Non-functioning pituitary adenoma (NFPA) is the most frequent type of pituitary tumor. This benign tumor is usually not life threatening and often presents as a macroadenoma larger than 10 mm. These macroadenomas can cause symptoms related to mass effect in which the optic apparatus is compressed, characteristically resulting in a bitemporal hemianopia. Patients can also suffer hypopituitarism secondary to compression of the normal pituitary gland. Most patients require surgery, and a trans-sphenoidal approach is considered the treatment of choice. Radical removal of the tumor mass results in improvement of visual symptoms in 80% of patients and relief of headache in almost 100% of patients [1], with most patients recovering completely after surgery.

A previous meta-analysis [2] found that most recurrence of NFPA occurs between one and five years after surgery, and that the rate of recurrence decreases after 10 years. However, in our experience, a significant proportion of NFPA recurs following a successful initial operation in the long-term follow-up period, suggesting that a longer follow-up period might reveal a higher recurrence rate. Despite possible tumor regrowth, recurrence cannot be detected before it is large enough to cause symptoms. NFPA is not related to the longevity survival and patients can expect normal life expectancy. Therefore, surgical resection of NFPA should not result in significant complications or morbidities. Residual or recurrent tumor can be treated with radiotherapy, stereotactic radiosurgery, or repeat surgery. However, obliteration of surgical landmarks, formation of scar tissue, and the effects of preoperative radiotherapy or medical treatment contribute to the difficulty of a repeat surgery. Complications are frequently followed by repeat surgery, and the rates of clinical remission are lower than those observed following a primary operation [3]. Radiotherapy or radiosurgery can be administered postoperatively as prophylaxis to inhibit recurrent growth.

Recurrence of NFPA after remission is well-recognized. However, the clinical predictive factors associated with recurrence are limited. Thus, the optimal treatment regimen and duration for this tumor have not yet been established. The purpose of this study was to determine the clinical outcome and risk factors of recurrence in order to provide an optimal therapeutic plan for NFPA.

Between January 2000 and January 2012, 1,592 consecutive patients underwent surgery for pituitary tumor at Samsung Medical Center. All surgical procedures were performed by one surgeon (Kim JH). With regard to the endocrine status of these tumors, 1,050 were hormone-secreting, functioning pituitary adenoma and were excluded from this study. From the remaining patients, those with insufficient data (such as loss of medical record, loss of MRI, or follow-up less than one year) and those initially treated at another institution were excluded from this study. The remaining 289 patients were enrolled in the study. Of these, 282 patients (97.6%) underwent surgery via the trans-sphenoidal approach, whereas the remaining seven patients (2.4%) received the trans-cranial approach. All patients underwent general anesthesia. In most cases, the standard microsurgical transseptal approach was used. The anterior wall of the sphenoid sinus was opened bilaterally, and any septum in the sphenoid was removed. The floor of the sella was opened with a high-speed drill, and the tumor was removed with standard instruments of the transsphenoidal approach. After tumor removal, the floor of the sella was reconstructed in most cases with harvested autograft abdominal fat and septal bone.

Initially, all tumors were diagnosed radiologically with MRI. In addition, MRI and CT results were evaluated to determine the size of tumor, extent of tumor, and invasion into the cavernous sinus. The size of the tumor was measured on the coronal view of gadolinium-enhanced T1-weighted image. The longest diameter measured was considered the tumor size. Post-operatively, MRI was performed in all patients to evaluate residual tumor. Gross-total resection (GTR) was defined as no residual enhancing mass on post-operative MRI. Near-total resection (NTR) was defined as suspicious residual enhancing mass on post-operative MRI or residual mass less than 10% of the initial size. Subtotal resection (STR) was defined as a significant residual mass greater than 10% of the initial size. We regarded the regrowth of a remnant tumor as a recurrence, because most recurrent pituitary tumors originate from remnant tumors. All treatments performed for residual masses before evidence of regrowth of residual tumor were considered adjuvant treatment. Conventional radiotherapy (RT) or gamma knife radiosurgery (GKS) was performed for adjuvant treatment of residual enhancing mass. After surgery, all tissue specimens were examined by specialized neuropathologists and were confirmed to be pituitary adenoma. The remnant tissue specimens were examined using immunohistochemistry.

NFPA has been reported to have a low probability of recur-rence, in part because many patients are not diagnosed until the recurrent tumor is large enough to cause a mass effect (i.e., compression of the optic apparatus or other structures). From this study, the PFS of NFPA was 60% at 10 years. These data suggest that a longer follow-up might reveal eventual tumor recurrence, and that it is important to find strategies to minimize recurrence. However, there is no consensus on the prognostic predictors of NFPA recurrence. Indeed, no single convincing prognostic factor for recurrence of NFPA was identi-fied in a previous meta-analysis study on NFPA [2]. In most studies, clinical factors of age, gender, tumor size and tumor invasion have had no predictive value on recurrence. Recently, many other factors that influence the proliferation of pituitary adenomas, such as angiogenesis, apoptosis, growth factors, oncogenes, tumor suppressor genes and hormone recep-tors, were introduced [456]. Ki-67 has been suggested as an independent marker of tumor progression and recurrence in pituitary adenomas in some previous studies [678]. However, in our study, Ki-67 was inconclusive as a prognostic indicator, possibly due to a lack of sufficient sample size. Still, such immunohistochemical staining approaches could help in determining whether patients need intensive follow-up MRI.

In this study, patients with no residual tumor on postoperative imaging and patients who underwent adjuvant radiotherapy (RT or GKS) showed a similar risk of tumor recurrence. This finding is in agreement with previous reports [91011] and suggests that gross total removal and/or adjuvant radiotherapy prevent the recurrence or regrowth of NFPA.

RT is usually reserved for NFPA patients whose tumors have the potential to behave more aggressively, are of considerable size, or have recurrence that might not be amenable to further surgery. In NFPA patients, RT results in excellent long-term local tumor control with reported rates of 90–97% at 10 years [12131415]. Previously, we found RT and GKS were efficient treatment modalities for the control of tumor growth in patients with pituitary adenomas; PFS was 99% at 2 years and 97% at 4 years, with no significant differences between the RT group and the GKS group [16]. Another study found that there was no major influence of RT on cognition in NFPA patients treated with RT compared to those treated with surgery alone [1718]. Brain abnormalities on MRI (white matter lesions and cerebral atrophy) were not observed more frequently in NFPA patients treated with postoperative RT compared to patients treated with surgery-alone [19]. Adjuvant radiotherapy should not be delayed because of such marginal complication rates. Radiosurgery such as GKS has reported fewer complications than RT; hence, it can be a better option for adjuvant treatment. We would like to recommend receiving GKS for adjuvant radiotherapy, when the residual mass is detected.

Considering the complications of radiation, gross total removal should be the goal of surgery. However, it is generally recognized that radical surgery is not possible in some patients with pituitary adenomas, and approximately 15–20% of patients require repeat surgery because of tumor recurrence [2021]. A meta-analysis of previous studies has found that the remission percentage of transsphenoidal surgery has not improved over the last three decades [2]. The majority of papers in that study were based on traditional surgery using microscopy. Endoscopic techniques have recently improved and are still advancing. The endoscopic technique is associated with shorter hospital stay, less blood loss, fewer nasal complications, and less frequent diabetes insipidus than conventional microscopic technique [222324]. One of the advantages of using an endoscope is the better view and resection of residual tumors due to the possibility of introducing the endoscope into the sella turcica and supra-sellar region, which would facilitate surgical cure [25]. Moreover, this might prevent major bleeding in the cavernous sinus and lesions in the internal carotid artery [26]. This endoscopic surgery might lead to better results in cases of NFPA.

In conclusion, NFPA is not a life threatening disease, and the patients can expect full life expectancy. There should not be significant complications or morbidities after operation. However, based on our experience and the findings of this study, there is a significant recurrence rate of NFPA even in long-term follow-up. Recurrence is one of the most troublesome clinical outcomes of NFPA. To reduce the recurrence rate of NFPA, neurosurgeons must attempt GTR. In addition, talented skill or endoscopic technique can be helpful. Despite all efforts for a cure, residual tumor can be controlled by adjuvant radiotherapy, especially GKS, with a minimal complication rate. We would like to recommend receiving GKS for adjuvant radiotherapy, when the residual mass is detected. Even though immunohistochemistry showed no promising results in the current study, a larger study population size will be needed to validate this finding. Investigation of the genetic pathophysiology of NFPA and improvement of surgical technique with advanced surgical equipment will lead to improved patient outcome.