A 48-year-old man was referred to our hospital for the study of cushingoid phenotype. Medical history included allergy to penicillin and dyslipidemia. He presented an ACTH of 152 pg/ml (range, 4.7-48.8 pg/ml) cortisol of 47 mug/dl (range, 5.27-22.45 mug/dl), dynamic endocrine laboratory tests were suggestive of CD, and the magnetic resonance imaging (MRI) revealed a macroadenoma. Therefore, initial treatment with a transsphenoidal resection was performed. The morphological changes were consistent with a pituitary adenoma, with a loss of reticulin network ( Figure 1B ). The cells displayed a pathological appearance with a glassy pale eosinophilic cytoplasm, with intranuclear or perinuclear vacuoles, consistent with Crooke's hyaline change ( Figure 1A ). ACTH cytoplasmic immunoreactivity was found at the periphery of the cell ( Figure 1C ); PAS positivity was found, stronger at the periphery ( Figure 1D ). The proliferation index (Ki-67) reached 2% to 4% of cells. Pituitary surgery was unsuccessful, and the follow-up pituitary MRI showed an 8-mm lesion on the right margin of the sella turcica. With this finding, a second surgical intervention was performed and the histology reported a pituitary adenoma with mild and diffuse expression of ACTH, absence of p53 overexpression, and a Ki-67 of 2%-3%. Despite surgical rescue, the patient remained with active Cushing and an increasing tumor volume in follow-up. Thus, a third surgical intervention was performed with adjuvant stereotaxic radiotherapy at a dose of 54 Gy in 27 fractions to prevent NS but was not expected to be curative. The last histological study showed again a pituitary adenoma with ACTH expression, absence of p53 overexpression, and a Ki-67 of 2%. The patient failed to control hypercortisolism with ketoconazole (200 mg/8 h) and pasireotide (40 mg/month). Therefore, the case was presented to the endocrine tumors committee, and treatment with TBA was indicated. After TBA, the cortisol levels became undetectable and steroid replacement was initiated with hydrocortisone 300 mg iv during the first 24 h. After the initial treatment, the corticosteroid dose was gradually decreased until an oral dose of hydrocortisone at 30 mg/day was reached. Moreover, oral fludrocortisone at 0.1 mg/day was initiated. The pathological anatomy report of the adrenal glands showed diffuse corticoadrenal hyperplasia with an absence of malignancy. During postsurgical TBA follow-up, the annual pituitary MRIs showed tumor stability for 2 years.
Two years and eleven months after the TBA, the patient presented to the emergency room with an intermittent bilateral diplopia of 3 weeks of evolution. He denied ocular symptoms like exudate, chemosis, or ecchymosis. He also denied fever, bulbar symptoms, nausea, vomiting, headache, or head trauma. On physical examination, he presented generalized skin and mucosa hyperpigmentation, horizontal diplopia to dextroversion, without ptosis or clear restrictions in the oculomotor muscles, and no peripheral sensory or motor neurological alterations were present. The ophthalmic funduscopy and ultrasound biomicroscopy were unremarkable. The presentation of diplopia to dextroversion as the main clinical sign suggested differential diagnoses such as lens ectopias, cataracts, and corneal opiates. The ocular fundus examination without pathological findings helped to dismiss these possible diagnoses. The diplopia was not accompanied by ocular exudate, chemosis, or ecchymosis, which made it unlikely to relate the symptom to an infectious process. The neurological evaluation with an absence of peripheral sensory or motor alterations made diagnoses such as multiple sclerosis or Eaton-lambert syndrome very unlikely. Diplopia was not associated with systemic symptoms such as fever or chills, which could suggest an orbital or brain abscess or cavernous sinus thrombosis. An emergency CT scan was requested and did not show growth of the lesion or signs of compression. However, during follow-up, the patient persisted with intermittent diplopia and subsequently presented ACTH levels at 1,838 pg/ml and chromogranin A of 41.5 ng/ml (range, 0-101.9 ng/ml). A pituitary MRI ( Figures 2A, C  ) reported an increase in the size of the pituitary tumor that invaded the clivus, a subacute bleeding component that affected the right margin of the tumor (9 x 14 mm), and an invasion of both cavernous sinuses extending to the lateral carotid line (Knosp grade III). With the three criteria of plasma ACTH level increase, imaging evidence of pituitary mass enlargement, and hyperpigmentation, the patient was diagnosed with NS. No other surgery was performed due to the low probability of success and no clear clinical benefit. Prior to the committee, a thoracic and abdominal CT scan was performed and was negative for extracranial disease. The case was presented to the endocrine tumors committee and the patient started treatment with CAP 2,500 mg daily on days 1 to 14 every 28 days for 14 days and TMZ 140 mg/m2 once daily on days 10 to 14 every 28 days. After two cycles of CAP-TMZ, the diplopia disappeared, hyperpigmentation improved, and ACTH levels decreased to 80% (from 1,838 to 414 pg/ml). The patient reported asthenia and diarrhea grade one during the first two cycles, which disappeared after four cycles. The patient completed four cycles of CAP-TMZ and started maintenance treatment with TMZ 140 mg/m2 once daily on days 10 to 14 every 28 days. After 14 months of initial CAP-TMZ treatment, the last pituitary MRI showed a 65% shrinkage of the tumor ( Figures 2  and  3B, D  ) compared with the prior brain MRI ( Figures 3A, C  ). At the time of this article's publication, after 18 months of the first dose of CAP-TMZ, the patient continues treatment with hormone replacement therapy and TMZ with excellent tolerance, maintaining a PS ECOG of 0 without new neurological focality in the last follow-up visit ( Table 1 ).