Introduction

Adrenal myelolipomas are benign tumors composed of mature adipose tissue and hematopoietic elements [1, 2] with an estimated incidence rate of 0.08–2.0% [2]. While most myelolipomas are endocrinologically inactive, some lesions in the setting of concurrent adrenal hyperplasia may be hormonally active [3]. While most adrenal myelolipomas are diagnosed at autopsy, they have been increasingly detected as incidental lesions on cross-sectional imaging [1, 4] and are the second most common type of adrenal incidentaloma after adrenocortical adenomas [5]. First described in 1905, adrenal myelolipomas have been mainly described through case reports and case series [2, 6, 7]. Management is usually with observation, although surgery may be indicated for large or increasing size, diagnostic ambiguity on whether a lesion is benign or malignant, or symptoms such as abdominal pain, constipation, or emesis. Congenital adrenal hyperplasia (CAH) has been reported to be associated with adrenal myelolipomas to varying rates [8,9,10], and few case reports describe giant adrenal myelolipomas (> 10 cm) in the context of CAH [5, 11,12,13]. In this case report, we describe a giant adrenal myelolipoma incidentally diagnosed in a woman with CAH who had previously undergone contralateral adrenalectomy.

Case Presentation

A 50-year-old woman with CAH presented to an outside hospital emergency department with abdominal pain. Computed tomography (CT) scan demonstrated uncomplicated left-sided diverticulitis and was also notable for a retroperitoneal mass measuring 23 cm in maximum diameter causing inferior-medial displacement of the duodenum, pancreas, and right kidney, and attenuation of the vena cava, however, without invasion. Following non-operative management of diverticulitis, the patient was referred to our surgical oncology clinic for evaluation.

The patient had a medical history significant for a childhood diagnosis of virilizing CAH (21-hydroxlase deficiency) for which she had been previously prescribed prednisone and spironolactone but stopped taking it 10 years prior due to changes in health insurance. Spironolactone had been prescribed for hirsutism which was presumed to be associated with her virilizing CAH. Pertinent surgical history consisted of vaginal reconstruction at a young age, open appendectomy, and ventral hernia repair with mesh. The patient’s surgical history was also notable for an open left adrenalectomy 18 years prior for a suspicious adrenal lesion that was reportedly benign on final pathologic evaluation.

At the time of consultation, the patient reported increasing abdominal girth for 3 months associated with a 15-lb weight loss, early satiety, and occasional abdominal pain managed with non-opioid analgesia. The patient denied headaches, respiratory symptoms, nausea, emesis, or changes in bowel function. The patient also reported that she had not menstruated for nearly 13 years since she was last taking prednisone, although her libido remained normal. On physical exam, the patient was normotensive, well appearing, and without hirsute or cushingoid features. Notable exam findings were faded abdominal surgical scars consistent with the patient’s prior surgical history and distension and firmness in the upper abdomen slightly tender to palpation.

Laboratory studies were remarkable for elevated adrenocorticotropic hormone (ACTH) 137 pg/mL [reference (ref): 6–50 pg/mL], free testosterone 29.3 pg/mL (ref: 0.1–6.4 pg/mL), total testosterone 177 ng/dL (ref: 2–45 ng/mL), and renin activity 14.64 ng/mL/h (ref: 0.25–5.82 ng/mL/h). Although renin activity was elevated, aldosterone levels were not obtained and potassium levels remained normal. Fractionated plasma metanephrines (ref: < 0.50 nmol/L metanephrine, < 0.90 nmol/L normetanephrine), luteinizing hormone (4 mIU/mL; ref: 0.6–89.1 mIU/mL), follicle-stimulating hormone (21.8 mIU/mL; ref: 1.4–133.4 mIU/mL), estradiol (27.0 pg/mL; ref: 21–312 pg/mL), morning cortisol level (5.2 µg/dL; ref: 3.7–19.4 µg/dL), hemoglobin A1C (5.6%; ref: < 5.7%), and thyroid function tests (TSH 1.41 mIU/L; ref: 0.39–4.60 mIU/L, free T4 1.03 ng/dL; ref: 0.70–1.48 ng/dL) were normal. Tumor markers were also notably normal with lactate dehydrogenase 129 U/L (ref: 120–246 U/L), alpha-fetoprotein < 6.0 ng/mL (ref: 0.0–8.0 ng/mL), and beta-human chorionic gonadotropin < 4 mIU/mL (ref: < 5 mIU/mL).

CT scan demonstrated a surgically absent left adrenal gland and a large fat-containing mass within the right retroperitoneum measuring at least 20 × 13.4 × 23 cm in diameter with mass effect on the liver, duodenum, and pancreas and displacement of the right kidney (Fig. 1). The right adrenal gland was unable to be visualized. CT chest was negative for metastatic disease.

Fig. 1
figure 1

A large right retroperitoneal mass incidentally detected on a CT scan caused inferior displacement of the right kidney and attenuation of the inferior vena cava

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Pathology from a CT-guided biopsy showed adrenal gland and adipose tissue with hematolymphoid aggregates possibly representing myelolipoma but unable to rule out malignancy. After multi-disciplinary discussions and evaluation by endocrinology and radiation oncology, it was determined that due to the large size of the mass and diagnostic uncertainty with concern for a retroperitoneal liposarcoma, the patient would benefit from surgical resection. In preparation for anticipated nephrectomy, a nuclear renal function scan was obtained and demonstrated severely decreased flow and initial extraction to the inferiorly displaced right kidney.

The patient underwent an exploratory laparotomy with resection of the right retroperitoneal mass, right nephrectomy, right adrenalectomy, cholecystectomy, lysis of adhesions, and complex abdominal closure (Fig. 2). Due to mass size, mass proximity to the inferior vena cava, and concern for malignancy, the patient was prepared for possible veno-venous bypass intra-operatively; however, bypass was not necessary. During the dissection, the superior aspect of the mass was noted to be adherent to the inferior vena cava and duodenum but without invasion and thus easily separated. Intra-operative frozen specimen pathology showed a mixed inflammatory cell population. The patient was treated with intravenous stress-dose hydrocortisone prior to the case, which was continued every 6 hours peri-operatively.

Fig. 2
figure 2

Surgical field (left) and gross specimen (right) after resection

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The final surgical pathology was myelolipoma. The specimen that was sent in two segments measuring 5.5 cm and at least 40 cm in dimension. The mass was described grossly as encapsulated, well-circumscribed, tan-yellow and red-brown, and made of fibro-adipose tissue containing hemorrhage and focal calcified necrosis (Fig. 3A). On microscopic pathology, the specimen was noted to have retroperitoneal extension, focal intra-tumoral ossification, hemorrhage, and diffuse cortical hyperplasia with pigment deposition and lymphoid aggregates (Fig. 3B–D). Margins were negative for tumors with no evidence of extension into adjacent structures. Cytogenetic studies were not performed due to the lack of any dividing cells in the specimen. At surgical follow-up 4 weeks post-operatively, the patient was doing well on a hydrocortisone taper (20 mg in the morning, 15 mg at night) and had no evidence of post-operative complications. The patient was planned for ongoing close outpatient follow-up with endocrinology, with plans to start fludrocortisone in the future.

Fig. 3
figure 3

Gross and microscopic specimens of the resected adrenal myelolipoma demonstrating the following. A Yellow-tan cut surface with red-gray areas. B Thinned adrenal cortex and presence of intra-tumoral hemorrhage, C Clear demarcation between the underlying lesion (*) and the adrenal cortex which is typically thinned, although this patient has adrenocortical hyperplasia. D Mature adipocytes (**) and three distinct hematopoietic cell lines (erythroid, myeloid, and megakaryocytic)

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Discussion

Adrenal myelolipomas are diagnosed at an average age of 51 years and occur equally between male and female patients [4, 5]. The etiology of adrenal myelolipomas remains unclear, although several hypotheses exist: (1) metaplastic changes of mesenchymal cortical cells in response to stress, infection, and/or necrosis; (2) metaplasia or hyperplasia of myeloid cells that migrated during embryogenesis in utero; (3) degeneration of adenomas or hyperplastic nodes within the adrenal cortex; (4) metaplasia of undifferentiated stromal cells; or (5) altered mesenchymal stem cell functions in the setting of abnormal hormonal stimuli [2, 5, 6, 8]. In the context of CAH, it has been theorized that myelolipomas develop as a result of chronic stimulation of the adrenal glands by ACTH [3, 7, 12].

On CT, an adrenal myelolipoma appears as a round, well-defined, heterogeneous mass containing low-density, high-attenuation fat less than − 30 Hounsfield units and may be associated with a pseudo-capsule, hemorrhage, or calcifications [4, 14, 15]. Ultrasound will demonstrate well-defined, hyperechoic fatty tissue mixed with hypoechoic myeloid tissue [4]. Magnetic resonance imaging may provide value in surgical planning [4] and differentiate myelolipomas from adrenal adenomas using fat suppression imaging protocols [16]. Radiologic features of extra-adrenal myelolipomas may resemble adrenal tissues but also liposarcomas, thus presenting a diagnostic challenge [15].

Depending on the differential diagnosis and level of concern for possible malignancy, additional work-up for an adrenal myelolipoma may include biopsy by fine needle aspiration [4]. Biopsy demonstrating mixed adipose and normal hematopoietic tissue is suggestive of adrenal myelolipoma [15, 17]. Gross surgical pathology will consist of a capsule or pseudocapsule of compressed zona glomerulosa and zona fasciculata with yellow and red or brown cut surfaces representing fat and hematopoietic tissue with varying levels of hemorrhage [5]. Microscopic pathology will show adipose tissue and hematopoietic tissue containing erythrocytes, granulocytes, lymphoid cells, and megakaryocytes [2, 5]. Additionally, it is not uncommon to find other adrenal anomalies such as hyperplasia, calcifications, and adrenocortical adenomas within the same surgical specimen [5].

The majority of adrenal myelolipomas can be safely managed with observation [4, 18, 19]. A retrospective review of patients with adrenal myelolipomas by Han et al. reported that 13 of 15 patients who did not undergo resection remained asymptomatic over a 3-year observation period suggesting that patients may be safely observed [4, 18]. Additionally, Han et al. found that although over half of the tumors grew in size on serial imaging, growth did not appear to correlate with the development of symptoms [18]. The frequency of imaging studies in observing adrenal myelolipomas remains to be clarified. While Patel et al. recommend ultrasound or CT periodically over 1–2 years of observation [19], Gershuni et al. recommend one additional imaging study at 6–12 months after which if the lesion is stable in size, no further imaging is recommended [20]. Contrastingly, the European Society of Endocrinology recommends against serial imaging for lesions measuring less than 4 cm in diameter with homogenous appearance and benign imaging [5].

Based on recent guidelines from the American Association of Endocrine Surgeons, adrenal myelolipomas are recommended for resection when the lesions are symptomatic from mass effect or bleeding and if there is interval growth on surveillance imaging [21]. Case studies have described a rare complication of spontaneous rupture and hemorrhage that is more likely to occur in myelolipomas > 10 cm in diameter. For this reason, current literature suggests that large myelolipomas should be considered for resection [13, 14, 17, 19]. Symptoms from larger lesions such as abdominal pain, constipation, and emesis are also relative indications for resection [1]. Sanders et al. performed a retrospective review of 7 patients with adrenal myelolipomas: of the 5 patients who underwent resection, 4 patients were symptomatic and had complete resolution of symptoms following resection. Meanwhile, asymptomatic patients remained asymptomatic without resections, thus supporting symptomatology as an indication for surgical intervention [2]. In our patient, it is unclear if her abdominal pain on presentation was solely attributed to diverticulitis; however, she did report several months of mild abdominal pain associated with early satiety and unintentional weight loss that were likely attributed to the mass. Furthermore, the large retroperitoneal mass had radiologic features concerning for myelolipoma versus malignancy as well as indeterminate pathology after biopsy, thus warranting excision.

Although adrenal myelolipomas are endocrinogically inactive, they are commonly associated with endocrine disorders such as CAH [4, 9]. It has been suggested that incompletely treated or untreated CAH patients are at greater risk of developing adrenal masses and lesions [3]. Nermoen et al. performed a population-based study of 101 adult Norwegian patients with 21-hydroxylase deficiency, of whom 6% were diagnosed with adrenal myelolipomas ranging from 33–55 mm in diameter [16]. Similarly, Decmann et al. reviewed 420 histologically verified cases of adrenal myelolipomas over a time period of nearly 50 years and found that CAH was associated with 10% of all reviewed cases [5]. Lastly, in a literature review of case series and case reports through PubMed and Cochrane Library databases, Shenoy et al. found that nearly half of the cases of adrenal myelolipomas associated with endocrine dysfunction occurred in the context of CAH [10].

The need for endocrine evaluation of suspected adrenal myelolipomas remains unclear with conflicting recommendations and guidelines. The American Association of Clinical Endocrinologists recommends endocrine screening of all adrenal incidentalomas and regular endocrine surveillance if they do not meet surgical resection criteria, with the exception of adrenal myelolipomas [22]. Contrastingly, the European Society of Endocrinology recommends at least overnight dexamethasone suppression testing in all patients with adrenal incidentalomas, without the exclusion of myelolipomas [23]. Varying approaches to endocrine testing have been described. Shenoy et al. suggest endocrine screening for patients at high risk of associated endocrine dysfunction (hypertension, diabetes, pre-diabetes, young age, bilateral adrenal myelolipomas) [10], while Maas et al. recommend hormonal screening of all incidentalomas with plasma-free metanephrines, urinary fractionated metanephrines, and 1 mg dexamethasone suppression test [24]. Gershuni et al. make similar recommendations in addition to considering evaluating for cortisol dysfunction and suggest excluding small adrenal myelolipomas from endocrine testing [20]. Because adrenal myelolipomas may be associated with hormonal hyper-secretion secondary to concurrent adenomas or adrenal hyperplasia, endocrine evaluation should be considered in patients with clinical features or suspected co-existing adenomas [7]. For example, Hamidi et al. have reported that patients with adrenal myelolipomas are at increased risk of primary hyperaldosteronism secondary to ipsilateral or contralateral adrenal adenoma or hyperplasia [3, 7]. Given our patient’s history of untreated CAH, we elected to pursue a full hormonal workup. While guidelines remain unclear, patients should be evaluated on a case-by-case basis with a low threshold for evaluation for hormone production abnormalities, especially in patients with predisposing conditions.

Our case report is one of several describing a giant myelolipoma in the context of CAH. Similar to our patient, German-Mena et al. described a patient with untreated CAH with a symptomatic 24-cm giant adrenal myelolipoma that was resected [12]. The patient described by German-Mena et al. also had a contralateral adrenal myelolipoma that was managed with observation due to its small size < 10 cm [12]. Additionally, Ioannidis et al. described a young woman with CAH with symptomatic, bilateral giant adrenal myelolipomas that were both resected: much like our patient, their patient also required post-operative steroids for iatrogenic adrenal insufficiency [13]. Our patient had bilateral adrenal masses occurring over 10 years apart, suggesting that CAH patients may remain at long-term risk of developing adrenal masses.

A limitation of this case report is that we did not have records or pathology reports from the outside institution where the patient had previously undergone a contralateral adrenalectomy. Despite this, we believe this case report provides strength in describing thorough diagnostic work-up and multi-disciplinary management.

In conclusion, we describe the successful management of a complex patient with untreated CAH and prior adrenalectomy who underwent resection of a giant adrenal myelolipoma with resultant iatrogenic complete adrenal insufficiency. Key considerations in the evaluation and management of a suspected giant adrenal myelolipoma include vigilance for the inability to rule out malignancy, staging, biopsy, endocrine function screening, and safe operative interventions that allow complete tumor resection, especially when malignancy remains part of the differential diagnosis. Additionally, in patients undergoing total bilateral adrenalectomy, glucocorticoid substitution is necessary. For this reason, we recommend early collaboration with endocrine specialists in guiding steroid therapies intra- and post-operatively for patients who will develop adrenal insufficiency.