Temozolomide Nonresponsiveness in Aggressive Prolactinomas and Carcinomas: Management and Outcomes

Abstract

Context: Temozolomide (TMZ) is endorsed as the treatment of choice in aggressive or malignant pituitary adenomas.

Objective: Herein we describe a case of an aggressive prolactinoma that was resistant to TMZ. We performed a literature review of similar nonresponsive, aggressive prolactinomas.

Methods: A 40-year-old woman presented with a giant prolactinoma that required cabergoline, transsphenoidal surgery, and radiotherapy to achieve near-normal prolactin and apparently no residual tumor. A year later, she presented with multiple cranial nerve involvement due to a recurrent tumor extending to the infratemporal fossa. She underwent transfrontal surgery, second radiotherapy, and was started on TMZ. Despite 8 cycles of temozolomide (200 mg/m², 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 about patients with aggressive prolactinomas who had been treated with TMZ. Data on demography, duration of therapy, and management outcomes were analyzed in those with progressive disease.

Results: We identified 94 cases of patients with aggressive/malignant prolactinomas in the literature who had received TMZ. Progressive disease despite TMZ was present in 36 cases (38%). There was a male preponderance (65%) among these and 40% had aggressive prolactinomas, whereas the rest had carcinomas. Patients received a median of 8 cycles (interquartile range, 3.5-11.5) of TMZ. O6-methylguanine-DNA-methyltransferase (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: TMZ resistance in aggressive/malignant prolactinomas is challenging. Progressive disease on optimal TMZ treatment entails the use of newer agents.

Keywords: MGMT; aggressive prolactinoma; temozolomide; temozolomide resistance.

Figure 1.

A to F, Panel of magnetic resonance imaging scans of the patient showing A, a 5 × 3 × 3-cm sellar mass extending into the suprasellar and sphenoid regions consistent with a giant macroprolactinoma; and B, showing T1 hyperintense lesions due to pituitary apoplexy in the tumor (hemorrhagic area 3 × 3.4 × 3.3 cm) after 6 months of cabergoline therapy. After transsphenoidal surgery, C, the tumor residue has a right (0.7 × 0.7 cm) and left (1.6 × 1.9 × 1.3 cm) parasellar aspect encasing the left carotid artery and D, shows minimal to absent residue. E and F, One year later an enhancing sellar suprasellar mass (2.1 × 1.9 × 2.7 cm) extends into the left cavernous sinus, middle cranial fossa, pterygopalatine fossa, infratemporal fossa, and left cisternal part of the optic nerve encasing the left cavernous sinus.

Figure 2.

A to I, Maximum intensity projection of the whole-body ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) shows A, abnormal focus of FDG uptake in the region of the base of the skull and in the left cervical region (black arrows). B and C, Transaxial contrast-enhanced CT and fused PET/CT images localized the uptake to a heterogeneously enhancing soft-tissue mass in the left sphenoid region and extending to the pituitary fossa, apex of left temporal bone, the nasal cavity, and apex of left orbit anteriorly with a maximum standardized uptake value (SUV_max) of 35.5. D and E, The mass was seen to cause bony erosion of the left greater wing of sphenoid and the left medial and lateral pterygoid plates. F and G, In the coronal CT and fused PET/CT images, the mass has intracranial extension to the left temporal lobe. H and I, There are significant FDG-avid enlarged lymph nodes at cervical level II (white arrow, with SUV_max 11.2) and level IV on the left side.

Figure 3.

A to D, Panel of photomicrographs depicting A, sphenoid mucosa, and B, bony trabeculae infiltration of the tumor specimen obtained at the second surgery. Ki67 is C, 15% in the first surgery, rising to D, 40% in the second surgery.

Figure 4.

A to H, Hematoxylin-eosin stain (H&E) and A, immunohistochemistry with B, positive prolactin; C, positive Pit-1; D, positive vascular endothelial growth factor (VEGF); E, negative O6‐methylguanine‐DNA‐methyltransferase (MGMT); E, negative p53; G, negative estrogen receptor α (ER-α); H, negative progesterone receptor; and I and J, negative MSH2 and MSH 6 (staining in the sample from the second surgery.

Figure 5.

Course and management of the patient using multimodal treatment strategy depicting serial changes in serum prolactin and tumor volume.