Adrenal Masses in Patients with Familial Adenomatous Polyposis
Pierenrico Marchesa, M.D., Victor W. Fazio, M.D., F.R.A.C.S., James M. Church, M.D., Ellen McGannon, B.S.N.
From the Department of Colorectal Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio
PURPOSE: The aims of this study were 1) to report the characteristics and the clinical outcome of familial adeno- matous polyposis (FAP) patients with adrenal masses in the FAP registry at the Cleveland Clinic Foundation and 2) to estimate the prevalence of adrenal masses detected by com- puted tomography in FAP patients compared with that expected in a normal population. METHODS: A retrospec- tive review was undertaken of the FAP registry database at our institution. Only 738 patients treated at the Cleveland Clinic Foundation were included in the study. A meta- analysis was conducted to determine the relative risk of adrenal incidentaloma in this series of FAP patients and in a general population as reported in the four largest pertinent studies published in the past 15 years. RESULTS: Fifteen patients (11 females) were identified. Two patients had symptoms related to cortisol hypersecretion (arterial hyper- tension) and underwent surgery. The final pathology was adrenocortical carcinoma and bilateral nodular hyperplasia. Adrenal masses were found incidentally (incidentalomas) in 13 patients: 12 were detected by computed tomography and one during laparotomy for total abdominal colectomy. Only one patient underwent left adrenalectomy for a 5-cm mass. Pathologic report revealed adrenocortical adenoma. Among the 738 patients considered in this study, only 162 underwent abdominal computed tomographic scan, mainly for assessing intra-abdominal desmoid. The prevalence of incidentaloma in our series compared with that reported in the literature is significantly different (7.4 vs. 0.6-3.4 per- cent; P < 0.001 (chi-squared test)). DISCUSSION: Although the presence of other extracolonic manifestations repre- sents a selection bias for computed tomographic study in our series, the incidence of incidentalomas in FAP patients seems to be higher than in a general population. However, incidental detection of an adrenal mass in FAP patients has probably a limited clinical relevance, and the management should be the same as that for the normal population. [Key words: Familial adenomatous polyposis; Adrenal neoplasms; Incidentalomas]
Marchesa P, Fazio VW, Church JM, McGannon E. Adrenal masses in patients with familial adenomatous polyposis. Dis Colon Rectum 1997;40:1023-1028.
F amilial adenomatous polyposis (FAP) is an auto- somal dominant disease characterized by forma- tion of multiple colorectal adenomas with a 100 per- cent potential for malignant transformation.1 FAP can be associated with diverse extracolonic manifesta-
tions that make the clinical appearance quite vari- able.2 In 1951, Gardner3 originally described a condi- tion characterized by colonic polyposis that was associated with epidermoid cyst and subcutaneous fibroma. Since then, the number of extracolonic man- ifestations considered to be part of the syndrome has grown.4,5 In recent years, investigators have demon- strated that mutation of the adenomatous polyposis coli gene (APC) located on chromosome 5q21 is re- sponsible for the progressive development of hun- dreds to thousands of adenomatous colorectal pol- yps.6,7 Although the role that the APC gene plays in the occurrence of various extracolonic tumors re- mains to be defined, FAP and Gardner’s syndrome are considered to be phenotypic variants of the same genetically determined disease.8, 9
Adrenal neoplasms have been described occasion- ally in association with FAP. The first case reported in the literature was described by Devic and Bussy in 1912.10 Since then, only ten adrenal adenomas and two adrenocortical carcinomas have been reported in the literature.11-18 All cases but two were asymptom- atic and were discovered at autopsy, making the prev- alence of these lesions in FAP difficult to define.
During the past decade, the wider application of imaging techniques such as computed tomography (CT) and, more recently, magnetic resonance imaging has resulted in the identification of clinically silent adrenal masses.19 Incidentally diagnosed masses are sometimes referred to as “incidentalomas.” The prev- alence of occasionally and unexpectedly discovered adrenal masses varies between 0.6 and 3.6 percent in abdominal CT scan series,20 and the most common pathologic finding in patients who underwent surgery for such masses was nonfunctioning cortical adeno- ma.21, 22 This study was undertaken to report the characteristics and clinical outcomes of FAP patients with adrenal masses in the FAP registry at the Cleve- land Clinic Foundation and to estimate the prevalence of adrenal masses detected by CT in FAP patients compared with that expected in a normal population.
Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Seattle, Washington, June 9 to 14, 1996. Address reprint requests to Dr. Fazio: Department of Colorectal Surgery, Desk A111, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio, 44195.
METHODS
Data were collected from the Cleveland Clinic FAP registry, which contained data on 3,738 patients at the time of this investigation. Only the 738 patients who were treated at our institution were included in the study. Patient information was obtained by medical records and questionnaires. The method of adrenal mass diagnosis (CT findings or clinical manifestations) was recorded.
In an attempt to obtain information on the preva- lence of adrenal incidentaloma detected by abdomi- nal CT scan in a normal population, we considered the four largest pertinent studies published in the past 15 years.23-26 The expected differences in detection rate of adrenal lesions attributable to the improve- ment in diagnostic imaging technology were obviated by the fact that the entire number of CT scans in our population of FAP patients was performed during the same period of time.
A meta-analysis was conducted to determine the relative risk of adrenal incidentaloma diagnosis among FAP patients compared with that in the gen- eral population. The odds ratio and corresponding 95 percent confidence interval were calculated for each control study and the combination of the four previ- ously published articles that are relative to the present study. Finally, the chi-squared test was used to com- pare the prevalence of adrenal incidentaloma be- tween each study and the present study.
RESULTS
Fifteen patients with adrenal masses were identi- fied. There were 11 women and 4 men, all of whom were Caucasian. All patients had a diagnosis of FAP before diagnosis of the adrenal mass. Median age at time of FAP diagnosis was 33 (range, 14-53) years, whereas median age at time of adrenal mass diagnosis was 46 (range, 27-65) years. Median follow-up from diagnosis of adrenal mass was 60 (range, 12-102) months.
Table 1 summarizes the characteristics of FAP pa- tients with adrenal mass analyzed in this study. All patients but one had other extracolonic manifesta- tions: duodenal and gastric polyp (9), epidermoid cyst (8), osteoma (5), desmoid (4), and congenital hyper- trophia of retinal epithelium (1).
Two patients had symptoms related to cortisol hy- persecretion. A 28-year-old woman with a history of FAP and subsequent total colectomy with ileorectal anastomosis manifested a blood pressure of 165/100, which was controlled with medications. Physical ex- amination revealed a left upper quadrant abdominal mass. Laboratory investigations included the follow- ing: morning serum cortisol level, 32.8 (normal range, 8.2-29) µg/dl; afternoon serum cortisol level, 25.3 (normal range, 3.3-15) µg/dl; 24-hour urine-free cor- tisol level, 357.5 (normal range, 80-370) µg per 24 hours; plasma aldosterone level, 8.2 (normal range, 4-32) µg/dl, urinary 17-ketosteroids, 8.1 (normal
| Table 1. Patient Data | ||||||
|---|---|---|---|---|---|---|
| Patient No. | Gender | Diagnosis | Site | Size (CM) | Other EM* | Surgery |
| 1 | F | Clinical | L | 10 | EPI | Y |
| 2 | M | Intraoperative | L | 3 | EPI | - |
| 3 | F | Clinical | BIL | 4/6 | EPI-BDG-OST | Y |
| 4 | F | CT | R | 2 | EPI | - |
| 5 | F | CT | R | 3 | BDG-OST | - |
| 6 | M | CT | L | 5 | EPI | Y |
| 7 | F | CT | R | 2.7 | BDG-DES-OST | - |
| 8 | F | CT | R | 1 | EPI-BDG-OST | - |
| 9 | F | CT | L | 1 | BDG-DES | - |
| 10 | M | CT | R | 2.5 | EPI-BDG-DES | - |
| 11 | F | CT | L | 1 | EPI-BDG-DES | |
| 12 | M | CT | L | 2.5 | BDG-OST | - |
| 13 | F | CT | R | 2.5 | BDG | - |
| 14 | F | CT | BIL | 3/3 | RPE-BDG | - |
| 15 | F | CT | L | 2 | - | - |
EM = extracolonic manifestations; F = female; M = male; EPI = epidermoid cyst; BDG = both duodenal and gastric polyps; OST = osteoma; DES = desmoid; RPE = congenital hypertrophia of retinal epithelium; CT = computed tomography; BIL = biliary; L = left; R = right.
range, 4-17) mg per 24 hours; 24-hour urine vanillyl- mandelic acid level, 5.3 (normal range, 0.7-6.8) mg per 24 hours; 24-hour urine metanephrines, 0.79 (nor- mal range, 0.3-0.9) mg per 24 hours; 24-hour urine catecholamines, 5.6 (normal range, 0-18) ¿ig/dl; se- rum catecholamines, 693 (mean, 260; upper limit of normal, 620) µg/l. A CT scan of the abdomen re- vealed a large nonhomogeneous retroperitoneal mass in the left upper quadrant. Preoperative CT-guided needle biopsy of the mass revealed poorly differenti- ated adenocarcinoma. At surgery, a 10-cm retroperi- toneal mass was removed along with the left kidney, spleen, and a portion of the diaphragm and overlying adjacent lung. Final pathology showed adrenocortical carcinoma with invasion of the diaphragm. The pa- tient died eight months after surgery with intra-ab- dominal and pulmonary recurrence.
The second patient was a 41-year-old woman with a history of FAP. Arterial hypertension (blood pres- sure values, 170/105) was diagnosed two years after proctocolectomy and end ileostomy. Laboratory ex- aminations revealed the following: morning serum cortisol level, 36.4 (normal range, 8.9-30) µg/dl, af- ternoon serum cortisol level, 23.8 (normal range, 3.7- 16) µg/dl; 24-hour urine-free cortisol level, 364.5 (normal range, 75-360) µg per 24 hours; plasma al- dosterone level, 15.4 (normal range, 5-31) ng/dl; uri- nary 17-ketosteroids, 7.5 (normal range, 4-17) mg per 24 hours; 24-hour urine vanillylmandelic acid level, 2.8 (normal range, 0.6-6.1) mg per 24 hours. Serum adrenocorticotropic hormone was undetectable, and there was an insensitive response to the high-dose dexamethasone test. Abdominal CT scan showed a bilateral increase of the size of the adrenal gland. The patient underwent resection of both left and right adrenal glands, measuring 4 and 6 cm in size, respec- tively. The pathologic finding was bilateral nodular hyperplasia. After surgery, the values of serum corti- sol, serum glucose, and urine-free cortisol and blood pressure levels returned to normal. The patient sub- sequently developed esophageal carcinoma and died 74 months after bilateral adrenalectomy.
Incidentalomas were found in 13 patients: 12 were detected by CT scan and 1 during laparotomy for total abdominal colectomy. Lesions were located in the right adrenal (6), left adrenal (6), and bilaterally (1) with a median size of 2.5 (range, 1-5) cm. The patient who had a 3-cm left adrenal mass detected intraop- eratively was diagnosed with adrenocortical adenoma by fine-needle biopsy performed during laparotomy. Postoperative functional evaluation, including morn-
ing serum cortisol, 24-hour urine-free cortisol, and urinary 17-ketosteroids, was negative for hypersecre- tion. This patient was followed up for 53 months after the diagnosis. Blood pressure values were always found to be lower than 145/90 mmHg. CT scan ex- amination performed 36 months after diagnosis re- vealed unchanged mass size.
Of the 12 patients with an incidental CT scan diag- nosis of adrenal mass, only one underwent ablative surgery. This patient was a 55-year-old man with a previous history of FAP, subtotal colectomy, and ileo- rectal anastomosis. He was evaluated at another hos- pital for chest pain and was found to have a pulmo- nary embolus. The patient was transferred to the Cleveland Clinic for treatment. Abdominal CT scan showed a 5-cm left adrenal mass. Blood pressure value was 130/75. Laboratory examinations included the following: serum glucose, 100 mg/dl; serum so- dium, 135 mEq/L; serum potassium, 4.3 mEq/L; morn- ing plasma cortisol levels, 18.8 (normal range, 8.2-19) µg/dl; 24-hour urinary hydroxycorticosteroids, 5.8 (normal range, 3-12) mg per 24 hours; 24-hour uri- nary ketosteroids, 4 (normal range, 6-21) mg per 24-hour. The consultant endocrinologist did not sug- gest any other laboratory investigation and gave an indication for surgery because of the mass size. Left adrenalectomy was then performed, and the final pathologic report revealed adrenocortical adenoma. This patient is alive 60 months after surgery with no clinical evidence of adrenocortical hypersecretion. Of the remaining 11 patients, none had either arterial hypertension or serum sodium, potassium, and glu- cose levels out of the normal range at the time of adrenal mass diagnosis. No laboratory hormonal anal- ysis was performed. No symptoms related to adreno- cortical hypersecretion were found during follow-up visits in the 11 patients. Radiologic follow-up did not demonstrate any change in mass size. CT scan was performed between 18 and 36 months after adrenal mass diagnosis unless concomitant problems (e.g., desmoid evaluation) required different timing. Two patients died of metastasis from colonic carcinoma and acute myocardial infarction four and five years, respectively, after the adrenal mass diagnosis.
Among the 738 FAP patients treated at the Cleve- land Clinic Foundation, only 162 had undergone an abdominal CT scan. One hundred thirty-two patients had one or more extracolonic manifestations of FAP at the time of CT. The prevalence of adrenal inciden- taloma was 12/162 (7.4 percent). Table 2 shows the indications for CT scan in groups of patients with or
without adrenal incidentaloma diagnosed radiologi- cally. The results of the meta-analysis conducted in the three previous studies and our findings are pre- sented in Table 3. The prevalence of adrenal inciden- taloma is higher in the present study than in the four historical control studies, either separately or com- bined.
DISCUSSION
Endocrine neoplasms are now recognized as part of the extracolonic manifestation associated with FAP. An analysis conducted by Schneider et al.13 suggests that endocrine neoplasia is significantly more frequent in FAP patients than in other cancer patients. Few reports on adrenal tumors associated with FAP have appeared in the literature, mostly deriving from autopsy series. Of these ten cases reported, only two diagnoses were made during clinical follow-up. 10-15, 17
This is the largest reported series of patients en- tered in a single FAP registry with the association between adrenal neoplasia and FAP, even though the number of adrenal masses with pathologic confirma- tion is limited (n = 4). All four patients had clinical manifestations, and the diagnosis was obtained ini-
| Adrenal Mass | No Adrenal Mass | |
|---|---|---|
| Desmoid rule out/evaluation | 8 | 105 |
| Cancer staging | 3 | 18 |
| Postoperative | - | 22 |
| Other | 1 | 5 |
| Total | 12 | 150 |
tially on the basis of laboratory and radiologic find- ings in three patients. However, it is still difficult to determine the true incidence of adrenal neoplasia in FAP patients because most of these tumors are clini- cally asymptomatic.
The availability of radiologic techniques capable of accurately imaging the retroperitoneal region has def- initely increased the chances of detecting adrenal neoplasms in patients with normal endocrine func- tion. Most of the incidentally discovered adrenal masses by CT scan proved to be benign adrenal cor- tical adenomas.20 Therefore, we have sought to de- termine the prevalence of adrenal incidentaloma di- agnosis in an FAP population. The accuracy of FAP registries together with the reliability of CT scan or magnetic resonance imaging studies can offer a unique opportunity to clarify this problem. Improve- ment in imaging techniques over time would have affected the series we used for comparison in a similar way to our own series, because both were accumu- lated over similar time periods.
Our findings demonstrate that the prevalence of adrenal incidentaloma diagnosed by CT scan is higher in FAP patients than in the normal population. Only 162 of 738 (22 percent) patients underwent an ab- dominal CT scan study, and the main reason for the selection of patients was the presence of intra-abdom- inal desmoid. This observation suggests that our data should be considered with caution because, perhaps, there is an association between desmoids and adrenal incidentalomas. However, the occurrence of these lesions in FAP seems to be the result of something other than chance.
The risk of being malignant for an incidentally dis- covered adrenal mass is directly correlate to its size. The size “cut-off” below which adrenal incidentaloma
| Meta-Analysis | ||||||
|---|---|---|---|---|---|---|
| Study | No. of Adrenal Incidentaloma | Total No. of Computed Tomographic Scans | Prevalence (%) | 95% CI | Odds Ratio (95% CI) | P Value |
| Present study | 12 | 162 | 7.4 | 3.4-11.4 | - | - |
| Glazer et al.23 (1982) | 14 | 2,200 | 0.6 | 0.3-1.0 | 12.5 (5.7-27.5) | <0.001* |
| Abecassis et al.24 (1985) | 19 | 1,459 | 1.3 | 0.7-1.9 | 6.1 (2.9-12.7) | <0.001* |
| Belledegrun et al.25 (1986) | 88 | 12,000 | 0.7 | 0.6-0.9 | 10.8 (5.8-20.2) | <0.001* |
| Herrera et al.26 (1991) | 2,066 | 61,054 | 3.4 | 3.2-3.5 | 2.3 (1.3-4.1) | 0.005* |
| Combined (4) | 2,187 | 76,713 | 2.9 | 2.7-3.0 | 2.7 (1.5-4.9) | <0.001* |
CI = confidence interval.
* Chi-squared test.
can be safely followed up without surgery varies be- tween 3.5 and 6 cm.24-27 Accepted criteria for surgical ablation of adrenal incidentaloma are considered to be as follows: size of the mass greater than 4 cm, increase in size at any re-evaluation, CT picture of intratumoral necrosis, hemorrhage or irregular mar- gins, and, finally, hormonal hypersecretion.20, 21, 27
Only one in our series of FAP patients with adrenal incidentaloma fulfilled one of these criteria (size greater than 5 cm) and underwent adrenalectomy. The remaining 12 patients followed a benign course, suggesting that the management of incidentally dis- covered adrenal masses in FAP patients should be the same as that for the normal population. In particular, recommendations for appropriate biochemical screening are predicated on the presence of symp- toms or signs suggestive of hormonal excess. In the absence of any clinical evidence of arterial hyperten- sion, hypercortisolism, or hyperandrogenism, it may be counterproductive and may result in an increased expense to extensively screen these patients.28 Fur- thermore, fine-needle biopsy of incidentally discov- ered adrenal mass is not generally recommended to differentiate primary adrenal neoplasms, because it is an invasive procedure with significant morbidity29, 30 and its reliability in the differential diagnosis remains questionable.31
CONCLUSION
The prevalence of adrenal masses in FAP patients may be higher than in the general population, espe- cially if the patient has other extracolonic manifesta- tions. However, the clinical outcome of the patients included in the present study indicates that incidental detection of an adrenal mass has probably a limited clinical relevance in cases of FAP. If an abdominal CT scan is required in FAP patient, the presence of an adrenal mass should be noted. If the criteria for sur- gery are fulfilled, resection needs to be considered. Otherwise the mass can be observed.
REFERENCES
1. Bussey HJ. Familial polyposis coli. Family studies, his- topathology, differential diagnosis, and results of treat- ment. Baltimore: Johns Hopkins University Press, 1975: 1-75.
2. Nelson RL, Orsay CP, Pearl RK, Abcarian H. The protean manifestations of familial polyposis coli. Dis Colon Rec- tum 1988;31:699-703.
3. Gardner EJ. A genetic and clinical study of intestinal
polyposis, a predisposing factor for carcinoma of the colon and rectum. Am J Hum Genet 1951;3:167-73.
4. Bulow S. Familial adenomatous polyposis. Ann Med 1989;21:299-307.
5. Jagelman DG. Extracolonic manifestations of familial polyposis coli. Cancer Genet Cytogenet 1987;27: 319-25.
6. Kinzler KW, Nilbert MC, Su LK, et al. Identification of FAP locus genes from chromosome 5q21. Science 1991; 253:661-5.
7. Nishisho I, Nakamura Y, Miyoshi Y, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991;253:665-9.
8. Davies DR, Armstrong JG, Thakker N, et al. Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. Am J Hum Genet 1995;57:1151-8.
9. Olschwang S, Tiret A, Laurent-Puig P, Muleris M, Parc R, Thomas G. Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients. Cell 1993;75:959-68.
10. Devic A, Bussy MM. Un cas de polypose adenomateuse: generalisee a tout l’intestin. Arch Mal Appar Dig Mal Nutr 1912;6:278-89.
11. MacDonald JM, Davis WC, Crago HR, Berk AD. Gard- ner’s syndrome and periampullary malignancy. Am J Surg 1967;113:425-30.
12. Coli RD, Moore JP, La Marche PH, DeLuca FG, Thayer WR Jr. Gardner’s syndrome; a revisit to a previously described family. Am J Dig Dis 1970;15:551-68.
13. Schneider WR, Cubilla AL, Chaganti RS. Association of endocrine neoplasia with familial multiple colon pol- yps. Am J Hum Genet 1980;32:128A.
14. Puig R, Herrera JM, Cassinelli JF. Gardner’s syndrome. Prensa Med Argent 1969;56:831-6.
15. Gosserez M, Tréheux A, Hoefell JC, Stricker M, Fays J, Valentin F. Une etiologie rare de tumeurs des maxillar- ies: le syndrome de Gardner. J Radiol Electrol Med Nucl 1970;51:503-6.
16. Marshall WH, Martin FI, MacKay IR. Gardner’s syn- drome with adrenal carcinoma. Aust Ann Med 1967;16: 242-4.
17. Naylor EW, Gardner EJ. Adrenal adenomas in a patient with Gardner’s syndrome. Clin Genet 1981;20:67-73.
18. Painter TA, Jagelman DG. Adrenal adenomas and adre- nal carcinomas in association with hereditary adenoma- tosis of the colon and rectum. Cancer 1985;55:2001-4.
19. Gross MD, Shapiro B. Clinical review 50: clinically silent adrenal masses [review]. J Clin Endocrinol Metab 1993; 77:885-8.
20. Gajraj H, Young AE. Adrenal incidentaloma [review]. Br J Surg 1993;80:422-6.
21. Osella G, Terzolo M, Borretta G, et al. Endocrine eval- uation of incidentally discovered adrenal masses (inci- dentalomas). J Clin Endocrinol Metab 1994;79:1532-9.
22. Siren JE, Haapiainen RK, Huikuri KT, Sivula AH. Inci- dentalomas of the adrenal gland: 36 operated patients and review of literature. World J Surg 1993;17:634-9.
23. Glazer HS, Weyman PJ, Sagel SS, Levitt RG, McClennan BL. Nonfunctioning adrenal masses: incidental discov- ery on computed tomography. AJR Am J Roentgenol 1982;139:81-5.
24. Abecassis M, McLoughlin MJ, Langer B, Kudlow JE. Serendipitous adrenal masses: prevalence, significance, and management. Am J Surg 1985;149:783-8.
25. Belldegrun A, Hussain S, Seletzer SE, Loughlin KR, Gitten RF, Richie JP. Incidentally discovered mass os the adrenal gland. Surg Gynecol Obstet 1986;163: 203-8.
26. Herrera MF, Grant CS, van Heerden JA, Sheedy PF II, Ilstrup DM. Incidentally discovered adrenal tumors: an institutional perspective. Surgery 1991;110:1014-21.
27. Staren ED, Prinz RA. Selection of patients with adrenal incidentalomas for operation [review]. Surg Clin North Am 1995;75:499-509.
28. Ross MS, Aron DC. Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 1990;323:1402-5.
29. Bernardino ME, Walther MM, Phillips VM, et al. CT- guided adrenal biopsy: accuracy, safety, and indica- tions. AJR Am J Roentgenol 1985;144:67-9.
30. Yankaskas BC, Staab EV, Craven MB, Blatt PM, Sokhan- dan M, Carney CN. Delayed complications from fine- needle biopsies of solid masses if the abdomen. Invest Radiol 1986;21:325-8.
31. Katz RL, Shirkoda A. Diagnostic approach to incidental adrenal nodules in the cancer patient: results of a clin- ical, radiologic, and fine-needle aspiration study. Can- cer 1985;55:1995-2000.
XVIIth Biennial Congress of the International Society of University Colon and Rectal Surgeons Malmo, Sweden June 7-11, 1998