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This Review summarizes the data on medical treatment of patients with prolactinomas. In particular, the authors focus on previous findings of an association between cardiac valve disease and treatment with dopamine agonists in patients with hyperprolactinemia and on the possibility that permanent control of prolactin levels can be achieved after withdrawal from these drugs. Prolactinomas, the most prevalent type of neuroendocrine disease, account for approximately 40% of all pituitary adenomas. The most important clinical problems associated with prolactinomas are hypogonadism, infertility and hyposexuality. In patients with macroprolactinomas, mass effects, including visual field defects, headaches and neurological disturbances, can also occur. The objectives of therapy are normalization of prolactin levels, to restore eugonadism, and reduction of tumor mass, both of which can be achieved in the majority of patients by treatment with dopamine agonists. Given their association with minimal morbidity, these drugs currently represent the mainstay of treatment for prolactinomas. Novel data indicate that these agents can be successfully withdrawn in a subset of patients after normalization of prolactin levels and tumor disappearance, which suggests the possibility that medical therapy may not be required throughout life. Nevertheless, multimodal therapy that involves surgery, radiotherapy or both may be necessary in some cases, such as patients who are resistant to the effects of dopamine agonists or for those with atypical prolactinomas. This Review reports on efficacy and safety of pharmacotherapy in patients with prolactinomas. Key Points Medical treatment of prolactinomas with cabergoline, quinagolide or bromocriptine is very efficacious; cabergoline has demonstrated superiority in efficacy to other drugs in many studies Cardiac valve disease induced by cabergoline treatment in patients with hyperprolactinemia is still a matter of debate In the absence of unequivocal proof excluding a negative effect of cabergoline in patients with hyperprolactinemia, all patients who receive long-term cabergoline treatment should undergo regular echocardiographic follow-up Long-term discontinuation of cabergoline or bromocriptine in patients with hyperprolactinemia of any cause has shown a variable rate of tumor recurrence; predictors of recurrence before cabergoline withdrawal are tumor diameter and prolactin levels Resistance to dopamine agonists is a rare phenomenon that characterizes a group of tumors that generally manifest with a more aggressive behavior than usual

Pituitary carcinoma is a rare entity comprising 0.1-0.2% of all pituitary tumors and presents significant diagnostic and therapeutic challenges. Intraspinal drop metastasis in these tumors is even rarer. We report a case of a prolactin secreting pituitary carcinoma with intracranial metastasis and multiple intraspinal drop metastasis. This is the first case where 68Gallium labelled [1,4,7,10 - tetraazacyclododecane - 1,4,7,10 - tetraacetic acid] -1- NaI3 - octreotide (68Ga-DOTANOC) whole-body positron emission tomography-computed tomography (PET-CT) has been used in a case of malignant prolactinoma, in an attempt to ascertain the somatostatin receptor (SSTR) expression on tumor cells. Through this paper, we suggest that SSTR targeted radionuclide therapy could have a potential role in aggressive pituitary tumors and pituitary carcinomas similar to the promising role of lutetium-labelled peptides in inoperable or metastasized gastroentero-pancreatic neuroendocrine tumors (GEP-NETs).

PurposeStereotactic radiosurgery is one of the treatment options for prolactinomas, the most commonly used being Gamma Knife Radiosurgery (GKRS). GKRS is indicated mainly in the treatment of dopamine agonist (DA)-resistant prolactinomas. In our study, we report on our experience in treating prolactinoma patients by GKRS.MethodsTwenty-eight patients were followed-up after GKRS for 26–195 months (median 140 months). Prior to GKRS, patients were treated with DAs and 9 of them (32.1%) underwent previous neurosurgery. Cavernous sinus invasion was present in 16 (57.1%) patients. Indications for GKRS were (i) resistance to DA treatment (17 patients), (ii) drug intolerance (5 patients), or (iii) attempts to reduce the dosage and/or shorten the length of DA treatment (6 patients).ResultsAfter GKRS, normoprolactinaemia was achieved in 82.1% of patients, out of which hormonal remission (normoprolactinaemia after discontinuation of DAs) was achieved in 13 (46.4%), and hormonal control (normoprolactinaemia while taking DAs) in 10 (35.7%) patients. GKRS arrested adenoma growth or decreased adenoma size in all cases. Two patients (8.3%) developed hypopituitarism after GKRS. Prolactinoma cystic transformation with expansive behaviour, manifested by bilateral hemianopsia, was observed in one patient.ConclusionsGKRS represents an effective treatment option, particularly for DA-resistant prolactinomas. Normoprolactinaemia was achieved in the majority of patients, either after discontinuation of, or while continuing to take, DAs. Tumour growth was arrested in all cases. The risk of the development of hypopituitarism can be limited if the safe dose to the pituitary and infundibulum is maintained.

Purpose There are limited treatment options for progressive atypical pituitary adenomas and carcinomas. Peptide receptor radionuclide therapy that targets somatostatin receptors has recently been proposed as a potential treatment option. The theoretical rationale for efficacy is elegant but evaluation of outcomes in the first patients treated for this indication is required to assess whether further study is warranted. Methods We performed a case review of the three pituitary patients we have treated with 177 Lutetium DOTATATE in our institution (two atypical adenomas, one carcinoma) and dosimetric analysis of the radiation uptake in one patient. Results Treatment was well tolerated. One patient with slowly progressive pituitary carcinoma has stable disease 40 months after completing the planned 4 cycles of treatment. Two patients with rapidly progressive atypical adenomas terminated treatment early due to continued disease progression. Dosimetric evaluation revealed inhomogenous uptake across the tumour (1.3–11.9 Gy with one cycle). Conclusion We have found mixed results in our first 3 patients with stable disease achieved only in the patient with the more slowly progressive tumour. As only a limited number of centres offer Peptide receptor radionuclide therapy, a formal study with prospective data collection may be feasible and if carried out should include dosimetric evaluation of absorbed dose.

We evaluated the efficacy of Gamma knife stereotactic radiosurgery (GKSR) as an adjunctive management modality for patients with drug resistant or intolerant cavernous sinus invasive prolactinomas. Twenty-two patients with cavernous sinus invasive prolactinoma underwent GKSR between 1994 and 2009. Thirteen patients were dopamine agonist (DA) resistant. Six patients were intolerant to DA. Three patients chose GKSR as their initial treatment modality in hopes they might avoid life long suppression medication. The median tumor volume was 3.0 cm 3 (range 0.3–11.6). The marginal tumor dose (median = 15 Gy, range 12–25 Gy) prescribed was based on the dose delivered to the optic apparatus. The median follow-up interval was 36 months (range, 12–185). Endocrine normalization was defined as a normal serum prolactin level off DA (cure) or on DA. Endocrine improvement was defined as a decreased but still elevated serum prolactin level. Endocrine deterioration was defined as an increased serum prolactin level. Endocrine normalization was achieved in six (27.3%) patients. Twelve (54.5%) patients had endocrine improvement. Four patients (18.2%) developed delayed increased prolactin. Imaging-defined local tumor control was achieved in 19 (86.4%) patients, 12 of whom had tumor regression. Three patients had a delayed tumor progression and required additional management. One patient developed a new pituitary axis deficiency after GKSR. Invasive prolactinomas continue to pose management challenges. GKSR is a non invasive adjunctive option that may reduce prolactin levels in patients who are resistant to or intolerant of suppression medication. In a minority of cases, patients may no longer require long term suppression therapy.

Review the medical and surgical management of patients with prolactinomas and provide an in-depth appraisal of the role of radiotherapy in the treatment of prolactinomas. A thorough review of the pertinent literature was carried out and relevant topics were identified. Topics covered in this comprehensive review include: indications for the use of radiotherapy, choice between conventional radiotherapy and stereotactic radiosurgery, as well as the benefits and potential complications associated with each modality. Due to the excellent response rates with medical management, and rapid symptom relief afforded by resection or debulking surgery in patients who do not respond or tolerate medical therapy, radiotherapy is reserved for patients who do not respond to dopamine agonists and surgery. Both external beam radiotherapy and stereotactic radiosurgery retain important roles in the treatment of refractory or recurrent prolactinomas. Choosing the optimal approach is crucial in maximizing tumor control outcomes and minimizing the risks associated with treatment. The primary determinants of optimal radiation approach are proximity of the tumor to the optic apparatus and tumor size, with radiosurgery being our recommended treatment of choice unless the tumor is larger than 3–4 cm or within 3 mm of the optic nerves, chiasm or tracts. Optimal multidisciplinary management requires the identification of appropriate candidates for radiotherapy in order to take full advantage of treatment options available for each patient.

We report clinical presentation, response to medical treatment, and long-term follow-up of 39 children and adolescents with prolactinoma (F:M; 30:9) (30 macro and 9 microadenoma) diagnosed at the age of 9-20 years. Mean duration of follow up was 56 months. All patients were treated with bromocriptine (BC) at doses ranging from 2.5 to 20 mg/day or by cabergoline at doses ranging from 0.5 to 2 mg/week orally. Two patients received external conventional radiotherapy after surgery. In patients with macroprolactinoma (F:M; 21:9), headache and/or visual defects were the first symptoms. All females had primary or secondary amenorrhea. Growth arrest was not observed in any patient and pubertal development was appropriate for their age. Spontaneous or provocative galactorrhea was observed in 23 patients (all females) and none of male patient had gynecomastia. Mean serum prolactin (PRL) concentration at the time of diagnosis was 322.50 ng/ml in patients with microadenoma, 522.38 ng/ml in patients with macroadenoma and 2,294.86 ng/ml in patients with macroadenoma with suprasellar extension. In 25 patients, BC normalized PRL levels and caused variable, but significant, tumor shrinkage. Cabergoline normalized PRL concentrations in 14 patients. Pregnancy occurred in 6 patients while on treatment. Pregnancies were uncomplicated, and the patients delivered normal newborns at term. Impairment of other pituitary hormone secretion was documented at the time of diagnosis in only one patient. Postoperatively six patients had other pituitary hormone deficiencies. In conclusion, the medical treatment with dopaminergic compounds is effective and safe in patients with prolactinoma with onset in childhood, allowing preservation of the anterior pituitary function.

This Review details treatment of prolactinomas that do not respond to dopamine agonists. Cabergoline is the most effective agonist and options include maximizing the dose and changing agonists. Trans-sphenoidal surgery is an option if medical therapy is ineffective. Radiation therapy is reserved for invasive tumors that do not respond to medical or surgical therapy. Resistance to dopamine agonists occurs in a subset of patients with prolactin-secreting pituitary tumors. The resistance is mediated by loss of pituitary D 2 receptors and occurs in both microadenomas and macroadenomas. Cabergoline is the most effective dopamine agonist and tumors that do not respond to bromocriptine or quinagolide frequently respond to cabergoline. Treatment options include maximizing the dose of the dopamine agonist, changing agonists, trans-sphenoidal surgery and radiation therapy. The goal of therapy is to restore and maintain gonadal and neurologic function, and this might occur in the absence of a normal prolactin level or a significant change in tumor size. Trans-sphenoidal pituitary surgery should be reserved for patients who are intolerant of medical therapy, or in whom this has failed. Radiation therapy has a limited role in treatment of resistant prolactinomas and should be reserved for patients in whom medical and surgical therapy has failed. Key Points 10–20% of patients with microprolactinomas and 20–30% of patients with macroadenomas demonstrate resistance to a dopamine agonist Treatment might restore and maintain gonadal and neurologic function without normalization of prolactin levels or a change in tumor size Tumors resistant to bromocriptine or quinagolide frequently respond to cabergoline Trans-sphenoidal surgery should be reserved for treatment of patients who are intolerant of medical therapy, or in whom this has failed

We report a case of sarcomatous transformation of a prolactin (PRL)-producing pituitary adenoma in a 27-year-old man. He originally presented with bitemporal visual disturbance, headache, and hyperprolactinemia 8 years earlier. Tumor shrinkage was confirmed by magnetic resonance imaging (MRI) during treatment with dopamine-receptor agonist. However, 3 years later transsphenoidal surgery had to be performed because of tumor re-growth. Histopathological examination revealed a PRL-producing adenoma with fibrotic changes. One year later, he presented with right-sided visual disturbance, and tumor re-growth was confirmed using MRI. He underwent transcranial surgery, followed by radiation therapy (50 Gy in 25 fractions). The histological and immunostaining features were similar in both specimens obtained from the two operations. Four years later, he presented with left-sided visual disturbance, and tumor re-growth was confirmed using MRI. The mass lesion dramatically increased in size within 2 months, and partial removal of the tumor by craniotomy was performed. The specimen was histologically diagnosed as malignant fibrous histiocytoma (MFH). Regardless of aggressive chemotherapy, his clinical symptoms and imaging findings worsened rapidly. He died 7 months after the diagnosis of MFH. Because patients with pituitary tumor undergoing radiotherapy face the possibility of developing such neoplasm, long-term follow-up is required.

Pituitary tumors are relatively uncommon, comprising 10-12% of all intracranial tumors. The treatment consisting of surgery, radiotherapy and drug therapy or a combination of these modalities is aimed at the control of tumor cell proliferation and--in endocrine active tumors--the reduction of hormone secretion. However, the slow proliferation characteristics of pituitary tumors necessitate long-term studies for the evaluation of the treatment results. In the last decade there has been continuous improvement in surgical procedures, radiotherapy techniques and drug generation. In this paper, literature will be reviewed to assess the role of modern radiotherapy and radiosurgery in the management of pituitary adenomas. Nowadays, magnetic resonance imaging for the definition of the target volume and a real three-dimensional (3-D) treatment planning with field conformation and the possibility for non-coplanar irradiation has to be recommended. Most groups irradiate these benign tumors with single doses of 1.8-2.0 Gy up to a total dose of 45 Gy or 50.4 Gy in extensive parasellar adenomas. Adenomas are mostly small, well circumscribed lesions, and have, therefore, attracted the use of stereotactically guided high-precision irradiation techniques which allow extreme focussing and provide steep dose gradients with selective treatment of the target and optimal protection of the surrounding brain tissue. Radiation therapy controls tumor growth in 80-98% of patients with non-secreting adenomas and 67-89% for endocrine active tumors. Reviewing the recent literature including endocrine active and non-secreting adenomas, irradiated postoperatively or in case of recurrence the 5-, 10- and 15-year local control rates amount 92%, 89% and 79%. In cases of microprolactinoma primary therapy consists of dopamine agonists. Irradiation should be preferred in patients with macroprolactinomas, when drug therapy and/or surgery failed or for patients medically unsuitable for surgery. Reduction and control of prolactin secretion can be achieved in 44-70% of patients. After radiotherapy in acromegaly patients somatomedin-C and growth hormone concentrations decrease to normal levels in 70-90%, with a decrease rate of 10-30% per year. Hypercortisolism is controlled in 50-83% of adults and 80% of children with Cushing's disease, generally in less than 9 months. Hypopituitarism is the most common side effect of pituitary irradiation with an incidence of 13-56%. Long-term overall risk for brain necrosis in a total of 1,388 analyzed patients was estimated to be 0.2%. Other side effects are rare too, and do also depend on the damage produced by tumor itself or preceding surgery. They include deterioration of vision in 1.7% of all cases, vascular changes in 6.3%, neuropsychological disorders such as dementia in 0.7% and secondary malignancies in 0.8%, if single doses of 2.0 Gy and total doses of 50 Gy are not exceeded. Conventional radiation therapy of pituitary adenoma is highly effective. It is recommended after subtotal resection of primary tumors such as macroadenomas, after gross total resection from endocrine active adenomas with postsurgical hormone secretion and for recurrent tumors. Radiosurgery seems to be a possible treatment alternative in experienced centers, and only in patients with adenomas smaller than 25-30 mm with a minimum distance of 2-3 mm to the chiasm.