The authors report the case of a 56-year-old woman who was diagnosed with Cushing’s disease 6 years earlier. At the moment of diagnosis, she presented a clinical picture of serious hypercortisolism with dramatic signs and symptoms including fatigue, weight loss, visceral obesity (BMI-29.5 kg/m2), “buffalo hump,” “moon face,” plethora, thin skin, hirsutism, hemorrhagic diathesis, purplish skin striae, proximal limbs muscle atrophy, and weakness as well as severe hypokalemia, hypertension, and secondary diabetes with high (about 70 U/day) insulin demand. A loss of cortisol circadian rhythm, fivefold increased urinary excretion of cortisol, and a lack of cortisol suppression after low and high dexamethasone dose were observed (Table 1)
Q What is the your interpretation of the investigations done for Cushing’s syndrome ?
- High baseline cortisol, high urine free cortisol and failure of Cortisol suppression with 1 mg of Dexamethasone confirms the diagnosis of Cushing’s syndrome.
- ACTH value of 81 pg/ml suggests ACTH dependent Cushing’s syndrome (ACTH > 25 pg/ml)
- Failure of Dexamethasone to fall by >50% on 8 mg Dexamethasone suppression goes in favour of either an ectopic source of ACTH or a Pituitary macroadenoma
- What would be your next step in this process ?
I would consider doing a MRI Sella with contrast. However another task would be to locate the source of Ectopic ACTH for which a CT Chest with contrast with abdomen or if facility is available a Gallium DOTANOC scan would be useful.
Magnetic resonance imaging (MRI) revealed a pituitary borderline microadenoma sized 9 × 7 mm. In somatostatin receptors scintigraphy (HYNIC-Tektrotyd 99mTc), a higher accumulation of isotope was found only in the anterior pituitary, and suspicion of ectopic Cushing’s syndrome was excluded.
Q Is this enough in this case ?
I would consider doing IPSS in this case. It is often possible that the pituitary microadenoma may be just an incidentaloma. Also the failure of the HDDST is another important point in this case. I really doubt that the ectopic source of ACTH can be ruled out in this case.
After 2 months of ketoconazole therapy, she underwent the first selective transsphenoidal adenomectomy. A postoperative pathologic exploration performed using an electron microscope revealed a sparsely granulated corticotroph tumour with an MIB-1 index of about 40%. After the neurosurgery, the patient experienced severe secondary hypoadrenalism (morning plasma cortisol level, 0.68 μg/dL; ACTH <10 pg/mL), and she needed hydrocortisone replacement treatment for 22 months. The patient’s general appearance and feeling improved and her blood pressure, serum potassium level, and glucose tolerance became normal.
However, after a 27-month period of remission, the patient developed recurrent hypercortisolism due to a regrowth of the tumour.
Q How common is recurrence of Cushing’s in adults after a successful surgery ?
It is not uncommon. 23% of patients with microadenoma and 33% of patients with macroadenoma have recurrence.
Q What gives a hint of early recurrence ?
Recovery of HPA axis within 6 months of therapy gives a hint of early recurrence.
Q Which is one of the earliest marker to be raised in case of recurrence ?
Late night salivary cortisol.
Q What are the options for treating the recurrence?
The best options would be either a repeat Transsphenoidal surgery or medical therapy.
Thirty-one months after the first neurosurgical intervention, the patient underwent a second, nontotal transsphenoidal reoperation, followed by stereotactic radiotherapy (system Brain Lab, one dose 20 Gy).
Because of a rapid regrowth of the pituitary tumour and the increase of hypercortisolism, the patient was then treated with mitotane (6 g/day) and ketoconazole (1200 mg/day) simultaneously for 3 months in order to prepare her to next surgery, but this treatment was ineffective. The third transsphenoidal neurosurgery was performed nine months after the second operation. This time only a short and transient decline of cortisol to 1.7 μg/dL was observed.
Q What is the role of Pasireotide in this case ?
In a phase 3 trial conducted in patients who had failed surgery or were no candidates for surgery , only 20% of patients had normalization of urine free cortisol after Pasireotide. It is a fair choice in this case, however we donot except a dramatic response. It is recommended for this indication in both US and Europe.
Afterwards, because of a continuing progression of the tumour and increasing hypercortisolism as well as medical treatment failures and a lack of further options of treating the patient using neurosurgery, a total bilateral adrenalectomy was performed endoscopically as a lifesaving procedure. Postoperative pathologic investigations revealed nodular hyperplasia of both adrenal cortex.
Subsequently, seven months after adrenalectomy, the patient developed Nelson’s syndrome with intense skin hyperpigmentation and aggressive pituitary tumour progression together with optic chiasm compression and penetration to the right cavernous sinus.
Four months later, the fourth transsphenoidal adenomectomy was conducted; however, there was a rapid recurrence of the tumour with an extended expansion to the right cavernous sinus causing ophthalmoplegia and with penetration to the sphenoid sinus and suprasellar region and the compression of the optic chiasm causing the blindness of the right eye. Five months later, she underwent the fifth neurosurgery intervention, a right frontotemporal craniotomy with a subtotal suprasellar adenomectomy, which was followed by the withdrawal of ophthalmoplegia.
Q What is Nelson’s syndrome ?
Macroscopic enlargement of the Pituitary tumor (>1 cm) along with hyperpigmentation because of ACTH in a patient with Cushing’s disease who has undergone bilateral adrenalectomy is known as Nelson’s syndrome.
Q How common is Nelson’s syndrome ?
21% of adults who had undergone bilateral adrenalectomy develop Nelson’s syndrome.
A consecutive pathologic electron microscopy showed an atypical sparsely granulated corticotroph tumour, with an MIB-1 index >5%, very low activity of O6-methylguanine DNA methyltransferase (MGMT) in tumour cells and positive receptor SSRT 2A (weak cytoplasmic) reaction. In order to help bridge the time gap until gamma-knife qualification, another desperate attempt of medical treatment was undertaken. Considering the fact that current literature proves the expression of somatostatin and dopamine receptors in corticotroph adenoma tissues and taking into account the result of the somatostatin receptor scintigraphy and postoperative tumour receptor SSRT 2A examination, the patient was administered 2 injections of long-acting release somatostatin analog (lanreotide 120 mg) at a 4-week interval and cabergoline (2 mg/week) for 8 weeks. No positive effect was observed.
What made the situation even more difficult was the fact that, three months later, the patient was not qualified for gamma-knife therapy as the size of the pituitary tumour was too large.
Based on reports from the literature which showed a positive response in similar, the second-line treatment with temozolomide was undertaken.
Q What is Temozolomide ?
It is an alkylating agent developed for Glioblastoma multiforme and Astrocytoma
Q What is the importance of O6 methylguanine DNA methyltransferase(MGMT) in cases where Temozolomide is considered for therapy ?
Temozolomide acts by methylation of DNA which triggers the death of tumor cells. Cell expressing MGMT may be able to escape this effect of Temozolomide. Hence the drug is more effective in tumors which are MGMT negative. In this case the cells show low MGMT activity which would be beneficial to the case.
Q How effective is Temozolomide in pituitary tumors ?
According to a study , Temozolomide showed beneficial effect in 60% of Pituitary adenoma and 69% of Pituitary carcinomas.
The patient received the most frequently recommended dose of TMZ = 150 mg/m2 of body surface area daily (total dose = 250 mg/day), administered orally for 5 days every 28 days.
Before each cycle of treatment, the clinical status of the patient was assessed as well as measuring the level of ACTH. MRI examinations were performed after the third and the sixth cycles. Tumour volume was measured based on the MRI picture using the computer program OsiriX. Treatment efficacy was evaluated after every three cycles.
When the TMZ treatment started, the patient complained about recurrent headaches and blindness of the right eye (earlier, after the neurosurgery, she had light sensitivity and could see the contours of objects). MRI scans performed before TMZ therapy are presented in Figure 4. Initial maximal tumour dimensions were 3.441 × 3.916 cm in frontal (Figure 4(a): (A)) and 5.132 × 3.332 cm (Figure 4(a): (B)) in sagittal images and its volume was 16.2 mL (Figure 4(a): (C)).
TMZ was well tolerated: only nausea and vomiting were observed. After the first cycle of therapy, light sensitivity in the patient’s right eye recurred. Simultaneously, the level of ACTH in the serum was reduced by half of its initial concentration.
After three cycles, the patient reported further improvement of vision and an MRI examination revealed a reduction of tumour volume of about 3.2 mL (19.8%). The ACTH concentration in the serum was also lower.
After six cycles, the improvement of vision and general condition of the patient were obvious and well-marked. MRI scans showed a further reduction of tumour size (3.554 × 2.466 cm) (Figure 4(b): (A)) and 4.787 × 2.345 cm (Figure 4(b): (B)) in frontal and sagittal images, respectively, and a reduction of volume of about 1,21 mL (Figure 4(b): (C)). A total reduction of tumour volume after six cycles received 4.4 mL (27.3%) and the ACTH concentration decreased to 1/4 of its initial value. The results of TMZ treatment are shown in Table 2
All in all, till September 2012, the patient received 9 cycles of TMZ without progression of the disease and with a stable volume of the tumour.
Unfortunately, after TMZ withdrawal and a 6-month period of remission, the tumour progression causing ophthalmoplegia and the blindness of the right eye relapsed. Then bevacizumab (anti-VEGF antibody) was introduced. Transient clinical stabilization of the disease has been observed. The patient died after another neurosurgery intervention, propter postsurgical complications.
Q What are the other chemotherapeutic options in such a case
- Anti VEGF inhibitor Bevacizumab
- EGFR tyrosine kinase inhibitor GEFITINIB
Q What is the dosing regimen for Temozolomide ?
150-200 mg/m2 for 5 days every 28 days
Q Are corticotroph tumors more aggressive than other pituitary adenomas ?
Learning points from this case
- About 1/3rd of cases of operated Cushing’s disease have recurrence
- About 20% of patients with bilateral adrenalectomy develop Nelson’s syndrome
- Temozolomide can be used in patients with aggressive pituitary tumors not responding to conventional therapy.
- O6 methylguanine methyltransferase activity should be low in the tumor before starting medical therapy with Temozolomide.