Society for Endocrinology
Beyond the three P’s: adrenal involvement in MEN1
Uriel Clemente-Gutierrez01, Carolina R C Pieterman2, Michael S Lui1, Thomas Szabo Yamashita1, Andrés Tame-Elorduy1, Bernice L Huang1, Aditya S ShiraliD1, Derek ] Erstad1, Jeffrey E Lee1, Sarah B Fisher1, Paul H Graham1, Elizabeth G Grubbs1, Steven G Waguespack3, Chaan S Ng4 and Nancy PerrierD1
1Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
3Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Correspondence should be addressed to N Perrier: nperrier@mdanderson.org
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 work-up (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 two 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 work-up is recommended, and no further biochemical work-up 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 reexamination 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 was 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 two 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-h urinary free cortisol (UFC). Hypercortisolism is considered when the 08:00 h plasma cortisol is >5 µg/dL, salivary cortisol level at 23:00 h is >100 ng/dL or 24-h UFC >300 µg/24 h. If hypercortisolism is diagnosed, ACTH is measured. Abnormally low ACTHlevels (<5pg/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 the 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 work-up 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; Fig. 1).
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 (Fig. 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 (Fig. 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 three nodules showed neoplasm of uncertain malignant potential.
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 (Fig. 4). The diagnoses were pheochromocytoma in two patients, adrenocorticotropic
MENI patients evaluated at MDACC 1990-2021 n=382
No adrenal abnormalities or cross-sectional abdominal imaging performed n=293 (76.7%)
Patients with adrenal abnormalities on imaging n=89 (23.3%)
Unilateral n=48 (53.9%)
Bilateral n=41 (46.1%)
Left n=32 (66.7%)
Right n=16 (33.3%)
Single nodule n=21 (65.6%) Multiple nodules n=8 (25%) Diffuse enlargement n=3 (9.4%)
Bilateral single nodule n= 10 (22%) Bilateral multiple nodules n=13 (31.7%) Bilateral diffuse enlargement n=11 (26.8%)
Combination of lesions n=7 (19.5%)
Single nodule n=15 (93.7%) Multiple nodules n=1 (6.3%)
Single nodule and multiple nodules n=3 (42.9%) Single nodule and diffuse enlargement n=2 (28.5%) Multiple nodules and diffuse enlargement n=1 (14.3%) Diffuse enlargement and pNET extension n=1 (14.3%)
Study population flowchart. MDACC, The University of Texas MD Anderson Cancer Center; MEN1, multiple endocrine neoplasia type 1; pNET, pancreatic neuroendocrine tumor.
Stable n= 51 (64.6%)
Adrenalectomy for concerning radiographical findings n= 1 (2%)
Diagnoses: Adrenocortical hyperplasia n=1 (100%)
Nodular adrenal lesions n=101 nodular lesions
Watchful waiting n=79 (78.2%)
Growth over time n= 28 (35.4%)
Adrenalectomy for concerning radiographical findings n=4 (14.3%)
Diagnoses:
· Adrenocortical neoplasm with uncertain malignant potential n=3* (75%)
· Adrenocortical carcinoma n=1 (25%)
Diagnoses:
· Pheochromocytoma n=2 (33.2%)
Not suitable for longitudinal follow-up n= 22 nodules (21.8%)
Upfront adrenalectomy n=6 (27.3%)
· Adrenal involvement of pNET n=1 (16.7%)
· Adrenocortical carcinoma n=1 (16.7%)
· Adrenal gland cyst n=1 (16.7%)
· Non-secretory adrenal adenoma n=1 (16.7%)
hormone (ACTH)-dependent hypercortisolism in two patients (one thymic neuroendocrine tumor and one pituitary adenoma), primary hyperaldosteronism in one patient, and hyperandrogenism in the setting of ACC in one patient. Four patients had single nodules, and the two 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.
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, two (14.3%) underwent retroperitoneoscopic adrenalectomy, and three (21.4%) underwent laparoscopic adrenalectomy; one 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 work-up 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
| 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 7 | Female/43 | Single nodule/33 mm | Enlargement | Follow-up | Nonfunctioning | Retroperitoneoscopic total adrenalectomy | Adrenal cortical neoplasm with oncocytic features, Ki-67 index 12.5% Adrenocortical carcinoma | 7-months follow-up without recurrence 1-year follow-up without recurrence |
| Male/48 | Single nodule/63 mm | Enlargement | Follow-up | Nonfunctioning | Open anterior total adrenalectomy | |||
| 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 |
https://doi.org/10.1530/ERC-23-0162
Endocrine-Related Cancer (2024) 31 e230162
| Outcome Pathology Surgical approach Functional status | - Left: 5-year - Right: 1-year recurrence recurrence follow-up without follow-up without - Left: atypical - Right: atypical cortical neoplasm cortical neoplasm Adrenal gland cyst myxoid adrenal myxoid adrenal adrenalectomy - Right: anterior adrenalectomy - Left: anterior Anterior laparoscopic total adrenalectomy laparoscopic total laparoscopic total Nonfunctioning evaluated | had functional assessment in the present study were diagnosed as nonfunctional lesions. Nonetheless, 15.8% of the lesions that underwent functional work-up was determined to have hormonal excess; two patients had pheochromocytoma, two had ACTH-dependent hypercortisolism, one had primary hyperaldosteronism, and one 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, 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, 1995, Burguess et al. 1996, Langer et al. 2002, Waldmann et al. 2007, Shaefer et al. 2008). Because of the heterogeneous 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. |
|---|---|---|
| Not | ||
| Treatment | Upfront Follow-up surgery | The growth of adrenal lesions over time |
| timing Indication for surgery Morphology/ size adrenal lesion Sex/age at diagnosis Patient | Enlargement Size nodule/76 mm nodule/ 31 mm - Right: nodule/ 20 mm - Left: single single Single Female/32 Male/51 12 11 | The reevaluation 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 two patients and adrenocortical neoplasm of uncertain malignant potential in two patients, one of whom had bilateral lesions, accounting for three adrenal nodules with this diagnosis. The Gatta-Cherifi study showed that increases in size were the triggers for pursuing the pNET, pancreatic neuroendocrine tumor. |
60
50
40
Size in mm
30
20
10
0
0
50
100
Months 150
200
250
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 two (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 heterogeneous 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, heterogeneous enhancement, and/or the invasion of tumors into adjacent structures (Bharwani et al. 2011).
Another important finding in this study is that two 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 one
Patients with functional adrenal lesions n=6/89 (6.7%)
V
V
Pheochromocytoma n=2 Type of adrenal lesion: unilateral single nodule Sizes 80 mm and 40 mm
Primary hyperaldosteronism n=1 Type of adrenal lesion: bilateral single nodule Size: 15 mm
ACTH-dependent hypercortisolism n=2 Type of adrenal lesion: bilateral diffuse enlargement
Hyperandrogenism n=1 Type of adrenal lesion: unilateral single nodule Size: 123 mm
Intervention: unilateral adrenalectomy
Intervention: medical therapy with spironolactone
.
Intervention: bilateral adrenalectomy
+
Intervention: unilateral adrenalectomy
Outcome: 1 without pheochromocytoma recurrence at 2- year follow-up 1 without pheochromocytoma recurrence at 8- year follow-up; death by metastatic gastrinoma
Outcome: 1 without hypercortisolism recurrence at 1-year follow-up; death by metastatic thymic neuroendocrine tumor 1 death secondary to bilateral adrenalectomy postoperative complications
Outcome: Controlled hypertension
Outcome: Diagnosis, adrenocortical carcinoma .; death by synchronous metastatic disease
+
₱
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 work-up, 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 work-up is recommended for all adrenal lesions greater than 1 cm, and if this shown 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, an instance of high suspicion by imaging should prompt timely surgical intervention.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding
This study was supported by the NIH/NCI under award number P30CA016672.
Acknowledgements
We thank Laura L. Russell, scientific editor, Research Medical Library, for editing this article.
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