ORIGINAL CONTRIBUTION
Characteristics of Adrenal Masses in Familial Adenomatous Polyposis
Jonah S. Shiroky, M.D., M.Sc.1 · Jordan P. Lerner-Ellis, Ph.D.2,3,4 Anand Govindarajan, M.D., M.Sc.1 · David R. Urbach, M.D., M.Sc.1 Karen M. Devon, M.D.1
1 Department of Surgery, University of Toronto, Toronto, Canada
2 Pathology and Laboratory Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
3 Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
4 Ontario Institute for Cancer Research, Toronto, Canada
BACKGROUND: Adrenal masses are a known extraintestinal manifestation of familial adenomatous polyposis. However, the literature on this association is largely confined to case reports.
OBJECTIVE: This study aimed to determine the characteristics of adrenal masses in familial adenomatous polyposis and their clinical significance, as well as to estimate their prevalence. Mutational analysis was conducted to determine if any potential genotype- phenotype correlations exist.
DESIGN: This is a retrospective cohort study.
SETTING: Analysis included all patients meeting the criteria of classic familial adenomatous polyposis who were registered with the Familial Gastrointestinal Cancer Registry, a national Canadian database.
PATIENTS: Appropriate imaging or autopsy reports were available in 311 registry patients. Patients with adrenal metastases were excluded.
OUTCOME MEASURES: Data collection included demographic data, mutation genotype, adrenal mass characteristics, surgical interventions and mortality.
RESULTS: The prevalence of adrenal masses was 16% (n = 48/311). The median age at diagnosis of adrenal
Funding/Support: None reported.
Financial Disclosures: None reported.
Poster presentation at the meeting of the American Association of Endocrine Surgeons, Baltimore, MD, April 10 to 12, 2016.
Correspondence: Karen Devon, M.D., Women’s College Hospital, Department of Surgery, 76 Grenville St, Toronto, ON, Canada M5S 1B2. E-mail: Karen.devon@wchospital.ca
Dis Colon Rectum 2018; 61: 00-00 DOI: 10.1097/DCR.0000000000001008 @ The ASCRS 2018
DISEASES OF THE COLON & RECTUM VOLUME 61: 5 (2018)
mass was 45 years. The median diameter of adrenal mass at diagnosis was 1.7 cm (interquartile range, 1.4-3.0) with a median maximal diameter of 2.5 cm (interquartile range, 1.7-4.1) with median imaging follow-up of 48 months. The majority of adrenal masses were benign (97%, n = 61/63). Surgery was performed on 7 patients because of concerns for size, malignancy, or hormonal secretion. One adrenal-related death was due to an adrenocortical carcinoma. Mutation analysis did not identify any specific genotype-phenotype correlations.
LIMITATIONS: There were incomplete or insufficient endocrinology data available in the registry to allow for the analysis of hormone secretion patterns.
CONCLUSIONS: Adrenal masses are approximately twice as prevalent in the familial adenomatous polyposis population as in previous studies of the general population. Nearly all mutations led to truncation of the APC gene; however, there was no genetic signature to help predict those at increased risk. The majority of adrenal lesions identified were of benign etiology; thus, an intensive management or surveillance strategy with imaging screening is likely unwarranted. See Video Abstract at http://links.lww. com/DCR/A507.
KEY WORDS: Adrenal adenoma; Adrenal incidentaloma; Adrenal neoplasms; Familial adenomatous polyposis; Pheochromocytoma.
F amilial adenomatous polyposis (FAP) is an autoso- mal-dominant inherited disease with near-complete penetrance, characterized by multiple colorectal ad- enomatous polyps, a high risk for colorectal cancer, and a diverse list of extracolonic manifestations including ad- renal masses. The development of FAP is attributed to a
germline mutation in the tumor suppressor gene, adeno- matous polyposis coli (APC). The majority of APC germ- line mutations are inherited; however, 11% to 25% of all cases have been estimated to occur de novo.1
Extracolonic manifestations of FAP can be malignant or benign. Benign manifestations include dental abnor- malities, osteomas, congenital hypertrophy of retinal pig- ment epithelium, and desmoid tumors. Aside from the risk of colorectal cancer, patients with FAP are at increased risk of developing duodenal/periampullary cancer, papil- lary thyroid cancer, pancreatic mucinous adenocarcino- ma, hepatoblastoma, and brain tumors.2 Several of these associations, for example, desmoid tumors and congenital hypertrophy of retinal pigment epithelium, are associated with mutations within specific regions on the APC gene.3
Previous studies on adrenal lesions in patients with FAP have been limited by small sample sizes along with no genetic analysis, with the exception of 2 case series.2,4,5 Al- though these lesions have been estimated to be increased in the FAP population, the paucity of data makes it chal- lenging to determine proper surveillance guidelines.5,6
The Familial Gastrointestinal Cancer Registry (FGI- CR), established in Toronto, Canada, includes the largest FAP registry in Canada. The goal of this study was to fur- ther investigate the association of adrenal masses in the FAP population using this large and comprehensive da- tabase by examining the prevalence and characteristics of these lesions along with their clinical outcomes. Mutation- al analysis was also conducted in an attempt to establish any potential genotype-phenotype correlations.
METHODS
The FGICR, established in 1980, collects demograph- ic, genetic, and medical data from registered patients throughout Canada with familial cancer syndromes. A retrospective cohort study was conducted using the charts of patients meeting the diagnosis of classic FAP. Patients were excluded if there was no documentation of imaging, autopsy, or pathology reports. These charts were then reviewed for the presence of adrenal masses. An ad- renal mass was defined as any adrenal lesion greater than 1 cm in maximal dimension on imaging, or any patholo- gy-proven primary adrenal neoplasm. Adrenal metastases were excluded.
Demographic information was collected for all FAP patients with adrenal masses and included age, sex, FAP genotype, age at adrenal mass diagnosis, and method of diagnosis. The characteristics of the adrenal masses, in- cluding size, laterality, and clinical diagnosis, were deter- mined from available imaging, pathology, and autopsy reports. Lesions were diagnosed based on imaging charac- teristics or pathology findings. The presence of hormonal activity was also noted when available.
| TABLE 1. Patient demographic data | |
|---|---|
| Characteristics | Value |
| Median age at diagnosis, y (IQR) | 45 (33-57) |
| Sex, n (%) | |
| Male | 31 (65) |
| Female | 17 (35) |
| Method of diagnosis (n = 63), n (%) | |
| Imaging (eg, CT, MRI) | 56 (92) |
| Autopsy | 4 (7) |
| Intraoperative | 1 (2) |
| Laterality | |
| Total left | 32 |
| Total right | 31 |
| Median diameter at diagnosis, cm (IQR), n =61 | 1.7 (1.4-3.0) |
| Median maximal diameter, cm (IQR), n = 61 | 2.5 (1.7-4.1) |
| Median follow-up, months (IQR) | 48 (7-121) |
| Diagnosis, n = 61 | |
| Adenoma | 51 |
| ACC | 1 |
| Neuroblastoma | 1 |
| Other benign lesionsª | 8 |
ACC = adrenocortical carcinoma; IQR = interquartile range. ªOther benign lesions include myelolipoma, cyst, hyperplasia, and indeterminate. n = 48 unless otherwise stated.
Genetic testing was conducted at Mount Sinai Hos- pital’s laboratory for Advanced Molecular Diagnostics for many of the FGICR’s patients. The FGICR database was reviewed for APC genetic testing of patients with adrenal masses as well as their kin. Genotype was de- termined when available. Variant classifications were determined following the American College of Medical Genetics Standards and Practices for Interpreting DNA Variation (2015).7 DNA variants are described using Hu- man Genome Variation Society nomenclature; reference sequence: NM_000038.5 with legacy numbering of the APC gene.
Familial Gastrointestinal Cancer Registry and health record access was approved by the Mount Sinai Hospital institutional Research Ethics Board. Statistical analyses were performed by using IBM SPSS software, version 23.
RESULTS
A total of 756 charts were reviewed and imaging, autop- sy, or pathology reports were available for 311 patients. Sixty-three adrenal masses were identified in 48 patients (16%, n = 48/311). Although the vast majority were di- agnosed radiologically, there was 1 intraoperative and 4 autopsy-reported findings of an adrenal mass. Results are summarized in Table 1. The median age at diagnosis of ad- renal mass was 45 years. The median diameter of adrenal mass at diagnosis was 1.7 cm (interquartile range (IQR) 1.4-3.0) with median maximal diameter of 2.5 cm (IQR 1.7-4.1). Laterality was evenly distributed (31 total right- sided, 32 total left-sided). Bilateral adrenal masses were
noted in 23% (11/48) of patients. Median imaging follow- up was 48 months (IQR 7-121 months).
Table 2 lists characteristics for each patient in the study. Almost all adrenal masses were benign (97%), of which 80% were adenomas. The remaining benign lesions were myelolipoma, hyperplasia, or indeterminate lesions. There were 2 aldosteronomas and 1 virilizing adrenal tu- mor. One patient had an adrenocortical carcinoma (ACC), and 1 patient had an adrenal neuroblastoma. Adrenal re- section was performed on 7 patients because of size, suspi- cion of malignancy, or hormonal secretion.
The 1 adrenal mass-associated mortality came from the patient with ACC. This patient was a 24-year-old woman who underwent a CT for follow-up of her desmoid tumor (Fig. 1). Size at initial diagnosis was 1 cm. One year later the mass had increased to 2.2 cm, and, by 5 years after ini- tial diagnosis, it measured 3.5 cm. Endocrine workup was negative. She appeared to have been lost to follow-up and then re-presented 2 years later, at which point the mass had grown to 10.4 cm. Metaiodobenzylguanidine (MIBG) was negative. Percutaneous biopsy was performed and consis- tent with ACC. The patient underwent surgery, but resec- tion was aborted given extensive invasion into the aorta, and she eventually died after developing lung metastases.
Of the 48 FAP patients with adrenal masses described, an APC genetic variant was noted in 33 individuals (see Table 2). A total of 24 variants were identified, most oc- curring on the last exon of the APC gene. All variants were classified as pathogenic, with the exception of c.1744- 4C>G, which was classified as a variant of unknown sig- nificance. However, computational analyses using splice prediction programs (SpliceSiteFinder-like, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) were sug- gestive of pathogenicity. More than 1 family member with adrenal masses was observed in 7 variants with 4 pairs be- ing first-degree relatives.
DISCUSSION
In the era of improved high-resolution abdominal imag- ing, incidentalomas are detected in approximately 5% of patients on CT.8 This appears consistent with previous au- topsy studies that estimate a prevalence of 1% to 8.6%, including a 7% estimated population prevalence in the Canadian population.9,10 Although previously described, the literature on adrenal masses in the FAP population is relatively sparse, and adrenal masses are often overlooked as an extraintestinal manifestation.
With the use of the FGICR registry, 48 of 311 FAP pa- tients (16%) had adrenal masses. This is similar to findings from the St Mark’s Polyposis Registry where 13% (14/107) of FAP patients who underwent CT scans were found to have adrenal masses.5 These masses were all characterized as benign adenomas with the exception of 1 pheochromo-
cytoma. A 12-year follow-up study of this population sug- gested that the natural history of these lesions reflected the general population.4 The only other large cohort comes from a retrospective review using the Cleveland Clinic Foundation FAP registry, which demonstrated a 7.4% (15/738) prevalence of adrenal lesions in their FAP popu- lation.6 It should be noted, however, that the prevalence in the general population reported in the literature at the time of this publication was estimated at 0.6% to 3.4%.
Adrenal masses become increasingly more common with increasing age, with a range of less than 1% in pa- tients less than 30 years to as high as 7% to 10% at age 70 years or older.11 In this study, the median age at diagnosis was 45. Similar to the general population, it is not pos- sible to assess age of onset, because these were primarily incidental findings on imaging. Indications for imaging were primarily for desmoid surveillance, abdominal pain assessment, or the assessment of patients postoperatively. However, given that many of the imaging reports available did not include indication, these data were not included in this study. Earlier and more frequent abdominal imag- ing in the FAP population for postoperative monitoring or desmoid surveillance may contribute to this finding. This may result in potential ascertainment bias. Never- theless, the prevalence was similar to Smith et al,5 where the indication for CT scan was specifically for detecting adrenal masses. The prevalence of bilateral adrenal le- sions was 23%, which mirrors the 17% to 23% preva- lence of bilaterality noted in previous studies on non-FAP populations.12,13
It is reassuring that the majority of masses in FAP were benign and had pathologic distribution similar to the normal population, where over 90% were benign and pri- marily comprised adenomas.10,14 As previously described, however, 1 adrenal lesion initially thought to be an ade- noma was eventually determined to be an ACC, thus rein- forcing the concept of adequate surveillance and workup for incidentalomas.
Although 24 APC gene variants were observed in this study, no specific genotype-phenotype correlations were identified. Most mutations were located in the last exon the APC gene, a region commonly altered in FAP patients. A novel variant not previously reported in the literature, c.1744-4C>G, was identified and computational analyses were suggestive of pathogenicity. There were 4 pairs of first-degree relatives with adrenal lesions, all of which were benign. The significance of this is unclear, but a greater- than-expected frequency in first-degree relatives suggests a possible modifier gene. A formal comparison of imaging analysis and mutation type in patients with FAP is needed to identify any specific genotype-phenotype correlation.
The APC gene’s involvement in the Wnt/ß-catenin pathway provides a potential explanation for the increase of adrenal lesions in the FAP population. - Catenin
| Sex | Genotype | Amino acid change | Age at diagnosis, y | Diagnostic method | Side | Initial size, cm | Final size, cm | Follow-up time, mo | Diagnosis | Surgical management | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | M | c.3927_3931del | p.Glu1309Aspfs*4 | 45 | CT | R | 1 | 2.9 | 135 | Adenoma | No |
| – | – | 45 | CT | R | 2 | 2.5 | 90 | Adenoma | No | ||
| – | – | 45 | CT | L | 1.3 | – | – | Adenoma | No | ||
| 2 | M | 1467_1479del | p.Asn490Valfs*4 | 61 | Autopsy | R | 2.5 | – | – | Adenoma | No |
| 3 | M | – | – | 55 | Angiography | R | 6.5 | – | – | Adenoma | No |
| 4 | F | c.3766C>T | p.Gln1256* | 25 | CT | L | 1 | 10.4 | 89 | Metastatic ACC | Yes (aborted, |
| unresectable) | |||||||||||
| 5 | M | – | – | 68 | CT | L | 2 | 1.7 | 186 | Adenoma | No |
| 6 | F | c.3183_3187delACAAA | p.Gln1062* | 34 | CT | L | 1.2 | 1.3 | 3 | Adenoma | No |
| 7* | F | c.694C>T | p.Arg232* | 45 | CT | L | 1.6 | 1.7 | 7 | Adenoma | No |
| – | – | 45 | CT | L | 1 | 1.3 | 7 | Adenoma | No | ||
| 8* | F | c.694C>T | p.Arg232 p.Gln1062* | 37 | CT | R | 1 | – | – | Adenoma | No |
| 9 | M | c.3297_5079del | p.Ser1100Alafs p.Gln1062*15 | 58 | CT | L | 3.7 | – | – | Adenoma | No |
| 10 | M | c.392dup | p.Gly132Trpfs*7 | 33 | CT | R | 2.5 | 3.5 | 68 | Adenoma | Yes (bilateral for increased size) |
| – | – | 33 | CT | L | 0.6 | 2.2 | 121 | Myelolipoma | No | ||
| 11. | F | c.392dup | p.Gly132Trpfs p.Gln1062*7 | 34 | CT | R | 1.9 | – | – | Adenoma | No |
| 12 | M | – | – | 42 | CT | L | 4.4 | 4.4 | 12 | Adenoma | No |
| 13 | M | c.706C>T | p.Gln236 p.Gln1062* | 41 | CT | L | 4.1 | 3.7 | 1 | Adenoma | No |
| 14 | M | c.1974_1975del | p.Asn659Glnfs | 58 | CT | L | 1.8 | 2.5 | 180 | Adenoma | No |
| p.Gln1062*14 | |||||||||||
| 15 | M | – | – | 1.5 | Intraoperative | R | NR | – | – | Neuroblastoma | Yes |
| 16 | F | – | – | 47 | CT | L | 2.5 | 2.8 | 99 | Adenoma | No |
| 17 | F | c.1 -?_ 1958+?del | p .? | 63 | CT | R | 4.3 | 5 | 4 | Diffuse adrenal | Yes (catecholamine |
| hyperplasia | secreting, suspicion of | ||||||||||
| 18 | M | c.3567dupA | p.Ser1190Ilefs*18 | 48 | CT | R | 2.5 | 6.6 | 262 | Adenoma | pheochromocytoma) Yes x2 (right partial adrenalectomy previously for size, right completion adrenalectomy planned for development of aldosterone secretion) |
| – | – | 48 | CT | R | 1.3 | 1.7 | 127 | Adenoma | No | ||
| – | – | 57 | CT | L | 1.2 | 1.3 | 158 | Adenoma | No | ||
| – | – | 57 | CT | L | 0.7 | 1.1 | 84 | Adenoma | No | ||
| 19 | M | c.4526dup | p.Ser1510Glufs p.Gln1062*4 | 60 | CT | R | 4.3 | 2.4 | 1 | Adenoma | No |
| – | – | 60 | CT | L | 1.6 | 1.2 | 1 | Adenoma | No | ||
| 20+ | M | c.3454C>T | p.Gln1152 p.Gln1062* | 78 | CT | L | 1.8 | 1.4 | 21 | Adenoma | No |
| 21# | M | c.3454C>T | p.Gln1152 p.Gln1062* | 73 | Unknown | R | NR | Adenoma | Yes (indication unknown) |
(Continued)
| Sex | Genotype | Amino acid change | Age at diagnosis, y | Diagnostic method | Side | Initial size, cm | Final size, cm | Follow-up time, mo | Diagnosis | Surgical management | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 22 | F | c.3927_3931del | p.Glu1309Aspfs | 31 | CT | L | 8 | 5.3 | 188 | Calcified mass | No |
| p.Gln1062*4 | (granuloma vs | ||||||||||
| hematoma) | |||||||||||
| – | – | ||||||||||
| 23 | M | c.1312+3A>G | r.spl? | 51 | CT | R | 3 | 3 | 149 | Adenoma | No |
| 24 | M | c.994C>T | p.Arg332 p.Gln1062* | 49 | Autopsy | R | 2.4 | – | – | Adenoma | n/a |
| 25 | M | c.1744-4C>G | r.(spl?) | 56 | CT | L | 1.5 | – | – | Adenoma | No |
| 26 | F | c.4391_4394del | p.Glu 1464Valfs | 30 | CT | R | 3.5 | – | – | Adenoma | Yes (planned, size) |
| p.Gln1062*8 | |||||||||||
| – | – | 30 | CT | L | 4.5 | – | – | Adenoma | No | ||
| 27 | F | – | – | 32 | CT | R | 3.7 | 4.4 | 37 | Adenoma | No |
| 28§ | M | c.423-1G>A | r.spl?3 | 51 | CT | R | 3 | 4.1 | 80 | Adenoma | No |
| 29§ | F | c.423-1G>A | r.spl?3 | 57 | CT | R | 2 | – | – | Adenoma | No |
| 30 | F | c.1993_1994del | p.Leu665Ilefs p.Gln1062*8 | 32 | CT | R | 2 | 2 | 2 | Adenoma | No |
| 31¥ | F | c.1621_1622dup | p.Gln541Hisfs*9 | 31 | MR | R | 2.5 | 4 | 48 | Indeterminate | Yes (planned, androgen- |
| (nonadenomatous features) | secreting) | ||||||||||
| – | – | 31 | MR | L | 2.5 | 2.5 | 48 | Adenoma | No | ||
| 32¥ | M | c.1621_1622dup | p.Gln541Hisfs p.Gln1062*9 | 37 | CT | R | 2 | 1.7 | 2 | Adenoma | No |
| – | – | 37 | CT | L | 1.6 | 1.4 | 2 | Adenoma | No | ||
| 33 | M | c.3183_3187del | p.Gln1062 p.Gln1062* | 40 | CT | R | 4 | 4.5 | 13 | Adenoma | No |
| 34ß | F | c.2093T>G | p.Leu698 p.Gln1062* | 45 | CT | L | 2.7 | – | – | Adenoma | No |
| 35ß | M | c.2093T>G | p.Leu698 p.Gln1062* | 47 | CT | L | 2 | – | – | Adenoma | No |
| 36ß | M | c.2093T>G | p.Leu698 p.Gln1062* | 56 | CT | L | 2.7 | 2.7 | 24 | Adenoma | No |
| 37 | F | – | – | 37 | Autopsy | B/L | NR | NR | – | Adenoma | No |
| 38 | M | – | – | 39 | Autopsy | B/L | NR | NR | – | Adenoma | No |
| 39 | M | c.594dupT | p.Ala 199Cysfs p.Gln1062*53 | 44 | CT | L | 4.5 | 4.8 | 34 | Adenoma | No |
| 40 | M | c.3183_3187del | p.Gln1062 p.Gln1062* | 53 | CT | L | 1 | 2.1 | 17 | Adenoma | No |
| 41 | M | c.1787C>G | p.Ser596 p.Gln1062* | 43 | CT | R | 1.4 | 0.8 | 54 | Adenoma | No |
| 42 | M | – | – | 48 | CT | R | 5.1 | 4.5 | 48 | Adenoma | No |
| 43 | M | – | – | 53 | CT | L | 2 | 1.6 | 37 | Myelolipoma | No |
| 44 | F | – | – | 52 | CT | R | 2.9 | 2.5 | 165 | Cyst | No |
| 45^ | M | – | – | 55 | CT | R | 2 | 1.6 | 65 | Adenoma | No |
| – | – | 55 | CT | L | 1.8 | 1.6 | 65 | Adenoma | No | ||
| 46^ | M | – | – | 35 | CT | R | 3 | 2.3 | 2 | Adenoma | No |
| – | – | 35 | CT | L | 1 | 1 | 2 | Adenoma | No | ||
| 47 | M | – | – | 41 | CT | L | 4 | – | – | Unknown | No |
| 48 | F | – | – | 41 | US | R | 3 | 2.1 | 7 | Indeterminate | No |
*, +, §, ., ¥, ß, ^: within the same family; . , ¥, ß (#35 and #36); ^: first-degree relatives.
ACC = adrenocortical carcinoma; L = left; R = right; US = ultrasound.
A
B
C
(CTNNB1) mutations are the most common alterations in both sporadic adrenal adenoma and adenocarcinoma.15 Inactivation of the APC gene leads to constitutive accu- mulation of the ß-catenin protein and the activation of the Wnt/B-catenin pathway. Indeed, biallelic inactivation with simultaneous somatic and germline alterations has been demonstrated in FAP adrenal adenoma and ACC samples.16 Similar inactivation has been demonstrated in ACC samples from FAP patients while not appearing to play a significant role in sporadic ACC cases.17 Given the retrospective nature of this study, it was not possible to perform any similar analyses.
Many patients did not have evidence of adrenal hor- monal testing, and, therefore, it was not possible to include any analysis of functional adenoma prevalence, although these were presumed nonfunctioning based on clinic reports and subsequent management. This represents a limitation of FGICR, which primarily comprises medical records sent from outside hospitals and therefore may be incomplete.
CONCLUSION
Adrenal masses are common in the FAP population. Nearly all mutations led to truncation of the APC gene; however, there was no genetic signature to help predict those at in- creased risk. The majority of adrenal lesions identified were of benign etiology; thus, an intensive management or sur- veillance strategy with imaging screening is likely unwar- ranted. This study is novel in the degree of genetic analysis; it also represents the largest sample size in the literature to date. A future direction could include an assessment of hor- monal status, because an increased functional prevalence would certainly have clinical implications, or a direct com- parison with patients with FAP and normal adrenal glands.
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