A primary adrenal non-Hodgkin's lymphoma presenting as an incidental adrenal mass.

The primary adrenal localization of a non-Hodgkin's lymphoma (NHL) is a rare event. We report the case of a 70-yr-old woman, who was admitted at our Institute for a hormonal evaluation after the incidental discovery of a right adrenal mass during ultrasonography (US) performed for cardiovascular disease. At the physical examination, no sign of adrenal hyperfunction was present. She showed only an androgenetic alopecia and her blood pressure was 180/70 mm Hg, with an arrhythmic heart rate of 100 beats/min. No alterations in hormonal and biochemical data were observed. US studies showed a right adrenal mass (major diameter 16 mm), and an abdominal computed tomography (CT) scan confirmed this solid lesion (major diameter 15 mm) with a high density. [75Se] methylnorcholesterol adrenal scintigraphy exhibited a normal symmetrical radiotracer uptake. After 8 months of follow-up, an abdominal CT scan demonstrated a significant increase of the right adrenal mass (major diameter: 40 mm), with a solid tissue density and enhancement after i.v. contrast. [75Se] methylnorcholesterol adrenal scintigraphy showed an absent uptake on the right side versus the contralateral side. The hematological, hormonal and radiological evaluation did not reveal any sign of malignancy. Owing to the mass enlargement and the modification of scintigraphic pattern, the patient underwent unilateral adrenalectomy. Histological examination revealed a primary diffuse large B-cell NHL (REAL classification) of the adrenal gland. After surgery, she underwent a combined polychemotherapy (cyclophospamide, adriamycin, vincristine and prednisone) and subsequently one cycle of radiotherapy. At present, the patient is in good conditions and there are no signs or symptoms of recurrent disease.

Evaluation of haemostatic and fibrinolytic markers in patients with Cushing's syndrome and in patients with adrenal incidentaloma.

It is known that either chronic glucocorticoid administration or endogenous hypercortisolism frequently induce an hypercoagulable condition. Since little is known about the evaluation of markers of haemostatic and fibrinolytic systems in other adrenal disorders, we studied plasminogen activator inhibitor (PAI-1), tissue-plasminogen activator (t-PA), fibrinogen and von Willebrand factor antigen (vWF-Ag) levels in 11 patients with Cushing's syndrome and in 12 patients with adrenal incidentaloma. In patients with Cushing's syndrome mean PAI-1, t-PA and vWF-Ag levels did not significantly differ from those found in 50 age- and sex-matched controls, while mean fibrinogen levels were significantly higher in patients (337.0+/-39.1 mg/dl) than in normal subjects (278.9+/-8.4 mg/dl). Patients with adrenal incidentaloma showed PAI-1, t-PA and vWF-Ag mean levels superimposable to those in controls, while fibrinogen (319.7+/-27.9 mg/dl) was slightly, although not significantly, higher than in normals. Considering the limits of normal values (as mean+/-2 SD) obtained in the control group, high PAI-1 levels were found in 2 patients with Cushing's syndrome and in 3 patients with incidentaloma. An elevation of fibrinogen levels was found in 3 patients with Cushing's syndrome and in 3 with incidentaloma. Increased vWF-Ag levels were found only in 1 patient with Cushing's syndrome. An increased t-PA level was occasionally observed only in the patient with adrenal carcinoma. On the whole, an alteration of at least one of haemostatic and fibrinolytic parameters was detected in 55% of the patients with Cushing's syndrome and in 42% of those with adrenal incidentaloma. In conclusion, early alterations of coagulation and fibrinolytic systems may be found in some patients with adrenal disorders, thus suggesting the opportunity of an accurate follow-up in order to identify possible risk factors for cardiovascular disease and thromboembolism.

Usefulness of the desmopressin test in the postoperative evaluation of patients with Cushing's disease.

OBJECTIVE: To evaluate the plasma ACTH and serum cortisol responses to desmopressin in patients with Cushing's disease either before or after pituitary adenomectomy during long-term follow-up, and to compare the results with those obtained after corticotrophin-releasing hormone (CRH) testing. DESIGN: Plasma ACTH and serum cortisol concentrations were evaluated after the administration of desmopressin (10 microg i.v.) or CRH (1 microg/kg i. v.) in 34 patients with Cushing's disease. Twenty-four patients with active Cushing's disease were evaluated both before and after transsphenoidal pituitary surgery (TSS); these patients were followed up for 1-36 months. Ten patients were studied only after a long-term period (1-19 years, median 4 years) after TSS (six patients), TSS plus external pituitary irradiation (three patients) and TSS plus radiosurgery (one patient). RESULTS: In 24 patients with active Cushing's disease a significant ACTH/cortisol response (P<0.001) was induced by either desmopressin (ACTH from a baseline of 15.3+/-2.7 pmol/l to a peak of 40.9+/-7.3 pmol/l; cortisol from 673+/-59 nmol/l to 1171+/-90 nmol/l) or CRH (ACTH from a basal of 14. 2+/-2.5 pmol/l to a peak of 47.2+/-7.7 pmol/l; cortisol from 672+/-50 nmol/l to 1192+/- 80 nmol/l). In all patients a positive cortisol response to desmopressin was found. After pituitary adenomectomy the 14 'cured' patients were followed up for 1-36 months; desmopressin administration never induced ACTH or cortisol responsiveness in any patient. In contrast, a progressive recovery of ACTH and cortisol responses after CRH was observed at different intervals of time in all patients but one. Five patients, in whom the cortisol concentration only normalized after surgery, showed a persistent responsiveness to desmopressin, and two of them relapsed 12 and 24 months later. In five patients who were not cured, the hormonal responsiveness to either CRH or desmopressin was similar before and after operation. Of 10 patients studied only after long-term follow-up, six were cured and a normal response to CRH was present, whereas no changes in ACTH/cortisol concentrations were induced by desmopressin. The other four unsuccessfully operated patients underwent pituitary irradiation and showed different and equivocal hormonal responses to desmopressin and to CRH. CONCLUSIONS: During the postoperative follow-up of patients with Cushing's disease, the maintenance or the disappearance of the hormonal response may be related to the persistence or the complete removal of adenomatous corticotrophs, respectively. It is suggested that desmopressin test should be performed in the preoperative evaluation and follow-up of patients with ACTH-dependent Cushing's syndrome.

Evaluation of markers of bone and collagen turnover in patients with active and preclinical Cushing's syndrome and in patients with adrenal incidentaloma.

Although steroid-induced negative effects on bone and collagen have been well described in corticosteroid-treated patients, few studies have extensively evaluated bone and collagen turnover in patients with endogenous Cushing's syndrome. In this work serum bone-Gla protein (BGP), C-terminal cross-linked telopeptide of type I collagen (ICTP) and N-terminal propeptide of type III procollagen (PIIINP) levels were determined in patients with active (n = 12) and preclinical (n = 6) Cushing's syndrome, adrenal incidentalomas (n = 35) and in healthy controls (n = 28). In patients with overt Cushing's syndrome, serum BGP (0.9+/-0.2 ng/ml), ICTP (2.7+/-0.2 ng/ml) and PIIINP (1.9+/-0.2 ng/ml) levels were significantly lower (P < 0.0001) than in controls (5.5+/-0.2, 3.9+/-0.2 and 3.2+/-0.2 ng/ml respectively). In preclinical Cushing's syndrome, serum BGP (2.5+/-0.8 ng/ml), ICTP (2.2+/-0.1 ng/ml) and PIIINP (2.2+/-0.2 ng/ml) levels were significantly lower than in normal subjects (P < 0.0001, P < 0.0001 and P < 0.02 respectively), being similar to those recorded in overt Cushing's syndrome. In patients with adrenal incidentaloma, serum BGP (4.2+/-0.5 ng/ml) and ICTP (2.9+/-0.2 ng/ml) levels were significantly lower than those found in controls (P < 0.05 and P < 0.001 respectively), while serum PIIINP levels (3.6+/-0.2 ng/ml) did not differ from those of normals. In particular, 9/35 patients with adrenal incidentaloma had markedly depressed BGP levels (<2.0 ng/ml; mean 0.8+/-0.1 ng/ml): all patients of this subgroup showed an exaggerated 17-hydroxyprogesterone increase after ACTH administration. In the same patients, serum ICTP (3.0+/-0.4 ng/ml) and PIIINP (3.6+/-0.2 ng/ml) levels did not differ from those found in the incidentaloma group. In conclusion, our study indicates that bone and collagen turnover are markedly affected in patients with overt and preclinical Cushing's syndrome. Although patients with adrenal incidentaloma do not show any signs or symptoms of overt hypercortisolism, the presence of reduced BGP and ICTP levels might be considered a further index of an 'abnormal' pattern of steroid secretion in some of them. As a consequence, the presence of early alterations in markers of bone turnover might be useful for selecting those patients who need more accurate follow-up of the adrenal mass.

The one microgram adrenocorticotropin test in the assessment of hypothalamic-pituitary-adrenal function.

The possibility of assessing hypothalamic-pituitary-adrenal (HPA) function by the standard ACTH test (250 microg) has been widely discussed in the past years and compared with the role of the insulin tolerance test (ITT). Recently, it was shown that low doses of ACTH, such as 1 microg i.v., induce a maximal adrenal response and, by reducing the discrepancies compared with the ITT also allow one to detect mild forms of secondary hypoadrenalism. In the present study the 1 microg ACTH test was performed in patients with hypothalamic-pituitary disease in order to assess adrenal function, and the results have been compared with those obtained after the insulin test. Fifty-seven patients (31 men and 26 women, aged 19-73 years) with hypothalamic-pituitary diseases were studied: 51 patients were affected with pituitary tumor and 6 patients had hypothalamic disorders. All these patients and 18 healthy volunteers (7 men and 11 women, aged 19-46 years) received 1 microg i.v. ACTH injection. In addition, the ITT (0.1-0.15 U/kg body weight) was performed in all patients. In normal subjects mean cortisol levels significantly (P<0.001) increased from a baseline of 393+/-43 nmol/l to a peak of 770+/-41 nmol/l after 1 microg ACTH. In 44 patients with hypothalamic-pituitary disease 1 microg ACTH caused a cortisol rise similar to that of normal subjects (from 332+/-17 to 769+/-24 nmol/l; P<0.001), while an impaired response (from 124+/-23 to 312+/-46 nmol/l) was observed in 13 cases (23%), 7 of them with low morning cortisol levels (10-127 nmol/l) and 6 with basal values at the lower limit of normality. The cortisol response to ITT was compared with that obtained after the 1 microg ACTH test: 10 patients failed both challenges, 4 patients who passed the ACTH test failed the ITT, while 3 patients who failed the ACTH test passed the ITT. The 23 out of 57 patients (40%) who showed a cortisol peak greater than 750 nmol/l after 1 microg ACTH had a normal response to ITT. A positive correlation between cortisol peaks after ACTH and after insulin was also found (r = 0.68, P<0.001). Assuming a 100% accuracy of ITT, the low dose ACTH test yielded a 71% sensitivity and a 93% specificity. In conclusion, the low-dose ACTH test is a useful, safe and inexpensive tool for the initial assessment of HPA function in patients with hypothalamic-pituitary disease. In fact, the ITT is unnecessary when cortisol peaks are greater than 750 nmol/l after 1 microg ACTH and also when very low cortisol basal levels indicate an overt hypoadrenalism. Within these limits the ITT is mandatory and its important role in the recognition of secondary adrenal failure is further confirmed.

Effect of desmopressin on ACTH and cortisol secretion in states of ACTH excess.

OBJECTIVE: To assess the ability of desmopressin administration to stimulate ACTH/cortisol secretion in patients with Cushing's disease, either before or after surgery, and in patients with other states characterized by ACTH hypersecretion, and to compare the results with those obtained after CRH testing. DESIGN AND SUBJECTS: Plasma ACTH and serum cortisol levels were evaluated after the administration of desmopressin (10 micrograms i.v.), CRH (1 microgram/kg i.v.) and saline on different days in 17 patients with Cushing's disease, 1 with occult ectopic ACTH syndrome, 5 with Addison's disease, 3 who had been bilaterally adrenalectomized for Cushing's syndrome and 4 normal subjects. After pituitary adenomectomy desmopressin and CRH were administered again to 13 of the patients who had undergone pituitary surgery for their Cushing's disease. RESULTS: In 16 patients with Cushing's disease with microadenoma a positive ACTH/cortisol rise occurred in 11 patients after both desmopressin and CRH, 2 other patients were responsive only to desmopressin and 2 only to CRH, while in 1 patient equivocal responses to both tests were found. The persistence of a hormonal response to desmopressin after pituitary adenomectomy for Cushing's disease correlated with unsuccessful surgery, while, contrary to CRH, absent ACTH/cortisol rises were found in cured patients 1 and 12 months after operation. In 1 patient suspected for ectopic ACTH hypersecretion, desmopressin and CRH administration did not cause any ACTH/cortisol rise. Significant ACTH rises occurred after both desmopressin and CRH testing in patients with Addison's disease. All the 3 patients adrenalectomized for Cushing's syndrome showed a rise of ACTH levels after CRH, while a similar response after desmopressin occurred in only one of them. CONCLUSIONS: Desmopressin is able to stimulate ACTH and hence cortisol release in Cushing's disease. It may be a useful test in patients with doubtful responses to CRH test, in those exhibiting responses to CRH indistinguishable from those of normal subjects and in the postoperative follow-up of Cushing's disease. In some patients with abolished or reduced cortisol feed-back at hypothalamic-pituitary level the sensitivity of normal corticotrophs to desmopressin is enhanced.

Serum bone Gla protein and carboxyterminal cross-linked telopeptide of type I collagen in patients with Cushing's syndrome.

Serum bone Gla protein, a marker of bone formation, and carboxyterminal cross-linked telopeptide of type I collagen levels, an index of bone resorption, were evaluated in eight patients with active Cushing's syndrome and in four with 'preclinical' Cushing's syndrome, before and after surgery. In basal conditions, serum bone Gla protein levels were significantly lower (p < 0.0001) in patients with active Cushing's syndrome (1.0 +/- 0.35 ng/ml) than in controls (5.4 +/- 0.15 ng/ml); two out of four patients with the 'preclinical' form had reduced bone Gla protein levels, while in the other two cases levels were in the normal range. Serum levels of carboxyterminal cross-linked telopeptide of type I collagen (3.0 +/- 0.4 ng/ml), although slightly reduced, were similar to those recorded in controls (4.1 +/- 0.3 ng ml), both in patients with active and with preclinical Cushing's syndrome. After surgery serum levels of both marker proteins significantly increased in seven out of eight patients with active Cushing's syndrome; in one patient, who was not cured after surgery, bone Gla proteins levels remained lower than in normals, while levels of carboxyterminal cross-linked telopeptide of type I collagen had a transient increase after six months. In the two patients with a 'preclinical' Cushing's syndrome who underwent surgery, a significant rise of the levels of both marker proteins was observed, similar to that observed in patients with active Cushing's syndrome. It was concluded that serial determinations of these new markers of bone formation and resorption may be usefully employed to follow-up the clinical course of Cushing's syndrome and provide information on the rate of bone turnover in response to medical and/or surgical therapies. Moreover, the evaluation of these markers in preclinical states of Cushing's syndrome might suggest the need for surgery.

Value of buserelin testing in the evaluation of hirsute women.

It has been recently reported that many hirsute women are affected with functional ovarian hyperandrogenism (FOH)-a term that encompasses the heterogeneous polycystic ovary syndrome- and show an abnormal ovarian steroidogenic response to gonadotropin-releasing hormone (Gn-RH) agonists. The aims of the present study were to determine the prevalence of FOH by the assessment of 17-hydroxyprogesterone (17-OHP) response to the Gn-RH agonist buserelin, to correlate these abnormal responses to other parameters suggestive of PCOS, and to assess the possible adrenal origin of hyperandrogenism. Therefore, in 33 consecutive women with hirsutism serum LH, FSH, 17-OHP, dehydroepiandrosterone sulfate (DHEA-S), androstenedione (A), cortisol levels were evaluated in basal conditions and after the administration of buserelin (0.5 mg sc) and ACTH (tetracosactide 0.25 mg iv). Two patients were affected with a non classic congenital adrenal hyperplasia (CAH)-21OH deficiency. In 5 other women ACTH test caused a rate increase 17-OHP (30-0)/30 min > 19 nmol/L/min (0.25 +/- 0.03; mean +/- SE), suggesting the possible existence of heterozygote non classic CAH-21OH. One patient showed a DHEA-S response to ACTH (from 10.3 to 17.2 mumol/L), which was compatible with late-onset 3 beta-Hydroxy-delta 5 steroid dehydrogenase deficiency. Out of the 25 patients with normal responsiveness to ACTH, 11 women (group A) showed higher 17-OHP and A levels, in comparison to normal women, both in basal conditions (17-OHP = 4.18 +/- 0.72 vs 1.74 +/- 0.34 nmol/L, p < 0.005; A = 11.8 +/- 1.2 vs 6.0 +/- 0.7 nmol/L, p < 0.05) and after buserelin (17-OHP = 15.61 +/- 1.31 vs 6.96 +/- 0.9 nmol/L; A = 19.0 +/- 1.9 vs 7.5 +/- 0.8 nmol/L; p < 0.001). In 6 of these 11 patients basal and buserelin-stimulated LH levels were higher than in normals. The remaining 14 patients (group B) showed normal baseline and buserelin-stimulated 17-OHP and A concentrations. In this group only 2 patients had high basal and stimulated LH levels. An augmented LH/FSH ratio was present in 5 and 1 cases of groups A and B, and polycystic ovaries at ultrasonography were observed in 7 and 8 cases of groups A and B, respectively. It is to note that an abnormal 17-OHP response to buserelin was present also in 3 of the 5 patients with abnormal 17-OHP rise after ACTH test, suggesting an adrenal and ovarian cause of hyperandrogenism. In conclusion, an abnormal response to one or both stimulation test was present in 57% of cases: an adrenal origin of hirsutism was detected in 15%, a combined adrenal and ovarian origin was found in 9% and an ovarian cause was present in 33%. Buserelin testing is an useful means to reveal the presence of FOH.

Abnormalities of endocrine function in patients with clinically "silent" adrenal masses.

Because, in recent years, patients with incidentally discovered adrenal masses have been encountered increasingly, their endocrine function was investigated in basal conditions and after dynamic tests. Thirty-two patients (23 women and 9 men, aged 28-74 years) were studied. Lesion diameter, as documented by computed tomography and/or nuclear magnetic resonance imaging, ranged between 5 and 65 mm; the tumors were localized on the right in 22 patients, on the left in 5 and bilaterally in 5 cases. In basal conditions, urinary free cortisol (UFC) excretion, plasma adrenocorticotropin (ACTH) and cortisol levels were normal, except for 4 patients who showed high UFC and ACTH levels in the low-normal range. Ovine corticotropin-releasing hormone (CRH, 1 microgram/kg iv) was given to 18 patients, inducing normal ACTH and cortisol responses in 12, blunted responses in 4 and no response in 2 cases. No reduction in ACTH and cortisol levels after suppression tests was observed in 4 of 29 patients after dexamethasone (1 mg overnight) or in 6 of 29 after loperamide. The 4 patients who were unresponsive to both tests did not show any further inhibition after high-dose dexamethasone administration, had low plasma ACTH levels and showed impaired or absent responses to the CRH test: they were diagnosed as affected with preclinical Cushing's syndrome. An exogenous ACTH test performed in 30 patients caused a normal cortisol rise. Basal mean 17-hydroxy-progesterone (17-OHP) levels were not different from those in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical and preclinical aspects of adrenal Cushing syndrome]. / Aspetti clinici e preclinici della sindrome di Cushing surrenalica.

Cushing's syndrome of adrenal origin encompasses different entities: besides the occurrence of adenoma and carcinoma, a not homogeneous group includes the ACTH-independent macro- or micronodular bilateral hyperplasia and the familial pigmented nodular hyperplasia (Carney's syndrome). Moreover, isolated cases of immunological origin and food-dependence have recently described. On clinical grounds no major characteristics may help to identify the adrenal origin of Cushing's syndrome, except for few situations as carcinoma or nodular dysplasia. Laboratory investigations of patients with adrenocortical tumor are based on ACTH and cortisol determinations in basal conditions and in response to high dose dexamethasone and CRH tests. However, isolated diagnostic problems may occur, as the presence of a black adrenocortical adenoma or the uncommon persistence of a circadian rhythmicity of glucocorticoid secretion. The evaluation of new markers of bone turnover (BGP, ICTP) and of collagen turnover (PIIINP) confirms the existence of corticosteroid-induced bone and collagen damages and may also be a useful prognostic index after treatment. Although up to now food-dependent Cushing's syndrome appears to be very rare, the adrenocortical sensitivity to GIP has been investigated in patients with either pituitary Cushing's disease, or clinically silent adrenal masses. No evidence of GIP-dependent cortisol secretion during the peptide infusion or after endogenous stimulation by OGTT was observed in any case. Since the wide availability of sensitive and noninvasive imaging techniques (CT and NMR), in recent years the finding of incidentalomas has become fairly common. In patients with incidentaloma abnormalities of the endocrine function are frequently encountered, and the "preclinical" Cushing's syndrome is increasingly recognized.(ABSTRACT TRUNCATED AT 250 WORDS)