Temozolomide non-responsiveness in aggressive prolactinomas and carcinomas: management and outcomes

Purpose Temozolomide is endorsed as the treatment of choice in aggressive or malignant pituitary adenomas. Herein we describe a case of an aggressive prolactinoma which was resistant to temozolomide and performed a literature review of similar non-responsive aggressive prolactinomas. Methods A 40-year-old female presented with a giant prolactinoma which required cabergoline, transsphenoidal surgery and radiotherapy to achieve near-normal prolactin and apparently no residual tumour. A year later, she presented with multiple cranial nerve involvement due to recurrent tumour extending to the infratemporal fossa. She underwent transfrontal surgery, second radiotherapy and was started on temozolomide. Despite 8 cycles of temozolomide (200mg/m 2, 5/28 day cycle), she had progressive disease and ultimately succumbed to the disease. Pubmed/MEDLINE, Google scholar and prior review articles were searched for manuscripts with aggressive prolactinomas who had been treated with temozolomide. Data on demography, duration of therapy and management outcomes were analysed in those with progressive disease. Literature review We identified 94 cases of aggressive/malignant prolactinomas in the literature who had received temozolomide. Progressive disease despite temozolomide was present in 36 cases (38%). There was a male preponderance (65%) and 40% had aggressive prolactinomas while the rest had carcinomas. Patients received a median of 8 cycles (IQR 3.5-11.5) of temozolomide. MGMT immunostaining was negative in 35%. Overall mortality at the time of publication was 40%, at a duration varying from 2 to 20 years from diagnosis. Conclusion Temozolomide resistance in aggressive/malignant prolactinomas is challenging. Progressive disease on optimal temozolomide treatment entails the use of newer agents.

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.

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.

A Case of Giant Prolactinoma Characterized by a Nasopharyngeal Extension and Diagnosed by Nasal Cavity Biopsy

Introduction: Giant prolactinomas represent 2-3% of all prolactinomas and less than 0.5% of all pituitary lesions. Uncommon extensions of giant pituitary adenomas to areas such as nasopharynx or paranasal sinuses are even rarer. There are about 50 cases described in the literature. Here, we report a giant prolactinoma case diagnosed by biopsy from the nasal cavity. Case: A 40-year-old male patient applied to the emergency room after falling on ice. Cranial CT revealed a giant sellar mass destroying the clivus and the sphenoid bone corpus. The patient has had frontotemporal headache for 5 years, and also loss of libido and erectile dysfunction. He had right superolateral visual field defect and right-sided ptosis. Pituitary MRI showed a T2-hyperintense sellar mass measuring 58x58x70 mm, with extension to the nasopharyngeal wall, right cavernous sinus, right petrous apex and ethmoid spaces at the base of the skull. A punch biopsy was taken from the vascular mass located in the right nasal cavity, in between the middle concha and the septum. Pathological examination revealed a neoplasm that showed strong diffuse immunostaining with PRL and CK8, and focal staining with GH. Ki-68 proliferation index was 2%. Serum PRL level was 11881 ng/mL, FSH: 1.5 mIU/mL, LH: 1.3 mIU/mL, testosterone: 35.7 ng/dL, GH: 0.5 ng/mL, IGF-1: 520 ng/mL, ACTH: 73 pg/mL, cortisol: 12 mcg/dL, TSH: 0.04 uIU/mL, fT4: 14.2 pmol/L, fT3: 4.9 pmol/L and electrolytes were normal. Five days later, a right pterygonal craniotomy was performed. The mass showed the same immunostaining characteristics as the earlier biopsy specimen, and also included fibrin, monotonous cells with ischemic necrosis and distorted architecture of the reticulin pattern. According to the post-operative MRI, the right cavernous and clival part of the mass was reduced in size. Cabergoline (0.5 mg/w), levothyroxine (100 mcg/d) and testosterone propionate (250 mg/m) were started. The patient received conventional radiotherapy in a total dose of 1250 Gy, because of the residual mass. Sixth months after radiotherapy, the nasopharyngeal part of the tumor was not visualized. Cabergoline was up-titrated to a maximum dose of 3 mg/w. Prolactin levels decreased to 136 and 22 ng/mL at the third and sixth months of the treatment, respectively. Superolateral right-sided visual field defect persisted. Five years after surgery, secondary hypocortisolism has emerged, and 5 mg/day prednisolone was added to the therapy. Eight years after diagnosis, MRI revealed significant reduction in the size of the heterogeneous residual mass lesion. Discussion: Giant macroadenomas extending to nasopharynx are mostly prolactinomas, but other functional or non-functional pituitary adenomas may also have the same presentation. These lesions tend to be surgically hard to excise due to uncommon localizations, as in our case, and radiotherapy may be needed to control the residual mass.

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.