Management of giant prolactinoma causing craniocervical instability: illustrative case

BACKGROUND Giant prolactinomas (>4 cm) are a rare entity, constituting less than 1% of all pituitary tumors. Diagnosis can usually be achieved through endocrinological analysis, but biopsy may be considered when trying to differentiate between invasive nonfunctioning pituitary adenomas and primary clival tumors such as chordomas. OBSERVATIONS The authors presented a rare case of a giant prolactinoma causing significant clival and occipital condyle erosion, which led to craniocervical instability. They provided a review of the multimodal management. Management involved medical therapy with dopamine agonists, and surgery was reserved for acute neural compression or dopamine agonist resistance, with the caveat that surgery was extremely unlikely to lead to normalization of serum prolactin in dopamine agonist–resistant tumors. LESSONS Adjunctive surgical therapy may be necessary in cases of skull base erosion, particularly when erosion or pathological fractures involve the occipital condyles. Modern posterior occipital-cervical fusion techniques have high rates of arthrodesis and can lead to symptomatic improvement. This procedure should be considered early in the multimodal approach to giant prolactinomas because of the often dramatic response to medical therapy and potential for further craniocervical instability.

Isolated Macroprolactinomas in Four Young Adult Males Harboring a Variant of the Aryl Hydrocarbon Interacting Protein (AIP) Gene: Isn’t It Too Much of a Coincidence?

Background: Germline mutations in the Aryl hydrocarbon receptor-Interacting Protein (AIP) gene are associated with pituitary adenomas in young patients usually in the setting of Familial Isolated Pituitary Adenomas (FIPA). The majority of these adenomas are somatotropinomas followed by prolactinomas, and rarely non-secreting adenomas. AIP-mutation-related prolactinomas predominantly affect men, as opposed to sporadic prolactinomas, that typically affect women. Clinical Case: We previously described an AIP gene mutation in two patients affected by prolactinomas. During the past years, we continued our study and have identified two more male patients with macroprolactinomas originally from the same small village and harboring the same AIP gene mutation. These male patients aged 19 to 44 years at the time of diagnosis. Two of them had neurological manifestations as the first clinical manifestation of the disease, one was studied because of hypogonadism and two patients had visual field defects. All of them had prolactin levels above 1000 ng/dl (mean 2946.5±948.7 ng/dl, reference range 10-21). In the imaging exams (CT/MRI) they presented pituitary adenomas larger than 20 mm (macroprolactinomas) and in two of the cases, the adenomas were even larger than 40 mm (giant prolactinomas). In order to exclude mutations most often associated with prolactinomas, DNA samples were obtained and analyzed by Next Generation Sequencing (NGS) using TruSightCancer Gene Set (Illumina) methodology. Investigation of significant deletions and/or duplications was performed using the MLPA (Multiplex ligation-dependent probe amplification) technique. None of the patients were positive for mutations of Multiple Endocrine Neoplasia type 1 (MEN1) gene. A variant of the AIP gene c.47G>A, expecting to lead to a substitution of arginine by histidine at position 16 (p.Arg16His) of the AIP was found in these four patients, including a father and his son. Seven asymptomatic carriers were identified among their first-degree relatives. In silico analysis and the information available in the literature, as well as in databases is not in agreement with the pathogenicity of this variant of the AIP gene. However, our findings point to a founder effect transmitted as a dominant trait with incomplete penetrance (4 out of 11 patients, 36%). Conclusion: The variant of the AIP gene identified in our patients behaved as a pathogenic mutation and was only associated with prolactinomas, including two giant prolactinomas.

Pediatric Giant Prolactinoma Presenting With Acute Obstructive Hydrocephalus and Intracranial Hypertension

Background: Pediatric prolactinomas (PP) are rare but represent 50% of all pediatric pituitary adenomas. Girls are affected more frequently than boys, although PP tend to be larger and more aggressive (earlier age, larger mass, and higher prolactin levels) in boys. Thus, microadenomas (tumors < 10 mm in diameter) are typical in females and macroadenomas (10–40 mm in diameter) are typical in males. Giant prolactinomas (> 40 mm in maximum diameter), an unusual subset of macroprolactinomas, are also commonly found in boys. In a large case series, the largest tumor volume reported was 93.5 cm3. Here we report a giant prolactinoma in a female requiring V/P shunt for decompression. Clinical Case: A 16-year old female presented with 2 weeks of intractable headache, nausea and vomiting, vision impairment, and changes in balance described as running into stationary household objects. Historical review revealed primary amenorrhea and short stature. On initial exam, the patient had a right eye afferent pupillary defect, concern for loss of color vision, and bilateral optic nerve edema with blurred disc margins. Brain MRI showed a large lobulated mass centered in the suprasellar cistern, measuring approximately 6.4 x 5.8 x 5.7 cm with a tumor volume of 105 cm3. There was extension superiorly, anteriorly, and laterally, with homogeneously enhancing and cystic components, and mass effect resulting in obstructive hydrocephalus. Differential diagnoses included craniopharyngioma, germinoma, and adenoma. Initial tests demonstrated prolactin of >2,000 ng/mL, with diluted result of 17,811.16 ng/mL. Morning fasting labs confirmed multiple anterior pituitary hormone deficiencies including central hypothyroidism, ACTH deficiency, GH deficiency, and hypogonadotropic hypogonadism. The patient was started on hydrocortisone and levothyroxine. Due to obstructive hydrocephalus and vision impairment, she underwent VP shunt placement for decompression. She was started on cabergoline for medical treatment of the tumor and did not require surgical resection. Repeat prolactin measurements have shown striking improvement (to 2,350 ng/ml, 824 ng/ml, and 152 ng/ml at 1 week, 1-month, and 2-month-follow-up, respectively) with central vision improved in both eyes, papilledema resolved, and resolution of headaches. Conclusion: Giant prolactinomas presenting with hydrocephalus and intracranial hypertension are very rare in pediatrics, especially in girls, and can vary greatly in mass characteristics and resulting hormone deficiencies. Our patient is unique with her large tumor volume and the extent of pituitary hormone deficiencies. Prolactin levels should be measured with all sellar masses, as this may prevent unnecessary invasive intervention and possibly provide prompt response to medical management.

Giant Prolactinoma Causing Proptosis and Stroke

Background: Although suprasellar and cavernous sinus invasion are common in giant prolactinomas, intra-orbital extension is extremely uncommon [1]. Even less reported are cases of giant prolactinomas causing cerebral ischemia or death. Clinical Case: A 51-year old woman presented to the ED with confusion, right-sided weakness and severe left eye proptosis with loss of vision. Five years prior, she underwent a partial transphenoidal resection for a macroprolactinoma due to acute vision changes with compression of the optic chiasm. Prior to surgery, prolactin level was elevated to 2,106 ng/mL (n 2.4-24.0 ng/mL). Post-operative MRI showed residual 2.7 x 3.1 x 2.6 cm mass. Thereafter she was prescribed cabergoline which she self-discontinued three years later. MRI of the brain at time of presentation demonstrated a 10.1 x 6.4 x 4.3 cm sellar/suprasellar mass extending into the left orbit causing severe proptosis and mass effect on the left frontal lobe, temporal lobe, midbrain, and basilar artery with encasement of the left cavernous internal carotid artery. A recent left striatocapsular infarct due to compression of the left middle cerebral artery was present. Prolactin level was elevated to 16,487 ng/mL. Neurosurgery was consulted and recommended medical management. Free thyroxine level was low and thyroid hormone replacement was started. Although the cosyntropin stimulation test showed an appropriate cortisol level peak of 21.5 mcg/dL, she was given stress dose glucocorticoids. Bromocriptine was initially started and titrated and later changed to cabergoline. Six weeks after discharge, she was readmitted with worsening confusion and seizure activity. On day 2 of admission, she decompensated. New hemorrhage inside the mass with increased vasogenic edema and a midline shift was discovered on a head CT. She underwent emergent craniotomy with surgical debulking of the tumor. Unfortunately, her mental status did not improve post-operatively. She was transitioned to hospice care and died 7 days after surgery. Surgical pathology showed a lactotroph adenoma with markedly elevated Ki67 proliferation index of 20-30%. Conclusion: This case demonstrates an unusually aggressive macroprolactinoma causing severe proptosis, ischemic stroke and death and adds to the very few cases previously reported [2]. References: 1. Karcioglu ZA, Aden LB, Cruz AA, Zaslow L, Saloom RJ. Orbital invasion with prolactinoma: a clinical review of four patients. Ophthalmic Plast Reconstr Surg. 2002 Jan;18(1):64-71. 2. Navarro-Bonnet J, Martínez-Anda JJ, Balderrama-Soto A, Pérez-Reyes SP, Pérez-Neri I, Portocarrero-Ortiz L. Stroke associated with pituitary apoplexy in a giant prolactinoma: a case report. Clin Neurol Neurosurg. 2014 Jan;116:101-3.

Giant Prolactinomas: An Experience From South India

Giant prolactinomas are large lactotroph adenomas, defined as those with maximum dimension of >4cm. They constitute <5% of all prolactin secreting tumors, and are more frequently seen in men. They present with features of hyperprolactinemia and hypopitutarism and are responsive to dopamine agonist therapies. In the current study we have shared our experience on management of giant prolactinomas over the last 15 years. We collected clinical data retrospectively from medical records of patients with giant prolactinoma managed at our institute over the last 15 years. This study describes the symptomatology, tumor characteristics and response to therapy. Our study included 21 patients with 15 males and 6 females. The mean age of presentation was 32 ± 10.3 years, ranging between 10 to 53 years. Vision defect was the predominant complaint (57%, 12 patients), followed by headache (52%, 11 patients). Erectile dysfunction was a presenting feature in 13% of men (2 patients) and amenorrhea/galactorrhea in 33% of women (2 patients). Seizure was seen in 10% of the patients (2 patients) and 10% (2 patients) were diagnosed with giant prolactinoma on evaluation for primary infertility. Tumor associated pituitary dysfunction manifested as hypogonadism in 67%, 14 patients, central hypothyroidism in 38%, 8 patients, and hypocortisolism in 1 patient. The median maximum tumor dimension was 4.4 cm with median basal PRL of 7168 ng/ml. Five patients underwent debulking surgery (24% of the patients) prior to endocrinology referral for indications such as apoplexy/raised intracranial tension. All patients received cabergoline and a mean dose of 2.1 ± 1.7 mg/week (range, 1-7 mg/week) was prescribed to attain a median nadir prolactin level of 48 ng/ml over a median period of 4 months (range, 1-40 months). The follow-up MRI data was analysed for 13 patients. Tumor shrinkage of >50% from the baseline was seen in all but 1 patient (92%) and 2 patients had disappearance of radiologically detectable tumor. Although giant prolactinomas have a greater tumor burden than the more common macroprolactinomas, the responsiveness to dopamine agonist therapy is excellent and surgical therapy is reserved for any exceedingly large tumors to relieve compression on vital structures.

Giant Prolactinoma presenting with facial nerve palsy and hemiparesis

Background Giant prolactinomas are an exceedingly uncommon type of pituitary adenomas that usually occur in men, cause extremely high prolactin levels and mass related symptoms. Rarely, patients may experience neurological deficits resembling ischemic events. Methods We describe an unusual case of a young man who presented with stroke-like symptoms and was found to have a giant prolactinoma. Clinical Case 25-year-old man presented with the left facial droop and gradually progressing upper and lower extremity weakness for evaluation of stroke. He reported recent weight gain and erectile dysfunction. Physical exam revealed left homonymous hemianopsia, left VII nerve palsy, and left hemiparesis. MRI of the brain showed an enormous mass in the sella turcica, which invaded the sphenoid sinus and right side of the skull base. Prolactin level was elevated at 13580 ng/mL, and the testosterone level was low. The patient was started on cabergoline and had marked improvement in his symptoms in a few months. Fifteen months after starting treatment, he has had more than 90% reduction in tumor volume and a 93% reduction in prolactin level. Conclusion Giant prolactinomas are uncommon and present with compressive symptoms that can be mistaken for a stroke. Our case is a unique report of a facial nerve palsy and hemiparesis secondary to giant prolactinoma in the absence of stroke or pituitary apoplexy.

SUN-285 Too Big to Be True, Too Young to Stroke!

BACKGROUND: Lactotroph adenomas are the most common type of pituitary adenomas and can cause infertility and menstrual irregularities in women; hypogonadism and gynecomastia in men.1 Giant prolactinomas are an unusual subset of pituitary macroadenomas with limited literature available on their management.2 We describe an unusual case of giant prolactinoma in a young man who presented with symptoms of stroke, that reversed with treatment with cabergoline. Clinical Case: 25-year old man presented with gradually progressing upper extremity weakness for evaluation of stroke. He reported stumbling into things when walking. There was a question of left sided facial droop and Bell’s palsy in recent past. He reported recent weight gain and erectile dysfunction. He was noted to have left homonymous hemianopsia on exam in addition to left upper and lower extremity weakness. MRI Brain showed an enormous mass that filled the sella turcica, invaded the sphenoid sinus and right side of the skull base, invaginating deep into the base of the right cerebral hemisphere with mass effect on the pons, right-sided midbrain, right temporal lobe and right basal nuclei, measuring 6.3 X 5.5 x 7.5 cm. Pituitary hormonal evaluation showed elevated prolactin (PRL) level with dilution at 13,580 ng/mL, with low testosterone (T) level (total T 42 ng/dL, free T 10 pg/mL, SHBG 15 nmol/L). Thyroid and adrenal axes were intact with normal IGF-1 level. In view of very high PRL level, he was started on cabergoline 0.5 mg daily initially and decreased to every other day after 2 weeks as PRL level began to decline. In 8 months, PRL levels decreased to 1293.07 ng/dl (90% reduction) and prolactinoma decreased to 6.0 x 3.7 x 4.7 cm (56% volume reduction). Total and free T improved to 134 ng/dL and 31 pg/dL respectively. He experienced marked improvement in left hemianopsia, with resolution of weakness and slurred speech. Energy level and erectile dysfunction improved. Currently he is being maintained on 0.5 mg cabergoline every other day Conclusion: Giant prolactinomas are uncommon and can present with compressive symptoms, that can be mistaken as stroke. Treatment with anticoagulation may cause hemorrhage and apoplexy with worsening of symptoms.1,2 There is limited data available regarding first line therapy for giant prolactinomas with 2 case reports where giant prolactinomas have been treated effectively with cabergoline.3,4 It is important to recognize the cause of such symptoms, and treated where possible with effective medical therapy to prevent morbidity. References: 1. Moraes A et al., Giant prolactinomas: the therapeutic approach. Clin Endo (Oxf). 2013 Oct;79(4):447-56 2. Acharya SV et al., Giant prolactinoma and effectiveness of medical management. Endocr Pract. 2010 Feb;16(1):42-6 3. Ahmed, M, et al., Large Prolactinoma. NEJM 2010; 363:177 4. Masoud, R et al., Giant prolactinoma: case report. J Diabetes Metab Disord. 2013; 12: 3

SAT-247 Use of Double Dopamine Agonists in Giant Prolactinomas: A Series of 6 Cases

Dopamine agonist monotherapy is first line therapy in giant prolactinomas even when visual field defect is present. The costlier cabergoline is often preferred over bromocriptine due to higher efficacy and tolerability profile. Described herein combined cabergoline and bromocriptine therapy in 6 cases of giant prolactinomas. Retrospective records review of 6 patients with giant prolactinoma (3 males: M1-M3, 3 females: F1-F3) in a single tertiary centre was performed. Mean age at diagnosis: 29 years (range 17-39). Mean duration of follow up: 7 years (range 3-11). Headache and visual field defect were the presenting symptoms in all cases. Basal prolactin concentration: 100000 to 468851 mIU/L (<300 for male, <600 for female). Three patients have hypopituitarism at presentation, one after surgery and one remained eupitary 5 years after diagnosis. One developed late onset hypopituitarism 4 years after normalisation of prolactin levels. Three patients underwent debulking at presentation because of significant mass effects with obstructive hydrocephalus. In all patients cabergoline 1-1.5 mg/wk was started at diagnosis and gradually increased to 0.5 mg daily, aiming for normoprolactinemia. From May 2017 bromocriptine were given to these patients who continued to have hyperprolactinemia despite cabergoline 3.5-4mg/wk. Bromocriptine was commenced 1.25-5mg/day and gradually increased to 10 mg/day on top of cabergoline with careful monitoring of prolactin levels and side effects. Cabergoline was tapered down to 1.5-2mg/wk if prolactin levels remained stable between 2-3x normal while maintaining dose of bromocriptine. In M1, cabergoline was tapered off while maintaining bromocriptine 10mg/day with stable prolactin levels (~1000 mIU/L). In M2, normoprolactinemia was achieved after adding on bromocriptine and is currently on cabergoline 2mg/week and bromocriptine 10mg/day. In M3, whose prolactin were 4x normal value despite cabergoline 3.5mg/week, decreased 50% with bromocriptine 5 mg/day and remained stable when cabergoline reduced to 1.5mg/week. F1 had transphenoidal section twice due to failure of medical therapy. Her prolactin remained markedly elevated 10000-20000 mIU/L despite cabergoline 3.5 mg/week and bromocriptine 10mg/day, with persistent bitemporal hemianopia. F2 developed erythema nodosum after starting bromocriptine which was stopped and continued with cabergoline 1 mg/week. F3 showed partial response with 50% reduction in prolactin to 4485 mIU/L with bromocriptine 10 mg/day and cabergoline 1.5mg/week. In patients who underwent debulking, residual tumour remained unchanged. Two patients - tumour shrank 40% (F2) and 90% (M3) with medical therapy alone. In conclusion, adding on bromocriptine can be considered when high dose cabergoline is required for treatment of giant prolactinoma with careful monitoring. This reduces cabergoline dose which saves cost.

MON-324 Management and Therapeutic Response Comparison in Prolactinomas According to Tumor Size

Prolactinomas are the most common type of functioning pituitary adenomas and up to 50% of all adenomas in clinical practice. Prolactinomas are more prevalent in women; nonetheless, they may occur at any age and in both genders, and represent the most common cause non-physiological hyperprolactinemia. Prolactin-secreting adenomas are classified by their tumor size as follows: microprolactinomas (<1 cm), macroprolactinomas (>1cm) and giant prolactinomas (>4 cm). The clinical presentation of these tumors might differ from age, sex and size. Dopamine agonists, such as cabergoline or bromocriptine, have become the first line of treatment, since these agents decrease tumor size and prolactin (PRL) secretion. In Mexico, recent studies have focused on giant prolactinomas but there is missing data of the clinical and biochemical manifestations of the tumor size-effect within the three types of prolactinomas in our population. Objective: To determine the effect of the tumor size in the clinical and biochemical presentation, and the follow up in prolactinomas. Methods: This an observational, retrospective, retrolective study. Results: Patients were classified according to their tumor size and 489 patients with confirmed diagnosis of prolactinoma were included. The mean age was 36+-12 years old and 86% were women. The size was different among sex with 14 (2.9%) and 259 (52.9%) patients with microprolactinoma and 34 (6.9) and 152 (31.1%) with macroprolactinoma in men and women, respectively (p <0.001). The median PRL levels were higher among patients with bigger tumors, 115 (97-150) ng/mL for microprolactinomas, 219 (115-777) ng/mL for macroprolactinomas and 2000 (154-4000) ng/m for giant prolactinomas (p <0.001). Clinically, hypogonadism was more prevalent in women with bigger tumor size (p <0.001), as well as visual defects (p <0.001) and headache (p 0.008). Conclusion: The tumor size of prolactinomas affects the clinical and biochemical presentation as well as the years of follow up required. References 1. Lopes M.B.S. (2019). Pathology of prolactinomas: any predictive value? Pituitary doi: 10.1007/s11102-019-00997-1