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prolactinoma

Prolactinoma

Prolactinomas are the most common Functioning pituitary adenomas.

Types

Current classification systems rely on phenotypic elements and have few molecular markers for complementary classification.

Giant prolactinoma

Macroprolactinoma

Microprolactinoma

Cystic prolactinoma

Gene and protein expression

Seltzer et al. aimed to summarize prior research exploring gene and protein expression in prolactinomas in order to highlight molecular variations associated with tumor development, growth, and prolactin secretion. A PubMed search of select MeSH terms was performed to identify all studies reporting gene and protein expression findings in prolactinomas from 1990 to 2014.

1392 abstracts were screened and 51 manuscripts were included in the analysis, yielding 54 upregulated and 95 downregulated genes measured by various direct and indirect analytical methods. Of the many genes identified, three upregulated (HMGA2, HST, SNAP25), and three downregulated (UGT2B7, Let7, miR-493) genes were selected for further analysis based on our subjective identification of strong potential targets.

Many significant genes have been identified and validated in prolactinomas and most have not been fully analyzed for therapeutic and diagnostic potential. These genes could become candidate molecular targets for biomarker development and precision drug targeting as well as catalyze deeper research efforts utilizing next generation profiling/sequencing techniques, particularly genome scale expression and epigenomic analyses 1).

A total of 52 genes were identified as being significantly different between prolactinomas and normal samples which were classified into 29 COG functional categories. Three TFs, ZIC3 (Zic family member 3), NGFIC (nerve growth factor-induced protein C) and SP1 (Specificity Protein 1) were screened out, which can regulate part of DEGs. Two down-regulated genes, FSHB (follicle stimulating hormone β subunit) and LHB (luteinizing hormone β subunit) were involved in GnRH (gonadotropin releasing hormone) signaling pathway 2).

Epidemiology

Prolactinomas account for approximately 40 % of all pituitary adenomas. Over 95 % of prolactinomas are microadenomas (< 10 mm diameter).

Treatment

Treatment protocols for prolactinomas are also devoid of molecular targets, leaving those refractory to standard treatments without many options.

Treatment is indicated to correct hypogonadism, restore other hormonal deficits, and alleviate local mass effects.

Dopamine agonists

Dopamine agonists (DA) are highly effective in achieving these goals and are well-tolerated.

Cabergoline

The vast majority of prolactinomas will respond to conventional doses of cabergoline (≤2 mg/week) that do not carry an increased risk of cardiac valvular abnormalities. DA therapy may be successful withdrawn in a subset of patients and thus is not necessarily a lifelong commitment.

Cabergoline is typically effective for treating prolactinomas; however, some patients display cabergoline resistance, and the early characteristics of these patients remain unclear.

In general, cabergoline is the preferred treatment for micro- and macroprolactinomas, because it is more effective with respect to normalization of prolactin levels and reduction of prolactinoma size and because it has fewer side-effects compared to bromocriptine. Recently, it has been suggested that a standardized, individualized, stepwise, dose-escalating regimen of cabergoline may normalize prolactin levels and reduce prolactinoma size in patients who were otherwise considered to be dopamine agonist resistant. In general, the cardiac adverse effects of dopamine agonists reported in Parkinson's disease are not of clinical concern in the treatment of prolactinomas, which are treated with much lower doses. Nonetheless, there is uncertainty with respect to the dose and duration of cabergoline treatment, which requires echocardiographic follow-up. Although withdrawal of dopamine agonists may be considered in patients with prolactinomas well controlled by dopamine agonists, especially in postmenopausal women, recurrence of signs and symptoms may occur in a considerable portion of patients 3).

Determining cabergoline response using tumor volume reduction (TVR) and NP 3 months after treatment is useful for predicting later outcomes. However, further cabergoline administration should be considered for patients with TVR >25% at 3 months without NP, particularly those with huge prolactinomas, because a delayed response may be achieved. As surgery can reduce the cabergoline dose necessary for successful disease control, it should be considered for cabergoline-resistant patients 4).


Surgery is typically necessary in patients refractory to DA or other medical therapies, or in emergency situations in pa- tients presenting with pituitary apoplexy and rapidly progressing neurological symptoms due to mass effect.

Surgery provides the additional benefit of sampling the tumor pathology and a means to gauge the aggressiveness of the tumor, which may be evident on histopathology. It also allows for an immediate decrease in the mass effect and tumor bur- den. Increasingly, these tumors are being treated using the endoscopic endonasal technique. In the large cohort of 200 patients, Dehdashti et al. treated 25 prolactinomas with endoscopic endonasal surgery with a 92 % gross total resection rate and 88 % remission rate 5).

Surgery

Although transsphenoidal surgery (TSS) is an option for prolactinoma treatment, it is less effective than medical management, carries considerably more risk, and is more expensive. The benefit/risk ratio for DA therapy compared to TSS actually becomes increasingly more favorable as tumor size increases. Therefore DA should remain the clear treatment of choice for essentially all patients with prolactinomas, reserving TSS as a second-line option for the very small number of patients that do not tolerate or are completely resistant to DA therapy 6).

Many guidelines and reports that caution against surgical treatment are based on data over a decade or more old using different techniques such as microsurgical transsphenoidal surgery or from the nascent era of endoscopic transphenoidal surgery 7).

Endoscopic techniques have continued to evolve and provide for excellent visualization, low CSF leak rates, and high rates of gross total resection. In a study of DA-resistant prolactinomas, Vroonen et al. showed that surgical debulking led to a significant de- crease in prolactin levels at a significantly lower DA dose 8).

Kreutzer et al. report a remission rate of 91 % in patients who had elective surgery of microprolactinomas, and Babey et al. also had a high long-term remission rate, without morbidity or mortality for patients with microprolactinomas 9) 10).

Cost considerations are also a concern, especially in countries such as the USA, which is undergoing rapid changes in its healthcare system. A study by Jethwa and Patel et al. found surgical resection of microprolactinomas to be more cost effective long term than medical therapy 11).


Tumor size and invasion of extrasellar and/or cavernous sinuses have typically been seen as limitations of surgery, and some patients with refractory very large or giant tumors may necessitate multistage surgical procedures with a combi- nation of endonasal and transcranial approaches.

Radiosurgery could be considered as an adjunct treatment for residual disease although there is a risk of hypopituitarism and potential damage to the optic apparatus. Refinements in radiosurgery technology including more precise imaging, planning software, and delivery devices have improved the efficacy and reduced morbidity.

Expanded endoscopic endonasal techniques have been developed that allow for safe treatment of larger adenomas that have extra-/parasellar extension as long as the extension is in the cranio-caudal direction and not lateral to the carotids. However, the issue of partial resection and the risk of apoplexy in the residual irritated tumor is of some concern. As in many other areas of neuro-oncology, a combination approach may be optimal. Surgical resection may allow for definitive removal of the tumor and relief of the mass effect and provide tissue for precisely targeted therapies to prevent recurrence. Sophisticated immunohistochemistry and genetic testing are rapidly being applied to many other tumors and may in the future allow for superior targeted adjuvant therapies in prolactinomas and help reduce recurrences. Finally, surgery might be an answer to the long-term cost of medical therapy specifically in younger patients. However, this issue should be carefully assessed on an individual basis to not jeopardize the standard of care in prolactinoma management by unnecessary surgical treatment. Medical treatment remains the first and the treatment of choice in the general population with recently diagnosed prolactinoma in the absence of rapidly progressive neurological symptoms 12).

Costs

Few studies address the cost of treating prolactinomas.

The Department of Neurological Surgery, University of California at San Francisco, performed a cost-utility analysis of surgical versus medical treatment for prolactinomas. Materials and Methods We determined total hospital costs for surgically and medically treated prolactinoma patients. Decision-tree analysis was performed to determine which treatment produced the highest quality-adjusted life years (QALYs). Outcome data were derived from published studies. Results Average total costs for surgical patients were $19,224 ( ± 18,920). Average cost for the first year of bromocriptine or cabergoline treatment was $3,935 and $6,042, with $2,622 and $4,729 for each additional treatment year. For a patient diagnosed with prolactinoma at 40 years of age, surgery has the lowest lifetime cost ($40,473), followed by bromocriptine ($41,601) and cabergoline ($70,696). Surgery also appears to generate high health state utility and thus more QALYs. In sensitivity analyses, surgery appears to be a cost-effective treatment option for prolactinomas across a range of ages, medical/surgical costs, and medical/surgical response rates, except when surgical cure rates are ≤ 30%. Conclusion Our single institution analysis suggests that surgery may be a more cost-effective treatment for prolactinomas than medical management for a range of patient ages, costs, and response rates. Direct empirical comparison of QALYs for different treatment strategies is needed to confirm these findings 13).

Books

MRI of the Pituitary Gland By Jean-François Bonneville, Fabrice Bonneville, Françoise Cattin, Sonia Nagi

This clinically oriented book will familiarize the reader with all aspects of the diagnosis of tumors and other disorders of the pituitary gland by means of magnetic resonance imaging (MRI). The coverage includes acromegaly, Cushing’s disease, Rathke cleft cysts, prolactinomas, incidentalomas, Clinically nonfunctioning pituitary adenomas, other lesions of the sellar region, hypophysitis, and central diabetes insipidus. Normal radiologic anatomy and the numerous normal variants are described, and guidance is also provided on difficulties, artifacts, and other pitfalls. The book combines concise text and high-quality images with a question and answer format geared toward the needs of the practitioner. MRI is today considered the cornerstone in the diagnosis of diseases of the hypophyseal-hypothalamic region but the relatively small size of the pituitary gland, its deep location, the many normal anatomic variants, and the often tiny size of lesions can hinder precise evaluation of the anatomic structures and particularly the pituitary gland itself. Radiologists and endocrinologists will find MRI of the Pituitary Gland to be full of helpful information on this essential examination, and the book will also be of interest to internists and neurosurgeons.

Literature review

A systematic literature review was performed utilizing the PRISMA guidelines. Seltzer et al. aimed to summarize prior research exploring gene and protein expression in prolactinomas in order to highlight molecular variations associated with tumor development, growth, and prolactin secretion. A PubMed search of select MeSH terms was performed to identify all studies reporting gene and protein expression findings in prolactinomas from 1990 to 2014.

1392 abstracts were screened and 51 manuscripts were included in the analysis, yielding 54 upregulated and 95 downregulated genes measured by various direct and indirect analytical methods. Of the many genes identified, three upregulated (HMGA2, HST, SNAP25), and three downregulated (UGT2B7, Let7, miR-493) genes were selected for further analysis based on our subjective identification of strong potential targets.

Many significant genes have been identified and validated in prolactinomas and most have not been fully analyzed for therapeutic and diagnostic potential. These genes could become candidate molecular targets for biomarker development and precision drug targeting as well as catalyze deeper research efforts utilizing next generation profiling/sequencing techniques, particularly genome scale expression and epigenomic analyses 14).

Case series

Akin et al report herein a retrospective analysis of the results of 142 consecutive prolactinoma cases operated upon using an endoscopic endonasal trans-sphenoidal approach over a period of 6 years.

Medical records of 142 cases were analysed with respect to indications for surgery, duration of hospital stay, early remission rates, failures and recurrence rates during a median follow-up of 36 months.

On the basis of magnetic resonance imaging (MRI) data, 19 patients (13.4 %) had microadenoma, 113 (79.6 %) had macroadenoma, and the remaining 10 (7.0 %) had giant adenomas. Cavernous sinus invasion was identified in 25 patients by MRI and confirmed during surgery. Atypical adenoma was diagnosed in 16 patients. Sparsely granulated prolactin adenoma was identified in 99 patients (69.7 %). Our results demonstrate that male sex and higher preoperative prolactin levels are independent factors predicting persistent disease. The post-surgical complications are as follows: 2.8 % patients had meningitis, 2.1 % patients had postoperative cerebrospinal fluid leak and 2.1 % patients had panhypopituitarism. At the end of follow-up, 74.6 % patients went into remission. During follow-up period, five patients who had initial remission developed recurrence.

This series together with literature data suggest that an endoscopic endonasal trans-sphenoidal approach in the treatment of proloctinomas has a favourable rate of remission. According to the findings of this study, endoscopic endonasal trans-sphenoidal surgery might be an appropriate therapy choice for patients with prolactinoma who could not have been managed with recommended therapeutic modalities 15).

Case reports

2016

Two cases of well-controlled prolactinoma on dopamine agonists with the development of acromegaly 10-20 years after the initial diagnoses. In both patients, a mixed PRL/GH-cosecreting adenoma was confirmed on the pathology examination after transsphenoidal surgery (TSS). Therefore, periodic routine measurements of IGF-1 should be considered regardless of the duration and biochemical control of prolactinoma.

Acromegaly can develop in patients with well-controlled prolactinoma on dopamine agonists.The interval between prolactinoma and acromegaly diagnoses can be several decades.Periodic screening of patients with prolactinoma for growth hormone excess should be considered and can 
lead to an early diagnosis of acromegaly before the development of complications 16).

2014

A case of sarcomatous transformation of a prolactin (PRL)-producing pituitary adenoma in a 27-year-old man, 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 17).

1) , 14)
Seltzer J, Scotton TC, Kang K, Zada G, Carmichael JD. Gene expression in prolactinomas: a systematic review. Pituitary. 2015 Aug 4. [Epub ahead of print] PubMed PMID: 26238304.
2)
Zhao L, Lin M, Wang S. Identification of human prolactinoma related genes by DNA microarray. J Cancer Res Ther. 2014 July-September;10(3):544-548. doi: 10.4103/0973-1482.137962. PubMed PMID: 25313736.
3)
Romijn JA. Hyperprolactinemia and prolactinoma. Handb Clin Neurol.2014;124:185-95. doi: 10.1016/B978-0-444-59602-4.00013-7. PubMed PMID: 25248588.
4)
Lee Y, Ku CR, Kim EH, Hong JW, Lee EJ, Kim SH. Early prediction of long-term response to cabergoline in patients with macroprolactinomas. Endocrinol Metab (Seoul). 2014 Sep;29(3):280-92. doi: 10.3803/EnM.2014.29.3.280. Epub 2014 Sep 25. PubMed PMID: 25309786.
5)
Dehdashti AR, Ganna A, Karabatsou K, Gentili F (2008) Pure en- doscopic endonasal approach for pituitary adenomas: early surgical results in 200 patients and comparison with previous microsurgical series. Neurosurgery 65:1006–1015
6)
Bloomgarden E, Molitch ME. Surgical treatment of prolactinomas: cons. Endocrine. 2014 Aug 12. [Epub ahead of print] PubMed PMID: 25112227.
7)
Casanueva FF, Molitch ME, Schlechte JA, Abs R, Bonert V, Bronstein MD, Brue T, Cappabianca P, Colao A, Fahlbusch R, Fideleff H, Hadani M, Kelly P, Kleinberg D, Laws E, Marek J, Scanlon M, Sobrinho LG, Wass JA, Giustina A (2006) Guidelines of the pituitary society for the diagnosis and management of prolactinomas. Clin Endocrinol 65:265–273
8)
Vroonen L, Jaffrain-Rea ML, Petrossians P, Tamagno G, Chanson P, Vilar L, Borson-Chazot F, Naves LA, Brue T, Gatta B, Delemer B, Ciccarelli E, Beck-Peccoz P, Caron P, Daly AF, Beckers A (2012) Prolactinomas resistant to standard doses of cabergoline: a multicen- ter study of 92 patients. Eur J Endocrinol 167:651–662
9)
Babey M, Sahli R, Vajtai I, Andres RH, Seiler RW (2011) Pituitary surgery for small prolactinomas as an alternative to treatment with dopamine agonists. Pituitary 14:222–230
10)
Kreutzer J, Buslei R, Wallaschofski H, Hofmann B, Nimsky C, Fahlbusch R, Buchfelder M (2008) Operative treatment of prolactinomas: indications and results in a current consecutive series of 212 patients. Eur J Endocrinol 158:11–18
11)
Jethwa PR, Patel TD, Hajart AF, Eloy JA, Couldwell WT, Liu JK (2015) Cost-effectiveness analysis of microscopic and endoscopic transsphenoidal surgery versus medical therapy in the management of microprolactinoma in the United States. World Neurosurg 5:2015
12)
Chakraborty S, Dehdashti AR. Does the medical treatment for prolactinoma remain the standard of care? Acta Neurochir (Wien). 2016 May;158(5):943-4. doi: 10.1007/s00701-016-2763-y. Epub 2016 Mar 11. PubMed PMID: 26965287.
13)
Zygourakis CC, Imber BS, Chen R, Han SJ, Blevins L, Molinaro A, Kahn JG, Aghi MK. Cost-Effectiveness Analysis of Surgical versus Medical Treatment of Prolactinomas. J Neurol Surg B Skull Base. 2017 Apr;78(2):125-131. doi: 10.1055/s-0036-1592193. Epub 2016 Sep 27. PubMed PMID: 28321375; PubMed Central PMCID: PMC5357228.
15)
Akin S, Isikay I, Soylemezoglu F, Yucel T, Gurlek A, Berker M. Reasons and results of endoscopic surgery for prolactinomas: 142 surgical cases. Acta Neurochir (Wien). 2016 May;158(5):933-42. doi: 10.1007/s00701-016-2762-z. Epub 2016 Mar 12. PubMed PMID: 26970763.
16)
Manuylova E, Calvi LM, Hastings C, Vates GE, Johnson MD, Cave WT Jr, Shafiq I. Late presentation of acromegaly in medically controlled prolactinoma patients. Endocrinol Diabetes Metab Case Rep. 2016;2016. pii: 16-0069. PubMed PMID: 27855229.
17)
Kurosaki M, Kambe A, Ishibashi M, Watanabe T, Horie Y. A case report of sarcoma of the sella caused by postoperative radiotherapy for a prolactin-producing pituitary adenoma. Brain Tumor Pathol. 2014 Jan 21. [Epub ahead of print] PubMed PMID: 24446079.
prolactinoma.txt · Last modified: 2017/06/15 00:51 by administrador