MSH6/2 and PD-L1 Expressions Are Associated with Tumor Growth and Invasiveness in Silent Pituitary Adenoma Subtypes

Mismatch repair genes mutS homologs 6/2 (MSH6/2) expressions are involved in tumor growth and programmed cell death 1 ligand 1 (PD-L1) expression in tumor immunity, but the direct association with pituitary adenomas (PAs) is not well understood. We aimed to clarify the effects of MSH6/2 and PD-L1 expression on tumor proliferation and invasiveness in nonfunctioning (NF) PAs. We performed immunohistochemistry to classify the NFPAs into gonadotroph adenoma (GAs), silent corticotroph adenomas (SCAs), null cell adenoma (NCAs), and pituitary transcription factor 1 (PIT1) lineage PAs. We evaluated MSH6/2 and PD-L1 mRNA expressions in NFPAs by real-time PCR (n = 73), and statistically analyzed the expressions and clinicopathological factors. We also investigated the effect of MSH6 knockout on PD-L1 expression in AtT-20ins and GH3. MSH6/2 expressions were significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. MSH6/2 expressions were positively associated with PD-L1 expression. PD-L1 expression was significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. Although MSH6/2 expressions also tended to be lower in PIT1 lineage PAs than in GAs, PIT1 lineage PAs expressed PD-L1 equivalently to GA, which was unlike SCAs and NCAs. MSH6 knockout in AtT-20ins and GH3 significantly decreased PD-L1 expression (75% and 34% reduction, respectively) with cell proliferation promotion. In conclusion, differences in MSH6/2 and PD-L1 expressions of SCAs, NCAs, and PIT1-lineage PAs from those of GAs appear to contribute to their clinically aggressive characteristics, such as more proliferation and invasiveness.

The Importance of Immunohistochemical Analysis in Silent Pituitary Adenoma

Pituitary adenoma contributes to 15% of all intracranial neoplasm. It is usually following benign course and some of them are silent (asymptomatic clinically, but hormone-secreting). Silent adenoma usually found incidentally or when the patients show mass effect (neurological deficits). Many of histologically aggressive silent adenoma subtypes are associated with invasiveness, recurrence and progression to clinically functioning adenomas. Aggressive silent adenoma radiologically tends to invade in downward direction, invading bone, sinus cavernosus, parasellar region. The nature of aggressive silent adenoma subtypes is differing in nature compared to benign nature of pituitary adenoma and should be confirmed immunohistochemically to determine the prognosis and anticipate the risk of recurrence or progression. The case illustration show a real case of 46 years old female progressive headache and visual disturbance diagnosed with non-functional pituitary macroadenoma but positive for more than one immunochemistry biomarker (plurihormonal aggressive silent adenoma).

Reduced Size of a Hormonally Silent Pituitary Adenoma during Treatment with CV 205-502, a New Dopamine Agonist Mainly Stimulating D2 Receptors

A 39-year-old woman with secondary amenorrhea and visual field defects underwent craniotomy for a large pituitary tumor that was hormonally silent according to measurement of plasma hormone levels and immunohistochemical analysis. During the preoperative investigation, bromocriptine was administered for 1 month, but there was no change in the tumor size as seen on computed tomographic scans. One month after surgery, visual field defects recurred, and a tumor mass comparable to the preoperative state was found on computed tomographic scan. The tumor size gradually diminished during treatment with CV 205-502, a tricyclic benzoquinoline which stimulates mainly D2receptors and is better tolerated than bromocriptine. The visual fields were completely normalized after 3 months of treatment with the drug, and surgical management of the tumor mass was no longer considered to be necessary. Thus, as in many similar cases, the hormonally silent pituitary tumor in this patient proved unresponsive to bromocriptine treatment. In contrast. the tumor was reduced by therapy with CV 205-502, a drug that is better tolerated and might permit a more intense stimulation of D2receptors.