Endocrine Abstracts

JOINT2151

A 55-year-old male was diagnosed with aggressive macroprolactinoma (APRL) in 2001. He underwent transsphenoidal surgery (TSS) in 2002 and 2005, followed by radiotherapy and further craniotomy in 2009. Temozolomide, an oral alkylating chemotherapeutic agent, was initiated in 2009, achieving biochemical control for over a decade. Patient was panhypopituitarism, requiring hormone replacement (levothyroxine, hydrocortisone, & testosterone) & severe sight impairment due to bilateral optic atrophy. In 2024, he presented with tumour relapse evidenced by rising prolactin levels. MRI confirmed subsellar and left cavernous sinus recurrence. Clinically, he had severe stabbing pain in the left V1 region along with left cranial nerve VI palsy. A cycle of Temozolomide was given but failed to control prolactin levels or alleviate pain. TSS was then undertaken which resulted in temporary prolactin reduction, but levels soon rebounded. Multidisciplinary discussion was undertaken, and tumour histology was analysed. Immunohistochemistry for DNA mismatch repair proteins (MSH2, MSH6, MLH1, PMS2) revealed absent MSH6 staining but others positive. Ki-67 proliferation index was 12%, and bone invasion confirmed aggressive behaviour. The findings were consistent with an aggressive prolactinoma/PITNET (WHO 2022). The patient is now undergoing radiotherapy, with further chemotherapy options being explored. Whole genome methylation and next-generation sequencing are underway to guide future treatment.

Conclusion: Aggressive prolactinomas are a rare subset of pituitary tumours. Effective management requires a multidisciplinary approach incorporating surgery, radiotherapy, and systemic therapy. We present a case of an aggressive prolactinoma successfully controlled with Temozolomide, from 2009 until 2022. However, in 2024, tumour recurrence demonstrated resistance to Temozolomide therapy. Immunohistochemical analysis of tumour tissue revealed absent MSH6 staining, suggesting a potential mutation in the MSH6 gene. Loss of MSH6 expression has been associated with poor response to temozolomide therapy, as highlighted in a study where intact MSH6 correlated with a favourable treatment response. [1] This case underscores the importance of molecular profiling in guiding therapeutic decisions for aggressive pituitary tumours. The observed MSH6 loss may provide an explanation for acquired resistance to Temozolomide and suggests the need for alternative treatment strategies, such as immune checkpoint inhibitors or other targeted therapies. Multidisciplinary management remains essential in optimizing outcomes for these challenging cases.

Reference: Hirohata T, etal. DNA Mismatch Repair Protein (MSH6) correlated with the responses of atypical pituitary adenomas and pituitary carcinomas to temozolomide: the national cooperative study by the Japan society for hypothalamic and pituitary tumors. Journal of Clinical Endocrinology and Metabolism 2013 98 1130–1136. (https://doi.org/10.1210/jc.2012-2924).