CYSTIC PROLACTINOMA: A SURGICAL DISEASE?

Transcription

1 AACE Clinical Case Reports Rapid Electronic Articles in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Case Report ACCR CYSTIC PROLACTINOMA: A SURGICAL DISEASE? Kayur R. Bhavsar DO 1, Kristi D. Silver MD 1 Running Title: Cystic Prolactinoma: A Surgical Disease? From: 1 Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA Corresponding author: Kristi D. Silver, M.D., University of Maryland School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, 670 West Baltimore Street, Room 4081, Baltimore, MD 21201, ksilver@som.umaryland.edu Keywords: Prolactinoma, Cystic, Transsphenoidal Surgery (TSS), Dopamine Agonists (DA)

2 ABSTRACT: Objective: Since the advent of dopamine agonists, prolactinomas have been primarily treated medically. However, studies show conflicting data on whether these agents are as effective as surgery for predominantly cystic prolactinomas. We present a case of a patient with a cystic prolactinoma for which surgery was selected as first line therapy. Methods: Literature review. Results: A 26-year-old African American man presented to an outside hospital with complaints of dull right-sided headaches for 1 week. The headache worsened over the next few days, which prompted him to go to the ER. The evaluation included a head CT which demonstrated a 4 cm solid/cystic pituitary mass with possible hemorrhagic conversion and compression of the optic chiasm. He was transferred to University of Maryland Medical Center for neurosurgical evaluation. He denied symptoms of pituitary hormone excess or deficiency. He denied visual symptoms, though formal visual field testing demonstrated temporal hemianopia. Hormonal evaluation revealed hyperprolactinemia (prolactin=1627 ng/ml) and central hypothyroidism (TSH=2.72 uiu/ml; FT4=0.5 ng/dl). Because of the large cystic component of the prolactinoma and clinical evidence for compression of the optic chiasm, the patient underwent transsphenoidal resection of the mass. Post-operatively, the patient was started on Bromocriptine for suppression of residual prolactinoma tissue. Notably, the patient developed several complications postoperatively including diabetes insipidus and secondary hypogonadism.

3 Conclusion: Initial management strategies for cystic prolactinomas have been debated. This case highlights the importance of careful consideration of both medical and surgical treatment options in patients with prolactinomas with large cystic components. Abbreviations: DDAVP = Desmopressin, DI = Diabetes Insipidus, DA = Dopamine Agonists, TSS = Transsphenoidal Surgery, UMMC = University of Maryland Medical Center. INTRODUCTION: Prolactinomas have long been considered a medically treatable disease. First line therapy, in most cases, are dopamine agonists. Indications for surgical treatment of prolactinomas include failure to respond or intolerable side effects to dopaminergic therapy, rapidly progressing visual or neurological deficits, cerebrospinal fluid leak and fistula formation, size of adenoma, degree of invasiveness, and patient preference. However, conflicting recommendations exist on whether a pharmacologic versus surgical approach be used to manage patients with predominantly cystic prolactinomas (defined as >50% being cystic).

4 CASE REPORT: A 26-year-old African American man presented to the emergency room of an outside hospital with complaints of dull right-sided headaches for 1 week. He first noticed the headache on waking, after drinking heavily the night before. He initially attributed this to a hangover, but the headache worsened over the next few days, which prompted him to go to the emergency room. The initial evaluation included a head CT which demonstrated a 4 cm solid/cystic pituitary mass with concern for hemorrhagic conversion and compression of the optic chiasm. He was transferred to University of Maryland Medical Center (UMMC) for neurosurgical evaluation. His past medical history was significant for childhood epilepsy; however, he was not on antiepileptic medication and denied having any seizures for many years. He drank socially, up to 5 beers on the weekends, smoked 5 cigarettes per day for about 5 years, and used marijuana intermittently. He was not taking any medications and denied any significant familial medical problems including pituitary adenomas or malignancy, MEN syndrome, craniopharyngiomas, or Rathke s cleft cysts. He denied symptoms of pituitary hormone excess or deficiency including galactorrhea, changes in ring or shoe size, weight gain, decreased libido, erectile dysfunction, heat or cold intolerance, changes in bowel function, dizziness, light-headedness, blurry vision, loss of peripheral vision, or diplopia.

5 On physical examination, the patient was afebrile, blood pressure 115/69, and pulse 60. He did not have central adiposity or a dorsocervical fat pad. His facies were not Cushingoid. He did not have prognathism, diastema or frontal bossing. His thyroid was normal size. He did not have gynecomastia or galactorrhea. His abdomen was non-tender without striae. Formal visual field testing performed on day 2 of hospitalization by ophthalmology demonstrated temporal hemianopia on the left and nasal step plus extensive superior and inferior arcuate defect on the right. Hormonal evaluation revealed hyperprolactinemia with a prolactin level of 1627 ng/ml ( ng/ml) and central hypothyroidism with a TSH of 2.72 uiu/ml ( miu/l) and free T4 of 0.5 ng/dl ( ng/dl). The patient was started on a weight-based dose of Levothyroxine 100 mcg daily. His 4:30 AM Cortisol was 13.1 mcg/dl, and his IGF-1 was 99 ng/ml ( ng/ml) (Table 1). MRI of the patient s brain confirmed the presence of a 4 cm heterogeneously enhancing solid and cystic mass, enlarging the sella turcica, extending into the suprasellar cistern, compressing the optic chiasm, hypothalamus, and elevating the third ventricle (Figure 1). Because large cystic components of prolactinomas may not resolve with medical treatment alone, coupled with clinical evidence for compression of the optic chiasm, the patient underwent transsphenoidal resection of the mass. Immunostaining of the resected adenoma showed that the tumor is strongly and diffusely positive for prolactin, and focally positive for growth hormone. The tumor was negative for ACTH, FSH, LH, and TSH. Post-operatively, the patient was started

6 on Bromocriptine 2.5 mg PO daily (later changed to Cabergoline 0.5 mg twice weekly as outpatient) for suppression of residual prolactinoma tissue. The patient developed Diabetes Insipidus (DI) on post-operative day 3 requiring desmopressin (DDAVP) for the remainder of his hospitalization. He was discharged on DDAVP 200 mcg orally twice daily, which was eventually tapered off about 1 month post-operatively. Outpatient testing of gonadotropins and testosterone demonstrated central hypogonadism with a total testosterone level of 21.4 ng/dl ( ng/dl), LH of 0.6 miu/ml ( miu/ml) and FSH of 3.1 miu/ml ( miu/ml). He was subsequently started on Testosterone 1.62% 2 pumps daily. The patient s 2-month post-operative MRI demonstrated a decrease in the size of the residual pituitary mass (4cm 1.5 cm), and decompression of the optic chiasm. At 4 months post-surgery, the MRI demonstrated a slight interval decrease in size and regional mass effect of the residual pituitary mass which measured 1.5 X 1.6 X 1.7 cm. The patient s prolactin levels trended down from 1627 ng/ml (pre-op) to 227 ng/ml (2 months post-op). His prolactin reached a nadir of 82.8 ng/ml at 4 months post-op; however with his 7 months post-operative labs, the prolactin level increased to ng/ml. He reported compliance taking Cabergoline 0.5 mg twice weekly. By 7 months after surgery, his thyroid function remained normal off of Levothyroxine with a TSH of uiu/ml and a FT4 of 0.86 ng/dl. His 8 am cortisol secretion was adequate at 12.6 ug/dl.

7 Testosterone remained low with a total testosterone of 71 ng/dl and a free testosterone of 3.7 pg/ml. The patient was lost to follow-up 7 months after surgery. DISCUSSION: Cystic prolactinomas are thought to have both prolactinoma and Rathke s cleft cyst components. As a result, cystic prolactinomas have been termed transitional cell tumors of the pituitary [2]. Older literature indicates that cystic prolactinomas are not amenable to dopamine agonist therapy due to the absence of dopamine receptors in the cystic portions of these tumors [6]. However, retrospective studies show comparable remission rates for primary medical versus surgical treatment for cystic prolactinomas [1]. For example, Kreutzer et al. showed that 80% of patients with cystic prolactinomas (n=50) had remission following transsphenoidal resection [1]. As shown by Faje et al. and others, this remission rate is similar to the most favorable remission rates for primary dopamine agonist therapy [7]. In Faje s study of 30 patients with cystic prolactinomas treated with dopamine agonists, prolactin normalized in 18 of 22 patients and persistent cyst volume was reduced in 20 of the patients by an average of 83.5%. Despite these improvements, 15 of the 30 patients eventually went on to need surgery for their prolactinomas. The authors theorized that the mechanism for decrease in cyst size with dopamine agonists may be the result of shifts in equilibrium of fluid turnover in tumor cells lining the cysts, or by inducing tumoral hemorrhage or cyst rupture [7].

8 While the WHO classification of pituitary tumors notes that men with prolactinomas have higher recurrence rates, studies have not examined if this finding is also the case for cystic prolactinomas. Prospective randomized control trials have not yet been performed to delineate whether surgical or medical interventions or a combination of both afford patients with cystic prolactinomas the best outcome. However, some small studies show positive responses to medical therapy alone [4]. For instance, Bahuleyan et al. demonstrated that in a group of 6 patients with cystic prolactinomas treated solely with dopamine agonists that at final follow-up (average of 4.75 years after initiation of bromocriptine), 3 patients had both hormonal and radiologic cure and 3 had reduction in the size of the tumor [4]. The main limitation to these studies was the small number of subjects. For patients in which dopamine agonists alone do not adequately shrink the cystic portion of the tumor, surgical resection may be required when visual impairment, neurologic sequelae, pressure effects of the tumor, CSF leak, and/or poor tolerance to dopamine agonist develop [5]. One such case published by Razzaq et al. describes a 23-year-old female with headaches, amenorrhea, and visual field defects with a prolactin level of 3800 ng/dl who was found to have a sellar mass with a large central cystic component. The patient was initially treated with Bromocriptine with reduction in the prolactin level to 1512 ng/dl. During a 3-month period, her visual field deficits progressed. As a result, she underwent resection of the cystic and solid portions of the tumor. Postoperatively the patient s visual field deficits improved with normalization of prolactin levels to 28 ng/dl [5]. Predictors of when to expect shrinkage of cystic components of prolactinomas after treatment with dopamine agonists have yet to be established.

9 CONCLUSION: Although morbidity and mortality of transsphenoidal surgery is low, outcomes are highly dependent on the skill and experience of the neurosurgeon. [3] Larger randomized studies are needed to compare medical versus surgical outcomes over time. Until this information is available, risks of surgical versus medical therapy should be evaluated on a case-by-case basis. Author Disclosure Statement: No competing financial interests exist for Kayur R. Bhavsar or Kristi D. Silver. REFERENCES: 1. Kreutzer J, Buslei R, Wallaschofski H, Hofmann B, Nimsky C, Fahlbusch R, Buchfelder M. Operative treatment of prolactinomas: indications and results in a current consecutive series of 212 patients. Eur J Endocrinol : Inder WJ, Macfarlane MR. Hyperprolactinaemia associated with a complex cystic pituitary mass: medical versus surgical therapy. Intern Med J : Ogiwara T, Horiuchi T, Nagm A, Goto T, Hongo K. Significance of surgical management for cystic prolactinoma. Pituitary : Bahuleyan B, Menon G, Nair S, Rao BR, Easwer HV, Krishna K. Non-surgical management of cystic prolactinomas. J Clin Neurosci. 2009;16: Razzaq AA1, Jooma R, Ahmed S. Surgery for prolactinomas. J Pak Med Assoc ;56:181-3.

10 6. Iglesias P1, Díez JJ. Macroprolactinoma: a diagnostic and therapeutic update. QJM. 2013;106: Faje A, Chunharojrith P, Nency J, Biller BM, Swearingen B, Klibanski A. Dopamine Agonists Can Reduce Cystic Prolactinomas. J Clin Endocrinol Metab ;101: Table 1. Test Results Reference AM Cortisol 13.1 mcg/dl mcg/dl TSH 2.72 miu/l miu/l FT4 0.5 ng/dl ng/dl IGF-1 99 ng/ml ng/ml Prolactin 1627 ng/ml ng/ml

11 Figure 1- Pre-operative MRI Figure 1a. Sagittal view: 4 cm heterogeneously enhancing solid and cystic mass enlarging the sella turcica and extending into the suprasellar cistern

12 Figure 1b. Coronal view: 4 cm mass with large central cystic component and blood/fluid level, elevating third ventricle, extending into the right cavernous sinus and compressing the optic chiasm