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. Author manuscript; available in PMC: 2024 Feb 9.
Published in final edited form as: Endocr Relat Cancer. 2024 Jan 16;31(2):e230162. doi: 10.1530/ERC-23-0162

Beyond the 3 Ps: Adrenal involvement in MEN1

Clemente-Gutierrez Uriel 1, Pieterman Carolina RC 2, Lui Michael S 1, Szabo Yamashita Thomas 1, Tame-Elorduy Andrés 1, Huang Bernice L 1, Shirali Aditya S 1, Erstad Derek J 1, Lee Jeffrey E 1, Fisher Sarah B 1, Graham Paul H 1, Grubbs Elizabeth G 1, Waguespack Steven G 3, Ng Chaan S 4, Perrier Nancy 1
PMCID: PMC10854230  NIHMSID: NIHMS1954900  PMID: 38108666

Abstract

Adrenal lesions (ALs) are often detected in patients with multiple endocrine neoplasia type 1 (MEN1). However, they are not well described in MEN1, making their clinical management unclear. This study examined the prevalence and outcomes of ALs found in MEN1. We performed a retrospective chart review of patients diagnosed with MEN1 from 1990 to 2021. ALs were diagnosed using abdominal or thoracic imaging and classified as being unilateral or bilateral, having single or multiple nodules, and as having diffuse enlargement or not. Measurable nodular lesions were analyzed for their size and growth over time. Patients’ clinical and radiographic characteristics were collected. We identified 382 patients with MEN1, 89 (23.3%) of whom had ALs. The mean age at detection was 47±11.9 years. We documented 101 measurable nodular lesions (mean size, 17.5 mm; range, 3–123 mm). Twenty-seven nodules (26.7%) were smaller than 1 cm. Watchful waiting was indicated in 79 (78.2%) patients, of whom 28 (35.4%) had growing lesions. Functional lesions were diagnosed in 6 (15.8%) of 38 that had functional workup (diagnoses: pheochromocytoma [n=2], adrenocorticotropic hormone–dependent hypercortisolism [n=2], hyperandrogenism [n=1], hyperaldosteronism [n=1]); surgery was indicated for 5 (83.3%; n=12 nodules), 2 of whom had bilateral, diffuse adrenal enlargement. Two patients were diagnosed with adrenocortical carcinoma and 2 with neoplasms of uncertain malignant potential. Radiographic or clinical progression of ALs is uncommon. Malignancy should be suspected on the basis of a lesion’s growth rate and size. A baseline hormonal workup is recommended, and no further biochemical workup is suggested when the initial assessment shows nonfunctioning lesions.

Keywords: adrenocortical carcinoma, multiple endocrine neoplasia type 1, adrenal nodules, adrenal incidentaloma

Introduction

Multiple endocrine neoplasia type 1 (MEN1) is a rare, genetically inherited disease classically characterized by the development of parathyroid hyperplasia, neuroendocrine tumors in the pancreas and duodenum, and pituitary adenomas (Shirali et al. 2021). Other endocrine and nonendocrine tumors have been described as well, including adrenal tumors, neuroendocrine tumors of the lungs and thymus, angiofibromas, lipomas, and collagenomas (Vidal et al. 2008, van den Broek et al. 2021). According to the literature, the prevalence of adrenal lesions in MEN1 cohorts ranges from 20% to 73% (Schaefer et al. 2008, Gatta-Cherifi et al. 2012). Although these lesions are found in a fair number of patients with MEN1, information about the natural history of adrenal lesions in MEN1 is scarce.

Most MEN1-related adrenal tumors reported in the literature are nonfunctional, benign adrenocortical tumors, although functional cortical tumors, including aldosteronomas (Beckers et al. 1992), adenomas producing cortisol (Simonds et al. 2012, Ventura et al. 2019) or sex steroids (Schaefer et al. 2008), and pheochromocytomas (Okada et al. 2016) also have been reported. Adrenocortical carcinoma (ACC) is rarely identified in patients with MEN1 and has an incidence ranging from 1.1% (Schaefer et al. 2008) to 7% (Skogseid et al. 1995). Because of MEN1’s heterogeneity, no true consensus on the appropriate initiation, modality, or interval for surveillance for adrenal abnormalities in patients with this disease has been reached. The Endocrine Society’s 2012 clinical guidelines for the management of patients with MEN1 suggest beginning with adrenal screening using imaging studies before patients reach the age of 10. These guidelines suggest not performing biochemical tests unless patients show symptoms or signs of hormonal excess or tumors larger than 1 cm are identified on imaging (Thakker et al. 2012).

Given such heterogeneity in experience and recommendations in regard to MEN1, we set out to review our own institution’s experience with patients with MEN1 and adrenal lesions. Our primary aim was to assess the prevalence of adrenal lesions within our institution’s MEN1 population, and the secondary aims were to determine the rates of growth and malignant degeneration of these nodules and to describe which patients underwent adrenalectomy and the indications for the procedure.

Patients and methods

Following approval from The University of Texas MD Anderson Cancer Center institutional review board, a retrospective chart review was conducted for all patients with MEN1 treated at our quaternary-care referral center from January 1990 to December 2021. All patients with a genetic, clinical, or familial diagnosis of MEN1 in accordance with the Endocrine Society 2012 clinical guidelines were included (Thakker et al. 2012).

Adrenal abnormalities were most commonly identified during routine MEN1 surveillance imaging. Imaging modalities included computed tomography (CT) and magnetic resonance imaging scans. The attending radiologist’s interpretation at the time of the exam was used for the retrospective identification of patients with adrenal lesions. Once these patients were identified, their imaging studies were examined by a radiologist with experience in adrenal imaging (CSN). During the re-examination of the imaging studies, we documented the lesions’ laterality (right, left, or bilateral) and morphology (single or multiple nodules) and noted the presence or absence of diffuse adrenal enlargement. For the measurable nodules, we documented the size of the lesion in millimeters at the times of the first and last imaging studies available at our institution. The density on non-contrast, and post-contrast imaging as well as the washout characteristics were not evaluated as not all the CT scans had a dedicated adrenal protocol.

Only measurable adrenal nodules were included in the growth analysis; lesions exhibiting diffuse adrenal enlargement were excluded. When multiple nodules were identified in an adrenal gland, the largest nodule or the nodule showing the greatest change over time was the one evaluated. In the presence of bilateral nodular lesions, a record for each adrenal gland was obtained. Patients with inadequate follow-up (defined as those not having at least 2 cross-sectional imaging evaluations with 6 months of separation between them), those who had undergone up-front adrenalectomy, and those with imaging studies performed outside our institution were also excluded from the growth analysis.

Patients with adrenal lesions > 1 cm were biochemically evaluated as suggested by the Endocrine Society guidelines (Thakker et al. 2012). The protocols at our institution are:

  1. For cortisol excess, we screen with 1-mg overnight dexamethasone suppression, late-night salivary cortisol level, or 24-hour urinary free cortisol (UFC). Hypercortisolism is considered when the 8 a.m. plasma cortisol is >5 μ/dL, salivary cortisol level at 11 p.m. is > 100 ng/dL or 24-hour UFC >300 μ/24 h. If hypercortisolism is diagnosed, ACTH is measured. Abnormally low ACTH levels (<5 pg/mL) are consistent with ACTH-independent hypercortisolism resulting from autonomous cortisol secretion of the adrenal gland and an abdominal imaging is obtained to evaluate the adrenal glands’ morphology. A normal or high ACTH level (20–200 pg/mL) is consistent with ACTH-dependent hypercortisolism, and pituitary MRI is used as first diagnostic imaging study.

  2. Biochemical testing for pheochromocytoma is performed measuring plasma free metanephrines and/or plasma catecholamines. Levels at least two times above the normal range are considered diagnostic.

  3. Primary hyperaldosteronism screening is performed determining the ratio of plasma aldosterone concentration (PAC) to plasma renin activity (PRA). Hyperaldosteronism is considered when the PAC is ≥15 ng/dL (or ≥416 pmol/L) and the PRA is <1.0 ng/mL/h or the PAC/PRA ratio is greater than 20.

  4. Biochemical workup for patients with suspected ACC also includes sex steroids and steroid precursors such as androstenedione, testosterone, dehydroepiandrosterone sulfate, and 17ß-estradiol.

Demographics and clinical characteristics were evaluated utilizing descriptive statistics.

Results

A total of 382 patients with MEN1 were evaluated, and adrenal lesions were identified in 89 (23.3%). Of the 89 patients with adrenal lesions, 45 (50.6%) were men and 44 (49.4%) were women. The mean age of the patients at the time the adrenal abnormality was detected was 47 ± 11.9 years. The median follow-up time for the cohort was 63 months (range, 4–268 months). Eighty-eight of the 89 patients with adrenal lesions had other MEN1-related neoplasms, the most common manifestations of which were primary hyperparathyroidism (87 [97.8%] patients), pancreatic neuroendocrine tumors (69 [77.5%] patients), and pituitary tumors (48 [53.9%] patients). In 68 (76.4%) patients, a genetic molecular analysis confirmed the diagnosis of MEN1; in 5 (5.6%) patients, no genetic testing was done, but a pathogenic variant of MEN1 was confirmed in family members obtained by the pedigree registry in our database; and in 16 (18.0%) patients, only a clinical diagnosis of MEN1 was made.

Radiologic characteristics and growth analysis of lesions

Unilateral lesions, most of which were in the left adrenal gland, were identified in 48 (53.9%) of the patients with adrenal lesions; 36 (75.0%) of these patients with unilateral nodules had single nodules. In the 41 (46.1%) patients with bilateral lesions, the most frequent morphologies were multiple, bilateral nodules (13 [31.7%] patients) and bilateral diffuse adrenal enlargement (11 [26.8%] patients; Figure 1).

Figure 1: Study population flowchart.

Figure 1:

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MDACC, The University of Texas MD Anderson Cancer Center; MEN1, multiple endocrine neoplasia type 1; pNET, pancreatic neuroendocrine tumor.

There were 101 measurable nodular lesions diagnosed in 75 patients. The mean size of the nodules was 17.5 mm (range, 3–123 mm), and 27 (26.7%) were less than 1 cm in size. Among the 101 measurable nodular lesions, 79 (78.2%) were suitable for the growth-over-time analysis (Figure 2). The mean time between the first and last imaging studies evaluating the adrenal lesion(s) was 78.7 months (range, 6–268 months). Fifty-one of these lesions (64.6%) showed stability during the follow-up period. One of these stable lesions was surgically removed with a right-cortical-sparing adrenalectomy after 50 months of follow-up. The indication for this procedure was a hypervascular 15-mm lesion with an attenuation of 14.3 HU. The decision to perform a cortical-sparing adrenalectomy was because the patient had a previous left adrenalectomy (Patient 3, Table 1). In the 28 (35.4%) lesions in which growth over time was observed, the median increase in size was 4 mm (range, 1–57 mm) over a 78.7-month (range, 6–268 months) follow-up period (Figure 3). Four adrenal nodules from the growth-over-time group were resected, and the indication for this was the increase in size (median increase, 21 mm [range, 5–57 mm] over a 96-month [range, 84–151 months] follow-up period). The surgical pathology exam showed adrenocortical carcinoma in one of the nodules and 3 nodules showed neoplasm of uncertain malignant potential.

Figure 2: Follow-up of nodular adrenal lesions.

Figure 2:

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pNET, pancreatic neuroendocrine tumor, * 3 nodules in 2 patients (1 patient had bilateral neoplasm with uncertain malignant potential)

Table 1:

Demographic, radiological, biochemical, surgical and pathology examination characteristics of patients undergoing adrenalectomy

Patient Sex/Age at adrenal lesion diagnosis Morphology/Size Indication for surgery Treatment timing Functional status Surgical approach Pathology Outcome
1 Male/29 Single nodule/80 mm Pheochromocytoma Upfront surgery Functioning (Pheochromocytoma) Open anterior total adrenalectomy Pheochromocytoma/adrenocortical hyperplasia No pheochromocytoma recurrence at 2-year follow-up
2 Male/54 Single nodule/123 mm Adrenocortical carcinoma Upfront surgery Functioning (Hyperandrogenism) Open anterior total adrenalectomy Adrenocortical carcinoma Death by metastatic disease at 5-year follow-up
3 Male/24 - Left: single nodule/21 mm
- Right: Single nodule/15 mm		 -Left: size 21 mm
-Right: Nodule hypervascularity		 Left: Upfront surgery
Right: Follow-up		 Nonfunctioning Left: Open anterior total adrenalectomy
Right: Open anterior cortical-sparing adrenalectomy		 -Left: Nodular hyperplasia
-Right: Adrenocortical hyperplasia		 -Left: 14-year follow-up without recurrence
-Right: 6-year follow-up without recurrence
4 Female/52 Single nodule/28 mm Size and concomitant planned distal pancreatectomy Upfront surgery Nonfunctioning Open anterior total adrenalectomy Adrenocortical adenoma 5-year follow-up without recurrence
5 Male/58 Single nodule/62 mm pNET extension Upfront surgery Not evaluated Open anterior total adrenalectomy Invasive pNET 11-year follow-up without recurrence
6 Female/43 Single nodule/33 mm Enlargement Follow-up Nonfunctioning Retroperitoneoscopic total adrenalectomy Adrenal cortical neoplasm with oncocytic features, Ki-67 index 12.5% 7-months follow-up without recurrence
7 Male/48 Single nodule/63 mm Enlargement Follow-up Nonfunctioning Open anterior total adrenalectomy Adrenocortical carcinoma 1-year follow-up without recurrence
8 Female/31 Single nodule/40 mm Pheochromocytoma Upfront surgery Functioning (Pheochromocytoma) Open anterior total adrenalectomy Pheochromocytoma 8-year follow-up without pheochromocytoma recurrence, death by metastatic gastrinoma
9 Male/44 Bilateral hyperplasia Medical treatment failure Follow-up Functioning (ACTH dependent hypercortisolism) Retroperitoneoscopic bilateral adrenalectomy Bilateral adrenal cortical hyperplasia 1-year follow-up with hypercortisolism resolution. Death by metastatic thymic neuroendocrine tumor
10 Male/56 Bilateral hyperplasia Medical treatment failure Follow-up Functioning
(ACTH dependent hypercortisolism)		 Anterior laparoscopic, converted to open anterior, bilateral adrenalectomy Bilateral adrenal cortical hyperplasia Death by postoperative pulmonary complications
11 Male/51 Single nodule/76 mm Size Upfront surgery Not evaluated Anterior laparoscopic total adrenalectomy Adrenal gland cyst
12 Female/32 -Left: Single nodule/31 mm
-Right: Single nodule/20 mm		 Enlargement Follow-up Nonfunctioning -Left: Anterior laparoscopic total adrenalectomy
-Right: Anterior laparoscopic total adrenalectomy		 -Left: Atypical myxoid adrenal cortical neoplasm
-Right: Atypical myxoid adrenal cortical neoplasm		 -Left: 5-year follow-up without recurrence
-Right: 1-year follow-up without recurrence
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pNET, pancreatic neuroendocrine tumor

Figure 3: Growth-over-time chart.

Figure 3:

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Nodules with growth over time are included in this chart (n=28). Red lines indicate nodules that required surgical treatment. Black lines indicate nodules followed up using watchful waiting.

Functional lesions

Thirty-eight (42.7%) of the 89 patients with MEN1 and adrenal lesions underwent a functional assessment of their adrenal abnormality. Hypercortisolism was evaluated in all these patients, and evaluations were also performed for excess catecholamine secretion (36 [94.7%] patients), hyperaldosteronism (32 [84.2%] patients), and hyperandrogenism (22 [57.9%] patients). Only 6 (15.8 %) patients that had functional assessment were proven to have functional lesions (Figure 4). The diagnoses were pheochromocytoma in 2 patients, adrenocorticotropic hormone (ACTH)-dependent hypercortisolism in 2 patients (1 thymic neuroendocrine tumor and 1 pituitary adenoma), primary hyperaldosteronism in 1 patient, and hyperandrogenism in the setting of ACC in 1 patient. Four patients had single nodules, and the 2 patients with ACTH-dependent hypercortisolism had bilateral diffuse adrenal enlargement. The lesions with diffuse adrenal enlargement were classified as non-measurable, and the remaining lesions were greater than 1 cm in size (median diameter, 40 mm [range, 12–123 mm]). Medical treatment was the preferred strategy for the patient with primary hyperaldosteronism and the preferred initial strategy for both patients with ACTH-dependent hypercortisolism. Adrenalectomy was indicated for both patients with pheochromocytoma and the patient with hyperandrogenism in the setting of ACC, and it was also indicated for the patients with ACTH-dependent hypercortisolism after medical management failed.

Figure 4: Diagnosis, management, and follow-up of functional adrenal lesions.

Figure 4:

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ACTH, adrenocorticotropic hormone.

Surgical treatment

Fourteen adrenal resections were done in 12 (13.5%) of the patients with adrenal nodules (Table 1). The median size of resected lesions was 36.5 mm (range, 15–123 mm). Nine (64.3%) patients underwent open anterior adrenalectomy, 2 (14.3%) underwent retroperitoneoscopic adrenalectomy, and 3 (21.4%) underwent laparoscopic adrenalectomy; 1 laparoscopic procedure was converted to an open procedure because of the patient’s body habitus. The pathological diagnoses in the 12 patients were ACC (2 patients), neoplasms of uncertain malignant potential (2 patients, one with bilateral lesions), pheochromocytoma (2 patients), bilateral cortical hyperplasia (2 patients), benign hyperplasia/adenomas (2 patients), invasive pancreatic neuroendocrine tumor (1 patient), and adrenal cyst (1 patient).

Discussion

Our study of 89 patients with adrenal lesions in the context of MEN1 evaluated the functionality of these lesions and their growth over time, as well as malignant adrenal neoplasms and neoplasms of uncertain malignant potential associated with MEN1. This paper represents one of the largest published single-institution series on the association between MEN1 and adrenal lesions. In our cohort, we found that 23.5% of patients with MEN1 had adrenal lesions found during abdominal imaging screening. This percentage is in keeping with the 20% to 73% range reported in the literature (Skogseid et al. 1995, Burgess et al. 1996, Schaefer et al. 2008, Gatta-Cherifi et al. 2012, Ventura et al. 2019). The high variability of these reported incidences is potentially related to small sample sizes and the use of more sensitive techniques for diagnosis of adrenal lesions. In the study reported by Schaefer et al. (2008), for example, endoscopic ultrasound was used to evaluate the adrenal glands, and this yielded a higher incidence of adrenal lesions in that cohort.

Functionality of adrenal lesions in patients with MEN1

Interestingly, only 38 (42.7%) of the 89 patients with MEN1 and adrenal lesions underwent a functional assessment of their adrenal abnormality. The decision to perform biochemical workup was individualized by the treating physician based on clinical symptoms of hormonal excess and imaging characteristics of the adrenal lesions. Most of the adrenal lesions that had functional assessment in the present study were diagnosed as nonfunctional lesions. Nonetheless, 15.8% of the lesions that underwent functional workup was determined to have hormonal excess; 2 patients had pheochromocytoma, 2 had ACTH-dependent hypercortisolism, 1 had primary hyperaldosteronism, and 1 had hyperandrogenism associated with ACC. These findings were similar to those of other studies, in which 6% to 39% of adrenal tumors in MEN1 were functional; most studies noted a rate of 15% or less (Skogseid et al. 1992, Skogseid et al. 1995, Langer et al. 2002, Waldmann et al. 2007, Shaefer et al. 2008). In line with the current study, most series of functional tumors are comprised of pheochromocytomas, with only the occasional aldosteronomas (0%–3%) or sex hormone–secreting tumors (0%–8%) (Skogseid et al. 1992, Skogseid et al. 1995, Burguess et al. 1996, Langer et al. 2002, Waldmann et al. 2007, Shaefer et al. 2008). Because of the heterogenous follow-up for functional lesions in the literature and at our institution during the time period in which the patients in our cohort were treated, it is not possible to determine the appropriate times for assessing the functionality of adrenal lesions. Because all the functional lesions in our cohort were greater than 1 cm in diameter, we recommend baseline biochemical screening for all patients with lesions greater than 1 cm, as suggested by The Endocrine Society’s 2012 clinical guidelines for the management of patients with MEN1 (Thakker et al. 2012). If lesions are nonfunctional at the initial assessment, reevaluation of them could be considered in patients with tumor growth or clinical evidence of hormonal excess.

The growth of adrenal lesions over time

The re-evaluation of abdominal imaging in this study allowed us to analyze lesions’ growth over time. We found that 35.4% of the nodular lesions showed growth over time. A previous study found that 24.5% of adrenal lesions in patients with MEN1 grew over time (Gatta-Cherifi et al. 2012). The percentage in the Gatta-Cherifi study is probably lower than the percentage in ours because the Gatta-Cherifi study only considered growth of over 10 mm to be significant, whereas in our study, any change in size was documented. The median observed increase in size in our study was 4 mm (range, 1–57 mm) over 78.7 months (range, 6–268 months), and of the 28 patients whose lesions grew over time, 4 (14.3%) underwent resection because of this growth. For those patients who underwent resection, the median increase in lesion size was 21 mm (range, 5–57 mm) over a 96-month (range, 84–151 months) follow-up period, and the final diagnosis was ACC in 2 patients and adrenocortical neoplasm of uncertain malignant potential in 2 patients, one of whom had bilateral lesions, accounting for 3 adrenal nodules with this diagnosis. The Gatta-Cherifi study showed that increases in size were the triggers for pursuing the surgical resection of nodules, many of which were later identified as malignant neoplasms.

Malignant adrenal neoplasms and neoplasms of uncertain malignant potential associated with MEN1

One of the most important observations in this study is that 2 (2.2%) of the patients with adrenal lesions developed ACC. One of these patients presented with a 12.3-cm left adrenal mass that had heterogenous density and irregular borders on CT evaluation. The second patient initially had a 1.2-cm lesion which rapidly grew to 6.3 cm in 6 months. In both patients, the size and concerning characteristics on CT examination led to a high suspicion for ACC. Other studies have found ACC in 5.5% to 17.6% of patients with MEN1 and adrenal lesions (Skogseid et al. 1995, Schaefer et al. 2008). Although the prevalence of ACC in our study was lower than that reported in the literature, ACC must remain a differential diagnosis, especially in patients with radiographic characteristics highly suspicious for rapidly growing tumors, tumor sizes greater than 4 cm, irregular tumor margins, central intratumoral necrosis, heterogenous enhancement, and/or the invasion of tumors into adjacent structures (Bharwani et al. 2011).

Another important finding in this study is that 2 patients developed an adrenal cortical neoplasm of uncertain malignant potential. The first patient was diagnosed with an adrenocortical neoplasm with oncocytic features. These are rare adrenocortical tumors; there are around 150 reported cases in the medical literature (Mearini et al. 2013). Similar to what was observed in our cohort, these tumors usually present in the fourth decade and are most frequently observed in women and in the left adrenal gland (Wong et al. 2011). With the objective of properly categorizing oncocytic adrenal tumors, Bisceglia et al. (2019) proposed a modification of the classic Weiss criteria that involved a separation of the criteria into major (mitotic rate > 5 mitoses/high power field, atypical mitoses, or venous invasion) and minor (large size [>10 cm] and/or >200 g, necrosis, capsular invasion, or sinusoidal invasion) criteria. According to this modification, if 1 major criterion is present, a neoplasm is considered malignant; if only minor criteria are present, a neoplasm is considered to be of uncertain malignant potential; and if no criterion is present, a neoplasm should be considered benign. The characteristics of the neoplasm diagnosed in our patient classified it as a neoplasm of uncertain malignant potential. Our multidisciplinary team decided to perform abdominal imaging on a yearly basis as follow-up.

The second patient with an adrenal cortical neoplasm with uncertain malignant potential was diagnosed with metachronous, bilateral, atypical, myxoid adrenal cortical neoplasms. This patient was initially treated outside our institution and started MEN1 follow-up after her second adrenalectomy. No recurrence has been documented after 5 years of follow-up for the left adrenalectomy and 1 year of follow-up for the right one. Different degrees of myxoid changes have been reported in adrenocortical tumors; these changes have been described in adrenocortical adenomas and carcinomas (Papotti et al. 2010). A review from Mayo Clinic showed that less than 3% of ACCs and 1% of adrenocortical adenomas have myxoid areas occupying greater than 10% of the tumor, and the age of presentation varies from 16 to 73 years (Brown et al. 2000). Pathologic evaluation of the tumors in our patient did not reveal atypical mitoses, necrosis, or vascular, capsular, or sinusoidal invasion. Yearly abdominal imaging is being performed as follow-up for this patient.

The current study has a limitation stemming from its retrospective nature. Clinical practice patterns have changed over the study period, and this has led to heterogeneity in biochemical workup, imaging techniques and treatment modalities. As seen in this report, adrenal lesions in MEN1 patients tend to be indolent, and exhaustive follow-up is needed to document their functional status and growth over time. The strengths of this study include its long-term follow-up and the fact that the patient cohort was from a single referral center.

Conclusion

The current study provides reassurance in deciding how to screen patients with MEN1 for adrenal disease, especially regarding smaller lesions. More than half of the patients in this study who underwent watchful waiting remained with unchanged lesions over time, suggesting that these patients are not at increased risk of developing malignant or otherwise clinically relevant disease and physicians can safely minimize follow-up regimens as suggested by current guidelines for adrenal incidentalomas. Functionality remained rare, nevertheless, baseline biochemical workup is recommended for all adrenal lesions greater than 1 cm, and if this show a nonfunctional lesion, follow-up should be done based on imaging characteristics and clinical features. Malignant neoplasms and neoplasms of uncertain malignant potential can be seen in up to 4.5% of MEN1 related adrenal lesions, thus, high suspicion by imaging should prompt timely surgical intervention.

Acknowledgments

We thank Laura L. Russell, scientific editor, Research Medical Library, for editing this article.

Funding

Supported by the NIH/NCI under award number P30CA016672.

Footnotes

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

References

  • •.Beckers A, Abs R, Willems PJ, van der Auwera B, Kovacs K, Reznik M, Stevenaert A. Aldosterone-secreting adrenal adenoma as part of multiple endocrine neoplasia type 1 (MEN1): Loss of heterozygosity for polymorphic chromosome 11 deoxyribonucleic acid markers, including the MEN1 locus. J Clin Endocrinol Metab. 1992;75(2):564–570. [DOI] [PubMed] [Google Scholar]
  • •.Bharwani N, Rockall AG, Sahdev A, Gueorguiev M, Drake W, Grossman AB, Reznek RH. Adrenocortical carcinoma: The range of appearances on CT and MRI. American Journal of Roentgenology. 2011;196(6):W706–W714. [DOI] [PubMed] [Google Scholar]
  • •.Bisceglia M, Ludovico O, Di Mattia A, Ben-Dor D, Sandbank J, Pasquinelli G, Lau SK, Weiss M. Adrenocortical oncocytic tumors: Report of 10 cases and review of the literature. International Journal of Surgical Pathology. 2004;12(3):231–243. [DOI] [PubMed] [Google Scholar]
  • •.Brown FM, Gaffey TA, Wold LE, Lloyd RV. Myxoid neoplasms of the adrenal cortex: A rare histologic variant. Am J Surg Pathol. 2000;24(3):396–401. [DOI] [PubMed] [Google Scholar]
  • •.Burgess JR, Harle RA, Tucker P, Parameswaran V, Davies P, Greenaway TM, Shepherd JJ. Adrenal lesions in a large kindred with multiple endocrine neoplasia type 1. Arch Surg. 1996;131(7):699–702. [DOI] [PubMed] [Google Scholar]
  • •.Gatta-Cherifi B, Chabre O, Murat A, Niccoli P, Cardot-Bauters C, Rohmer V, Young J, Delemer B, Du Boullay H, Verger MF, Kuhn JM, Sadoul JL, Ruszniewski PH, Beckers A, Monsaingeon M, Baudin E, Goudet P, Tabarin A. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d’etude des Tumeurs Endocrines database. Eur J Endocrinol. 2012;166(2):269–279. [DOI] [PubMed] [Google Scholar]
  • •.Langer P, Cupisti K, Bartsch DK, Nies C, Gortzki PE, Rothmund M, Röher HD. Adrenal involvement in multiple endocrine neoplasia type 1. World Journal of Surgery. 2002;26(8):891–896. [DOI] [PubMed] [Google Scholar]
  • •.Mearini L, Del Sordo R, Costantini E, Nunzi E, Porena M. Adrenal oncocytic neoplasm: A systematic review. Urologia Internationalis. 2013;91(2):125–133. [DOI] [PubMed] [Google Scholar]
  • •.Okada R, Shimura T, Tsukida S, Ando J, Kofunato Y, Momma T, Yashima R, Koyama Y, Suzuki S, Takenoshita S. Concomitant existence of pheochromocytoma in a patient with multiple endocrine neoplasia type 1. Surgical Case Reports. 2016;2(1):84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • •.Papotti M, Volante M, Duregon E, Delsedime L, Terzolo M, Berruti A, Rosai J. Adrenocortical tumors with myxoid features: A distinct morphologic and phenotypical variant exhibiting malignant behavior. Am J Surg Pathol. 2010;34(7):973–983. [DOI] [PubMed] [Google Scholar]
  • •.Schaefer S, Shipotko M, Meyer S, Ivan D, Klose KJ, Waldmann J, Langer P, Kann PH. Natural course of small adrenal lesions in multiple endocrine neoplasia type 1: an endoscopic ultrasound imaging study. Eur J Endocrinol. 2008;158(5):699–704. [DOI] [PubMed] [Google Scholar]
  • •.Shirali AS, Pieterman CRC, Lewis MA, Hyde SM, Makawita S, Dasari A, Thosani N, Ikoma N, McCutcheon IE, Waguespack S, Perrier ND. It’s not a mystery, it’s in the history: Multidisciplinary management of multiple endocrine neoplasia type 1. CA Cancer J Clin. 2021;71(5):369–380. [DOI] [PubMed] [Google Scholar]
  • •.Simonds WF, Varghese S, Marx SJ, Nieman LK Cushing’s syndrome in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf). 2012;76(3):379–386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • •.Skogseid B, Larsson C, Lindgren PG, Kvanta E, Rastad J, Theodorsson E, Wide L, Wilander E, Oberg K. Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 1992. Jul;75(1):76–81. [DOI] [PubMed] [Google Scholar]
  • •.Skogseid B Rastad J, Gobl A, Larsson C, Backlin K, Juhlin C, Akerström G, Oberg K. Adrenal lesion in multiple endocrine neoplasia type 1. Surgery. 1995. Dec;118(6):1077–82. [DOI] [PubMed] [Google Scholar]
  • •.Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012. Sep;97(9):2990–3011. [DOI] [PubMed] [Google Scholar]
  • •.van den Broek MFM, de Laat JM, van Leeuwaarde RS, van de Ven AC, de Herder WW, Dekkers OM, Drent ML, Kerstens MN, Bisschop PH, Havekes B, Hackeng WM, Brosens LAA, Vriens MR, Buikhuisen WA, Valk GD. The Management of Neuroendocrine Tumors of the Lung in MEN1: Results From the Dutch MEN1 Study Group. J Clin Endocrinol Metab. 2021. Jan 23;106(2):e1014–e1027. [DOI] [PubMed] [Google Scholar]
  • •.Ventura M, Melo M, Carrilho F. Outcome and long-term follow-up of adrenal lesions in multiple endocrine neoplasia type 1. Arch Endocrinol Metab. 2019;63(5):516–523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • •.Vidal A, Iglesias MJ, Fernández B, Fonseca E, Cordido. Cutaneous lesions associated to multiple endocrine neoplasia syndrome type 1. J Eur Acad Dermatol Venereol. 2008;22(7):835–838. [DOI] [PubMed] [Google Scholar]
  • •.Waldmann J, Bartsch DK, Kann PH Fendrich V, Rothmund M, Langer P. Adrenal involvement in multiple endocrine neoplasia type 1: results of 7 years prospective screening. Langenbeck’s Archives of Surgery. 2007;392(4):437. [DOI] [PubMed] [Google Scholar]
  • •.Wong DD, Spagnolo DV, Bisceglia M, Havlat M, McCallum D, Platten MA. Oncocytic adrenocortical neoplasms—a clinicopathologic study of 13 new cases emphasizing the importance of their recognition. Human Pathology. 2011;42(4):489–4 [DOI] [PubMed] [Google Scholar]

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