The main goal of the surgical treatment in patients with acromegaly is to reduce the rate of morbidity and mortality to the normal rates in the general population, by managing the tumor growth and lowering the GH and IGF-I levels (
17,
23).
Better visualization and improvement in the resection of suprasellar and parasellar components of the adenoma with the development of expanded endoscopic transsphenoidal surgery are associated with better results (
24). The current study presented the results of biochemical remission, short-term outcome, and the predictive factors of endocrinological remission in a series of 49 patients with acromegaly who underwent expanded endoscopic transsphenoidal pituitary surgeries.
Over the past decades, the definition of biochemical remission of acromegaly changed noticeably. The 2000 consensus criteria, defined remission as normal age- and gender-adjusted IGF-I level and a random GH value > 2.5 ng/mL or GH value > 1 ng/mL during an OGTT test (
20). However; mortality rates remained high with these GH and IGF-I levels (
25). Therefore, with the recent development of highly sensitive and specific GH assays, more stringent criteria to define the biochemical remission of acromegaly are proposed. Recent 2010 consensus described remission as a random GH < 1 ng/mL or nadir GH levels < 0.4 ng/mL with OGTT and IGF-I levels within an age- and gender-adjusted normal range (
21). The current study used more stringent 2010 consensus criteria to describe the endocrinological remission of patients with acromegaly.
Several previous reports on microscopic or endoscopic resection of GH secreting pituitary adenomas used different criteria to define biochemical remission; thus, they cannot be directly compared to the current study results. In the current study, reanalyzing data, applying 2000 criteria, led to 8.2% higher remission rate (
Table 3).
Currently, there are a few published endoscopic studies using the 2010 criteria with the reported remission rates of 28.8% to 70.8% (
7,
19,
26-
33). The current study results showed an overall remission rate of 71.4% with the mean follow-up of 25.4 months. The current study used the minimum time of 3 months, since it was previously shown that postoperative IGF-I levels fluctuate and only stabilize at 3 months (
34). The remission rate of the current study was comparable to other endoscopic results using the 2010 criteria (
Table 5).
| First Author | Year of Publication | Number of Patients | Remission Rate, % | Follow-up Duration, mo |
|---|
| Xie | 2016 | 43 | 69.8 | 3-12 |
| Fathalla | 2015 | 42 | 45.2 | 66.1 |
| Sarkar | 2014 | 66 | 28.8 | 22.4 |
| Yildirim | 2014 | 56 | 66.1 | 6 |
| Fathalla | 2014 | 20 | 35 | 11 |
| Starke | 2013 | 72 | 70.8 | 18.4 |
| Shin | 2013 | 53 | 50.9 | 30 |
| Hazer | 2013 | 214 | 64.5 | 12 |
| Wang | 2012 | 43 | 67.0 | 34 |
| Jane | 2011 | 60 | 69.7 | 21.8 |
| Hofstetter | 2010 | 24 | 46 | 23 |
Several studies, similar to the current study result, reported that preoperative GH levels predicted remission using 2010 consensus criteria (
19,
27,
28). Various preoperative GH levels were predictive. Sarkar et al., and Starke et al., showed that a preoperative GH level < 40 ng/mL and GH < 45 ng/mL were associated with higher rates of remission, respectively (
27,
28).
In the current study, microadenomas had higher biochemical remission rates than macroadenomas (77.8% vs. 70%); but the difference was not significant. In contrast to earlier publications, tumor size was not an important predictive factor for remission in the current study (
19,
32,
33). Sarkar et al., revealed that an adenoma size < 20 mm was the predictor of outcome at follow-up (
27).
According to the Hardy-Wilson classification, there was no significant difference in remission rate among different stages or grades. This finding showed that suprasellar extension or sphenoid sinus invasions did not affect the success of endoscopic transsphenoidal surgery. Recent studies stated that the Hardy-Wilson grades and stages were the predictive values in achieving remission. Similar to the current study, Yildirim et al., reported that suprasellar extension did not affect the remission rate. However, cavernous sinus invasion and sphenoid sinus invasion were associated with lower rates of disease control (
30). Shin et al., showed that the Hardy stages C, D, and E were predictive against remission after endoscopic approach, albeit, no difference in remission were found between the Hardy grades (
32). As described earlier in the current study, 36.7% of the cases were classified as the Hardy-Wilson stage E (cavernous sinus invasion) with remission rate of 77.8%, which was considerably higher than reported in the literature. However, in the current study series, adenoma size and the Hardy grades and stages had no effect on achieving remission. Endoscopes enhance the visualization of the lateral and suprasellar extent of larger tumors; thus, suprasellar compartment and lateral extensions of tumor may be more accessible to the surgeon under direct vision (
35). In the current study, the extended approach significantly helped to explore the wall of the cavernous sinus directly and resect tumor extensions.
The current study analyzed the rate of remission according to the Knosp classification. In grade 0, 1, and 2 groups, there were 42 patients out of which 32 (76.2%) achieved remission. In grade 3 and 4 groups, there were 7 patients out of which 3 (42.9%) achieved remission. Although cavernous sinus involvement (the Hardy-Wilson stage E) did not solely affect the surgical outcome, these findings showed that the Knosp grade and degree of cavernous sinus involvement was an important predictive factor for hormonal remission. Higher degree of cavernous sinus invasion (the Knosp grades III and IV) associated with lower rate of remission. This finding was in accordance with those of the earlier studies (
19,
28,
30,
32). Due to the importance of the Knosp grade, careful preoperative review of MRI is necessary for surgical planning and the extent of resection (
36). Because of the better illumination, direct visualization, and by use of an angled endoscope, the endoscopic technique seemed superior to microscopic techniques to treat adenomas with cavernous sinus invasion (
37).
Age, gender, primary or secondary surgery, and basal IGF-I levels had no effect on achieving a remission (
Table 4).
Among 6 patients with discordant IGF-I and OGTT results at 3 months of follow-up, 2 patients achieved remission and 1 did not. Discordance rate was 6.1% (3 of 49 patients) in the last follow-up. Various studies obtained different discordance rates. In the endoscopic series, discordant values were observed in 11.5% to 35% of the patients (
19,
27,
28,
31). Despite the use of current sensitive assays and more stringent criteria to define remission, the rate of discordance still remains high. Several mechanisms are proposed to explain the postoperative discordance of GH and IGF-I including altered dynamics of the GH secretion after surgery, early postoperative hormone assay, GH nadir values not adjusted to age, gender, body mass index (BMI), the influence of concomitant medication, and co-existing physiologic, and pathologic conditions (
38).
One of the limitations of the presented series was the relatively small number of patients that may lead to failure to detect significant differences in outcomes. There were no cases classified as the Hardy stages C and D. Additionally, a long-term follow-up is necessary to determine the rates of remission and the growing experience of the surgeon may affect the outcomes and the rate of complications. Also, the role of pathobiological markers such as p53 and Ki 67 on the long-term outcome of growth hormone-secreting pituitary adenomas should be considered (
39).
4.1. Conclusion
The current study results demonstrated that the expanded endoscopic transsphenoidal approach to the resection of GH-secreting pituitary adenomas led to biochemical remission in 71.4% of patients, based on the 2010 criteria. Endoscopic technique facilitated the resection of suprasellar tumor extensions. It was observed that the lower preoperative GH and the Knosp scores significantly associated with achieving the higher rate of remission.