Objective: To observe the long-term efficacy of comprehensive treatment of invasive giant prolactinomas (IGPs) with bromocriptine as the first choice. Methods: Thirty-four patients who met the diagnostic criteria of IGPs were treated with bromocriptine, and 11 of them were treated with radiotherapy. The decision of surgery or stereotactic radiosurgery or the combination of both was made according to the residual site of tumor shrinkage, whether it continued to shrink significantly and whether there was drug resistance during the drug administration period. After surgery, maintenance treatment with low-dose bromocriptine was continued.
Results: The average follow-up period was 3316 months, 33 patients had significant improvement in symptoms, and 1 patient had no significant improvement in vision after radiotherapy. The mean reduction of tumor volume was 9114%, the mean decrease of prolactin was about 9711%, and the decrease of testosterone and hypocortisolism were reduced from 17 and 10 cases before treatment to 6 and 6 cases, respectively. Two cases of cerebrospinal fluid nasal leakage occurred during bromocriptine treatment, one case resolved on its own, and one case had a combined transsphenoidal and cranial approach to remove the tumor and repair the fistula.
Conclusion: IGPs should be treated with drugs first, and some patients can achieve the goal of tumor disappearance on imaging by drug therapy alone.
Prolactinomas; tumor infiltration; drug therapy; radiation therapy invasive giantp rolactinomas (IGPs) account for about 015%-210% of all pituitary adenomas [ 1, 2 ], because of the huge and invasive growth of the tumor, the effect of single surgery, drug and radiation therapy are not ideal, and the cure rate is low. In our report, 34 patients with IGPs were treated with bromocriptine as the first choice, supplemented with surgery and/or gamma knife therapy if necessary, and followed up for a long time.
Data and methods 1. General data: 34 patients with IGPs were admitted from December 1999 to April 2006, including 25 males and 9 females, aged 17-70 years, with an average age of 36 years. The duration of the disease ranged from 1 month to 10 years, with a mean of 313 years. The patients presented with decreased visual acuity and/or visual field changes in 28 cases (8214%); headache in 22 cases (6417%); sexual dysfunction in 18 cases (5215%), including decreased libido, erectile dysfunction and inability to ejaculate; menopause in 9 cases (100%); and lactation in 4 cases (4414%). The patients were selected strictly according to the diagnostic criteria of IGPs [ 3 ], among which 4 cases were recurrence after external transsphenoidal surgery, 1 case was stage I transsphenoidal resection of the pterygoid sinus and tumor in the nasal cavity, and the intracranial part of the tumor was to be removed in stage II craniotomy, and 2 cases were recurrence after external craniotomy.
2. Treatment: All patients were treated with bromocriptine at a dose of 215 mg/d at the beginning and gradually increased to 715 mg/d in three doses within 2 weeks. If the gastrointestinal reaction is heavy, the dosage should be increased slowly and started from 1125 mg/d. The PRL should be rechecked once every 1 to 2 months, and MRI, endocrine, blood routine, liver function, visual acuity and visual field should be rechecked once in the second half of the year in general. If PRL does not decrease significantly for 3 consecutive months, the dose of bromocriptine can be increased (but not more than 15 mg/d), and the majority of patients can achieve satisfactory efficacy with a dose of 715 mg/d. If the tumor does not continue to shrink, shrink significantly, shrink completely to the saddle, cannot tolerate the side effects of bromocriptine, or have white blood cell decline or abnormal liver function, the drug will be stopped and the decision of whether to perform transsphenoidal surgery or stereotactic radiosurgery or the combination of both will be made according to the site of residual tumor.
3.Follow-up: Outpatient follow-up mainly, together with telephone and internet, including the recovery of clinical symptoms, endocrine hormone measurement, cranial magnetic resonance visual acuity and visual field examination.
4. Statistical methods: The tumor volume on MRI (coronal) was calculated as V = V1 +V2 + ? +Vn = a1 b1 c1 + a2 b2 c2 + ? + an bn cn (a and b are the maximum diameter of each level perpendicular to each other, and c is the thickness of the level, usually 1 cm). The t-test was used for comparison between groups, the chi-square test was used for endocrine changes before and after treatment, and the relationship between decrease in PRL and tumor shrinkage was used for correlation analysis.
The follow-up time of this group of cases ranged from 6 to 77 months, with a mean time of 3316 months. 6 cases achieved the goal of tumor disappearance on imaging through drug treatment only, 4 cases achieved the goal of tumor disappearance through drug treatment with radiotherapy; 11 cases are still taking drugs for observation and follow-up (3 of them were treated with radiotherapy at the same time); 7 cases needed to cooperate with transsphenoidal surgery during drug treatment, supplemented with gamma knife treatment in 2 cases, and 2 cases were treated with gamma knife. Gamma knife treatment in 2 cases, proton knife treatment in 1 case, transsphenoidal + gamma knife treatment in 1 case, craniotomy + gamma knife treatment in 1 case, craniotomy and transsphenoidal surgery at the same time in 1 case (4 cases were treated with radiotherapy during the previous drug treatment).
The majority of patients showed good tolerance of bromocriptine during the first choice of treatment, and some patients showed gastrointestinal and neurological reactions such as nausea, vomiting and dizziness in the early stage of treatment, which improved after gradual increase of dosage. 1 case was treated by transsphenoidal surgery because of the more serious gastrointestinal reactions and 2 cases were treated by transsphenoidal surgery because of the decrease of white blood cells after 1 year of treatment. Two cases of cerebrospinal fluid nasal leakage, one of which recovered on its own and one of which was treated by combined craniotomy and transsphenoidal surgery after stopping the drug. After taking bromocriptine for 3-4 d, the majority of patients showed significant improvement in symptoms and recovery of pituitary function (see Table 1). 4 cases (1117% ) showed some degree of drug resistance.
2. Effect of radiotherapy Eleven patients were treated with radiotherapy at the same time as bromocriptine, and the average treatment time had reached 4216 months. In the 11 cases with radiotherapy, during the average follow-up period of 4216 months, 3 cases had more definite radiotherapy reactions such as slow response and significant memory loss.
3. Changes in PRL level and tumor volume control The average follow-up period of 34 patients was 3316 months, and the decrease of PRL was 9711%, and the average reduction of tumor volume on MRI was 9114%, while the average reduction of tumor was 9711% when 11 patients who were still taking medication and continued to be observed were excluded. In one of the female patients, after taking the medicine for 1 year, all the symptoms such as menopause, lactation and vision loss were restored and PRL was normal, but the size of tumor did not change.
The correlation between the reduction of tumor volume and the decrease of PRL was analyzed, and the correlation coefficient was r = 01606, and the hypothesis test of correlation coefficient was P < 0101, which indicated that the two were significantly correlated (Figure 1). Discussion The results of direct surgery for IGPs are high postoperative complications, long treatment time, and high treatment costs [ 1, 3 ], with mortality rates of 512% to 3112% and disability rates of 10% to 62% reported in the literature [ 4, 5 ], and recurrence rates of up to 100% at 5 years after surgery alone [ 6 ]. Most foreign scholars have consistently used dopamine agonists as the first-line treatment for prolactinomas, especially for large and giant adenomas, but the treatment of IGPs has been reported less frequently and in a limited number of cases [ 729 ]. In this study, a comprehensive treatment of IGPs with bromocriptine as the first choice was attempted, and transsphenoidal surgery or gamma knife treatment or a combination of both was promptly chosen if the following occurred during the observation period: (1) drug resistance or intolerance of drug side effects (2) complete reduction of the tumor to the saddle (3) residual tumor only in the cavernous sinus or slope site < 210 cm, (4) complications such as cerebrospinal fluid (4) complications such as cerebrospinal fluid leakage or pituitary stroke. The results showed that the tumor shrunk by 9114%, PRL decreased by 9711%, clinical symptoms were significantly improved, testosterone decreased and cortisol hypofunction was significantly restored, and most patients could return to normal life. Due to the good control of prolactinomatous pituitary adenoma by drug therapy and the development of microsurgical techniques, conventional radiotherapy is no longer necessary, and this study suggests that the choice of radiotherapy should be careful. The correlation analysis between tumor volume reduction and decrease in PRL level in our group of 34 patients showed r = 01606 with a hypothesis test of correlation coefficient of P < 0101, indicating a significant correlation between the two, indicating that the majority of patients had a gradual decrease in tumor size as PRL level decreased, contrary to the literature, where Shrivatava et al [ 2 ] reported 10 cases of giant prolactin adenomas, The correlation coefficient r = 0158, and there was no clear correlation between the two after hypothesis testing. The reasons for these differences may be related to the larger number of cases in this group and the longer duration of drug administration in some patients. However, one of the patients was special in that the decrease in PRL was not proportional to the decrease in tumor volume, the reason for which needs to be further investigated. The improvement of visual acuity and visual field of IGPs after bromocriptine treatment was significant and better than that of the surgical treatment group[ 1 ], and the difference was not statistically significant when compared with surgery[ 10, 11 ]. 34 patients had different degrees of improvement in clinical symptoms during drug treatment (one case had no significant improvement in visual acuity due to radiotherapy), and the visual acuity improved significantly even though MRI showed no significant tumor shrinkage. As to whether the tumor can be completely discontinued after the tumor disappears on imaging after long-term medication to achieve the real cure, longer follow-up is needed, but theoretically it cannot be achieved because the tumor has encroached into the normal structures such as cavernous sinus. The tumors of the three cases in this group disappeared after taking the medication and the follow-up time was more than 515 years, but the PRL did not drop to normal, and the PRL would rebound after stopping the medication, but the electron microscopic results after long-term medication and surgical treatment showed that the tumor cells were not completely concentrated, and some of the cells were necrotic. In our group, we also observed tumor fibrosis in some patients after long-term medication, but some patients did not have this phenomenon, so it is worth to further explore the deeper reasons.