Pituitary Carcinoma in a Patient with an SDHB Mutation

Abstract

We present the first case of pituitary carcinoma occurring in a patient with a succinate dehydrogenase subunit B (SDHB) mutation and history of paraganglioma. She was initially treated for a glomus tumour with external beam radiotherapy. Twenty-five years later, she was diagnosed with a non-functioning pituitary adenoma, having developed bitemporal hemianopia. Recurrence of the pituitary lesion (Ki-67 10% and p53 overexpressed) occurred 5 years after her transsphenoidal surgery, for which she underwent two further operations followed by radiotherapy. Histology showed large cells with vacuolated clear cytoplasm with positive immunostaining for steroidogenic factor 1 (SF1) and negative staining for pituitary hormones. Four years after the pituitary radiotherapy, two metastatic deposits were identified: a foramen magnum lesion and an intradural extra-medullary cervical lesion at the level of C3/C4. There was also significant growth of the primary pituitary lesion with associated visual deterioration. A biopsy of the foramen magnum lesion, demonstrating cells with vacuolated, clear cytoplasm and positive SF1 staining confirmed a pituitary carcinoma, for which she was commenced on temozolomide chemotherapy. There was dramatic clinical improvement after three cycles and reduction in the size of the lesions was observed following six cycles of temozolomide, and further shrinkage after 10 cycles. The plan is for a total of 12 cycles of temozolomide chemotherapy. SDH mutation-related pituitary tumours have an aggressive phenotype which, in this case, led to metastatic disease. SF1 immunostaining was helpful to identify the tissue origin of the metastatic deposit and to confirm the pituitary carcinoma.

Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects

“…This patient's pituitary tumour showed loss of heterozygosity at the SDHD locus and reduced protein expression of both SDHD and SDHB (Xekouki et al 2012). Other reports (Benn et al 2006, Dwight et al 2013, Varsavsky et al 2013, Gill et al 2014, Papathomas et al 2014, Tufton et al 2017, Maher et al 2018, including a study showing that Sdhb +/− mice develop pituitary lactotroph hyperplasia (Xekouki et al 2015), have further strengthened the link between germline SDHx mutations and PAs, and this has allowed the definition of a novel clinical entity called 3PAs (phaeochromocytoma/ paraganglioma with PAs). Notably, only one case of a double somatic mutation (detected by loss of SDHB and SDHA immunostaining and confirmed by sequencing) was described in 1/309 sporadic PAs, implying that this is an extremely rare event (Gill et al 2014).…”

“…However, this might be an underestimation, considering that subjects carrying SDHx mutations are not routinely screened for pituitary tumours. Among 18 cases of SDHxrelated PAs which were confirmed by genetic testing (Benn et al 2006, Xekouki et al 2012, Dwight et al 2013, Varsavsky et al 2013, Papathomas et al 2014, Tufton et al 2017, Maher et al 2018, data regarding family history are available from 16 patients. Among these, 14 patients had a positive family history of PPGL (and PAs in two kindreds), while only two patients presented with sporadic disease.…”

“…Among the 16 patients with available clinical data, most (10) were affected by prolactinomas, while somatotroph or NFPAs occurred in three cases each. Most of the reported cases were macroadenomas, in some cases displaying an aggressive behaviour, including a nonfunctioning pituitary carcinoma in a patient harbouring an SDHB mutation (Tufton et al 2017). Notably, SDHxrelated PAs showed peculiar histopathology features, with typical intracytoplasmic vacuoles (Denes et al 2015, Tufton et al 2017, Maher et al 2018.…”

“…Most of the reported cases were macroadenomas, in some cases displaying an aggressive behaviour, including a nonfunctioning pituitary carcinoma in a patient harbouring an SDHB mutation (Tufton et al 2017). Notably, SDHxrelated PAs showed peculiar histopathology features, with typical intracytoplasmic vacuoles (Denes et al 2015, Tufton et al 2017, Maher et al 2018. As SDHx mutations are extremely rare in patients with sporadic PAs (Gill et al 2014, sequencing of SDHx genes should be reserved for patients with a personal or family history of paraganglioma or phaeochromocytoma.…”

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

“…Pituitary adenoma have been reported in nine cases, but only three had proven LoH (loss of heterozygosity) and abnormal SDHB expression, thus confirming involvement of SDHB mutation . Tufton et al reported a case of a SDHB mutation carrier with pituitary carcinoma …”