Giant prolactinomas: experience of a single tertiary center in Mexico

Background: Giant prolactinomas are rare tumors representing only 0.5-4.4% of pituitary adenomas, and 2-3% of prolactin secreting tumors. Clinical presentation is similar than smaller prolactinomas. However, due to the large adenoma size (≥4 cm), the normalization of prolactin levels and reduction of the tumor volume becomes a significant therapeutic challenge and multimodal treatment might be necessary. Methods: Comparative, cross-sectional, observational, retrolective cohort, from January 1988 to December 2017. We included all patients with hyperprolactinemia, those with non-tumoral etiologies were eliminated. Our final sample consisted of 327 patients with prolactinomas. We classified them according to tumor diameter using magnetic resonance imaging (MRI), in microprolactinomas (<10mm), macroprolactinomas (≥10 mm) and giant prolactinomas with a diameter of ≥4 cm, together with prolactin level > 1000 ng/dl, and no concomitant growth hormone (GH) or adrenocorticotropic hormone (ACTH) secretion. Results: 244 (74.6%) cases had a microprolactinoma, 72 (22%) had a macroprolactinoma, and 11 patients (3.4%) met the selection criteria for giant prolactinomas (9 males). The most common presenting features included headache, impaired vision, and erectile dysfunction. The main hormone deficiency found in men was testosterone (77.8%), followed by Thyroid-stimulating Hormone (TSH) (63%). Mean prolactin (PRL) at presentation was 2,000 ng/mL (IC 95% 1727 - 4374). All patients were treated with dopamine agonists (DA), and only 3 (27%) patients required surgery. Tumor shrinkage for giant prolactinomas with dopamine agonist was 63% on average. All patients had improved visual field defects. Since patients responded well to DA, none required further treatment modalities. Conclusions: Giant prolactinomas are rare tumors with a male predominance. Dopamine agonists

index and giant adenomas have higher frequency of C540G polymorphisms 6 . While prolactinomas occur most frequently in 20-50-year-old females, giant forms are much more prevalent in middle aged men, with a male to female ratio of about 9:1 and a similar mean age at diagnosis around 40 years (27-68 years) 7 . Giant prolactinomas cause clinical symptoms mainly as a result of its mass effect and to a lesser degree due to hyperprolactinaemia resulting in visual field defects and/or ophthalmoplegia due to compression of the optic chiasm or cranial nerves, as well as headaches 8 .
The most common site of extrasellar extension is into the suprasellar cistern, although large tumors can also have sphenoid sinus extension or laterally into the cavernous sinuses. Rare presentations include invasion of temporal or frontal lobes causing seizures or personality disorders. Skull base infiltration is another rare presentation, that may mimic primary bone dysplasia, as well as irruption of the nasopharynx, which may cause epistaxis 1,9 . Hyperprolactinaemia typically presents with signs and symptoms such as decreased libido, impotence, infertility, galactorrhea, oligomenorrhea or amenorrhea and gynecomastia 10 . By means of the agonist effect on dopamine receptors, cabergoline (CAB) is the first-line treatment for these tumors, decreasing PRL production and tumor size, even after a few days of treatment. However, due to the large tumor volume, multitherapeutic approaches are necessary to normalize the serum PRL level and control tumor volume 11,12 . Finally, a subgroup of prolactinomas exhibits aggressive clinical behavior, which results in a true challenge to control its biochemical function and tumor volume 4,13 .

Methods
We conducted a comparative, cross-sectional, observational, retrolective study. All patients with hyperprolactinemia confirmed in at least 2 laboratory measurements with a prolactin value for women > 25 ng/mL, and >20 ng/mL for men who attended the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán at Mexico City, Mexico, from 1988 to December 2017, were included for review of their medical records. We excluded cases with an incomplete medical record (n=42), patients with a previously treated prolactinoma showing normal prolactin value (n=65), and those who only had one laboratory value of hyperprolactinemia without any further diagnostic approach (n=84) ( Figure 1). Data was retrieved from clinical records by certified medical personnel.
Our final sample consisted of 327 patients. We classified them according to their tumor diameter using MRI in: microprolactinomas (<10mm), macroprolactinomas (≥10 mm), and giant prolactinomas. We defined a giant prolactinoma when: 1) a tumor diameter on MRI was equal or more than 40 mm, 2) prolactin levels were equal or more than 1,000 ng/mL, The complete database is available upon request of any reader.
Imaging, biochemical assessment PRL determination was performed with the Access Prolactin chemiluminescence immunoassay from 2011-2016 (with a detection limit of 0.25-20000 ng/mL). Patients whose prolactin level were performed before 2011 was done with the radioimmunoassay technique (RIA) with a detection limit of (2-133 ng/ml). In these patients, when PRL level had not a direct relationship with tumor size, serum was diluted 1:20 and 1:100 times to check for hook effect. Central hypothyroidism was defined as low free T4 level and low or inappropriate normal TSH concentrations, with negative thyroid antibodies. Central hypogonadism was defined as a serum low testosterone for men, and low estradiol in women, with low or normal LH and FSH. Central hypocortisolism was diagnosed with serum morning cortisol below 3 mcg/dL, or cortisol below 18 mcg/dL after induced-hypoglycemia or after 250 mcg of synthetic ACTH (Cosyntropin) stimulation test. Growth hormone deficiency was diagnosed with low IGF-1 adjusted for sex and age. Hypopituitarism was diagnosed when two or more hormonal deficiencies were present.

Statistical analysis
Dimensional data with normal or non-normal distribution was expressed with means and standard deviations (SD), or medians and interquartile ranges, respectively. Categorical variables are expressed with frequencies and proportions. Student "t" test or Mann-Whitney U was used to compare prolactin levels before and after treatment. Categorical differences were analyzed with chi square test. Statistical analyses were performed using SPSS 23.

Results
Eleven patients (9 males and 2 females) met the diagnostic criteria for having a giant prolactinoma which resulted in a prevalence of 3.4% among all prolactin-secreting adenomas (n= 327). Mean age at diagnosis was 33 years (25-40). Median follow-up was 6 months (1-12). Baseline patient characteristics are presented in Table 1.

Baseline PRL and MRI findings
Median baseline serum PRL concentration was 2,000 ng/mL (1,727 -4,374

Effects of treatment on serum PRL and tumor size
At follow up, patients had PRL levels of 187 ng/mL (99-340). Prolactin normalization, defined as a PRL level of <25 ng/dl, was achieved in four patients (27%). PRL levels decreased 5 to 10 times of its baseline initial value in 5 cases (54.5%). Follow-up was less than six months in three cases because of lost follow-up (case 3), death of septic shock after liver transplantation due to cryptogenic cirrhosis (case 6), and a recent diagnosed (case 11). Median tumor volume decreased from 251 mm 3 (183.1-374) to 94 mm 3 (10-143), representing a reduction of 62.6%. Similarly, a reduction of tumor size from 47 mm (42-51) to 24 mm (14.5-38.5) was documented, representing a 49% reduction in tumor diameter. (Table 3)

Discussion
We described the clinical presentation, biochemical, and tumor response to DA in patients from a single tertiary center in Mexico diagnosed with a giant prolactinoma. Of all prolactin pituitary tumors in our series, microprolactinomas represented 75%, macroprolactinomas 22%, and giant prolactinomas 3.3%, with a similar prevalence to that reported previously 7,8 . Consistent with our results, a higher prevalence was seen in male patients (9 male; 2 female) 7,8 . However, our patients were significantly younger at diagnosis (33 years old, 25-40), in comparison with another Mexican series that reported a mean age of 44±14 years (n=47) 7 . One of our male patients identified at 17-years-old was diagnosed with endocrine neoplasia type 1 (MEN1) syndrome. As referred in literature, pituitary tumors in patients with MEN1 syndrome are larger, more frequently invasive and more symptomatic, prompting early diagnosis in younger patients 14 15 . Interestingly, although small doses of CAB 1.0 mg/week were used, tumor shrinkage up to 67% was seen in one patient. The tumor volume reduction achieved in our patients (62.5%) is similar to that found in other series with higher doses of DA 16,17 . However, PRL normalization was only seen in 27% of cases, which is not consistent with data reported by S. Yarman of 100% of their cases 18  The majority of giant prolactinomas respond to DA, nevertheless, some patients require surgical treatment due to its mass effect 8,16,17 . In our series, three patients required surgery for tumor debulking and to protect visual fields. It is important to point out that giant and invasive prolactinomas usually cannot be cured by surgery. Therefore, medical treatment is the first line therapy even though visual impairment is present 17 . With medical therapy, tumor volume and diameter decreased in 62.6 % and 49 % of our patients respectively, which was enough to decompress optic chiasm. Acharya et al. 19 , reported ten giant prolactinomas treated with CAB, with a decrease in mean tumor diameter by 49.28 %. In case of prolactinomas that do not respond to medical therapy, surgery might be an option, in addition to other medical therapy approaches such as temozolamide, a chemotherapeutic agent that has been used in aggressive pituitary tumors including giant prolactinomas 4 . It is important to consider that up to 99.3 % of prolactinomas respond to CAB (doses up to 12 mg/week) 15 . Therefore, progressively increasing CAB dosage is needed first, in order to confirm a true resistant tumor. In addition, if there is no "prolactinoma" response, a differential diagnosis that may mimic a giant prolactinoma has to be ruled out; such as, craniopharyngioma, Rathke's cleft cyst, germinoma, giant aneurysm, cavernous sinus meningioma, and sphenoid neoplasms, such as cell carcinoma, metastases, chordoma and chondrosarcoma 20 .

CONCLUSION
We report eleven cases with giant prolactinomas, with a male gender predominance. All patients received dopamine agonists with good response despite low doses. Only three patients required surgery due to tumor-related complications. None of the tumors were resistant to treatment with dopamine agonists, which highlights their efficacy. In general, even though our patients had a short-term follow-up, their response to dopamine agonists was a 63 % tumor volume reduction and reduction of 51 % in tumor diameter. None of them received radiotherapy or temozolamide.    Figure 1 Patients with hyperprolactinemia included in the study.