Current Status of Surgery in Management of Prolactinomas
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.287668
Source of Support: None, Conflict of Interest: None
Keywords: Dopamine agonists, neuro-endocrinology, neurosurgery, prolactinomaKey Message: In carefully selected patients, over long-term, surgery for prolactinomas may be both cost-effective and efficient than medical management.
Prolactinomas, which constitute nearly 40% of all pituitary adenomas are also the most common functional pituitary adenomas. The reported prevalence of prolactinomas is 35 cases per 100,000 population with an annual incidence of 1.6-2.2 per 100,000 people.,, The incidence of prolactinomas is highest in child-bearing women and inpatients with multiple endocrine neoplasia, type 1. The goals of management of prolactinoma are to prevent neurologic morbidity and avoid derangement of endocrine function. Since managing a patient with a potential prolactinoma begins with correctly interpreting the prolactin level, growing evidence suggests that cut-off values should also consider size/volume of tumor (prolactin per cubic centimetre) and not just absolute prolactin level. In the current review, we will discuss the role of surgery and current trends in neurosurgery for these patients. Additionally, we also report our experience with surgical management of prolactinomas with apt case examples.
Although surgical management was preferred option of treatment of prolactinomas till early 1980, with the advent of dopamine agonists (DA), medical management assumed preference. Case 1 illustrates the role of DA like cabergoline (1 mg per week administered for 4 months) in the medical management of prolactinomas, witnessed by reduction in prolactin levels, improvement in visual fields and radiological improvement [Figure 1]. Although medical management is desirable, the necessity of long-term use of DAs, costs of medical management over long term, resistance and/or intolerance to DAs and requirement of continuous monitoring of prolactin levels form few drawbacks of long-term medical management. Additionally, in subsets of patients, like those with hyperprolactinemia, macro-prolactinomas and prolactinomas destructing the sella surgical management should be considered at the earliest possible. Additionally, women with prolactinomas (irrespective of the size of prolactinoma) planning pregnancy should prefer surgical management. Therefore, each prolactinoma should be treated on an individual case basis. [Table 1] summarizes indications where surgery may perhaps be the preferred option.
It is important that patient preference should always be respected, but it is advisable to explain the patients about benefits of medical therapy too. Importantly, the safety of the surgical cure should be explained to patients before scheduling surgery. Most often reported reasons for preference of surgery over medication in our practise are:
1. Avoiding the need for lifelong medication and cost-effectiveness
Current guidelines advise DAs for at least two years after normalization of hyperprolactinemia, followed by gradual tapering (to reduce side-effects). It should be noted that if DAs are discontinued, the reported rates of recurrence in 18 months are nearly 60%.
Therefore there is need for long term use of DAs in these patients, leading to increased costs incurred both due to medications and frequent screening of prolactin levels and radiological investigations as required. In fact, Zygourakis C C et al. have recently shown that in an average patient, if diagnosed of prolactinoma at an age of 40 years, lifetime cost of surgical management was 40.473 dollars. While the lifetime cost for 41,601 dollars for bromocriptine, it was 70,696 dollars for those prescribed cabergoline. Therefore, when carefully selected, surgery if more cost-effective management option. However, while elaborating the role of surgery as a definitive management, it should be explained to the patient that if surgery results in hypopituitarism or a residual lesion, DA therapy will be considered post-operatively, even if not previously attempted.
2. Plan pregnancy
Since the normalization of prolactin and resumption of menstrual cycles can take several months after initiating DA therapy, surgery is preferred in patients who plan pregnancy in near future. However, in these patients, guidelines suggest that surgical option should be undertaken only after failure of DA agents like cabergoline, especially despite failure of bromocriptine. Nayan Lamba et al. have very recently reported that in patients with prolactinomas, surgical management significantly improved the chances of fertility. Importantly, symptomatic enlargement of microprolactinomas in 5% and enlargement of macroprolactinomas in 35% pregnant patients with prolactinomas necessitated surgical management of prolactinomas. Especially in pregnant women with macroprolactinomas, increase in the size of prolactinoma may result in worsening of neurological deficits and vision loss, which may lead to untoward incidents. Hence, surgical removal of prolactinomas could be the management of choice in women desiring pregnancy.
3. Prolactinoma with Apoplexy and cystic prolactinomas
In patients with prolactinoma with apoplexy, acute changes in size are often reported during the apoplectic event with resultant neurologic compromise [Figure 2] and [Figure 3]. Optimal interventions should aim to change the size of the prolactinoma. Therefore, surgery has evolved as the recommendation for patients with symptomatic prolactinoma with apoplexy. Importantly, it is now well established that patients with pituitary adenomas and apoplexy should undergo neurosurgery at the earliest possible. Furthermore, timing of surgery in prolactinoma with apoplexy is similar to the urgency as in other types of pituitary adenomas. Similarly, in patients with cystic prolactinomas affecting/intruding the sella, surgical management should be the treatment of choice [Figure 2]. Current literature in patients with cystic prolactinomas reports more severe symptoms in these patients possibly due to the mass effect of “hypocellular” cyst. Studies have also reported these patients be “less responsive to DA”. Faje et al. reported their findings in 30 patients with cystic prolactinomas. Among the 30 patients, 22 underwent DA therapy and eight had surgery. The authors reported that 33% of patients in the DA- first group ultimately required surgery, which included three patients whose cysts grew. On the contrary, all patients undergoing surgery had optic chiasm decompression and reduction in cyst volume. Therefore, current guidelines recommend that surgery should the choice of intervention in these patients.
4. Prolactinoma with Visual Loss or Other Neurologic Deficits
Another scenario where surgical intervention is opted includes, prolactinoma patients with neurologic deficits (visual field deficits or cranial neuropathies), that are often reported in the subacute period without apoplexy. If meticulously managed at optimal dosages, when carefully selected, these patients may respond to medical management. However, patients in this subset are probably the best candidates for neurosurgical intervention. Therefore, the authors opine that all patients with prolactinomas and neurologic deficits should undergo neurosurgical consult. Patients who are too sick to undergo surgery, those who opt to avoid surgery and patients with early visual changes, medical management should be attempted.
5. Surgery after Dopamine Agonist Therapy – Intolerance
In most patients, DAs are well tolerated. However, the adverse effects from DA administration, documented in the literature, are often dose-dependent, especially due to the need to take these medications for many years. In patients treated with bromocriptine; 78% of patients experienced adverse effects with resultant discontinuation reported in 5% of patients.
Among other DAs, though less frequent, cabergoline is associated with headaches and rare adverse events such as intratumoral haemorrhage and cerebrospinal fluid, Case illustration - 2. Importantly, a small sub-set of patients are intolerant to both DA medications, making them ideal for surgical management. Importantly, in patients treated with cabergoline, while 8% had DA intolerance, the reported rates of DA resistance were marginally high at 10%. Similarly, in patients treated with bromocriptine, while DA intolerance was reported in 14% patients, DA resistance was observed in 18%. It is therefore very important to both differentiate and correctly identify intolerance and resistance to DA in these patients.
6. Dopamine Agonist Resistant Prolactinomas (DARP)
In a sub-set of patients, despite optimal dosages of DA (2 mg of cabergoiline per week for three months or 15 mg of bromocriptine per day), failure to demonstrate normalization of prolactin levels or achieve levels of ovulation or enable 50% reduction of hyperprolactinemia size are observed. This sub-set of patients are categorized as DA resistant prolactinomas (DARP), an accepted criteria for considering surgery [Figure 4]. In fact, almost half of surgical cases are after DA treatment failure. Additionally, 15.6% patients have a mixture of treatment failure and adverse effect intolerance. Encouragingly, surgical results in these patients are reportedly favourable, with 60.7% achieving normal prolactin levels. However, more than one-third of patients did not achieve prolactin normalization, this is often attributed to residual tumor which requires radiation. Case 4 illustrates a patient with increase in size of prolactinoma despite optimal medical management.
7. Surgery for Recurrent Prolactinomas
Although very rare, recurrent and aggressive prolactinoma is a treatment challenge. Most of these patients may be effectively treated using the multimodal strategy. Importantly, all patients with prolactinoma undergoing radiation therapy after surgical therapy should be closely monitored, and chemotherapy should be considered. Although prolactinomas rarely progress to pituitary carcinoma, when progressed, they often have extremely elevated MIB-1 and p53 expression and have a poor long-term prognosis., Andereggen L et al. have reported that the primary therapeutic strategy, but not adenoma size, was an independent risk factor for long-term dependence on dopamine-agonists. The authors in this comparative study reported that at final follow-up at 90 months, control of hyper-prolactinaemia required dopamine-agonist therapy in 64 % of women who had undergone primary medical therapy vs. 32 % of those who had primary surgical therapy (P = 0.003). The authors summarized that surgical management offered better control of prolactin levels than medical management.
In our centre, over the last 10 years, out of the 452 patients diagnosed with pituitary adenomas, 62 (13.7%) underwent surgery for prolactinoma. Representative images of the various indications for surgery for prolactinomas from our series of patients is illustrated as [Figure 1], [Figure 2], [Figure 3], [Figure 4] of the article.
Although, medical management using DA therapy is most widely used in patients with prolactinomas, patients who have neurologic symptoms related to the lesion and those at risk for treatment failure should be referred to a neurosurgeon. Surgical management should be strongly considered, in selected patients with prolactinoma with acute visual loss, or those intolerant to medical therapy, or with documented treatment failures and especially in patients with resistance to DA. Additionally, surgery is useful in women with prolactinomas who desire pregnancy/fertility. In carefully selected patients, over long-term, surgery for prolactinomas is not only more cost-effective than medical management with DA but also offers better control of prolactin levels.[18-20]
Case 1 illustrates the case of a 48-year-old male patient with a prolactinoma who showed Reduction in tumor size in response to cabergoline.
Case 2 illustrates the case of a 25-year-old male initial managed with medical treatment [Figure 2]a, but later on patient presented with CSF rhinorrhoea. Although in MRI there was reduction of lesion of size of tumor patient underwent surgery [Figure 2]b and [Figure 2]c.
Case 3 A 26-year-old female patients with cystic pituitary tumor [Figure 3] with high serum prolactin level was not responded with medical treatment and later on underwent surgical treatment.
Case 4 illustrates the case of a 33-year-old female patient with a prolactinoma [Figure 4]a who showed increase in tumor size despite optimal medical management using cabergoline (reduction in serum prolactin level) [Figure 4]b. This patient underwent surgical management due to increase in size of tumor.
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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]