Reclassification of “Null Cell Adenomas” Based on Transcription Factor Staining

Introduction: Null cell adenomas (NCA) are a subtype of non-functional pituitary adenomas (NFPA) that stain negatively for anterior pituitary hormones (ACTH, FSH/LH, TSH, GH, PRL) and pituitary transcription factors (PTF; SF-1, PIT-1, T-PIT). Historically, NCA comprised 30-40% of all NFPAs, but with the advent of PTF staining, many of these tumors may be reclassified. Reclassification of NCA may yield important insights regarding behavior of “true” NCA, compared to hormone negative tumors that stain positively for PTFs. Objective: To reclassify null cell adenomas based on PTF staining and compare clinical features of “true” null cell adenomas compared to other NFPA. Methods: Out of 578 transsphenoidal surgeries for tumor resection performed at a single institution from 2012 to 2024, there were 376 PitNETs, of which 223 were nonfunctional. Of these, 54 stained negatively for hormone IHC. Formalin-fixed paraffin embedded tissue was available for 36 of these cases. Slides were created and sent to the Mayo Clinic (Rochester, MN) for PTF staining. Once the staining was complete, two neuropathologists independently reviewed each slide and provided an updated diagnosis. Tumor volume (AxBxC/2) and Knosp grade were determined based on preoperative T1-post contrast MRI. Residual disease at 3 months postoperative and reoperations were recorded. Statistical analysis was performed using Prism GraphPad. Results: Of 36 hormone-negative PAs, 11 stained positively for SF-1 (gonadotroph), 5 for PIT-1 (somatotroph, lactotroph, or thyrotroph), and 5 for both SF-1 and PIT-1. Thirteen tumors had negative PTF staining suggesting they are true null cell adenomas, while 2 had equivocal staining and were excluded. There were no significant differences in tumor volume, Knosp ≥ 3, residual disease, reoperation, age, or sex among SF-1(+), PIT-1(+), NCA, or pleurihormonal tumors (PHT). However, tumor volume trended higher in the gonadotroph group than the others (20.3 cm3 vs. 15.1 [NCA] 6.0 [PIT-1(+)], 7.3 [PHT], p=0.66). Proportion of Knosp ≥ 3 (46.2%), residual disease (66.7%), and need for reoperation (30.8%) trended higher in the Null Cell group but were not significant (all p>0.05). When comparing the SF-1(+) tumors with a separate cohort of 121 FSH/LH (+) silent gonadotroph adenomas, tumor volume was significantly higher in the SF-1(+) group (20.3 cm3 vs. 8.6 cm3, p