Two Rare Cases of Cushing’s Disease in Functional Pleurihormonal Pituitary Neuroendocrine Tumors Positive for TPIT, ACTH, and FSH

Introduction: The World Health Organization (WHO) classification for pituitary neuroendocrine tumors (PitNETs) expanded to include pituitary transcription factors (PTF) PIT1, TPIT, and SF1, which delineate PitNETs and their distinct cell lineage. This novel paradigm has led to changes in the landscape of PitNET diagnosis and has promise in providing additional prognostic value based on subtype. Although PitNETs typically express one PTF, on rare occasion they express PTFs or hormone markers from multiple lineages rendering them as pleurihormonal tumors (PHT). Most PHT are clinically silent, and when they do secrete hormones, it is most commonly growth hormone or prolactin (PIT1 lineage). We report two rare cases of functional pleurihormonal tumors arising from TPIT and SF1 lineages in patients presenting with Cushing’s Disease.

Example Case: A 39-year-old male presented with 27 lb weight gain over several months, and magnetic resonance imaging demonstrating an ~1.7 × 1.4 × 0.7 cm (0.8 cm³) enhancing sellar mass. Physical examination revealed truncal obesity with abdominal striae, dorsocervical and supraclavicular fat pads, and facial adiposity. Endocrinological workup was notable for elevated midnight salivary cortisol (4,900 ng/dL; ref <100), 24-hour urine cortisol (1193 mcg; ref 3.5–45 mcg), and low-dose dexamethasone suppression test (90 mcg/dL, ref<10), as well as elevated ACTH and 8:00 am cortisol on several occasions. Hemoglobin A1c was elevated at 6.4. He underwent a multidisciplinary endoscopic endonasal transsphenoidal approach for resection. Postoperatively, his cortisol downtrended to a nadir of 3 before he sustained a brief hypotensive episode when out of bed on postoperative day 1. Hydrocortisone replacement was initiated and slowly tapered to physiologic dosing. Histopathology was positive for TPIT and ACTH with abundant Crooke cell change, as well as FSH. It was negative for SF1, PIT1, and other pituitary hormones. The patient recovered very well without complication and was discharged on postoperative day 4.

Discussion: We present two rare cases of individuals who presented with clinical and biochemical hypercortisolism and was found to have a pleurihormonal tumor co-expressing TPIT, ACTH, and FSH with Crooke cell change. PHT are a rare subset of PitNETs whose diagnosis has expanded with the 2017 WHO update to include tumors of multiple transcription factor lineages. Previous literature has shown ACTH-secreting PHTs to be exceedingly rare, and even less common to include an SF1 lineage hormone marker, with several large case series showing no cases of Cushing disease from a PitNET with TPIT/SF1 co-lineage. As ACTH-secreting PHTs have a demonstrated a higher recurrence risk than other PHTs6, and are associated with a morbid clinical syndrome, this rare subclass of PHT warrants careful attention, biochemical workup, and close follow up.

Conclusion: We describe an exceedingly rare case of a functional pleurihormonal tumor with ACTH secretion and immunohistochemical staining for TPIT, ACTH, and FSH. This is a rare subset of pleurihormonal tumor that has seldom been described in the literature. Given its morbid clinical syndrome and propensity for recurrence, this type of PHT warrants a careful biochemical workup, complete surgical resection for biochemical remission, and careful follow up.