Complete Response of a Patient With a Mismatch Repair Deficient Aggressive Pituitary Adenoma to Immune Checkpoint Inhibitor Therapy: A Case Report

Abstract

BACKGROUND AND IMPORTANCE: Aggressive pituitary adenomas (APAs) are pituitary tumors that are refractory to standard treatments and carry a poor prognosis. Current treatment guidelines are not standardized but combine surgical resection, radiation therapy, and chemotherapy. Temozolomide is the only chemotherapeutic agent with documented effectiveness and is recommended for APA in European Society of Endocrinology clinical guidelines. CLINICAL PRESENTATION: A 57-year-old man presented with visual deterioration and bitemporal hemianopsia. MRI of the brain demonstrated a sellar mass suspected to be pituitary macroadenoma with displacement of the stalk and optic nerve impingement. The patient underwent stereotactic endoscopic transsphenoidal resection of the mass. Postoperative MRI demonstrated gross total resection. Pathology revealed a sparsely granulated corticotroph adenoma with malignant transformation. Immunohistochemistry showed loss of expression of MLH1 and PMS2 in the tumor cells. Proton therapy was recommended given an elevated Ki67 index and p53 positivity. Before radiotherapy, there was no radiographic evidence of residual tumor. Temozolomide therapy was initiated after surveillance MRI showed recurrence at 16 months postoperatively. However, MRI demonstrated marked progression after 3 cycles. Next-generation sequencing using the MSK-IMPACT platform identified somatic mutations in MLH1 Y548lfs*9 and TP53 R337C. Immunotherapy with ipilimumab/nivolumab was initiated, and MRI demonstrated no residual tumor burden 34 months postoperatively. CONCLUSION: APA is a tumor with frequent recurrence and a short median expected length of survival. Here, we demonstrate the utility of immunotherapy in a single case report of APA, with complete resolution of recurrent APA and improved survival compared with life expectancy.

Immunotherapy for Aggressive and Metastatic Pituitary Neuroendocrine Tumors (PitNETs): State-of-the Art

“…A complete response (CR) was reported in 3 cases (1 metastatic lactotroph and 1 metastatic corticotroph, both with hormone suppression to undetectable levels, and 1 silent aggressive corticotroph) (cases 6, 11, and 12) [ 17 , 21 , 23 ]. A partial response (PR) was present in 2 metastatic PitNETs (1 corticotroph, with a decrease in ACTH secretion and 1 silent-Pit1) (cases 7 and 13) [ 17 ] and this report.…”

“…Mismatch repair deficiency (MMRd) was reported in 4 corticotroph PitNETs and associated either with CR ( n = 2) [ 17 , 23 ], delayed PD ( n = 1) [ 22 ] or rapid PD [ 16 ]. MMRd was diagnosed: (i) by IHC at the primary pituitary site in 2 aggressive cases [ 16 , 23 ], supported in one case by an MLH1 mutation [ 23 ]; (ii) at a liver metastatic site only, by IHC and supported by an MSH6 mutation [ 15 ]; (iii) at an orbital site harboring MSH2/6 mutations in a “hypermutated” phenotype [ 17 ]. In the remaining cases, no abnormality was found ( n = 6) or searched for ( n = 4).…”

“…To review the data, tumor mutational burden (TMB) was re-defined according to Goodman (2017) as high (>20 mutations/megabase of DNA (mut/Mb), intermediate (6–19 mut/Mb), or low (up to 5 mut/Mb) [ 25 ]. Accordingly, TMB was high in a single case at a metastatic site [ 15 ] and intermediate in 3 cases—at primary site [ 23 ], metastatic site [ 17 ], or uncertain site [ 19 ]. In the first case [ 15 ], the high TMB observed at the liver metastatic site was associated with an MMRd state, which was in contrast with the absence of mutations at the primary site (before TMZ)—although both responded to dual ICIs—and with a low TMB at a further adnexal metastatic site appearing on maintenance ICIs—treated by surgery [ 22 ].…”

“…In the first case [ 15 ], the high TMB observed at the liver metastatic site was associated with an MMRd state, which was in contrast with the absence of mutations at the primary site (before TMZ)—although both responded to dual ICIs—and with a low TMB at a further adnexal metastatic site appearing on maintenance ICIs—treated by surgery [ 22 ]. Among those with an intermediate TMB, one aggressive corticotroph PitNET was MMRd and had a CR [ 23 ], the others were either MMR-proficient or MSS and had PD. TMB was low in 2 additional PitNETs, an aggressive lactotroph [ 18 ] and a silent corticotroph met-PitNET [ 17 ], both were MSS and experienced PD.…”

“…Based on their potential clinical efficacy and acceptable tolerance, ICIs are currently under active evaluation in patients with neuroendocrine tumors (NETs) of different origin, based on either single or combined therapeutic protocols [ 9 , 10 , 11 , 12 , 13 , 14 ]. In PitNETs, the experience is yet limited to case reports or small case series reported since 2018 [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ], including aggressive and metastatic tumors—which will be respectively designed as ag-PitNETs and met-PitNETs. All patients had previously received TMZ and the outcome of ICIs was variable despite very encouraging reports.…”