**Figure 6.**

*Diagnosis algorithm for Cushing disease.*

#### **Figure 7.**

*Bilateral internal jugular vein catheterization (A) and selective contrast injection and sampling of bilateral inferior petrosal sinuses (B).*

It is important to mention that IPS sampling is not recommended for adenoma localization in previous surgically treated patients because the venous drainage of the pituitary gland lateralizes unpredictably after initial surgery [50].

*Pituitary Adenomas: Classification, Clinical Evaluation and Management DOI: http://dx.doi.org/10.5772/intechopen.103778*

### **7.3 Management**

The only current treatment is surgery, and the aim should be total adenomectomy. Surgical cure and recurrence rate depends on surgeon experience, adenoma size, extra-sellar extension, and adenoma detection on preoperative MRI. The definition of postoperative biochemical remission varies in the literature but cortisol levels in the early morning after surgery <5 μg/dl within 2–7 days of adenomectomy is widely considered to have high positive predictive value of remission [51].

Remission rate in surgically treated CD is 69–93% [52–54]. Recurrence rate after successful management is between 3 and 22% of patients after 3 years [50]. However, in patients whose preoperative MRI failed to show the adenoma, remission rate drops to 50–70% [54]. Adenomectomy resection using pseudocapsule technique in which the tumor is resected with its surrounding adherent pituitary cells is associated with higher success rate, longer remission rate, and higher rate of cortisol decline in the post-operative period (**Figure 8**) [45, 55].

In cases where the adenoma is small or not visualized on MRI, several options are available which will aid in intraoperative tumor localization. Waston et al. could localize ACTH-secreting adenomas by using intraoperative ultrasound in 69% of their patients with negative preoperative MRI [56]. If intraoperative ultrasound is not available or inconclusive, sellar exploration with making multiple cuts within the pituitary gland looking for the adenoma may be warranted. However, in such cases it is very important to expose the whole pituitary gland by wide removal of sellar floor bone and wide dural opening. Additionally, it is crucial to expose the anterior and medial walls of cavernous sinuses bilaterally for adequate visualization. If the exploration was not fruitful, then a partial hypophysectomy of the side that was lateralized by IPS sampling should be considered. Total hypophysectomy (i.e. removal of the anterior pituitary gland while leaving the posterior gland attached to the stalk) may be considered in cases where IPS sampling was unable to lateralize the adenoma, or in cases where intraoperative localization of the adenoma failed.

But the question is when to consider that patient has failed the surgical management and did not achieve remission?

Determining when to consider a patient has failed surgical management is difficult. As stated, all patients should have their cortisol levels evaluated the morning

#### **Figure 8.**

*A 30-year-old female patient presented with typical features of Cushing disease. Preoperative workup revealed high cortisol level. She was investigated with MRI pituitary with contrast which showed microadenoma involving the left half of the pituitary gland (A). The patient underwent endoscopic transsphenoidal total resection by utilizing pseudocapsular technique (B). She went to complete remission 36 hours after surgery.*

after surgery. Immediate postoperative cortisol levels may fluctuate. Generally after 72 h, cortisol level is stabilized, and therefore can be a better determinant of whether that the patient did not reach the remission state [57]. However, it was found that cortisol level ≤2 μg/dl within first 24 h after surgery there is a 100% sensitivity for durable remission [58]. A serum cortisol value >5 μg/dl up to 6 weeks post-surgery is considered to have persistent disease and should be considered for repeat surgery. Ten percent of patients who had durable remission after adenomectomy will develop recurrence of the disease, therefore, all patients need regular long follow-up for recurrence monitoring [59].

Then, what if the patient failed first surgery and remission did not achieved?

If a patient failed to achieve remission after their first surgery, it is always advisable to do an exploration of the pituitary gland and resect any remnant of the adenoma. Firstly, a pituitary MRI should be repeated; if MRI shows remnant adenoma, resection is needed as soon as possible. If MRI failed to show the remnant disease, surgical exploration of the resected cavity and possible partial or total hypophysectomy should be considered.

But, what if partial or total hypophysectomy have been done in first operation? In such cases, patient should receive medical therapy, radiotherapy, or other adjuvant therapy.

The aforementioned plan can also be adopted for recurrent disease after an initial biochemical cure. In terms of radiotherapy, stereotactic radiosurgery has the highest incidence of CD remission with rate of 70–75% according to recent reports [60, 61].

Most patients who had successful resection of the adenoma will develop hypocortisolism. This is happens due to longstanding suppression of normal corticotroph cells by high cortisol levels and it takes more than 6 months for those cells to recover. In our practice, we do the first cortisol level measurement 6 h after the surgery and we repeat it every 6 h for the first 3 days. We give replacement therapy (hydrocortisone 8 mg/m2 on early morning and 4 mg/m2 on evening) only if cortisol level < 1.8 ug/dl. Hypopituitarism occurs after adenoma resection in <5% of cases, therefore, pituitary function assessment should be usually done 2 weeks after surgery by measuring prolactin and T4 levels [45].

Lastly, Cushing's disease patients have an increased risk of venous thromboembolism (VTE). The incidence of postoperative VTE was found to be 3.4% in one study. Excess circulating corticosteroids cause inhibition of fibrinolysis and accelerated activation of coagulation factors. Even after correction of high cortisol level, Hypercoagulability state persist for extended period and the exact time of hemostatic parameters normalization is not well studied [62]. One proposed plan is to keep the VTE chemoprophylaxis up to 30 days after surgery [62].

### **8. Nonfunctional pituitary adenoma**

Non-functional, or non-secretory, adenomas constitute about 10–20% of all intracranial tumors and 15–30% of all pituitary adenomas [63]. They are the second most common pituitary adenoma after prolactinoma. However, if only macroadenomas are considered, NFPA is the most common one [64]. NFPA is unique compared to functional pituitary adenomas in different aspects. First, NFPA are usually seen in old age groups compared to functional adenomas. Second, patients present mainly with signs and symptoms of mass effect. Third, large number of patients have hypopituitarism in one or more of pituitary axes. On the other side, many of NFPA patients are detected incidentally (pituitary incidentalomas). The incidence of asymptomatic NFPA varies in the literature, but one large meta-analysis-autopsy study found the mean prevalence of pituitary incidentalomas was 10.7% [65].

The natural history of incidentally discovered NFPA remains relatively unknown. However, the risk of tumor expansion is related closely to tumor size on presentation and, to lesser extent, tumor relation to optic apparatus [66]. Microadenomas have a low chance of expansion (19%) compared to macroadenomas (25–50% of macroadenoma patients show tumor expansion on follow-up imaging) [66].
