adrenocortical neoplasms are summarized in Table 1. There were 2 male and 2 female patients ranging in age from 37 to 61 years, with mean age of 48 years. All but 1 patient had hormone-related symptoms. The follow-up period ranged from 14 to 20 months. All patients are alive, with no recurrence of their tumors or evidence of metastasis.
3.1. Pathologic findings
The tumors ranged in size from 4.1 to 9.8 cm and weighed from 24.1 to 94 g. Three tumors were benign ACAs (no mitosis, no necrosis, no pleomorphism), and 1 tumor was of borderline morphology with average mitoses of 3/10 high- power fields (HPFs), mild to moderate nuclear pleomorph- ism without tumor necrosis, and a weight of 94 g. Two cases contained areas of myelolipomatous component.
They were variably encapsulated with focal areas of hemorrhage (3 cases were well encapsulated and 1 border- line case was partially encapsulated). Histologically, the tumor cells were arranged in delicate arborizing cords or trabeculae that possessed delicate capillary vessels. A common feature to all 4 cases was the presence of a prominent myxoid matrix material ranging from 30% to 70%. The tumor cells were polygonal in shape with distinct
| Case | Age (y)/Sex | Hormonal status | Tumor size (cm)/weight (g) | Myxoid area (%) | Follow-up (mo) |
|---|---|---|---|---|---|
| 1 | 41/M | Gynecomastia, breast pain | 4.1/24.1 | 70 | 20 |
| 2 | 53/M | Normal laboratory values | 9.8/75.1 | 40 | 14 |
| 3 | 37/F | Cushing syndrome | 4.5/29.8 | 40 | 15 |
| 4 | 61/F | Increased cortisol, low potassium | 7.0/94.0 | 30 | 18 |
A
50.0 um
B
100 um
C
100 um
cell borders and had moderate amounts of clear, finely granular, eosinophilic, or amphophilic cytoplasm. The nuclei were enlarged, round to oval, hyperchromatic, and showed no (in the cases with adenomas) or mild to moderate
pleomorphism with nuclear variability of more than 3 times in some areas (in the case with borderline malignancy).
A number of cellular architectural patterns over the myxoid background were noted (Fig. 1A-C). Some tumors had thin, delicate, anastomosing cords, whereas others formed broad, irregularly bordered clusters. The cells appeared to float loosely in a copious acellular myxoid background divided into small lobules by thin, fibrovascular stroma. Other tumors had a nested pattern, with the constituent cells separated from their fibrous stromal frame- works by variable amounts of myxoid matrix. One case showed a well-formed pseudoglandular architecture in which the cell nests acquired distinct central lumens with myxoid changes in the lumen. In all the cases, the cells retained ample cytoplasm that was predominantly eosino- philic, with occasional clear cells.
All 4 tumors stained diffusely for synaptophysin and vimentin. Staining for a-inhibin was positive at least focally in all 4 cases (Fig. 2A and B). Cytokeratin was negative in all the 4 cases.
A
B
4. Discussion
Myxoid ACC was first reported by Tang et al in 1979 [11], and a second case was described 15 years later by Forsthoefel in 1994 [3]. In 2002, Brown et al [4] described 14 cases of myxoid adrenocortical neoplasms, including 6 adenomas and 8 carcinomas. As a consequence of these reports, the presence of myxoid foci in adrenal cortical neoplasms often raises the possibility of malignancy. However, they have been identified in both ACAs and ACCs (Table 2).
Histologically, the usual adrenocortical neoplasms have architectural patterns ranging from diffuse to alveolar, with a trabecular pattern being most common. The rare myxoid variant is composed of polygonal or elongated cells with moderate amounts of eosinophilic cytoplasm. The cells are usually arranged in delicate arborizing cords or trabeculae, 1 to 2 cells thick that are surrounding relatively large acellular clear myxoid spaces resembling the background of a myxoma. Because these lesions are rare, the presence of myxoid change in a needle biopsy may raise the suspicion of carcinoma.
The myxoid material in these lesions is Alcian blue positive (sensitive to digestion with hyaluronidase) but negative with diastase-periodic acid-Schiff and mucicar- mine stains, consistent with connective tissue-type mucin [2-7]. Previous ultrastructural studies merely described the myxoid areas as free of any structures [2] or as acellular myxoid material [4], or abundant proteoglycan particles, or as flocculent and fibrillar material [9]. The significance of the myxoid material and its mechanism of production remain uncertain. We did not do any special stains or ultrastructural studies for the myxoid material in our cases.
Differentiation of benign from malignant adrenocortical tumors is often difficult, as are other endocrine neoplasms of other organs. The criteria for malignancy proposed by Weiss in 1984 [12] and restudied in 1989 [13] include combination of the following 9 features: nuclear grade; mitotic rate greater than 5/50 HPFs; atypical mitoses; clear cells comprising 25% or less of the tumor; a diffuse architecture; microscopic necrosis; and invasion of venous, sinusoidal, and capsular structures. A study by Evans and Vassilopoulou-Sellin [14] of 56 adrenal cortical neoplasms with a minimum of 5 years of follow-up found that adenomas typically had a maximal mitotic rate of fewer than 2 mitotic figures per 10 HPFs (this is in contrast with Weiss’ 5/50 HPFs-1 mitosis per 10 HPFs), a prominent small nest growth pattern, predominantly clear or foamy cytoplasm, and no tumor necrosis. On the other hand, carcinomas were characterized by at least 4 mitotic figures (often many more) per 10 HPFs, a lack of nested growth pattern, a dominance of compact eosinophilic cells, and tumor necrosis [14]. Malignant adrenal cortical neoplasms tended to be larger and heavier than their benign counter- parts. The criteria used for differentiation of myxoid ACAs from myxoid ACCs are similar.
| Study | No. of cases | Age (y) | Sex | Diagnosis | Size/Weight of tumor | Hormonal status | Follow-up | |
|---|---|---|---|---|---|---|---|---|
| Tang et al (1979) | 1 | 41 | F | Carcinoma | 9 cm | Parathyroid hyperplasia, pituitary adenoma | Developed metastasis | |
| Forsthoefel (1994) | 1 | Carcinoma | 17.5 cm/900 g | Cushing syndrome | Died | |||
| Brown et al (2000) | 14 | 21-63 | 10 | F, 4 | Adenoma (6 patients), | 3.5-16 cm/13-700 g | Cushing syndrome (6 patients), | Adenomas (5/6 alive), |
| M | carcinoma (8 patients) | concomitant feminization (1 patient), | carcinoma (1 alive, | |||||
| increased aldosterone (1 patient) | 1 alive with metastatic disease, and 4 dead) | |||||||
| Honda et al (2001) | 1 | 56 | M | Adenoma | 3.2 cm | None | Alive | |
| Dundr et al (2003) | 1 | 45 | M | Adenoma | 5 cm/58 g | Hypertension | Alive | |
| Izumi et al (2003) | 1 | 38 | M | Carcinoma | 13.5 cm/380 g | Hypertension and heart failure | – | |
| Bollito | 1 | 58 | M | Adenoma | 5 cm/55 g | Mild hypertension | 0 - | |
| et al (2004) | ||||||||
| Fine et al (2005) | 1 | 64 | M | Adenoma | 8.8 cm/110 g | – | – | |
| Suresh et al (2005) | 1 | 49 | M | Carcinoma | 6 cm | Hypertension | Alive (follow-up period 1 year) | |
| Karim et al (2006) | 1 | 61 | M | Carcinoma | 10 cm/192.8 g | Cushing syndrome | – | |
| Present (2007) | 4 | 37-61 | 2 M, 2 F | Adenoma (3 patients), borderline (1 patient) | 4.1-9.8 cm/24.1-94 g | Cushing syndrome(1 patient), gynecomastia (1 patient), increased cortisol (1 patient) | Alive (4 patients) | |
The presence of myxoid material in a retroperitoneal lesion raises a broad differential diagnosis to include chordoma, carcinomas with myxoid areas, myxoma, atypical lipomatous tumors with myxoid changes, benign or malignant nerve sheath tumors, myxoid leiomyomas and leiomyosarcomas, extraskeletal myxoid chondrosarcoma, gastrointestinal stromal tumor, and myxoid malignant fibrous histiocytoma [1-3]. The clinical information of an adrenal location of the neoplasm rules out most myxoid lesions. However, when there is lack of typical areas of adrenocortical differentiation and when there is no clinical evidence of active adrenal hormone production, immuno- histochemistry (S-100 protein, cytokeratin, epithelial mem- brane antigen, smooth muscle actin, and desmin) and ultrastructural examination may be necessary to establish the diagnosis.
The myxoid adrenocortical neoplasms reported to date (27 cases) show an age range of 21 to 63 years, with a mean age of 48 years. Although Brown et al found a female-to-male preponderance in both malignant (5:3) and benign myxoid adrenal tumors (5:1), to date, the total cases of myxoid adrenal cortical neoplasms (including the current case series) have been equally distributed between male and female patients-14 men and 13 women. Of the 27 cases reported so far, including our 4 cases, there are 13 adenomas, 1 borderline neoplasm, and 13 carcinomas.
All reported patients with myxoid adrenal cortical neo- plasms have shown increased serum hormone levels, including cortisol, aldosterone, adrenocorticotrophic hormone (ACTH), follicle-stimulating hormone (FSH), and/or luteinizing hor- mone (LH). Nine patients, which constitute majority of patients, clinically manifested a Cushing syndrome.
Grossly, these myxoid neoplasms weighed between 13 and 900 g and ranged in diameter from 3.2 to 17.5 cm. As
with conventional adrenal cortical tumors, adenomas are generally smaller than carcinomas, generally weighing less than 100 g and measuring 7.5 cm or less in greatest diameter.
With regard to the immunophenotypical profile, the presently described cases, as well as those reported in the literature, expressed vimentin, synaptophysin, and a-inhibin, as expected in adrenocortical neoplasms. In our cases and the cases reported from the literature, these tumors failed to demonstrate cytokeratin expression.
In the adrenal gland, myelolipomatous metaplasia has been described in benign lesions, such as cortical hyperplasia, ACAs, and carcinomas [6,15]. In our series, 2 cases contained areas of myelolipomatous component, one in an adenoma and the other one in the tumor of borderline malignancy.
Both typical and myxoid ACCs each have a poor prognosis of 70% to 90% mortality. Of the 13 patients with carcinoma, 6 died, 2 were alive with metastatic disease, 2 were alive, and 3 had no follow-up data. Early metastasis often occurs, especially to the lung and liver. Myxoid ACAs show good prognosis, with almost 100% survival rates. Of the 13 patients reported so far, 10 were alive and 3 had no follow-up data.
The pathogenesis of the myxoid adrenocortical neo- plasms is not known. From the rare reported cases, no data on possible associations with genetic disorders are currently available.
5. Conclusion
Myxoid changes in adrenal cortical neoplasms are rare but can be seen in adenomas, carcinomas, and tumors of uncertain malignant potential. Because of prominent myxoid changes, other myxoid tumors occurring in the retrope- ritoneum should be excluded. Clinicoradiological correlation
may be helpful, but special stains and immunohistochemical and ultrastructural examination may be necessary to establish the diagnosis. The usual clinical and histological features can be applied to classify the lesions as benign, borderline tumor, or malignant.
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