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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 11 5328-5336
Copyright © 2004 by The Endocrine Society

Cutaneous Tumors in Patients with Multiple Endocrine Neoplasm Type 1 (MEN1) and Gastrinomas: Prospective Study of Frequency and Development of Criteria with High Sensitivity and Specificity for MEN1

Behnam Asgharian, Maria L. Turner, Fathia Gibril, Laurence K. Entsuah, Jose Serrano and Robert T. Jensen

Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (B.A., F.G., L.K.E., J.S., R.T.J.); and Dermatology Branch, National Cancer Institute (M.L.T.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Robert T. Jensen, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9C-103, 10 Center Drive, MSC 1804, Bethesda, Maryland 20892-1804. E-mail: robertj{at}bdg10.niddk.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Multiple endocrine neoplasm type 1 (MEN1) is associated with parathyroid, pancreatic, and pituitary tumors. Although most patients present with hyperparathyroidism, the diagnosis can be difficult, because a significant proportion present with other endocrinopathies or may lack a family history, and other MEN1 manifestations may be mild. Recently, multiple cutaneous lesions (angiofibromas and collagenomas) were reported to be frequent in MEN1 patients, and it was proposed that their discovery suggested the diagnosis of MEN1. The purpose of this study was to prospectively assess the frequency and sensitivity/specificity of various cutaneous criteria for MEN1 in 110 consecutive patients with gastrinomas with or without MEN1. All patients had hormonal and functional studies to determine MEN1 status (48 with MEN1, 62 without MEN1), dermatological evaluation, and tumor imaging studies. Angiofibromas and collagenomas were more frequent in MEN1 patients (64% vs. 8% and 62% vs. 5%; P < 0.00001) and were multiple in 77–81% of the MEN1 patients. Lipomas occurred in 17%. The presence of these skin lesions did not correlate with age, disease duration, or other MEN1 features. Angiofibromas or collagenomas (single or multiple) had 50–65% sensitivity for MEN1 and 92–100% specificity. The combination criterion of multiple angiofibromas (more than three) and any collagenomas had the highest sensitivity (75%) and specificity (95%). This criterion has greater sensitivity than pituitary or adrenal disease and is comparable to hyperparathyroidism in some studies of patients with MEN1 with gastrinoma. This criterion should have sufficient sensitivity/specificity to be clinically useful.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
MULTIPLE ENDOCRINE NEOPLASIA type 1 (MEN1) is an autosomal dominant disorder caused by mutations in the MEN1 gene on chromosome 11q13 (1, 2). Patients characteristically develop tumors of the parathyroid (83–97%), pancreas (38–84%), and anterior pituitary (18–65%) (1, 2, 3, 4, 5, 6, 7).

The diagnosis of MEN1 is usually not made until the patient is in the fourth decade of life in most studies (2, 3, 5); however, some patients are in the fifth decade (6). The diagnosis of MEN1 is important because it allows proper treatment of the existing endocrinopathies, screening for the development of additional features of MEN1, and family screening (8). Although most patients present with hyperparathyroidism (HPT), the diagnosis of MEN1 may be difficult, because a significant proportion can present with other endocrinopathies, particularly pancreatic endocrine tumors (PETs); the family history may be negative for MEN1; and other features of MEN1, such as HPT, may be mild and difficult to detect (5, 9, 10, 11, 12, 13). Genetic testing could be helpful, but it is expensive, not frequently available, and not always positive, especially in patients with a negative family history (5). Therefore, the availability of any clinical study that has a high sensitivity and specificity for diagnosing MEN1 would be a useful.

Recently, other endocrine and nonendocrine tumors were reported in patients with MEN1, including carcinoids (thymus, lung, and gastric), adrenal and smooth tumors, central nervous system tumors, and skin tumors (angiofibromas, collagenous, melanomas, and lipomas) (1, 2, 5, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24). The skin lesions, particularly multiple facial angiofibromas, are of particular note because they were reported to occur in 88% of MEN1 patients (17), and their multiple occurrence was only reported in addition to occurring in tuberous sclerosis, so this finding was relatively specific (17). It was therefore proposed that finding multiple angiofibromas should suggest MEN1 (17).

Patients with Zollinger-Ellison syndrome (ZES) are a good group for assessment of the potential usefulness of dermatological findings in identifying patients with MEN1, because 18–48% have MEN1, the patients with MEN1 with gastrinomas frequently present with the features of ZES, and MEN1 can be difficult to diagnose in this subset (5, 6, 11, 25). Furthermore, the diagnosis of MEN1 in patients with gastrinomas is essential to their proper management, because they are treated differently from patients with sporadic disease (5, 8, 26, 27).

Therefore, the purpose of the present study was to assess prospectively the frequency of cutaneous findings in consecutive patients with gastrinomas with and without MEN1 to determine their sensitivity and specificity for identifying patients with MEN1. Combinations of the different findings were also analyzed to attempt to develop a cutaneous criterion with the highest sensitivity and specificity for identifying MEN1 in these patients.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
All patients admitted to the NIH with a possible diagnosis of ZES with or without MEN1 between January 2000 and April 2003 were eligible for this study. These patients were followed at or referred to the NIH to participate in the various protocols involving prospective studies of patients with ZES that had been approved by the clinical research committee of the NIDDK. All patients gave informed consent on entering the protocols, and all were treated under protocol guidelines that contained provisions for the appropriate treatment of human subjects.

Patients were entered into this study if they agreed to take part in the specific study protocol described below and had a complete dermatological evaluation during the study period as part of their overall investigation.

The diagnostic criteria for ZES have been described previously (28, 29), including the combination of an elevated basal gastric output (>15 mEq/h in patients with no prior gastric acid-reducing surgery or >5 mEq/h in patients with prior gastric acid-reducing surgery), an elevated fasting serum gastrin at the time of the gastric analysis; a positive gastrin provocative test with secretin injection (an increase of >200 pg/ml in fasting serum gastrin) (30), or a histological confirmation of gastrinoma.

The diagnosis of MEN1 was based on the criteria described previously (5, 9, 20) and included a combination of PET, pituitary disease, HPT, genetic test for MEN1, or any of the above diagnoses with a family history of MEN1. Germline mutation analysis of the MEN1 gene was performed in 70 patients as described previously (31, 32). An MEN1 gene mutation was detected in 91% (39 of 43 patients) of the patients with MEN1 and in none of the 27 patients without MEN1 in the present study. The presence of PET was determined by surgical exploration (26, 33), functional studies, or imaging alone (33, 34). Serum gastrin determinations were made by Mayo Clinic Laboratories (Rochester, MN). The secretin test was performed with an iv injection of secretin (2 µg/kg body weight; Ferring AB, Malmo, Sweden), and serum gastrin was then serially analyzed (a value >200 pg/ml was considered positive) (30).

Specific study protocol

The initial evaluation of all patients involved in the protocol included a complete personal and family medical history (5, 29). This included a detailed review of gastrointestinal symptoms, personal or family history of possible MEN1-related symptoms, prior operations, or any endocrinopathies. Also, a review of any previous skin diseases was obtained. Based on previous hospital records and patient history, data were recorded regarding previous acid-reducing surgery, surgical explorations, prior imaging, or any previous surgeries with regard to possible MEN1-related skin findings (lipomas, etc.).

During the initial admission to the study as well as on subsequent follow-up visits, all patients underwent laboratory testing, including routine biochemical and hematological studies as well as serum hormone assays to assess the presence of MEN1 (5, 9). The MEN1-related laboratory studies included measurement of serum PTH (both intact and mid-molecule), prolactin, fasting serum gastrin, calcium (ionized and total), thyroid function tests, including TSH, proinsulin, insulin, and simultaneous glucose, GH, glucagon, ACTH, cortisol, chromogranin A, pancreatic polypeptide, albumin, and urinary cortisol. All patients also had gastric acid analysis at the initial visit and on periodic visits if they had ZES (28, 29, 35). For diagnosis of ZES, serum gastrin was measured on 3 separate days, and a secretin provocative test was performed (28, 30). To define the extent of PETs, all patients had abdominal imaging that included CT scanning with iv contrast, magnetic resonance imaging (MRI), ultrasound, and selective abdominal arteriography if the results were not clear (26, 34, 36). Somatostatin receptor scintigraphy was performed routinely by injection of 6 mCi [111In-DTPA-DPhe1]octreotide, followed by obtaining whole body and single photon emission computed tomography (CT) images as described previously (34). All patients also had a chest CT scan and an MRI or CT scan of the sella turcica (when MRI was not available or contraindicated) on the initial visit and on subsequent visits if they had a diagnosis of MEN1. The criteria for surgical exploration were described previously (26, 33, 37) and included all patients with ZES without MEN1 and all patients with ZES and MEN1 who had lesions greater than 2.5 cm on imaging with no evidence of diffuse liver metastases and without an accompanying illness that limited life expectancy or increased surgical risk.

The time of onset of ZES was determined as the time when the first symptoms of gastric acid hypersecretion were noted as described previously (29, 38). The time of onset of MEN1 was recorded as the time of the first symptom of hormone excess (including nephrolithiasis, pituitary disease, and symptomatic PET), detection of PET, or detection of an abnormal laboratory value compatible with endocrine hyperfunction found in an asymptomatic patient with known family history of MEN1 (5, 9, 20). The time of diagnosis of ZES, MEN1, or HPT was determined as the time of confirmation at the initial visit or the time of first diagnosis at an outside institution (5, 9, 20). Accordingly, the duration of the disease was determined as the time of onset until the end of the study.

The dermatology evaluation was performed by experienced dermatologists familiar with MEN1 dermatological lesions from previous investigations (17, 39, 40). The dermatologists had no information about the MEN1 status of the patients before or at the time of the dermatological examination and therefore were blinded to the MEN1 status. All patients underwent a thorough skin evaluation. As described previously (17), the clinical criteria for diagnosis of angiofibroma was a papular lesion, usually localized in midface, appearing telangiectatic, and skin-colored to pink or light brown (Fig. 1Go). A collagenoma was a raised dome-shaped papule of firm skin colored to hypopigmented mostly in the neck, torso, and back area (17) (Fig. 1Go). Biopsies of the lesions were performed if identification was not clear, but were not required for the diagnosis.



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  		FIG. 1. Multiple facial angiofibromas (top panel) and multiple collagenomas (bottom panel) in two patients with MEN1 and ZES.

 
Statistical analysis

All data were entered into an Excel spreadsheet and analyzed using either StatView (SAS Institute, Inc., Cary, NC) or Statistica MAC (Statsoft, Tulsa, OK) software programs. Continuous variables were compared using the Mann-Whitney U test or unpaired t test. Descriptive statistics were also performed on all of those variables. Discontinuous variables were measured using the Fisher exact test or the {chi}2 test. P < 0.05 was considered significant. Results were reported as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
General characteristics of the patients in the study (Table 1Go)

One hundred and ten consecutive patients with a possible diagnosis of ZES were entered into the study. This included 48 patients found to have MEN1 and 62 patients with sporadic ZES (Table 1Go). One hundred and three (94%) were subsequently proven to have ZES. The patients with MEN1 were younger than those with sporadic ZES (48.6 ± 1.8 vs. 59.8 ± 1.4 yr; P < 0.0001) and contained a smaller proportion of males (35% vs. 55%; P < 0.05). The two groups both had a long duration of ZES from onset at the time of the study (17–18 yr), long duration since gastrinoma resection (9–10 yr), high basal acid output (38–46 mEq/h), and low frequency of patients with previous gastric acid-reducing surgery (2–4%). Fasting gastrin levels were significantly higher in the patients with MEN1 (median, 820 vs. 540 pg/ml; P < 0.01); patients with MEN1 were also less likely to have ZES (85% vs. 100%; P < 0.01) and, because of the selection criteria for surgery, were less likely to have had a previous resection of a PET (52% vs. 94%; P < 0.0001). Although the frequency of metastatic disease in the liver (11–13%) was similar in the two groups of patients, patients with MEN1 as a group were less likely to have a PET not localized (15% vs. 0%; P < 0.01; Table 1Go).


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  		TABLE 1. General characteristics of patients with MEN1 and sporadic pancreatic endocrine tumors studied

 
MEN1-related features in patients with MEN1

In the 48 patients found to have MEN1, the age of onset of symptoms of MEN1 was 31.1 ± 1.4 yr, similar to the mean age of onset of ZES of 31.7 ± 1.4 yr (Table 2Go). The diagnosis of MEN1 lagged, on the average, 5 yr after onset of MEN1 symptoms (36.2 ± 1.7 yr), and the diagnosis of PET occurred even later, at a mean age of 37 ± 1.4 yr. The total duration of MEN1 at the time of the study varied from 1–40 yr, with a mean of 18.2 ± 1.5 yr. The most frequent manifestation of MEN1 was HPT (98%), and 90% of the patients had undergone parathyroidectomy. Thirty-eight percent of these patients had pituitary disease, and 95% had a PET. All patients with PET had ZES, and 25% of them had either thymic or gastric carcinoids. A family history of MEN1 was obtained in 77% of the patients found to have MEN1.


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  		TABLE 2. Characteristics of disease in patients with MEN1 studied

 
Cutaneous findings in all patients in the study (Tables 3Go and 4Go and Figs. 1–3GoGoGo)

The frequency of specific cutaneous findings in patients with or without MEN1 are compared in Table 3Go. Angiofibromas were found in 64% of the MEN1 patients, which was significantly higher (P = 0.00001) than the 8% of patients with sporadic ZES with angiofibromas (Table 3Go). Whereas the frequency of finding three or fewer angiofibromas was comparable in each patient group (8–15%), only patients with MEN1 had a large number of angiofibromas (more than three per patient; 50% vs. 0%; P < 0.00001). A typical finding in a patient with MEN1 with multiple facial angiofibromas is shown in Fig. 1Go (top panel). Collagenomas occurred in both groups of patients, but were much more frequent in patients with MEN1 (62% vs. 5%; P < 0.00001; Table 3Go). A typical finding in a patient with MEN1 with multiple collagenomas is shown in Fig. 1Go (bottom panel). The frequency of multiple collagenomas also differed in the two groups. Whereas the MEN1 patients had a slight increase in the frequency of a small number of collagenomas (three or fewer per patient) over the sporadic patients (10% vs. 2%; P = 0.045), the finding of a large number of collagenomas (more than three per patient) occurred almost entirely in the MEN1 patients (52% vs. 3%; P < 0.00001; Table 3Go). Lipomas and melanomas are also reported to occur in patients with MEN1 (1, 4, 7, 8, 15, 16, 41, 42, 43), but neither of these was more frequent in patients with MEN1 than in those without MEN1 in our study (Table 3Go). Other cutaneous findings, including café-au-lait macules or gingival hyperplasia reported previously in some MEN1 series (17), also did not have an increased frequency in the MEN1 patients (Table 3Go). Common cutaneous findings, such as atypical nevi, basal cell carcinoma, squamous cell carcinoma or achrocodons, were not more frequent in patients with MEN1 (Table 3Go).


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  		TABLE 3. Comparison of cutaneous findings in patients with or without MEN1

 

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  		TABLE 4. Evaluation of different cutaneous criteria for diagnosis of MEN1

 


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  		FIG. 2. Comparison of the ages of patients with ZES and MEN1 with or without various cutaneous manifestations of MEN1. Each dot represents results from one patient. The mean ± 1 SEM is shown.

 


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  		FIG. 3. Comparison of MEN1 disease duration in patients with MEN1 and ZES with or without various cutaneous manifestations of MEN1. Each dot represents results from one patient. The duration was calculated from the onset of MEN1, determined as described in Patients and Methods, to the time of the study. The mean ± 1 SEM are shown.

 
To further define the potential discriminatory value for recognizing MEN1 of each cutaneous finding, the sensitivity and specificity of the various cutaneous findings, either alone or in combination, for identifying patients with MEN1 were determined (Table 4Go). The criterion for the presence of any angiofibroma and the criterion for the presence of any collagenoma had similar sensitivities (63–65%) and specificities (92–95%) for identifying MEN1 patients (Table 4Go). The requirement for more than three angiofibromas or collagenomas decreased the sensitivity (50–52%); however, it increased the specificity (97–100%; Table 4Go). The presence of any lipoma or more than three lipomas had a very low sensitivity (2–17%; Table 4Go), but a relatively high specificity (84–100%; Table 4Go). The criterion for the presence of café-au-lait spots and the criterion for the presence of gingival hyperplasia both had low sensitivities (4–8%) for identifying patients with MEN1 (Table 4Go). To improve the combination of sensitivity and specificity, various combinations of cutaneous findings were assessed (Table 4Go).

Each of the combinations of criteria for angiofibroma or collagenoma requiring any of these present or more than three had relatively high sensitivity (67–81%) and specificity (87–97%) for identifying patients with MEN1 (Table 4Go). However, combination criteria requiring the presence of angiofibroma and collagenoma(s), collagenoma and lipoma, or angiofibroma and lipoma had low sensitivities (2–46%), although they maintained high specificities (89–100%) (Table 4Go). Of these criteria, the criterion for the presence of more than three angiofibromas or any collagenoma had the highest combination of sensitivity (75%) and specificity (95%) and was designated the best NIH cutaneous MEN1 criterion to use for further comparisons.

To investigate the affect of patient age or MEN1 disease duration on the presence or absence of specific cutaneous findings, these variables were compared in patients with or without the various skin lesions in MEN1 patients (Figs. 2Go and 3Go). Neither patient age (Fig. 2Go) nor MEN1 disease duration (Fig. 3Go) differed in MEN1 patients with or without more than three angiofibromas, any collagenoma, or lipoma. In contrast, patients with any angiofibroma present were significantly younger than those without an angiofibroma (45.6 ± 1.6 vs. 54 ± 4; P = 0.030); however, patients with or without angiofibroma did not differ in MEN1 disease duration (Fig. 3Go).

MEN1 characteristics in patients with or without the best NIH cutaneous criterion for MEN1 (Table 5Go and Fig. 4Go)

The best NIH cutaneous MEN1 criteria [highest sensitivity and specificity (presence of more than three angiofibromas or any collagenoma); Table 4Go] was met by 36 patients with MEN1 and was not present in 12 patients with MEN1 (Table 5Go). The presence or absence of this criterion was influenced by the patient’s age, because 53% of the patients meeting this criterion were 50 yr of age or older, whereas only 17% without the criterion were 50 yr or older (P = 0.02). Although the mean age of patients meeting the best NIH cutaneous MEN1 criterion tended to be older than patients not meeting this criterion, this difference for all patients was not significant (50.1 ± 1.9 vs. 44.0 ± 4.3; P = 0.14; Fig. 4Go). There was no difference between patients meeting the best NIH cutaneous MEN1 criterion and those without it in gender, presence of other MEN1-related diseases (including HPT, pituitary disease, and PETs), fasting serum gastrin levels in patients with ZES, or basal acid output in patients with ZES (Table 5Go). Also, neither the duration of the HPT nor the frequency of a family history of MEN1 was a significant factor in determining whether the criterion was fulfilled (Table 5Go).


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  		TABLE 5. Comparison of characteristics of MEN1 patients with or without the best NIH cutaneous criterion for diagnosis of MEN1

 


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  		FIG. 4. Comparison of age in patients with MEN1 and ZES with or without the most sensitive and specific NIH MEN1 dermatological criterion. The MEN1 dermatological criterion used was the presence of more than three angiofibromas or any collagenoma, which was the criterion with the highest sensitivity and specificity for MEN1 found in our study (see Table 4Go). Each dot represents results from a single patient. The mean ± 1 SEM of each subgroup is shown.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The purpose of the study was to determine whether dermatological assessment of patients with PETs might be useful in diagnosing MEN1 and, if so, to develop criteria with the best sensitivity and specificity. This study was undertaken for a number of reasons. First, a significant proportion of patients with gastrinomas (18–48%), insulinomas (1–10%), glucagonomas (1–20%), and other PETs (6–45%) have MEN1 (1, 5, 29, 44), and it is important to recognize these patients because they differ from patients with sporadic disease in treatment approaches, occurrence of other endocrinopathies requiring treatment, need for family screening, and natural history (5, 44, 45). Second, in some series, up to 45% of the patients with MEN1 present with PET, and other MEN1 clinical manifestations, such as HPT, may be either absent or difficult to detect (5), so MEN1 may not be suspected. Third, genetic tests for MEN1 are expensive, and they are negative in 10–20% of patients with familial MEN1 and in a greater proportion of patients with MEN1 with a negative family history (5). Fourth, 23–58% of patients with gastrinomas with MEN1 have no family or personal history suggestive of MEN1, and thus only biochemical, clinical, or genetic tests will detect the MEN1 (5, 46). Therefore, a clinical screening test, such as a positive dermatological study, suggesting MEN1 would be very useful.

In the present study dermatological findings were studied because in 1997 it was reported (17) in 32 patients with MEN1 that facial angiofibromas were found in 88%, collagenomas were found in 72%, café-au-lait spots were present in 38%, lipomas occurred in 34%, and confetti-like hypopigmented macules were present in 6%. In greater than 50% of the patients five or more facial angiofibromas were found, which was a relatively specific finding, having been previously described only in tuberous sclerosis, leading the researchers to propose that dermatological screening might be useful to assess the presence of MEN1 (17). Subsequently, the angiofibromas were shown to be an intrinsic MEN1 tumor with loss of heterozygosity at the MEN1 11q13 locus in some (39, 40), but not all (16), studies, demonstrating that loss of function of the MEN1 gene probably plays a role in their development. In subsequent studies, angiofibromas were reported in 43% of 28 Japanese patients with MEN1 by Sakurai et al. (47), 5% of 43 MEN1 patients by Kouvaraki et al. (48), and 7.6% of 26 MEN1 patients from Portugal by Cavaco et al. (49). In our study we confirm that angiofibromas are a frequent finding in MEN1 patients; they were detected in 64% of our patients. Furthermore, similar to the original 1997 study by Darling et al. (17), but in contrast to a recent Japanese study (47), we found that the majority of MEN1 patients with angiofibroma had multiple angiofibromas. Specifically, we found that 77% (24 of 31) of MEN1 patients with any angiofibroma possessed more than three angiofibromas, which is greater than the 33% reported by Sakurai et al. (47), but similar to the 57% of MEN1 patients possessing more than four angiofibromas originally reported by Darling et al. (17). At present, the basis for the marked difference in frequency, varying from 5–88% of patients with MEN1 having angiofibromas in the five different series (17, 47, 48), is unclear. In one study (17) there was a significant association of angiofibromas with older age in patients with MEN1 (P = 0.02); however, this was not found in a second study (47). It is unlikely that differences in patient age accounted for the marked difference in frequency of angiofibromas, because the mean age was similar in the different studies, being 39 ± 14 yr (17), 43 ± 17 yr (47), 36 ± 17 yr (49), and 48 ± 12 yr in our study. Furthermore, we did not find an association between the presence of any angiofibroma alone and age in the MEN1 patients. In our study the occurrence of angiofibromas in MEN1 patients, either single or multiple, did not correlate with patient age and, in the presence of multiple angofibromas with any collagenoma, did not correlate with gender, other manifestations of MEN1, family history of MEN1, tumor extent, fasting gastrin levels, or levels of acid hypersecretion. The most likely explanation for the marked difference in frequency in angiofibromas in patients with MEN1 in the different studies is the dermatologists’ familiarity with this lesion, and the thoroughness with which it is sought. This is supported by the finding that both our study and the previous one reporting 88% of MEN1 patients positive for angiofibromas (17) were performed by dermatologists specifically searching for this type of lesion.

Other dermatological lesions, including lipomas (5, 16, 17, 41, 43), collagenomas (17), and melanomas (15), have been reported to occur with increased frequency in patients with MEN1. In the present study we found that collagenomas were also frequent in MEN1 patients, occurring in 63% of patients, which is consistent with the high frequency of 72% reported by Darling et al. (17). Furthermore, we confirmed their report (17) that the collagenomas are usually multiple, with 83% of our MEN1 patients having at least four collagenomas, similar to the 91% reported by Darling et al. (17). In contrast to their finding, we found no correlation with the frequency of occurrence of collagenomas and increasing age. We also found no correlation with disease duration. Lipomas are reported in 3–34% (5, 16, 17, 41, 43) of patients with MEN1, and in the present study we found them in 17% of MEN1 patients. In contrast to the angiofibromas and collagenomas, lipomas were usually single lesions with only 12% of patients having at least four lipomas. Similar to angiofibromas and collagenomas, their presence correlated with neither patient age nor disease duration. Melanomas were reported in two studies of patients with MEN1 (15, 42); and two MEN1 patients had melanomas in our study.

Whereas the occurrence of any angiofibroma or collagenoma had a high specificity for MEN1 patients (92–95%), their sensitivity was only 63–65%. Similarly, the occurrence of any lipoma had a high specificity of 84% for MEN1 patients, but an unacceptably low sensitivity of 17%. The possibility that other criteria involving dermatological findings might be valuable was further explored, because we found single angiofibromas occurred in a small percentage (8%) of patients without MEN1, which reduced the specificity of finding any angiofibromas as a criterion. This result differed from what is generally thought to occur in the literature (17) and reported in a previous study (47) involving 20 Japanese patients with HPT without MEN1 in whom no angiofibromas were reported. However, it was pointed out in that study (47) that solitary angiofibromas can be commonly observed in Caucasians, although their exact frequency in the general population is unclear. There are a number of possible explanations that could be proposed for the finding of single angiofibromas in the non-MEN1 group in our study. First, angiofibromas are known as fibrous papules in the dermatological literature, and it is possible that we have too low of a clinical threshold for their diagnosis, and we should have included histological confirmation of all clinical diagnoses. Biopsies were not routinely performed in this study for two reasons. We wanted to make the dermatological examination as representative as possible of what might occur in a typical clinic and not of what would occur in a rigorous research environment, as occurred in our first study (17) in which biopsies were routinely performed. We believed that biopsies of each suspicious lesion, especially facial lesions, would not be applicable to the typical dermatological clinic. In our first study (17) histological confirmation of the clinical diagnosis of collagenoma or angiofibroma was obtained in more than 95% of the lesions. These results showed our clinical diagnosis had excellent specificity for making the diagnosis of these lesions and also supported the recommendation not to perform routine biopsies. These results also show our clinical threshold for diagnosis of angiofibromas is not inappropriately low. Second, we believe it is unlikely that MEN1 patients were mistakenly included in the non-MEN1 group, accounting for the angiofibromas in this latter group, for a number of reasons. Of the 62 patients without MEN1, zero of 62 (0%) had more than one angiofibroma (i.e. the five positive non-MEN1 patients had only one angiofibroma each). All five of the patients with one angiofibroma without MEN1 had been evaluated yearly for MEN1 over a mean of 9 yr without any other endocrinopathy suggestive of MEN1. All had repeatedly normal (well within normal range) total calcium, ionized calcium, PTH (intact and mid), and other endocrine markers of MEN1. Furthermore, of the five patients with one angiofibroma without MEN1, two have undergone MEN1 gene testing, and each was negative. None of these five patients had any family or personal history suggesting MEN1. Third, an alternative explanation, and the one we favor, for the occurrence of single angiofibromas in the non-MEN1 patients is the statement made in a previous study (47) that angiofibromas can occur in older, normal, healthy subjects, especially in Caucasians. In our experience, one or two angiofibromas on the nose or perinasally in older, healthy individuals is of no consequence and is not infrequent, especially in Caucasians. It is for this reason that we emphasized in our initial study (17) the importance of multiple angiofibromas. Multiple lesions, especially in younger individuals, had been considered pathogenomic of tuberous sclerosis. We were the first to notice that multiple (more than three) such lesions could also be linked to MEN1 (17). Whereas the criterion of either multiple angiofibromas (more than three) or collagenomas (more than three) had excellent specificity (97–100%), each had a lower sensitivity (50–52%). To identify a dermatological criterion with higher sensitivity and specificity, combinations of the occurrence of angiofibromas, collagenomas, and lipomas [either single or multiple (more than three)] were analyzed for each statistical parameter. The combination of multiple angiofibromas (more than three) and any collagenoma had a relative high sensitivity (75%) and excellent specificity (95%) and was identified as the best criterion. This criterion has a greater sensitivity than the occurrence of pituitary disease in MEN1 patients with PETs in four studies [28% (11), 32% (50), 32% (5), and 60% (5)]. It is also similar to the frequency of detecting HPT at presentation of gastrinomas in some studies [78% (11) and 79% (9)] of patients with MEN1, but lower than that reported in other studies [88–91% (5, 50)]. This criterion also has a greater sensitivity than the occurrence of adrenal tumor for suggesting the presence of MEN1, which is present in 11–45% of patients with PETs in various studies (5, 18, 51). These findings suggest that the dermatological criterion identified has sufficient sensitivity and specificity to be generally useful for suggesting the diagnosis of MEN1 in a patient with a PET syndrome. These results support the proposal (17) that dermatological examinations should be part of the initial evaluation of patients with PETs to identify which patients have MEN1.


   Footnotes
 
Abbreviations: CT, Computed tomography; HPT, hyperparathyroidism; MEN1, multiple endocrine neoplasm type 1; MRI, magnetic resonance imaging; PET, pancreatic endocrine tumor; ZES, Zollinger-Ellison syndrome.

Received February 6, 2004.

Accepted July 26, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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