Giant prolactinoma with progressive cranial settling and central herniation: a case report

Abstract

Background

Giant prolactinoma (size > 4 cm) is a rare condition and accounts for less than 1% of pituitary adenomas. In even rarer cases, these lesions may involve craniocervical structures requiring surgical intervention. The present 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.

Case presentation

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. On the basis of 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.

Conclusion

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.

Background

The most common functional pituitary tumor is a prolactinoma with a prevalence of 3.5–5/10,000 of the population [1]. According to size, these tumors are classified into micro- (< 1 cm), macro- (1–4 cm), and giant prolactinoma (GP) (> 4 cm). GP is a rare entity accounting for 1–5% of all prolactinomas. They are typically detected in men aged 20–50 years (median 42) and sporadically in older or postmenopausal women. The male-to-female ratio is estimated to be 9:1 [2].

In even rarer cases, these lesions can cause craniometrical structure abnormalities, which require surgical intervention. We found only five cases with similar features [3,4,5,6,7]. Here we presented the largest reported GP with a diffuse, infiltrative growth pattern into the skull base, resulting in cranial settling and substantial central herniation at the foramen magnum.

Case presentation

A 39-year-old Iranian man from a village around Hamadan city presented with muscle weakness and paresthesia in both upper and lower extremities from 2 years ago that impaired his daily activities. He also complained of headache, vertigo, and several fainting spells over the past 6 months. However, he did not mention blurred vision, diplopia, facial hypoesthesia, paresis, hearing impairment, and seizure. On the other hand, the patient mentioned decreased libido and impotence in addition to anorexia and a weight loss of 8 kg.

Deep tendon reflex (DTR) tests were increased in both upper and lower extremities, and the forces were symmetrically decreased to 3/5 in all limbs, that he obviously needed help to stand upright and walk. Other neurological examinations were completely normal.

Imaging

Brain computed tomography (CT) showed an extensive osteolytic infiltrative lesion at the skull base (Fig. 1). The lesion had extended from the posterior border of the frontal sinus anteriorly to the occipital condyles posteriorly. The lesion extended to the sphenoid’s large wings and the petrous bone’s tip laterally. Inferiorly, the lesion had extended downward to the pterygoid process, nasal cavity, clivus, and occipital condyles. Severe osteomalacia had led into substantial cranial settling. The lateral masses of the first cervical vertebra (C1) were pushed into the occipital condyles, and the skull base bulged upward.

Fig. 1

Red arrow shows lateral extension of tumor (A). Blue arrow shows occiput condyle involvement (B). Green arrow shows pterygoid process involvement (C). Yellow arrow shows settling of occiput condyle over C1 lateral mass and severe osteolysis (D). White arrow shows lateral extension of tumor (E). Yellow arrow shows anterior limit posterior to frontal sinus and green arrow shows posterior limit of tumor involvement at occipital condyle (F). Red arrow shows superior extension of tumor into interhemispheric fissure (G). Blue arrow shows central herniation of brain stem and cerebellar tonsils through foramen magnum down to C2. Black arrow shows cervical cord syrinx (H)

Magnetic resonance imaging (MRI) of the brain showed a large, avidly enhancing, infiltrating lesion that had predominantly spread extradurally into the skull base (Fig. 1). The lesion was extended from frontal sinus to occipital condyles (anteroposterior diameter: 99 mm). In addition, the tumor had encased both carotid arteries, invaded both petrous bones, and had a component in the left petroclival region (width: 72 mm). The tumor extended from the interhemispheric fissure downward to the pterygoid process (height: 57 mm). There was no compression effect on the adjacent structures as in focally growing tumors. Moreover, there was severe central herniation of the brainstem and cerebellar tonsils (20 mm) below the foramen magnum owing to osteolysis and cranial settlement. It was associated with the syrinx of the cervical spinal cord and myelopathy.

Management

The patient underwent an endoscopic endonasal biopsy. Two samples were taken from sphenoid sinus (not the sella) and septum. The tumor was extradural and the dura was intact at biopsy.

On admission after the biopsy, patient developed sudden sever quadriparesis 1/5 symmetrically along with respiratory distress. Therefore, an emergent midline suboccipital decompressive craniectomy and expansive duraplasty were performed.

On microscopic pathologic evaluation, cells with monomorphic hyperchromatic nuclei and eosinophilic granular cytoplasm without nucleolus were observed with prominent mitotic activity in a proliferative vascular background (Fig. 2). Amorphous eosinophilic deposits, mainly amyloid-like, were also observed in the vascular wall. No evidence of histiocytes was found. All these findings initially suggested an extensive pituitary adenoma and then a bone plasmacytoma.

Fig. 2

High-power (× 100) view of cells with monomorphic hyperchromic nuclei with noticeable mitosis activity in a proliferative vascular background are shown

With a sample dilution of 1:100, the prolactin level was 1120 ng/ml. The other lab tests were completely normal. The results of the markers in immunohistochemistry (IHC) were positive for prolactin, positive in rare tumor cells for Synaptophysin, weakly positive for CK 5/2, and positive for Ki-67 in 1% of tumor cells. On the basis of the IHC results and the elevated prolactin level in the serum, the diagnosis of GP was confirmed.

A bone mineral density (BMD) test revealed only mild osteopenia. Perimetry showed a bitemporal hemianopic scotoma.

Treatment with 0.5 mg of cabergoline was started twice a week and was increased to 1 mg twice a week after 4 weeks. Owing to the stability of the craniocervical segment at the time of the patient’s presentation, fixation and fusion were not primarily considered. Out of concern for exacerbation of central herniation owing to rapid resorption of the skull base tumor, cabergoline was initially started at a lower dose.

At the next 3-month follow-up, the prolactin level dropped to 168.23 ng/ml. Along with increasing the cabergoline dose to 1.5 mg twice a week, the patient was given 250 mg of testosterone every 3 weeks. The patient was followed up 3 months later and adequate response to treatment was observed and the serum prolactin level decreased to 123.8 ng/ml. Despite the significant decrease in serum prolactin level compared with baseline, he still had gait disturbance and ataxia. Brain MRI, illustrated a noticeable shrinkage of the tumor (Fig. 3). The patient underwent occipitocervical fixation and fusion (OCF) to control cranial settling owing to the persistence of symptoms, progressive gait disturbance, and quadriparesis (Fig. 4). The intervention led to a significant improvement and the patient was able to perform his daily activities independently after OCF; however, ataxia and muscle weakness had not completely disappeared. Therefore, the cabergoline dose was increased to 2 mg three times a week, and at the 3-month follow-up, the latest serum prolactin level was 82.1 ng/ml.

Fig. 3

Yellow arrows show same portion of tumor before (A) and after treatment with cabergoline (B) and tumor shrinkage is clearly evident. Green arrows show same portion of tumor before (C) and after treatment with cabergoline (D) in post contrast imaging, and tumor shrinkage is noted

Fig. 4

Intraoperative image of occipito-cervical fixation (A). Postoperative lateral X-ray showing occipito-cervical fixation (B)

Discussion

GP is a rare presentation of prolactinoma. This case is the largest reported GP (99 × 72 × 57 mm) with an unusual presentation of cranial settlement and central herniation causing quadriparesis, and it required urgent surgery for decompression. In addition to medical treatment of the tumor, subsequent OCF was performed to control the progression of the cranial subsidence.

Only five cases with similar features have been described in literature of which the case presented here is the largest.

Yecies et al. (2015) reported a case (28-year-old male) with decreased libido, headache and neck pain treated with cabergoline followed by OCF [6]. Chugh et al. (2021) presented a case (39-year-old male) with a history of unilateral orchiectomy treated with OCF followed by cabergoline [3]. Laws and Ivins (1979) reported a case (48-year-old female) with neck pain and eventual hydrocephalus with episodes of cardiopulmonary arrest, initially treated with radiotherapy and then with OCF [4]. Zaben et al. (2011) described a case (31-year-old male) with headache, visual loss, and rapidly progressive cranial nerve palsies treated with OCF and cabergoline [7]. Murphy et al. (1987) reported a case (44-year-old male) complaining about headache and bitemporal hemianopsia treated with cabergoline followed by OCF [5] (Table 1).

Table 1 Characteristics of the included studies in literature review

These cases showed that the severity of symptoms in GP can vary and that instability and cranial settling may lead to devastating consequences. Therefore, it is crucial to consider surgical intervention including decompression and OCF at the right time.

In this case, owing to the sudden deterioration of the patient’s neurological condition during his admission, an emergent decompressive craniotomy and duraplasty had to be performed which resulted in improvement. Nevertheless, in the other reported cases, surgery was performed mainly to stabilize the craniocervical component rather than for decompression.

The technique used in this case was OCF in the form of an occiput-to-C1 lateral mass and C2 pedicle screw insertion. There is no consensus on the extent of cervical instrumentation and it depends on the pathology, although the construct usually extends at least down to C2. Occiput-C1 is rarely used because the extracted data demonstrated a high rate of associated C1-C2 injuries [8].

In two of the five mentioned cases, occioput-C5 instrumentation was performed [3, 4]. Although this can provide more stability and reduce the risk of subaxial deformity, especially if there is preoperative sub-axial subluxation or significant anteversion of the occiput, such an extension below C2 is not necessary in all patients [9, 10]. When choosing long-segment instrumentation over occiput-C1-C2, the following should be considered: the patient’s preoperative condition, long-term adverse outcomes—such as degeneration of the distal adjacent segment—and the need for greater stability [9, 10].

In the present case and in the case of Yecies et al. (2015), OCF was occiput-C1–C2 [6]. If the construct is extended sub-axially, this may increase the risk of limiting the range of motion and excessive degeneration of the adjacent segment in the short- and long-term follow-up, respectively. Therefore, the strategy in this case was limited to C1–C2 to preserve the range of motion and prevent long-term degeneration of the adjacent segment.

In the other two cases, the exact levels were not specified, but wiring was used in one case [5, 7]. In addition, the use of screws in the midline plate is more effective than wiring in terms of resistance to cranial settling and pull-out strength [11].

Prolactinoma usually grows as a focal tumor. Hence, when a lesion appears to be infiltrative (as in this case), it is essential to consider a differential diagnosis, including plasmacytoma, lymphoproliferative, and histiocytic diseases. Thus, in such cases, along with a biopsy, laboratory values and hormone determination are also necessary for skull base lesions. The infiltrating lesion is usually extensive and surgery is usually unnecessary, and curative surgery for tumor control is impossible. Consequently, the primary treatment options are chemotherapy or radiotherapy. Surgery is only considered in special situations, such as instability or the need for decompression and in some cases for cytoreduction or treatment of hydrocephalus. In the future, new imaging modalities like MRS or MR perfusion, which is used to differentiate lesions or predict the grade of tumors maybe could be helpful to better preoperative diagnosis [12].

Typically, the size of the prolactinoma correlates with the degree of hyperprolactinemia. If the serum prolactin level is greater than 1000 ng/ml, the diagnosis of GP is highly suggestive [2]. Considering laboratory investigations, in the two-site immunoradiometric technique, excessive prolactin concentrations may saturate the detecting antibodies, resulting in artificially low prolactin results [13]. This phenomenon known as the Hook effect should be considered by clinicians, especially in large prolactin-secreting adenomas associated with mild hyperprolactinemia. In this case, after the report of primary prolactin level (489 ng/ml), a 1:100 diluted sample was tested, that resulted in a significant increase in the prolactin level (1120 ng/ml) supporting the diagnosis of GP.

Suppression of the hypothalamic–pituitary–gonadal axis by elevated levels of prolactin primarily leads to infertility, loss of libido, and osteoporosis in both sexes. This could also cause amenorrhea, oligomenorrhea, and galactorrhea in women and erectile dysfunction in men [14,15,16]. However, the exact mechanism is not clear, but typically erectile dysfunction in men improves significantly following hyperprolactinemia correction [17, 18].

Dopamine agonists, as the first-line therapy, could decrease prolactin release and reduce the size of the tumor by binding to the dopamine receptors on the cell surface. Cabergoline has been shown to be more effective than bromocriptine in reducing tumor size and normalizing prolactin levels, with fewer side effects [14,15,16].

The cabergoline therapy regimen usually starts at 0.5–1.0 mg/week and is then adjusted according to the patient’s prolactin response. Rapid dosage increase may cause a significant reduction in tumor size with a risk of apoplexy or CSF leak [19]. In almost all patients, continuous long-term therapy with dopamine agonists is required to suppress and stop tumor re-expansion. However, if a long-lasting normal prolactin level is maintained and tumor size remains under control, a dose reduction can be considered [20]. Discontinuation of treatment carries the risk of rapid tumor regrowth [20]. Although complete remission is difficult to obtain, complete cure following long-term therapy has been reported [21]. Of note, inability to maintain a normal prolactin levels or to reduce the size of tumor by at least 50% is known as dopamine agonist resistance [15].

Conclusions

Prolactinoma that is treatable with dopamine agonists should be considered as a differential diagnosis of skull base lesions even those extradural, diffuse, and infiltrative. Giant prolactinoma can lead to craniocervical settling and central herniation that requires surgery and multidisciplinary management.