Virilizing Adrenocortical Adenoma with Cushing’s Syndrome, Thyroid Papillary Carcinoma and Hypergastrinemia in a Middle-Aged Woman
AYUMI FUKUSHIMA, YOSUKE OKADA, TAKAHISA TANIKAWA, CHIE KAWAHARA, HARUO MISAWA, KAZUKO KANDA, EMIKO MORITA, HIRONOBU SASANO* AND YOSHIYA TANAKA
First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, School of Medicine, Kitakyushu 807-8555, Japan
*Second Department of Pathology, Tohoku University, Sendai, Japan
Abstract. We report a rare case of virilizing adrenocortical adenoma complicated with Cushing’s syndrome, thyroid papillary carcinoma and hypergastrinemia. A 45-year-old woman had a history of amenorrhea for 10 years, hypertension for 8 years, and diabetes mellitus for 3 years. Physical examination showed a masculinized woman with severe hirsutism, male-like baldness, deep voice, acne in the precordia, and clitorism. Plasma testosterone, DHEA-S and urinary 17-KS were high, and plasma cortisol level was it at the upper limit of the normal range, but it did not show a diurnal rhythm nor was suppressed by 2 and 8 mg of dexamethasone. Abdominal CT scan showed a left adrenal tumor (4.5 cm in size). Adrenal scintigram revealed uptake of the tracer on the left side, and plasma cortisol concentration was high in a blood sample from the left adrenal vein. Left adrenalectomy was performed. Histopathological features of resected adrenal tumor were consistent with those of adrenocortical adenoma, consisting of tumor cells with eosinophilic compact cytoplasm. Immunohistochemical staining for steroidogenic enzymes showed reactivity for P450scc, 3 beta-HSD, P450c17, P450c21 and P450c11. Plasma testosterone and cortisol levels decreased to the normal range postoperatively. The patient was also found to have a papillary thyroid carcinoma and hypergastrinemia. Our patient is a rare case of virilizing adrenocortical adenoma associated with Cushing’s syndrome, thyroid papillary carcinoma, and hypergastrinemia.
Key words: Virilizing adrenocortical tumor, Thyroid papillary carcinoma, Hypergastrinemia, Multiple endocrine neoplasia (Endocrine Journal 50: 179-187, 2003)
VIRILIZING adrenocortical tumors are classified into benign adenomas and carcinomas. The latter type is commonly observed in children, but adenoma and cancer are almost equally seen in adult women. Al- though about 100 cases of virilizing adrenocortical tu- mor have been reported in the past 30 years in Japan, 80% of the reported cases were children, and virilizing adrenocortical tumor seems to be rare in middle-aged women [1, 2]. Here we report a middle-aged woman
with virilizing adrenocortical adenoma complicated with Cushing’s syndrome, thyroid papillary carcinoma and hypergastrinemia. To our knowledge, such a com- plex combination of endocrine diseases is the first in a Japanese patient.
Case Report
A 45-year-old woman started to notice extensive hirsutism and secondary amenorrhea at the age of 35 years. At 37 years of age, she was found to be hypertensive and prescribed anti-hypertensive agents. Five years later, she was diagnosed with diabetes mel- litus and subsequently treated 2 years later with insu- lin. Endocrinological examination performed in the
local hospital at the age of 45 years showed elevated urinary 17-KS and dehydroepiandrosterone sulfate (DHEA-S). Abdominal computed tomography (CT) revealed a left adrenal tumor. In November 1995, the patient was admitted to our hospital for further man- agement of the clinical symptoms and left adrenal tu- mor.
Body height was 160 cm and weight 55.2 kg. Phys- ical examination on admission showed a typical mas- culinized woman, with extensive hirsutism (Fig. 1), male-like baldness, deep voice, acne in the precordia, and clitorism. In addition, diffuse goiter and a hard mobile mass (1 cm in size) were identified in the left thyroid lobe. However, she had no pathognomonic
C
symptoms of Cushing’s syndrome, such as moon face, buffalo hump, and central obesity. Examination of the abdomen and extremities was negative as was neurological examination. Arterial blood pressure was 128/90 mmHg while on antihypertensive agents (amlodipine besilate 2.5 mg/day). Laboratory findings are listed in Table 1: urine glucose, 3+; hemoglobin, 18.2 g/dl; and hematocrit, 53.3%. The white blood cell count was 7,800/mm3 and platelet count was 17.7 × 104/mm3. Serum electrolytes were Na 142 mEq/1; K 4.2 mEq/l; Cl 101 mEq/l. Renal and liver functions were normal. Plasma total cholesterol was 230 mg/dl and triglyceride was 165 mg/dl. Fasting blood glucose was 127 mg/dl and HbAlc was high at 9.3%. Urine C-peptide was 101.9 µg/day and insulin resistance was suspected.
Endocrinological examinations
The following endocrinological examinations were undertaken while the patient was on 7 g/day of NaCl diet without antihypertensive agent. Basal hormonal levels are shown in Table 2. Plasma concentrations of testosterone and DHEA-S were high. Plasma cortisol level was at the upper limit of the normal range. Plas- ma cortisol did not exhibit a diurnal rhythm and ACTH was low. Urinary 17-KS was high and urinary 17-OHCS was slightly above the normal range. Serum free T3 and free T4 were normal and serum TSH was slightly low. Microsomal test was positive. HTG (hu- man thyroglobulin) and adrenomedullary hormones
| Urine | pH 5.5, protein (-), | Biochemistry | BUN | 22 mg/dl | |
|---|---|---|---|---|---|
| glucose (3+), | Cre | 0.4 mg/dl | |||
| ketone (-), O.B (-) | Na | 142 mEq/l | |||
| Complete blood count | WBC | 7800/μl | K | 4.2 mEq/1 | |
| RBC | 540x104/μl | CI | 101 mEq/l | ||
| Hb | 18.2 g/dl | Ca | 9.4 mg/dl | ||
| HT | 53.3% | IP | 3.8 mg/dl | ||
| Plt | 17.7x104/μl | UA | 4.0 mg/dl | ||
| Serology Biochemistry | CRP | 0.1 mg/dl | TTT | 1.4 KU | |
| TP | 6.6 g/dl | ZTT | 1.7 KU | ||
| Alb | 4.1 g/dl | Glu | 127 mg/dl | ||
| T-bil | 0.6 mg/dl | T-cho | 230 mg/dl | ||
| AST | 24 IU/1 | TG | 165 mg/dl | ||
| ALT | 36 IU/1 | Amy | 114 IU/1 | ||
| LDH | 256 IU/1 | Urine-Biochemistry | HbAlc | 9.3% | |
| ALP | 444 IU/1 | U-CRP | 101.9 µg/day | ||
| Y-GTP | 74 IU/1 |
| preoperative | normal range | preoperative | postoperative | normal range | ||
|---|---|---|---|---|---|---|
| TSH (uU/ml) | 0.12 | 0.34-6.50 | ACTH (pg/ml) | 6.9 | 5.7 | 4.4-48.0 |
| fT3 (pg/ml) | 3.00 | 2.47-4.34 | Aldosterone (pg/ml) | 3.4 | 13.0 | 35.7-240 |
| fT4 (ng/dl) | 1.10 | 0.97-1.79 | Cortisol (µg/dl) | 1 | ||
| Thyroid test | <100 | <100 | (5:00) | 11.2 | 6.4 | 2.7-15.5 |
| Microsome test | ×400 | <100 | (13:00) | 11.6 | n.d. | |
| HTG (ng/ml) | 26 | 0-30 | (21:00) | 10.8 | n.d. | |
| LH (mIU/ml) | <0.5 | 17-OHCS (mg/day) | 10.8 | 21.4 | 2.3-7.8 | |
| FSH (mIU/ml) | 3.4 | 17-KS (mg/day) | 35.1 | 15.7 | 4-8 | |
| PRL (ng/ml) | 13.0 | 4.6-24.5 | Testosterone (ng/dl) | 146.0 | <5.0 | 10-60 |
| GH (ng/ml) | 1.0 | 0.6-3.7 | DHEA-S (ng/ml) | 2850 | n.d. | 400-1500 |
| Calcitonin (pg/ml) | 14.9 | Estradiol (pg/ml) | 28.0 | n.d. | 0-2.5 | |
| Adrenaline (pg/ml) | 6 | <100 | Gastrin (pg/ml) | 1390.0 | 1070 | 30-150 |
| Noradrenaline (pg/ml) | 103 | 100-450 | Glucagon (pg/ml) | 125.0 | n.d. | 40-140 |
| Dopamine (pg/ml) | <5.0 | <20 | ||||
| U-VMA (mg/day) | 4.68 | 2-8 |
Operation: Lt. adrenalectomy, Resection of the pancreatic tumor, Resection of the left thyroid lobe
were normal. Plasma level of LH was below the de- tection limit, and LH/FSH ratio was very low. Serum gastrin level was markedly high.
Administration of dexamethasone, at 2 or 8 mg, failed to suppress plasma cortisol, plasma testosterone, urine 17-OHCS, and urine 17-KS (Table 3). It was noted that although HCG (human chorionic gonado- tropin) test was very important for diagnosis, it could result in ovarian hyperstimulation. Thus after obtaining an informed consent, we conducted the HCG loading test as follows; after a bolus intramuscular injection of 3000 units of HCG for three days, blood samples were obtained at 0, 48, and 96 hours for measurements of plasma testosterone and urinary 17-KS. Although both of these parameters were markedly high at 0 hours, testosterone level was more elevated at 96 hours (Table 3). Plasma levels of TSH, PRL, and GH showed almost normal response to intravenous admin- istration of TRH and GRH. Although plasma level of testosterone was high, plasma levels of LH and FSH showed almost normal response to LH-RH test. We suspected that estradiol (E2) did not suppress the re- sponse to LH-RH test. Intravenous administration of CRH did not affect ACTH level and the plasma corti- sol level remained high (Fig. 2). Secretin loading test demonstrated no gastrin response (Table 3).
Ultrasonography and CT showed a large mass meas- uring 4.5 × 4.6 cm in diameter in the left adrenal gland area (Fig. 3a). No ovarian cysts were found by ultrasonography. An adrenocortical scintigram with
| Dexamethasone suppression test | 2 mg | 8 mg |
|---|---|---|
| ACTH (pg/ml) | 4.1 | <4.0 |
| Cortisol (µg/dl) | 15.8 | 14.6 |
| Testosterone (ng/dl) | 224 | 163 |
| Urine 17-OHCS (mg/day) | 12.1 | 15 |
| Urine 17-KS (mg/day) | 32.1 | 44.8 |
| HCG loading test | Baseline | 48 hr | 96 hr |
|---|---|---|---|
| Testosterone (ng/dl) | 146 | 115 | 246 |
| Cortisol (ug/dl) | 17.7 | 17.4 | 19.8 |
| Urine-17-KS (mg/day) | 37.5 | 25.8 | 28.1 |
| Hormonal assay using blood samples from the left adrenal vein | Cortisol (ug/dl) | Aldosterone (pg/ml) |
|---|---|---|
| Left adrenal vein | 68.1 | 950.0 |
| Inferior vena cava | 16.7 | 88.0 |
| Secretin loading test | Time (min) | |||
|---|---|---|---|---|
| 0 | 2 | 5 | 10 | |
| Gastrin (ng/ml) | 832 | 819 | 801 | 805 |
131I-adsterol revealed a greater uptake of the tracer on the left side (Fig. 3b). Magnetic resonance imaging (MRI) of the left adrenal tumor showed a low signal- intensity on T1-weighted, slightly higher intensity than in the liver on T2-weighted and Gd-DTPA enhanced MRI revealed homogeneous enhancement of the left
(a)
(b)
GH (ng/ml)
LH . FSH (mIU/ml)
10
50
8
40
6
30
4
20
2
10
0
0
-15
0
15
30
60
90
120
(min)
-15
0
15
30
60
90
120
(min)
(c)
(d)
PRL (ng/ml)
TSH ( _ U/ml)
ACTH (pg/ml)
Cortisol ( 4 g/dl)
100
10
100
30
80
8
80
25
60
6
60
20
15
40
4
40
10
20
2
20
5
.
0
0
0
0
-15
0
15
30
60
90
120 (min)
-15
0
15
30
60
90
120 (min)
Fig. 2. (a) GRH test (GH
). (b) LH-RH test (FSH
,
LH
(c) TRH test (PRL
,
TSH
ACTH
)
).
(d) CRH test (cortisol
,
adrenal tumor. Digital angiography revealed a hyper- vascular mass in the left adrenal gland (Fig. 4). Right adrenal venous sampling was unsuccessful because of the difficulties in insertion of the catheter into the right adrenal vein. Although blood sample could not be ob- tained from the right adrenal venous sampling, plasma cortisol levels in the left adrenal vein were higher than that in the junction of inferior vena cava (IVC) and right adrenal vein (left: 68.1 µg/dl, IVC: 16.7 µg/dl). Both ultrasonography and abdominal CT detected a 1.0 × 1.0 cm mass on the tail of the pancreas, but digi- tal angiography revealed no hypervascular staining. Thyroid ultrasonography revealed a mass measuring 1.8 cm with calcification. 201Thallium scintigram dem- onstrated an intense uptake at the same region (Fig. 5) and aspiration biopsy cytology from the thyroid mass was class IV with a pathological diagnosis of papillary adenocarcinoma. Gastroscopy showed only atrophic gastritis and no ulcers. Brain MRI revealed no abnor- mality in the pituitary gland.
Pathological findings
Based on the clinical features and results of endo- crinological assays and radiological surveys, the pro- visional diagnosis was a left functional adrenocortical adenoma secreting androgen and cortisol. The mass was resected surgically in December 1995 via a transverse abdominal incision. The tumor was well- encapsulated without any invasion into the surrounding tissue, and could be easily removed from the abdomi- nal lumen. The resected tumor appeared yellowish brown on the cut surface, measured 4.5 x 3.7 x 2.5 cm in size and weighed 170 g. No areas of necrosis or hemorrhage were detected on the cut surface. Histo- pathologically, the well-circumscribed tumor was composed of a proliferation of a mixture of compact epithelial cells with eosinophilic granular cytoplasm and large cells with a foamy appearance arranged in sheets or trabeculae, occasionally associated with some pleomorphic cells (Fig. 6a). Neither extension beyond the adrenal capsule nor mitotic figures of the nuclei were detected. No foci of metastasis were de-
(b)
952481
1 L
POST
R
045Y FEMALE
Adrenalis Oct. 5.1995 11:19
(a)
1311-Adsterol 18.50Mq
H.E.G.P
Im : 10 +C
512
1.22 c
DFOV 32.0cm
300000
STND/P
0h24m17s
(0.0) 512x512
Black&White Linear
MU=IS W .= 0 (0-100%)
Chikuhou Rousai
GCA-901A/HG
POST IV 3 Days
952481
1 L
POST
R
045Y FEMALE
Adrenalis
Oct. 9.1995 10:47
R
L
1311-Msterol 18.50MB4
H.E.G.P
kV 120
1.2 C
200164
0h29-21s
(0.0) 512x512
Black&White Linear
WU=15
WL-0 (0-100%)
Chikuhou Rousal
GCA-901A/HG
POST IV 7 Days
tected in adjacent lymph nodes. There was no evi- dence of adrenocortical malignancy based on the criteria of Weiss [3, 4]. Immunohistochemical analy-
1-14-95
_201CL
74
512 .512
MBq
508595-7
DOM X= 1.00 Y= 1.00
AX =9
De
K
SEC
CL 18
2 100
1
sis demonstrated that the tumor cells markedly ex- pressed P450scc, 3ß-hydroxysteroid dehydrogenase (3-HSD), P450c21, P450c17 (Fig.6b), and P450c11.
(a)
(b1)
(b2)
(b3)
(b4)
(b5)
(a)
(b)
On the other hand, a pathological study of the pancre- atic tumor revealed no evidence of neoplastic lesion or of malignancy (Fig. 7a). The partially calcified mass (2.0 × 1.5 cm) on the inferior part of the left thyroid lobe was also detected at surgery. A pathological
study of thyroid tumor revealed papillary adenocarci- noma with lymphatic permeation, associated with psammoma bodies, invading the adjacent thyroid glands (Fig. 7b).
Clinical course
Following left adrenalectomy, the patient received hydrocortisone (40 mg). One week after the operation, urinary 17-KS was 15.7 mg/day, but 3 days later it de- creased to 5.0 mg/day. Plasma testosterone and corti- sol were also diminished to 5.0 ng/dl and 6.4 µg/dl, respectively, but regrettably DHEA-S was not meas- ured. Furthermore, one month after the operation, menstruation returned to normal and plasma glucose control and blood pressure control improved. Two months after the operation, she did not require anti- hypertensive agents or insulin. One year after the operation, plasma testosterone and cortisol levels were still normal (12.1 ng/dl and 2.4 µg/dl, respectively). The replacement therapy was tapered off gradually and there was no need for treatment with hydrocortisone three years later. Furthermore, no metastasis has been detected until the writing of this report. Although plasma gastrin slightly decreased after the operation, it remained at high level.
Discussion
We reported a 45-year-old woman who presented with hirsutism and was found to have virilizing adrenocortical adenoma complicated with Cushing’s syndrome, thyroid papillary carcinoma, and hyper- gastrinemia. Ross and Aron [5] reported the incidental detection of adrenal mass in 2% of patients undergoing CT of the upper abdomen. Shimazaki et al. [6] report- ed 374 Japanese patients with adrenocortical tumors and that 68 (18%) of the tumors resulted in virilization. Virilizing adrenal tumors predominantly occur in child- hood, as 51 (75%) of the above cases were reported in children aged 10 years or less. However, in our patient, virilization-related clinical features became evident at the age of 35 years.
The most common causes of high androgen levels in adult women are polycystic ovary syndrome (POS) (75%), idiopathic hirsutism (15%), and congenital ad- renal hyperplasia with 21-hydroxylase deficiency (3%) [7]. Other causes include Cushing’s syndrome, hyper- prolactinemic, ovarian tumor, hormonal therapy with androgen, and virilizing adrenal tumor [8]. Our patient showed a positive testosterone response to HCG in the HCG loading test, which was suggestive of an ovarian tumor. However, there were no abnormal findings re-
lated to ovarian tumors. In this regard, Werk et al. [9] reported that a small adrenal adenoma in woman can secrete testosterone and that such nodules are often re- sponsive to gonadotropin. Previous studies considered the adrenal gland and ovary to share a common geneal- ogy [10]. The differential diagnosis in our case also included ovarian thecal metaplasia but this condition is more common in the adrenal glands of postmenopaus- al women [11] but no associated clinical signs and symptoms were evident. POS was ruled out due to the very low plasma basal LH/FSH ratio, lack of excessive response to intravenous administration of LH-RH, and failure to detect any ovarian cysts by ultrasonogra- phy. Based on a myriad of clinical features, hormonal assays, radiological workup and laboratory tests, the case was diagnosed as left virilizing adrenocortical tu- mor but no ovarian growth.
Virilizing adrenal tumors are associated with high levels of plasma DHEA and DHEA-S in almost all cases, but rarely with testosterone [1, 2]. Furthermore, the urinary 17-KS level is generally normal in a testosterone-secreting adrenal tumor. However, both plasma DHEA-S and testosterone levels were high in our case. We considered that the elevated serum testo- sterone level was due to peripheral conversion. On the other hand, plasma glucocorticoids and their urinary metabolite, 17-OHCS, are not always elevated but are frequently normal [6]. This is because virilizing adre- nal tumors tend to have normal or diminished activi- ties of the enzyme 3ß-hydroxysteroid dehydrogenase- isomerase, 21-hydroxylase and 11-hydroxylase [12- 14]. All these enzymes are indispensable for the syn- theses of glucocorticoids, but not for the synthesis of DHEA or DHEA-S in the adrenal gland. Therefore, only approximately 25% of virilizing adrenocortical tumors has been reported to secrete sufficient levels of glucocorticoids in the circulation to induce Cushing’s syndrome [1]. In our case, the adrenal tumor was con- sidered to independently secrete cortisol in the absence of ACTH, hCG, loss of circadian rhythm of serum cortisol and negative dexamethasone suppression test (8 mg). Therefore, the diagnosis also included Cushing’s syndrome. The pathological findings of the resected specimen confirmed the adrenal origin of the tumor. Plasma adrenal androgen and cortisol levels and their metabolites in the urine returned to normal after surgery, indicating that the tumor itself clearly se- creted adrenal androgens and cortisol into the circula- tion, thereby causing virilization in this patient.
Virilizing adrenocortical tumor is a rare disease in adult women, and complication with Cushing’s syn- drome is even more rare [15, 16]. This patient was diagnosed as having adrenocortical adenoma that secreted androgen and cortisol, which was complicat- ed by thyroid papillary carcinoma, and hypergastri- nemia with atrophic gastritis. With regard to the cause of hypergastrinemia, the question was left whether the pancreatic tumor was producing a functional and secreted gastrin, because the secretin loading test demonstrated no gastrin response and gastrin concentrations remained high. Even after the opera- tion, gastrin levels remained high and never returned to within the normal range. However, gastrin showed a non-regulatory secretion pattern, probably due to the lack of suppression during the secretin loading test in spite of a remarkably high level before secretin load- ing. The finding of atrophic gastritis in our patient might explain the hypergastrinemic state [17].
Cases with neoplasms originating in at least two or more endocrine glands have been known for some time. These cases of endocrinoma are sometimes ex- plained by an autosomal dominant inheritance. Such
endocrine neoplasia syndrome is called multiple endo- crine neoplasia (MEN), and it is classified into MEN type 1, MEN type 2, MEN type 2b or type 3, and sev- eral responsible genes have been identified [18,19,20]. In our case, there was no familial history and she could not be classified under any of these types; the two endo- crinomas detected in the adrenal and thyroid glands were most likely incidental and did not reflect MEN. A thorough diagnostic workup including brain MRI and ultrasonography failed to show any abnormality in the pituitary and parathyroid glands in our case. So it might be a multiple endocrine tumor accidentally complicated with virilizing adrenocortical adenoma, thyroid papillary carcinoma, and hypergastrinemia. However, there is a remote possibility that the case might be a subtype of the MEN type 1 because adreno- cortical tumors are reported to be present in 20% of MEN type 1, associated together with pancreatic tu- mor, or be a new type of multiple endocrine neoplasia.
In conclusion, we reported a very rare and important case of a virilizing adrenocortical adenoma complicat- ed by endocrinoma.
References
1. Yanase T, Nawata S (2001) Virilizing adrenocortical tumors, feminizing adrenocortical tumors. Clin Endo- crinol 46: 559-561 (in Japanese).
2. Del Gaudio A, Del Gaudio GA (1993) Virilizing adrenocortical tumors in adult women. Report of 10 patients, 2 of whom each had a tumor secreting only testosterone. Cancer 72: 1997-2003.
3. Weiss LM (1984) Comparable histologic study of 43 metastasizing and nonmetastazing adrenocortical tu- mors. Am J Surg Pathol 18: 163-169.
4. Weiss LM, Mederios LJ, Vickery AL (1989) Patholog- ic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 13: 202-206.
5. Ross NS, Aron DC (1990) Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 323: 1401-1405.
6. Shimazaki J, Ichikawa T, Shiseki Y, Kuramochi H (1993) Statistical review of adrenal cortical carcinoma. Nippon Rinsho 51 (Suppl): 766-782 (in Japanese).
7. Barbieri RL (1990): Hyperandrogenic disorders. Clin Obstet Gynecol 33: 640-654.
8. Lipsett MB, Hertz R, Ross GT (1963) Clinical and pathophysiologic aspects of adrenocortical carcinoma. Am J Med 35: 374.
9. Werk EE, Sholiton LJ, Kalejs L (1973) Testosterone-
secreting adrenal adenoma under gonadotropin control. N Engl J Med 289: 767-770.
10. Goldzieher JW (1968) The interplay of adrenocortical and ovarian function, In: Mack HC(ed) The Ovary. Springfield, IL, Charles C Thomas, 106-130.
11. Wong TW, Warner NE (1971) Ovarian thecal metapla- sia in the adrenal gland. Arch Pathol 92: 319-328.
12. Fukushima DK, Gallagher TF (1963) Steroid produc- tion in “non-functioning” adrenal cortical tumor. J Clin Endocrinol Metab 23: 923.
13. Copeland PM (1983) The incidentally discovered adre- nal mass. Ann Intern Med 98: 940-945.
14. Lee PDK, Winter RJ, Green OC (1985) Virilizing adrenocortical tumors in childhood: Eight cases and a review of the literature. Pediatrics 76: 437-444.
15. Cacciari E, Cicognani A, Pirazzolli P, Paolucci G, Mancini A, Tassinari D, Pascucci MG, Tacconi M (1986) Adrenocortical tumors in children: Our experi- ence with nine cases. Acta Endocrinol 279: 264-274.
16. Salt AT, Savage MO, Grant DB (1992) Growth patterns after surgery for virilizing adrenocortical adenoma. Arch Dis Child 67: 234-236.
17. Huang SM, Lin HH, Wen TY, Hsu YH (2001) Extreme hypergastrinemia caused by atrophic gastritis and Heli- cobacter pylori infection-A case report. Hepatogastro-
enterology 48: 1215-1216.
18. Wells SA Jr, Chi DD, Toshima K, Dehner LP, Coffin CM, Dowton SB, Ivanovich JL, DeBenedetti MK, Dilley WG, Moley JF (1994) Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 220: 237-247.
19. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree
JS, Wang Y, Robe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ (1997) Positional cloning of the gene for multiple endocrine neoplasia- type 1. Science 276: 404-407.
20. Yamashita T, Suzuki S, Yumita W, Ikeno Y, Uehara Y, Minemura K, Sakurai A, Hashizume K (2001) A case of familial isolated hyperparathyroidism with ectopic parahtyroid canser. Endocr J 48: 453-458.