Their definition should be restricted to pituitary neuroendocrine tumors with a diameter of 40 mm or more, significant extrasellar extension, very high prolactin concentrations (usually above 1000 µg/L), and no concomitant GH or ACTH secretion.
They represent only 2-3 % of all prolactinomas.
Giant prolactinoma are rare tumours. They are much more frequent in young to middle-aged men than in women with a male to female ratio of about 9:1. 1) 2).
Endocrine symptoms are often present but overlooked for a long period of time and diagnosis is eventually made when neurological complications arise from massive extension into the surrounding structures, leading to cranial nerve palsy, hydrocephalus, temporal lobe epilepsy or exophthalmos.
Prolactin concentrations are usually in the range of 1,000 to 100,000 µg/L, but may be underestimated by the so-called 'high dose hook effect'.
Because giant prolactinomas can expand significantly, they often compress nearby structures, such as the optic chiasm, leading to vision problems. If they grow further, they can invade surrounding brain tissues and cause neurological deficits like headaches, diplopia (double vision), or even cranial nerve palsies. In some extreme cases, they can lead to cranial settling and central herniation 3) , which can result in quadriparesis and other serious symptoms
Sexual dysfunction is a hallmark of prolactinomas in males. Tumors that co-secrete prolactin and LH are extremely rare and and only a case reported in an adult male. In this case, normal testosterone was maintained by intact LH levels even in the face of the highest prolactin level reported to date 4).
As in every prolactinoma, dopamine agonists are the first-line treatment allowing rapid alleviation of neurologic symptoms in the majority of the cases, a significant reduction of tumour size in three-fourths; of the patients and PRL normalization in 60-70%. These extensive tumours are usually not completely resectable and neurosurgery has significant morbidity and mortality. It should therefore be restricted to acute complications such as apoplexy or leakage of cerebrospinal fluid (often induced by medical treatment), or to patients with insufficient tumoral response or progression. Irradiation and temozolomide are useful adjuvant therapies in a subset of patients with aggressive/invasive tumours which are not controlled despite combined medical and surgical treatments. Because of these various challenges, it needs a multidisciplinary management in expert centres 5).
Shimon I. Giant Prolactinomas. Neuroendocrinology. 2019;109(1):51-56. doi: 10.1159/000495184. Epub 2018 Nov 7. PMID: 30404098 6).
196 cases were included [age: 38 (28-50) years, F/M ratio: 1/3.6]. Median tumor diameter was 53 (43-69) mm. Pituitary deficiency was present in 91% of cases, with hypogonadotropic hypogonadism being the most frequent. The most common presenting symptoms were visual impairment (73%) and headache (50%) in men and amenorrhea (58%) in women. 82% of cases were treated with a dopamine agonist (DA) as first-line treatment which led to normoprolactinemia, tumor shrinkage, and visual improvement in 51%, 88%, and 85% of cases, respectively. Surgery was performed in 29% of cases and all showed tumor remnant and persistent hyperprolactinemia. Women had a lower prolactin level and a smaller tumor diameter at diagnosis but pituitary deficiencies were more frequent and the outcome was worse.
Giant prolactinomas are rare and have a male predominance. Visual impairment is the most frequent presenting symptom in men and amenorrhea in women. The gender-related difference in tumor size and level of prolactin was confirmed in this analysis where men had a larger diameter and a higher baseline prolactin level. DAs are the treatment of choice, irrespective of tumor size and presence of visual impairment. As only half of the cases achieved normoprolactinemia we do not, in contrast to previous literature, state giant prolactinomas to be exquisitely sensitive to DAs. Patient characteristics associated with persistent hyperprolactinemia after treatment with a DA were female gender, higher baseline prolactin, and larger tumor size. This analysis did show TSH- and ACTH deficiency to be more frequent after surgery which was not seen for LH/FSH deficiency 7).
This study provides a comprehensive review of the clinical characteristics, treatment outcomes, and gender-related differences in patients with giant prolactinomas. While dopamine agonists remain the cornerstone of treatment, the fact that only half of the patients achieved normoprolactinemia suggests that these tumors may be less responsive to medical therapy than smaller prolactinomas. The study highlights the importance of a combined treatment approach, including surgery and DA therapy, while also emphasizing the need for more detailed long-term data to fully assess the outcomes of giant prolactinoma treatment. Future studies should focus on identifying predictive factors for treatment response and the role of adjunct therapies like radiotherapy.
A retrospective and multicenter study of Madrid and Barcelona of gPRLomas in men diagnosed in a 20-year period was performed. Clinical data and treatment outcome were registered. The diagnosis of gPRLoma was established when the maximal tumor diameter was ≥40 mm or the tumor had ≥20 mm of suprasellar extension associated to hyperprolactinemia (PRL>1000 ng/ml). Non-gPRLoma was considered when tumor diameter was ≥ 10 mm and<40 mm associated to hyperprolactinemia (PRL≥200 ng/ml). Twenty-three patients with gPRLoma (age 38.3±13.5 years) followed for at least 3 months (follow-up 87.1±60.5 months, range 3-211 months) were evaluated. A group of 42 patients with non-gPRLoma (age 42±16.6 years; NS; follow-up 89±65.9 months, range 3-222 months; NS) served as a control group. More than half (56.5%) of the gPRLoma patients were younger than 40 years at diagnosis. Visual disturbances were significantly more common in gPRLoma than in non-gPRLoma patients (65.2 vs. 25.6%; p=0.004). Prevalence of hypopituitarism was similar in both groups of patients (73.9% vs. 80.9%; gPRLoma vs non-gPRLoma; NS). Serum PRL concentrations were significantly higher in gPRLoma than in non-gPRLoma patients [median (IR), 3978 ng/ml (1179-9012) vs. 907 ng/ml (428-3119); p<0.001]. Maximum tumor diameter in gPRLomas was 4.8±0.8 cm and 2.4±0.7 cm in non-gPRLoma (p<0.001). All patients were treated with dopamine agonists (DA). Twelve (52.2%) gPRLoma patients and 32 (73.8%) non-gPRLoma patients were treated with DA as monotherapy (p=0.045). Surgery was used in 12 (52.2%) gPRLoma patients and in 12 (28.6%) non-gPRLoma patients (p=0.054). Lastly, radiotherapy was used in 5 (21.7%) gPRLoma patients and in 6 (14.2%) non-gPRLoma patients (NS). At last visit, PRL was similar in both groups of patients [16 ng/ml (4-30) vs. 11 ng/ml (4-25); gPRLomas vs. non-gPRLomas; ns] and tumor size decreased significantly (p<0.001) in both groups of patients. Clinical cure (maintained normoprolactinemia without therapy for>1 year and no radiological evidence of pituitary tumor) was achieved in 2 (8.7%) gPRLoma patients and in 2 (4.8%) non-gPRLoma patients (NS). gPRLomas in men are usually diagnosed at a mean age of 40 years, an age similar to that of non-gPRLomas. The only clinical difference with non-gPRLomas is their greater prevalence of visual disturbances. The therapeutic approaches and tumor outcomes were similar to those obtained in patients with non-gPRLomas. Complete cure in gPRLoma is rare, but similar to that achieved in non-gPRLomas, reached in less than 10% of patients 8).
In 42 cases, male patients accounted for 71.4% of this series and were relatively younger (35.70±2.42 vs. 52.00±3.55 years, p=0.0011) and harbored bigger tumors (14.57 vs. 7.74 cm3, p=0.0179) compared to females. Almost all of these tumors showed suprasellar extension (97.6%) and cavernous sinus invasion (92.9%). Dopamine agonist represented an efficient method to control PRL concentrations (98.8%) and reduce tumor burdens (81.2 %). PRL normalization was detected in 13 out of the 27 patients initially treated with bromocriptine (BRC) whereas none of the 14 patients with first-line operation gained a normalization of PRL concentration after surgery. Although there was no reliable predictor of tumor response, First PRL reduction was a predictive criterion for the nadir PRL level during the long-time period of follow-up for first-line bromocriptine treatment. In conclusion, patients with giant prolactinomas did not gain more benefits from initial surgery. Dopamine agonist (BRC) should be first-line treatment for giant prolactinomas whereas operation merely served as a remedy for acute compression symptoms and dopamine agonist resistance. Consecutive monitoring of serum PRL levels in the early stage of initial BRC treatment is useful for evaluation of therapeutic effect and further therapeutic decision 9).
16 patients (43.7 % women); mean age at diagnosis: 42.1 ± 21 years. The most frequent presentation was compressive symptoms. The delay in diagnosis was higher in women (median of 150 months vs. 12 in men; p = 0.09). The mean maximum tumor diameter at diagnosis was 56.9 ± 15.5 mm, and mean prolactin levels were 10,995.9 ± 12,157.8 ng/mL. Dopamine agonists were the first-line treatment in 11 patients (mean maximum dose: 3.9 ± 3.2 mg/week). Surgery was the initial treatment in five patients and the second-line treatment in six. Radiotherapy was used in four cases. All patients but one, are still with dopamine agonists. After a mean follow-up of 9 years, prolactin normalized in 7/16 patients (43.7 %) and 13 patients (81 %) reached prolactin levels lower than twice the upper limit of normal. Mean prolactin level at last visit: 79.5 ± 143 ng/mL. Tumor volume was decreased by 93.8 ± 11.3 %, and final maximum tumor diameter was 18.4 ± 18.8 mm. Three patients are actually tumor free. Giant prolactinomas are characterized by a large tumor volume and extreme prolactin hypersecretion. Multimodal treatment is frequently required to obtain biochemical and tumor control 10).
A case is the largest reported giant prolactinoma (99 × 72 × 57 mm). It led to cranial settling and significant central herniation at the foramen magnum, causing quadriparesis.
The patient was a 39-year-old Iranian man from a village around Hamadan city who presented with quadriparesis and paresthesia as well as loss of libido and impotence. Magnetic resonance imaging and computed tomography showed a huge diffuse avid enhancing infiltrating osteolytic lesion at the skull base. It had spread predominantly extramurally into the skull base resulting in cranial deposition, significant central herniation, myelopathy, and acute exacerbation of quadriparesis. Based on the pathology, immunohistochemistry, and elevated serum prolactin levels, the diagnosis of giant prolactinoma was almost definite. In addition to urgent midline suboccipital craniotomy for the central herniation and quadriparesis, he was treated with cabergoline followed by occiput cervical fixation and fusion to control the progressive subsidence.
Prolactinoma that is treatable with dopamine agonists should be considered as a differential diagnosis of skull base lesions, even those that are extradural, diffuse, and infiltrative. Giant prolactinoma can lead to craniocervical settling and central herniation that requires surgery and multidisciplinary management 11)
This case report offers valuable insight into the management of a giant prolactinoma with progressive cranial settling and central herniation. It underscores the importance of considering prolactinoma in the differential diagnosis of skull base lesions, even in rare and severe forms. The case is well-documented and emphasizes the importance of multidisciplinary management for such complex conditions. However, a more thorough review of similar cases and additional follow-up data could have enhanced the impact and completeness of the report.
A young man was diagnosed with a giant invasive prolactin-secreting pituitary macroadenoma with skull base destruction. A few months before this diagnosis, he presented with spontaneous CSF rhinorrhea with no history of previous medical or surgical treatment. In this case report, we report an uncommon presentation of giant invasive macroprolactinoma with a CSF leak treated with cabergoline that was subsequently complicated by meningitis and pneumocephalus. This is a very rare complication of cabergoline therapy, which occurred approximately 1 month after treatment initiation 12).