Cushing's Disease Associated with both Pituitary Microadenoma and Corticotroph Hyperplasia

Abstract

Herein, we present the case of a 63-year old female patient with initial symptoms of myopathy, hypokaliemia, glucosuria and psychotic symptoms. Laboratory analysis demonstrated elevated plasma levels of ACTH and cortisol. Additionally, urine cortisol excretion was increased approximately 60-fold. MRI imaging revealed a possible pituitary microadenoma. To confirm the diagnosis a bilateral inferior petrosal sinus sampling was performed presenting higher ACTH levels on the right side. However, after surgery cortisol levels did not return to normal range. Histological examination of the tumor revealed a microadenoma. Six days postoperatively, the patient developed several pneumonic infiltrations and fever therefore antibiotic and antifungal therapy was started immediately. In addition aspergillus antigen was elevated. During this septic condition, cortisol levels further increased. The patient died despite optimal intensive care under septical conditions 8 days after surgery. Microbiological analysis identified Aspergillus fumigatus in broncho-alveolar lavage and several organ systems including the heart and brain. Neuropathological autopsy revealed nodular proliferations of corticotropic cells in the pituitary gland that are assumed to be morphological entities between diffuse hyperplasias and adenomas, termed as tumorlets. In single reports, multiple pituitary lesions in patients with Cushing's disease have been demonstrated, but to our knowledge none of these cases presented the combination of an ACTH-producing microadenoma and corticotroph cell hyperplasia in the same patient. Therefore, even after resection of a pituitary microadenoma one should be aware of the possibility of continuously elevated ACTH level being due to multifocal nodular corticotroph hyperplasia which is invisible by neuroradiological examination.

hypercortisolism - pituitary gland - ACTH - microadenoma - nodular corticotroph hyperplasia - Cushing's disease

References

• 1 Aucott JN. Glucocorticoids and infection.  Endocrinol Metab Clin North Am. 1994;  23 655-670
• 2 Bakker RC, Gallas PR, Romijn JA. et al . Cushing's syndrome complicated by multiple opportunistic infections.  J Endocrinol Invest. 1998;  21 329-333
• 3 Bochicchio D, Losa M, Buchfelder M. Factors influencing the immediate and late outcome of Cushing's disease treated by transsphenoidal surgery: a retrospective study by the European Cushing's Disease Survey Group.  J Clin Endocrinol Metab. 1995;  80 3114-3120
• 4 Boggan JE, Tyrrell JB, Wilson CB. Transsphenoidal microsurgical management of Cushing's disease. Report of 100 cases.  J Neurosurg. 1983;  59 195-200
• 5 Burrow GN, Wortzman G, Rewcastle NB. et al . Microadenomas of the pituitary and abnormal sellar tomograms in an unselected autopsy series.  N Engl J Med. 1981;  304 156-158
• 6 Carey RM, Varma SK, Drake  Jr  CR. et al . Ectopic secretion of corticotropin-releasing factor as a cause of Cushing's syndrome. A clinical, morphologic, and biochemical study.  N Engl J Med. 1984;  311 13-20
• 7 Catargi B, Rigalleau V, Poussin A. et al . Occult Cushing's syndrome in type-2 diabetes.  J Clin Endocrinol Metab. 2003;  88 5808-5813
• 8 Cavagnini F, Pecori GF. Epidemiology and follow-up of Cushing's disease.  Ann Endocrinol (Paris). 2001;  62 168-172
• 9 Colao A, Faggiano A, Pivonello R. et al . Inferior petrosal sinus sampling in the differential diagnosis of Cushing's syndrome: results of an Italian multicenter study.  Eur J Endocrinol. 2001;  144 499-507
• 10 Cupps TR, Fauci AS. Corticosteroid-mediated immunoregulation in man.  Immunol Rev. 1982;  65 133-155
• 11 Dale DC, Petersdorf RG. Corticosteroids and infectious diseases.  Med Clin North Am. 1973;  57 1277-1287
• 12 Donovan LE, Corenblum B. The natural history of the pituitary incidentaloma.  Arch Intern Med. 1995;  155 181-183
• 13 Erem C, Algun E, Ozbey N. et al . Clinical laboratory findings and results of therapy in 55 patients with Cushing's syndrome.  J Endocrinol Invest. 2003;  26 65-72
• 14 Etxabe J, Vazquez JA. Morbidity and mortality in Cushing's disease: an epidemiological approach.  Clin Endocrinol (Oxf). 1994;  40 479-484
• 15 Findling JW, Doppman JL. Biochemical and radiologic diagnosis of Cushing's syndrome.  Endocrinol Metab Clin North Am. 1994;  23 511-537
• 16 Flitsch J, Ludecke DK, Knappe UJ. et al . Cavernous sinus sampling in selected cases of Cushing's disease.  Exp Clin Endocrinol Diabetes. 2002;  110 329-335
• 17 George DH, Scheithauer BW, Kovacs K. et al . Crooke's cell adenoma of the pituitary: an aggressive variant of corticotroph adenoma.  Am J Surg Pathol. 2003;  27 1330-1336
• 18 Graham BS, Tucker  Jr  WS. Opportunistic infections in endogenous Cushing's syndrome.  Ann Intern Med. 1984;  101 334-338
• 19 Hall WA, Luciano MG, Doppman JL. et al . Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population.  Ann Intern Med. 1994;  120 817-820
• 20 Horvath E, Kovacs K, Scheithauer BW. Pituitary hyperplasia.  Pituitary. 1999;  1 169-179
• 21 Kai Y, Hamada J, Nishi T. et al . Usefulness of multiple-site venous sampling in the treatment of adrenocorticotropic hormone-producing pituitary adenomas.  Surg Neurol. 2003;  59 292-298
• 22 Kontogeorgos G, Kovacs K, Horvath E. et al . Multiple adenomas of the human pituitary. A retrospective autopsy study with clinical implications.  J Neurosurg. 1991;  74 243-247
• 23 Lee HW, Caldwell JE, Wilson CB. et al . Venous bleeding during transsphenoidal surgery: its association with pre- and intraoperative factors and with cavernous sinus and central venous pressures.  Anesth Analg. 1997;  84 ((3)) 545-550
• 24 Lefournier V, Martinie M, Vasdev A. et al . Accuracy of bilateral inferior petrosal or cavernous sinuses sampling in predicting the lateralization of Cushing's disease pituitary microadenoma: influence of catheter position and anatomy of venous drainage.  J Clin Endocrinol Metab. 2003;  88 196-203
• 25 Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections.  Lancet. 2003;  362 1828-1838
• 26 Ludecke DK, Flitsch J, Knappe UJ. et al . Cushing's disease: a surgical view.  J Neurooncol. 2001;  54 151-166
• 27 Mazarakis N, Kontogeorgos G, Kovacs K. et al . Composite somatotroph--ACTH-immunoreactive pituitary adenoma with transformation of hyperplasia to adenoma.  Pituitary. 2001;  4 215-221
• 28 Meij BP, Lopes MB, Vance ML. et al . Double pituitary lesions in three patients with Cushing's disease.  Pituitary. 2000;  3 159-168
• 29 Newell-Price J, Trainer P, Besser M. et al . The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states.  Endocr Rev. 1998;  19 647-672
• 30 Ng TT, Robson GD, Denning DW. Hydrocortisone-enhanced growth of Aspergillus spp. implications for pathogenesis.  Microbiology. 1994;  140 ((Pt 9)) 2475-2479
• 31 Oldfield EH, Doppman JL, Nieman LK. et al . Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome.  N Engl J Med. 1991;  325 897-905
• 32 Orth DN. Cushing's syndrome.  N Engl J Med. 1995;  332 791-803
• 33 Rees DA, Hanna FW, Davies JS. et al . Long-term follow-up results of transsphenoidal surgery for Cushing's disease in a single centre using strict criteria for remission.  Clin Endocrinol (Oxf). 2002;  56 541-551
• 34 Reincke M, Allolio B, Saeger W. et al . The ‘incidentaloma’ of the pituitary gland.  Is neurosurgery required? JAMA. 1990;  263 2772-2776
• 35 Salenave S, Gatta B, Pecheur S. et al . Pituitary magnetic resonance imaging findings do not influence surgical outcome in adrenocorticotropin-secreting microadenomas.  J Clin Endocrinol Metab. 2004;  89 3371-3376
• 36 Sarlis NJ, Chanock SJ, Nieman LK. Cortisolemic indices predict severe infections in Cushing syndrome due to ectopic production of adrenocorticotropin.  J Clin Endocrinol Metab. 2000;  85 42-47
• 37 Schteingart DE, Lloyd RV, Akil H. et al . Cushing's syndrome secondary to ectopic corticotropin-releasing hormone-adrenocorticotropin secretion.  J Clin Endocrinol Metab. 1986;  63 770-775
• 38 Semple PL, Laws  Jr  ER. Complications in a contemporary series of patients who underwent transsphenoidal surgery for Cushing's disease.  J Neurosurg. 1999;  91 175-179
• 39 Simard M. The biochemical investigation of Cushing syndrome.  Neurosurg Focus. 2004;  16 E4
• 40 Tran M, Elias AN. Severe myopathy and psychosis in a patient with Cushing's disease macroadenoma.  Clin Neurol Neurosurg. 2003;  106 1-4
• 41 Wurzburger MI, Prelevic GM, Brkic SD. et al . Cushing's syndrome – transitory immune deficiency state?.  Postgrad Med J. 1986;  62 657-659
• 42 Yamakita N, Murai T, Miyamoto K. et al . Variant of pre-clinical Cushing's syndrome: hypertension and hypokalemia associated with normoreninemic normoaldosteronism.  Hypertens Res. 2002;  25 623-630
• 43 Yanovski JA, Cutler  Jr  GB. Glucocorticoid action and the clinical features of Cushing's syndrome.  Endocrinol Metab Clin North Am. 1994;  23 487-509
• 44 Yanovski JA, Cutler  Jr  GB, Chrousos GP. et al . The dexamethasone-suppressed corticotropin-releasing hormone stimulation test differentiates mild Cushing's disease from normal physiology.  J Clin Endocrinol Metab. 1998;  83 348-352

Correspondence