Endocrine Journal 1994, 41(4), 461-466

Cushing 's Disease Associated with Adrenal Myelol ipoma, Adrenal Calcificat ion and

MITsuAKI YOSHIOKA, KATSUYAFUJIMORI, MINAKOWAKASUGI, NoBUYASUYAMAZAKI*, Mizuo KUROKI**, TADASHITSUCHIDA**, HIROsHI SEKI***, MASAOSEKIYA****, ANDTETSURO TAMURA***** Departmentsof Internal Medicine,*Surgery, **Neurosurgery, ***Radiology, and ****pathology, Niigata PrefecturalCentral Hospital, Joetsu 943, and *****Departmentof Neurosurgery, Niigata UniversitySchool of Medicine, Niigata 951, Japan

Abstract. A 51-year-old woman with Cushing's disease associated with adrenal is re- ported. A further characteristic feature was the coexistence of bilateral adrenal calcification and thyroid cancer. Previously several cases of adrenal myelolipoma associated with endocrine dysfunction were reported. The combination of Cushing's disease and adrenal myelolipoma has only been described in two cases of recurrent Cushing's disease but never in an initial occurrence of Cushing's disease. Contin- ued stimulation by excessive adrenocorticotropic hormone (ACTH) not only developed adrenal hyperplasia but also might be involved in the pathogenesis of adrenal myelolipoma.

Key words: Cushing's disease, Adrenal myelolipoma, Adrenal calcification, Thyroid cancer. (Endocrine Journal 41: 461-466,1994)

ADRENAL myelolipoma, being a non-functioning benign tumor consisting of admixtures of fat cells Case Report and hematopoietic tissue, is usually discovered ac- cidentally at because this disease usually In February, 1991, a 51-year-old female was ad- progresses asymptomatically. However, cases di- mitted to our hospital with Cushing's syndrome. agnosed during the lifetime of the patient have in- Hypertension was pointed out in a medical check creased because of the recent advance in imaging in autumn, 1990. On admission, she was 154 cm diagnosis. On the other hand, participation of the tall and weighed 61 kg. Her blood pressure was adrenocorticotropic hormone (ACTH) or cortisol 130/90 mmHg. Cushingoid signs such as moon has received attention as its cause, because some face, central , acne and hirsutism were ob- cases associated with dysfunction of the pituitary- served. A little finger tip sized node was palpable adrenal axis have been reported. in the left lobe of the thyroid gland. Routine ex- In this article, we report a case of Cushing's dis- aminations including urinalysis, peripheral blood, ease associated with adrenal myelolipoma, adrenal biochemistry and electrolytes were within the nor- calcification and thyroid cancer. mal range. Neurological and ophthalmological ex- aminations were normal.

Endocrinological examination Received: December 18, 1993 Accepted: April 15, 1994 Correspondence to: Dr. Mitsuaki YOSHIOKA, Department The blood cortisol value was increased, with the of Internal Medicine, Niigata Prefectural Central Hospital, disappearance of circadian rhythm (0800 h, 17.4 µg/ 3-20 Ootemachi, Joetsu, Niigata 943, Japan dl; 2000 h, 10.1 jig/dl). Overnight dexamethasone 462 YOSHIOKA et al.

suppression test elicited no suppression of cortisol calcification were found in the internal region (Fig. (0800 h, 19.3 µg/dl). The fasting basal ACTH level 1a). Left adrenal gland: A 3 X 2 cm mass lesion was 43.8 pg/ml and its responsiveness to CRH was found, and its edge was slightly uneven. Fine (100 µg: Peptide Institute, Osaka) was exaggerated spotted calcifications were observed in the upper (peak: 210.0 pg/ml). (ACTH was measured with region of the mass. (Fig. 1b). A round low dense an IRMA kit.). The basal 24-h urine 17-OHCS was area was found in the lower region of the mass increased (8.7-11.6 mg/day) and it was completely (Fig. 1c). suppressed by 8 mg dexamethasone administra- CT of the head revealed a low dense area on the tion (1.4 mg/day). Metyrapone administration left side of the pituitary gland, and a further low doubled the urine 17-OHCS (20.2 mg/day). Selec- dense area 4 mm in diameter in its central region tive venous sampling, by means of catheterization after administration of contrast medium (Fig. 2). of the inferior petrosal sinus, revealed that the Magnetic resonance imaging (MRI) on the head blood level of ACTH on the left side was twice as showed that the circumference of the low intensity high as on the right side. The thyroid function was lesion on the left side of the pituitary gland was normal. A 75 g oral glucose tolerance test (OGTT) slightly enhanced after Gd-DTPA. showed a borderline pattern (fasting; 102, 2-h; 138 CT of the revealed an irregular low dense mg/dl). area 1 cm in diameter in the left lobe of the thyroid gland, and a low absorption area 7 mm in diameter Radiological examination also in the isthmus. The class V was diagnosed by aspiration biopsy cytology under echographic ex- Computed tomography (CT) of the abdomen: amination. Right adrenal gland: Slight swell ing and a spotted An I-131 adosterol scintigram revealed enhanced

Fig. 1. a: Enhanced CT scan shows a spotted calcification in the internal region and slight swelling of the right adrenal gland. b: Enhanced CT scan shows fine spotted calcifications in the upper region of the left adrenal gland. c: Enhanced CT scan shows round low dense area in the lower region of the left adrenal gland. CUSHING'S DISEASE AND MYELOLIPOMA 463 uptake in both adrenal glands. The patient was diagnosed as having an ACTH Discussion secreting , left adrenal mass, bi- lateral adrenal calcifications and thyroid carci- The concept of adrenal myelolipoma was clari- noma. Malignancy of the left adrenal mass could fied by Gierke [1] in 1905, and the first case extir- not be ruled out. pated surgically was reported by Dyckman and In May, 1991, total , left adrenal- Freedman [2] in 1957. It is known that this tumor ectomy and biopsy of the right adrenal gland were is endocrinologically non-functional. As to the eti- carried out. In September, 1991, the pituitary tu- ology of this disease, various theories such as the mor was extirpated by a transsphenoidal route. presence of marrow rest during embryonic life and establishment of viable areas of bone mar- row and metaplasia of the adrenal tissue had been proposed, but the latter theory has been mainly Adrenal gland: The left adrenal gland was extir- considered in recent years. Selye and Stone [3] re- pated and found to be 15 X 25 X 50 mm and 11 g ported in 1950 that myelolipoma-like change in the and to have many nodules with a maximum diam- occurred following the administra- eter less than 8 mm on its cut surface (Fig. 3). Jelly- tion of crude anterior pituitary extracts and test- shaped contents 10 mm in diameter were found in osterone in rats. Moreover, Olsson et al. [4] re- the lower region which corresponded to the low ported in 1973 that metaplasia of the adrenal tis- dense area detected by CT. Histologically, the sues might be induced by development of necrotic hyperplasia of the cortex, and nodular lesions due tissues in patients who were subject to chronic ail- to compact-type cells, intermediate-type cells and ments such as malignant diseases and cardiovascu- clear-type cells were found here and there (Fig. 4). Moreover, small calcification foci were found scat- tered in the cortex. An adrenal myelolipoma was diagnosed because the jelly-shaped lesion con- sisted of hematopoietic cells with 3 lines and fatty tissue (Fig. 5). Biopsy of the right adrenal cortical section revealed hyperplasia and a nodular lesion in the adrenal cortex. Pituitary adenoma: Chromophobe adenoma were composed mainly of cells characterized by scant cytoplasm (Fig. 6). Only anti-ACTH anti- body was positively stained by immunohistochem- lstry.

Fig. 3. Gross appearance: The cut surface reveals nodules of varying size, which are yellow and/or dark brown in color. The part of the adrenal myelolipoma already removed Fig. 2. Enhanced CT scan shows small low density area on from the left adrenal gland tissue is the left side of the pituitary gland. indicated in this photo by an arrow. 464 YOSHIOKA et al.

Fig. 4. Microscopical findings show adrenocortical nodular hyperplasia (HE stain, original magnification X 13).

Fig. 5. Pathological specimen shows diffuse fat tissue with myeloid elements. The border of the myelolipoma is well defined (HE stain, original magnification x 33).

lar diseases. In 1958, Plaut [5] suggested a some- cotropic hormone (ACTH) or cortisol may be re- what causal relationship because endocrinological lated to the pathology because adrenal complications were found in 9 of 100 autopsied myelolipoma clinically occurs often in cases with cases with myelolipoma. hypercortisolism. In recent years, Bennett et al. [6] carried out sub- Our case is similar to the case reported by total adrenalectomy in Cushing's disease, and re- Bennett et al. [6], but pituitary lesion was not histo- ported recurrent cases of Cushing's disease com- logically studied in their case and complication of plicated with adrenal myelolipoma after 13 years. the adrenal myelolipoma was not found at the ini- They reported that stimulation of the adrenocorti- tial subtotal adrenalectomy. It is considered that CUSHING'S DISEASE AND MYELOLIPOMA 465

Fig. 6. Microscopic examination shows chromophobic adenoma (HE stain, original magnification X 33). this is the first reported case in which both ACTH- adrenal myelolipoma was only found in the unilat- secreting pituitary adenoma and adrenal eral adrenal gland. In this case also, calcification myelolipoma were extirpated. As cases in which foci were clearly found in the bilateral adrenal excessive ACTH is considered to cause the adrenal glands, whereas imaging findings did not show myelolipoma, cases with Nelson's syndrome [7] or complication with myelolipoma in the right adre- congenital adrenal hyperplasia [8, 9] have been al- nal gland. ready reported. As cases in which hypercortisolism Furthermore, papillary cancer in the thyroid is considered to cause the adrenal myelolipoma, gland was also a complication in this case. It is cases [10,11] with Cushing's syndrome or Kanj et well known that multiple endocrine neoplasia type al's case [12] have also been reported. I (MEN-I) is a disease developing tumor or On the other hand, calcified lesion was found in hyperplasia in the pituitary, parathyroid and pan- the bilateral adrenal glands in this case. It is well creas. It also frequently complicates adrenal corti- known that calcified lesion is complicated with cal lesion or thyroid lesion [16]. Banik et al. [17] myelolipoma and Biressi [13] reported in 1954 that reported an unusual case of MEN-I complicated calcified lesion was found in 10 of 54 cases, and with papillary cancer in the thyroid gland, adrenal Sasano [14] also suggested in 1964 that calcification cortical cancer and adrenal myelolipoma. It was was rare, but occasionally occurred. Subsequently, considered that complication of the thyroid lesion Behan et al. [15] reported that complication of adre- developed accidentally in our case because abnor- nal calcifications was found in 3 of 14 cases in mality of the has not been observed until roentgenographical study of the adrenal now and no parathyroid lesion was found at total myelolipoma, and that calcified lesions were found thyroidectomy. in the bilateral adrenal glands in their cases, but

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