Primary pigmented nodular adrenocortical disease

Primary pigmented nodular adrenocortical disease (PPNAD), found in the mid 1980s, is a rare type of ACTH-independent hypercortisolism, can be part of Carney complex (CNC), an autosomal dominant multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac myxomas and endocrine tumors. One of the putative CNC genes, located on 17q22-24, has been identified as the regulatory subunit R1A of protein kinase A (PRKAR1A). Patients with isolated PPNAD and no familial history of CNC can also present a germline de novo mutation of PRKAR1A. In China, five patients with PPNAD underwent surgical treatment in our department from 2001 to August 2004.1 CASE REPORT In 5 cases of PPNAD, 2 were male and 3 were female. The age ranged 12 to 53 years old, averaged 31.6 years. Four cases were less than 38 years old. The patients' chief complains were progressive weight gain together with hypertension, the disease process was 2 – 5 years. The blood pressure was 145 – 240/95 – 165 mmHg, all the cases were with dizziness, hypodynamia, chest distress, palpitation. Severe pain of hip joint occurred in one case, the other one with edema of the lower extremities. All of the cases had moon facies, buffalo humps, plethora, violaceous striaes appeared at the abdomen and medial thighs, and also hairiness, acne, and other typical symptoms of Cushing syndrome. One 27-year-old female patient had numerous pigmentation in the skin and mucosa of lips, congenital absence of the vagina, amenorrhea, infantile uterus, and left oophoritic cysts. Bilateral cryptorchidism occurred in one male patient, and the father of another male patient had history of CNC. Investigation of the very group we found no family history of PPNAD. Serum cortisol elevated markedly in all the cases from 624 nmol/L to 850 nmol/L (normal range: 193 – 607 nmol/L) without circadian rhythms, 24-hour urine cortisol excretion elevated from 707 nmol/24 h to 3535 nmol/24 h (normal range: 55-248 nmol/24 h), serum ACTH values were 1.8-6.1 pmol/L (normal range: 4.4 – 14.3 pmol/L). All the cases showed resistance to suppression to high- and low-dose dexamethasone. All the cases had elevation of serum glucose or abnormal glucose tolerance. Severe proteinuria was found in one case, and hypokalemia (2.9-3.2 mmol/L) occurred in 3. No abnormal sign was found in the 5 cases by KUB + IVU. B-ultrasound scan found that bilateral adrenals were normal in 4 cases, hypoechoic space-occupying lesion was presented at the right adrenal area in one case. CT scan showed bilateral adrenal nodular hyperplasia in 3 cases (Fig. 1), and left adrenal possibly occupying lesions in 2. Bilateral adrenal enlargement and right adrenal nodular change was revealed in one case by MRI scan. Pituitary CT scan showed no obvious changes in all the cases. Pelvic X-ray displayed severe osteoporosis in one case. It was diagnosed as ACTH-independent hypercortisolism preoperatively. After the hypertension was controlled (systolic blood pressure≤160 mmHg, diastolic blood pressure≤ 100 mmHg), hyperglycemia (fasting glucose ≤ 8 mmol/L) and blood electrolytes were corrected, adrenal exploration was performed according to the result of image examination. Adrenal occupying lesion was detected in 3 cases, and bilateral adrenal nodular hyperplasia changes in 2. Then right adrenalectomy was preformed, and according to the postoperation pathological diagnosis and the patient's conditions, further treatment was decided based on the extent of bilateral adrena lesion to Cushing syndrome. The explored adrena was mildly to moderately enlarged or thickened, several big or small nodules were shown on the surface of each adrena, the diameter of most of the nodules were between 0.5-1.5 cm. The diameter of the largest nodule in multiple-nodules was 3.5 cm in one case. The appearance of the nodule was dark brown with pigment deposition and without capsule (Fig. 2). Adrenalectomy were performed in all the explored adrenas, the removal tissues weighed 8.3 g -17.5 g.Fig.1.: Adrenal CT showing bilateral adrenal nodular hyperplasia (↑).Fig.2.: Gross specimen examination showing mildly to moderately enlarged, thick adrena with several various-sized of nodules on the surface. The diameter of most nodules is between 0.5 cm to 1.5 cm, the appearance of the nodules is dark brown or with black pigmentation, without capsule.Adrenocorticosteroid was routinely administered postoperation, hypoadrenocorticism occurred in one case two days after the operation, but the symptoms were remitted by hydrocortisone administered intravenously. One week after the operation, blood pressure of the patients decreased apparently. The discharge was at 9 to 12 days after the operation when the blood pressure was at normal range in 2 cases. The follow-up examinations were taken in 2 cases one week after operation; 24-hour urine cortisol was at normal range (92.5 nmol/24 h) in one case. Though in the other case the 24-hour urine cortisol was higher than normal range (346.1 nmol/24 h), but markedly decreased compared to the data of preoperation (1977.5 nmol/24 h). The other 3 cases were followed up in outpatient department. Under a light microscope, adrenocortical cells showed multiple nodular hyperplasia, intranodular tissues of the adrena were atrophic, the nodular cells were enlarged and polygonal, some of them were clear cell. Intracellular hematoxylin staining exhibited granular cytoplasma, some nucleus were enlarged atypically and stained strong, nucleoli were evident, giant cells could be observed, mitotic figure was not found. Some of the granular pigment in cytoplasma showed the characteristics of lipofuscin pigments (Fig. 3). All the cases were diagnosed with PPNAD.Fig.3.: Evident lipofuscin pigments are shown in the adrenocortical nodules (HE, original magnification×40).One case is urine cortisol decreased to normal range one week after operation, blood pressure was normalized, Cushing syndrome disappeared 6 months after the operation, but the patient dropped out of follow-up 3 years ago. The other three cases survived over 2 years after the operation, the appearances of Cushing syndrome disappeared 6 months after the surgery, the blood pressure of one case tuned normal and the other 2 cases were controlled well by medicine. Compared to the level before operation, their serum and urine free cortisol excretion decreased, but were still higher than the normal. In the other one patient, Cushing syndrome were improved 4 months after the operation, the blood pressure was controlled by medicine, but the serum and urine free cortisol excretion was still higher than normal. Till now, 4 cases were still under follow-up. DISCUSSION PPNAD was first described by Chute in 1949, but was recognized as a rare type of hypercortisolism clinically until the mid of 1980s. In 1984, PPNAD was named by Shenoy et al2 and then was widely recognized. The data of our report showed that the age of PPNAD onset was young; the gender ratio was close to 1:1. Generally the disease process was over 2 years. Compared to the hypercortisolism caused by other reasons, the clinical manifestations of PPNAD were nearly the same, but the symptoms were relatively mild, some patients were under sub-clinical status.3 One female case of our group was client attending as diabetes and proteinuria, PPNAD was discovered during the medical diagnostic process. Severe osteoporosis is another clinical sign of PPNAD, about 20%-30% PPNAD is complicated with CNC, the patients and family members could also be with PPNAD and other special symptoms.4 One case of this report had severe pain of hip joint, the X-ray of pelvic indicated severe osteoporosis. Another female patient had numerous pigmentation in the skin and mucosa of lips (the clinical signs of CNC). The father of one male case had history of CNC. So during the process of follow-up of PPNAD, any clinical signs of CNC should be noticed. The serum and urine free cortisol excretion of PPNAD increased, cortisol secretion without circadian rhythms, serum ACTH decreased or could not be measured. All the cases show resistance to suppression by high- and low-dose dexamethasone.5 Our result was the sameness with literatures reported. By analyzing the laboratory and imaging findings of this report, the main cause of Cushing syndrome was adrenocortical tumors, but according to B-ultrasonography and MRI, no evident occupying lesions were found in all the 5 cases. As limited recognition of PPNAD, no precise diagnosis was made before the operation. To those the laboratory investigation indicated Cushing syndrome caused by adrenocortical tumors, but no obvious occupying lesions were observed by imaging examinations, the possibility of PPNAD should be considered. From the result of our report, the imaging value of local diagnosis for PPNAD before operation was limited; no evident lesion was detected in the 5 cases by B-ultrasonography, CT, or MRI. To those patients when CT or MRI indicated bilateral adrenal lesions, the right adrenal exploration should be performed first, if left probable adrenal occupying lesions were indicated, the left adrenal exploration would be adopted. Most of the PPNADs were bilateral adrenal lesions. Mild enlargement can be observed in about 30%-40% of cases, adrenals were in normal sizes or shrink. Multiple nodules≤1 cm can be found at the surface of adrenocortex, but the nodular diameter over 3 cm was rare. The appearance of gross specimens were dark brown with black pigmentation, without capsule.6 The internodular tissues were atrophic and showed the characteristics of fascicular cells, while the intranodular cells had characteristics of reticular cells, the lipofuscin was full of cytoplasma.7 Sasano et al8 studied the status of several steroid synthetases needed by cortisol synthesized in the adrenocortical cells in 8 patients with PPNAD by immunohistochemistry, and discovered that all the enzymes were positive in cortical nodular cells, P-45017α was in concentrative status which indicated that cortical nodular cells increased cortical synthesis. The observations under light microscope in our report were the same as the that reported in literatures. The adrenalectomy was an effective method to cure PPNAD. The curative rate of PPNAD was about 30% by unilateral adrenalectomy, 60% by sub-total adrenalectomy, and nearly 100% by total adrenalectomy.9 The Nelson syndrome could be prevented by routine dosage of adrenocorticosteroid replacement.10 One case of our report had been survived for 6 years after right adrenalectomy whose serum and urine free cortisol level decreased to the normal range 1 week after the operation, Cushing syndrome disappeared half year later, but the patient dropped out of follow-up later. Only according to these clinical data, unilateral adrenal disease was estimated. Three cases survived for more than 2 years, the follow-up showed that the hyperadrenocorticism in all the patients were remitted, but the serum cortisol excretion circadian rhythms did not recover. If the symptoms advanced, the adrenalectomy of the opposite side should be performed and cortisol replacement was necessary for patients with contraindications, a few of them could achieve continuous remission by cortisol replacement; the cortical receptor antagonists could remit the symptoms rapidly, but could not correct hypercortisolism.