Unusual Variants of Adrenal Pseudocysts with Intracystic Fat, Myelolipomatous Metaplasia, and Metastatic Carcinoma
MICHAEL J. GAFFEY, M.D., STACEY E. MILLS, M.D., L. JEFFREY MEDEIROS, M.D., AND LAWRENCE M. WEISS, M.D.
Five previously unreported cases of adrenal pseudocysts are de- scribed that demonstrate a wider range of histologic appearances than has been previously recognized in these lesions. One pseu- docyst removed from an asymptomatic 59-year-old female con- tained intracystic nests of cytologically malignant cells of un- known origin. Workup revealed a left breast mass, which on biopsy showed an infiltrating ductal carcinoma with neoplastic cells that were cytologically similar to those found within the cyst contents. Four other pseudocysts are described with variable numbers of intracystic vascular structures and benign adrenal cortical cells. In addition, intracystic mature adipose tissue was observed in all four cases, with myelolipomatous metaplasia found in one. Awareness of the wide histologic variability of these lesions should improve diagnostic accuracy and allow dis- tinction from adrenocortical neoplasia and myelolipoma. (Key words: Adrenal; Pseudocysts; Myelolipoma; Fat; Metastatic carcinoma) Am J Clin Pathol 1990;94:706-713
ADRENAL PSEUDOCYSTS are uncommon lesions that characteristically contain hemorrhagic or thrombotic material on cut section and lack a demonstrable cellular lining. The large size of the lesions, from 5 to 20 cm, in combination with the characteristic hemorrhagic appear- ance and the presence of intracystic islands of adrenal cortical cells, frequently results in confusion with adrenal cortical neoplasia.2,13,14,21,32 The recent demonstration of pseudocysts with anomalous intracystic vascular channels has led to postulates of a vascular origin with secondary disruption of the adrenal cortex.14,15.21 In an effort to fur- ther define these histologically variable lesions, we describe four previously unreported pseudocysts that exhibited the unusual features of mature adipose tissue or myelolipo- matous metaplasia within the lesion, leading to initial dif- ficulties in interpretation. Breast carcinoma initially manifesting as an intracystic metastasis was found in a fifth case. To our knowledge, these phenomena have not been previously reported.
Materials and Methods
Five cases were studied. Two cases were seen at Stanford University Medical Center, Stanford, California, and three
Departments of Pathology, Divisions of Surgical Pathology, City of Hope National Medical Center, Duarte, California; University of Virginia Health Sciences Center, Charlottesville, Virginia; and the National Cancer Institute, National Institutes of Health, Bethesda, Maryland
cases were seen in consultation by one of us (L.M.W.). Clinical information and follow-up were obtained from the hospital record, referring pathologist, or the patient’s physician. Multiple representative hematoxylin and eosin-stained sections were available for each case.
Report of Five Cases
Case 1
A 59-year-old female was evaluated for asymptomatic hematuria dis- covered on routine physical examination. Abdominal computerized to- mography scan (CT) revealed a 14 × 10 × 9 cm left suprarenal mass that directly abutted both the pancreas and spleen with inferior displace- ment of the ipsilateral kidney. The mass was partially cystic and thick- walled with peripheral calcifications. A tomographically guided fine-nee- dle aspiration revealed acellular, brown, turbid fluid. The patient was followed and approximately one year later had upper abdominal dis- comfort. Repeat abdominal tomography showed the mass to be minimally increased in size. Vanillylmandelic acid, metanephrine, normetanephrine, and 17-ketosteroid levels were within normal limits. Surgical exploration performed 15 months after presentation revealed a hemorrhagic mass that was initially interpreted as as an adrenal pseudocyst by several pa- thologists. Additional scrutiny of the sections, however, demonstrated rare clusters of partially degenerated, cytologically malignant cells within the cystic contents. The diagnosis of malignant neoplasm was rendered, with the possibility of metastatic disease raised.
The postoperative course was uneventful, and the patient was dis- charged for metastatic workup on an outpatient basis. Six weeks later, calcifications were discovered in the patient’s left breast on mammogram, and a subsequent breast biopsy revealed a moderately differentiated in- filtrating ductal carcinoma with neoplastic cells cytologically similar to those in the cystic contents. A modified radical mastectomy was per- formed with no evidence of residual carcinoma in both the breast pa- renchyma and axillary lymph nodes.
Cases 2-5
Clinical information was available on all four of the other pseudocysts studied (Table 1). Two patients were male and two were female, ranging in age from 50 to 72 years. Three lesions were found in the right adrenal gland, with one in the left. Symptoms attributable to the adrenal lesions were observed in two patients (patients 4 and 5); one had a 12-month
Address reprint requests to Dr. Gaffey: Department of Anatomic Pa- thology, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, California 91010.
| Case | Age/Sex | Side | Weight (g) | Cyst Size (cm) | Vascular Channels | Adipose Tissue | Myelolipomatous Changes | Cortical Islands | Original Diagnosis |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 57/F | Left | NA | 10× 8 × 8 | Absent | Absent | Absent | Absent | Malignant neoplasm, not otherwise specified |
| 2 | 68/M | Right | 54 | NA* | Present | Present | Absent | Absent | Benign pseudoangiomatoid necrosis of adrenal gland |
| 3 | 72/M | Right | 136 | 9×6×6 | Present | Present | Absent | Absent | Adrenal gland with pseudocystic degeneration |
| 4 | 69/F | Left | 84 | 7× 4 | Present | Present | Absent | Present | Adrenal cortical adenoma with mature fat (myelolipoma) |
| 5 | 50/F | Right | 75 | 7×5×5 | Present | Present | Present | Present | Adrenal cortical tumor with areas of myelolipoma |
* Specimen received in fragmented state.
history of postprandial abdominal discomfort, whereas the other patient had vague back pain of unknown duration. Work-up of another patient (patient 2) with recent onset of hypertension and weight loss revealed a suprarenal mass on abdominal tomography. Extirpation of the lesion resulted in immediate resolution of the patient’s hypertension. A history of antecedent trauma or manifestations of paraneoplastic endocrine dys- function were absent in all patients. Referral diagnoses included adrenal gland with benign pseudoangiomatous necrosis, adrenal gland with pseudocystic degeneration, adrenal cortical adenoma with mature fat (myelolipoma), and adrenal cortical tumor with areas of myelolipoma in one case each.
Pathologic Observations
Case 1
The specimen consisted of a 6 × 2 × 0.6 cm flattened adrenal gland contiguous with a 10 × 8 X 8 cm cystic structure that had been previously ruptured. Golden yel- low adrenal tissue was identified within the gritty cyst wall, the inner aspect of which was lined by reddish-brown hemorrhagic material (Fig. 1).
On microscopic examination, 11 of 12 sections showed the histologic features of a hemorrhagic pseudocyst, with incorporated clusters of cytologically benign adrenal cor- tical cells within the fibrocollagenous cyst wall. The center of the lesion contained abundant hemorrhagic and thrombotic material. However, rare clusters and nests of degenerated, cytologically malignant, epithelioid cells were found within the cystic contents in a single section (Fig 2). The atypical cells demonstrated scant, amphophilic to eosinophilic cytoplasm and irregular, hyperchromatic nuclei with occasionally prominent nucleoli. The cells were not present on deeper sectioning and thus could not be immunohistochemically characterized.
NA = not available.
Cases 2-5
Dimensions were available in three cases, two of which measured 7 cm, the other 9 cm in widest dimension (Table 1). Specimen weight was available in all four, with three weighing less than 100 g, the third 136 g. Three lesions were described as spheric, solid, smooth-walled masses (cases 3-5), and another (case 2) consisted of multiple fragments of hemorrhagic adrenal cortical tissue. On cut section, the cysts were composed of hemorrhagic material interrupted by irregular, pale yellow, thrombotic streaks, encircled by thin walls with incorporated strips of golden yellow adrenal tissue. Sectioning demonstrated gritty ma- terial within the cystic contents suggestive of calcification in all cases.
Microscopically, all cases had a fibrocollagenous wall with nests of adrenal cortical cells, and an inner layer of granulation tissue without a detectable epithelial lining. The cyst contents consisted of recent and old hemorrhage. Variable numbers of intracystic, thin-walled, interanas- tomosing vascular channels were seen in four cases (Fig. 3), with detached islands of cytologically benign adrenal cortical cells present in two cases (Fig. 4). Mature adipose tissue was identified within the wall and cyst contents in all four cases. In one case, small nests of adipose tissue were present in a single section, whereas in the remaining cases, large fatty aggregates were seen in multiple sections. The fat was located both within the cystic walls and oc- casional fibrous septa that projected into the cystic con- tents (Fig. 5). Admixed adrenal cortical cells were not seen within the adipose tissue. However, bone marrow elements from all three hematopoietic cell lines were fo- cally identified within the fat in a single case (Fig. 6). The
METRIC 1
FIG. 1 (upper). Case 1. This pseudocyst contained cloudy yellow fluid. As seen, the inner cyst wall consists of necrotic debris, which had a gritty texture. Fragments of apparent adrenal tissue were seen within the surrounding fibrous wall (arrow).
FIG. 2 (lower). Case 1. Normal adrenal cortical tissue is seen at right with the fibrous pseudocyst wall seen at center, with an intervening layer of chronic inflammatory cells. One focus, seen at left, shows a group of highly atypical, partially necrotic cells. Hematoxylin and eosin (X100).
residual adrenal cortex in the latter case was histologically and architecturally normal but significantly thickened, in excess of what could be attributed to tangential sectioning. The residual adrenal tissue in the remaining cases con- sisted of characteristically thin strips of histologically nor- mal adrenal cortex without evidence of necrosis, mitotic activity, atypia, or cytologic vacuolization.
Discussion
Metastases to the adrenal gland are a common finding at autopsy in patients with disseminated carcinoma, with the highest incidence rate found in patients with malig- nancies of the breast and lung. 1,3,6,7,19.30 In an autopsy study of 144 patients with infiltrating breast carcinoma, Cho and Choi found adrenal metastases in 36%, whereas Brown and associates reported adrenal metastases in 26 of 95 patients with breast cancer undergoing palliative adrenalectomy.6.7 Whether case 1 represents carcinoma- tous dissemination into a previously existing pseudocyst or the hemorrhagic necrosis of an antecedent metastasis is unclear. Of greater significance is that, with the excep- tion of the rare, cytologically malignant intracystic cellular clusters, the mass was otherwise grossly and microscopi- cally indistinguishable from an adrenal pseudocyst. That the intracystic malignant cells are of breast origin is sup- ported both by their cytologic similarity with the breast primary and the inability to demonstrate an alternative source. The presentation of a metastatic carcinoma in an adrenal pseudocyst is apparently unique, and we are not aware of a similar case in the literature. The case indicates, however, that adrenal pseudocysts with an atypical intra- cystic cellular component deserve a thorough histologic examination with clinicopathologic correlation.
The remaining cases are clinically similar to those pseudocysts previously reported.2,13,14,21,23,32 All age groups are affected, with most patients in the fourth or fifth decade of life. There is no apparent preference for the left or right adrenal gland, and sexual distribution is variable, with some authors reporting a moderate female predilec- tion,2,13,21 whereas others have found an equal distribu- tion.14.32 Referable symptoms are observed in approxi- mately half of those patients affected. Although an asso- ciation with pregnancy has been suggested elsewhere, no such association was reported in the current cases.9
The current cases are pathologically similar to those described previously.2,13,14,21,23,32 Most adrenal pseudocysts
consist of a circumscribed, spherical mass, containing red- brown, hemorrhagic, and thrombotic material, encircled by thin fibrous walls. Histologically, the fibrocollagenous walls often contain foci of dystrophic calcification and nests of adrenal cortical tissue without evidence of atypia or mitotic activity. The inner walls often show a variable number of anastomosing endothelial-lined sinusoids with occasional extension into the cyst contents. The presence of intracystic vascular channels, as observed in four of the current cases, has been observed elsewhere and has been used to support a vascular origin.14.15,21 The obser- vation in three cases of benign adrenal cortical cells within the cystic contents has also been previously described and proposed to be a result of hemorrhagic adrenal cortical disruption with cellular entrapment.14.21
The presence of intracystic adipose tissue has not been previously described in adrenal pseudocysts. The abnor- mal intracellular accumulation of fat is well known and may occur in either parenchymal cells (fatty change), as encountered in the liver, kidney, and heart, or within stromal connective tissue cells (fatty ingrowth), as seen in the heart, thyroid, and pancreas.10 The intracystic fat ag- gregates in the current cases are histologically typical, without the polygonal nuclei or multivacuolated cyto- plasm characteristic of adrenal cortical cells with fatty change. The absence of either intermixed adrenal cortical cells within the fat or cytoplasmic vacuolation within the residual adrenal cortical tissue also supports the lipoma- tous metaplastic transformation of stromal mesenchymal cells.
Although signs or symptoms referable to endocrine dysfunction were absent in most patients, the resolution of one patient’s hypertension after surgical extirpation is suggestive of a hormonally active lesion, although extrinsic compression of the adjacent renal vessels by tumor cannot be excluded. The presence of a significantly thickened adrenal cortex in another case is also suggestive of a func- tional lesion, although clinical evidence of endocrine dys- function was absent in this patient. The previous associ- ation of intraadrenal fat and myelolipomatous metaplasia in a variety of hyperfunctional adrenal cortical disorders, however, including macronodular adrenal cortical hy- perplasia,12,28 functional pigmented (“black”) adrenal cortical adenomas,18 and adrenal cortical carcinomas, 18 provides additional evidence that these histologic changes are hormonally mediated and their presence alone may be suggestive of adrenal overactivity. Additional support
of this concept stems from reports of myelolipomas in patients with Conn’s syndrome31 and congenital adrenal hyperplasia secondary to both 17-hydroxylase8 and 21-hydroxylase deficiency,5 and Cushing’s syn- drome.4.17,18,22,29
Experimental evidence that the development of intra- adrenal fat and hematopoietic tissue is hormonally me- diated includes the production of myelolipomatous lesions in rats by the administration of testosterone and crude anterior pituitary extract,27 the in vitro stimulation of adi- pogenesis in bone marrow fibroblasts by hydroxycorti- sone,20 and the proliferative effects of the bovine adrenal cortical hormone, adroxazine, on hematopoiesis.26 This evidence, in combination with previous reports that in- tracystic levels of both glucocorticoids and mineralocor- ticoids are elevated compared with those in normal plasma,9,16.24 suggests that the adrenal cortical disruption associated with pseudocyst formation results in localized hormonal elevations with the secondary induction of fatty and myelolipomatous metaplasia. In addition, the thick- ened cortex in patient 5 may be an anatomic correlate of inefficient transport of hormones to the bloodstream.
Whether extensive myelolipomatous metaplasia of ad- renal pseudocysts may eventually result in the production of a myelolipoma is unclear. The patient populations are similar, because both adrenal myelolipomas and pseu- docysts have an equal sexual distribution and predominate in older patients in the fifth to seventh decades of life. 11.25.28 Pathologically, however, the two lesions are quite different. Grossly, myelolipomas are typically unencapsulated, bright yellow lesions with varying areas of red-brown dis- coloration, whereas adrenal pseudocysts are smooth- walled, encapsulated, solid masses with hemorrhagic ma- terial on cut section. Microscopically, myelolipomas con- sist of mature fat and hematopoietic tissue with minimal connective tissue, whereas adrenal pseudocysts demon- strate intracystic hemorrhagic material surrounded by well-defined fibrous walls. Although hemorrhagic infarc- tion with hematoma formation and fibrosis may occur in myelolipomas, such cases are unusual, and we are not aware of a previously reported, predominantly myeloli- pomatous lesion with evidence of a preexisting pseudo- cyst.28
Once extirpated, pseudocysts should be easily recog- nized. Although the size, hemorrhagic appearance, and presence of cortical islands in these lesions may result in their misinterpretation as cortical neoplasms, avoidance of this diagnostic pitfall has been emphasized recently and will not be reiterated here.14.21 The misinterpretation of adrenal pseudocysts with prominent fatty or myeloli- pomatous metaplasia as myelolipomas is clinically less significant, but awareness of the variable presence of ma- ture fat and hematopoietic tissue in these lesions should
improve diagnostic accuracy. In addition, the presentation of an infiltrating breast carcinoma as an intracystic me- tastasis suggests that all pseudocysts should be sampled thoroughly, with the discovery of atypical intracystic cel- lular islands necessitating clinicopathologic correlation.
Acknowledgments. The authors thank the following for referring cases used in this study and providing follow-up information: Roger P. Ilvonen, M.D., Denver, Colorado (case 2); Jon C. Ross, M.D., San Francisco, California (case 3); and Michael F. Schaldenbrand, M.D., Dearborn, Michigan (case 5). They also thank Roger Reichert, M.D., Palo Alto, California, for the gross photography of case 1.
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