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

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.

ABBREVIATIONS:

ACTH

adrenocorticotropic hormone

APA

aggressive pituitary adenoma

CTLA

cytotoxic T-lymphocyte-associated protein

ICI

immune checkpoint inhibitor

IHC

immunohistochemical

MMR

mismatch repair

MMRd

mismatch repair deficient

PC

pituitary carcinoma

TMZ

temozolomide.

Pituitary tumors comprise 10% to 25% of intracranial neoplasms; although most are benign, approximately 35% are invasive and a small portion malignant.^1-3 Aggressive pituitary adenomas (APAs) are characterized by a high Ki-67 index, rapid growth, and resistance to treatment.^4,5 Pituitary carcinoma (PC) is defined by metastasis, typically presents in the third to fifth decades, and historically has 1-year survival rates of 57% to 66%.^6,7 Recent studies demonstrate a 71% survival rate at 2 years, reflecting therapeutic advances.⁸ Currently, temozolomide (TMZ) is the only chemotherapeutic agent recommended for APA and PC in European Society of Endocrinology clinical practice guidelines.⁹ Temozolomide is a DNA-alkylating agent that causes base excision repairs, triggering cell arrest/apoptosis, and is only cytotoxic in mismatch repair (MMR) sufficient tumors. Only 37% of patients with APA respond to TMZ, with average progression occurring 1 year after cessation of therapy.⁹ Data suggest that loss of MMR gene expression is associated with TMZ treatment failure in pituitary tumors.^10,11

Lin et al¹² first reported successful treatment of adrenocorticotropic hormone (ACTH)-secreting PC with ipilimumab (cytotoxic T-lymphocyte-associated protein [CTLA] 4 inhibitor) and nivolumab (PD-1 inhibitor) combination therapy; although the hormonal and volumetric responses were impressive, this study was limited by short follow-up. There are only a handful of case reports of ACTH-staining pituitary tumors treated with immune checkpoint inhibitor (ICI) therapy.^13-15 Here, we report the first case of ACTH-staining APA with somatic MMR deficiency and TMZ resistance treated with ICI combination therapy with a complete response.

CLINICAL PRESENTATION

A 57-year-old man presented with bitemporal hemianopsia, weight gain, and cold intolerance in December 2018 (Supplemental Digital Content 1, http://links.lww.com/NEU/D168). MRI of the brain revealed a 3.6 × 2.0 × 2.7 cm sellar/suprasellar mass causing severe optic chiasm impingement and cavernous sinus invasion (Figure 1). Laboratory evaluation demonstrated elevated ACTH, afternoon cortisol, and secondary hypothyroidism (Table 1). Informed consent was obtained before treatment in accordance with Institutional Review Board protocols.

FIGURE 1.

MRI of the brain with and without contrast demonstrating: A, preoperative images demonstrate sellar and suprasellar mass with diffuse homogeneous enhancement and peripheral enhancing rim (circle) resulting in marked mass effect on the optic chiasm and midline structures. There is involvement of the left greater than right cavernous sinuses (arrows). B, After 6 months, postoperative images demonstrate resection of the pituitary mass with no evidence of recurrence and thickening of the infundibulum (circles) believed to represent postoperative changes. There is interval decompression of the optic chiasm with no residual mass effect. C, Follow-up images after 19 months demonstrated persistence of recurrent disease while on temozolomide treatment with increased superior and posterior extent of enhancing sellar tumor (white circle), with nodular enhancement inferiorly on the right (arrows). There is also mild involvement of the bilateral cavernous sinuses. D, After ICI therapy, there is near-complete resolution of sellar and suprasellar mass with no residual mass effect. Sellar tissue thickening is believed to represent post-treatment changes (circle). E, Follow-up 15 months after initiation of ICI therapy showing continued complete resolution of sellar and suprasellar mass. ICI, immune checkpoint inhibitor; TMZ, temozolomide.

TABLE 1.

Endocrinological Hormone Values From Time of Diagnosis Through Current Therapy

Hormone	Reference range	Preoperative	Immediately postoperative	Postoperative day 14	18 mo postoperative (recurrence)	19 mo postoperative (after TMZ initiation)	22 mo postoperative (after ICI combination therapy)
ACTH	0-46 pg/mL	155	87.4	23.7	100	117	1.5
Cortisol	0-10 mg/dL	22	57.4	3.6	8.0	18.6	4.8
Prolactin	2.6-13.1 ng/mL	9.55	3.2	—	—	—	—
TSH	0.45-4.12 uIU/mL	0.92	0.2	—	—	0.09	0.09
Free T4	0.61-1.76 ng/dL	0.57	0.75	0.82	0.83	0.69	0.70
FSH	1.27-19.26 mIU/mL	3.6	2.2	—	—	—	—
LH	1.24-8.62 mIU/mL	2.2	1.6	—	—	—	—

ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone, ICI, immune checkpoint inhibitor; LH, luteinizing hormone, TMZ, temozolomide; TSH, thyroid-stimulating hormone.

Preoperative laboratory results were remarkable for high ACTH and cortisol (PM) levels, secondary hypothyroidism, and low gonadotropin levels (though preoperative testosterone levels were not available). ACTH levels returned to normal on postoperative day 14, increased again with tumor recurrence, but remained normal since treatment with combination ICI therapy along with radiographic proof of remission. Cortisol levels decreased on postoperative day 14 requiring initiation of hydrocortisone for secondary adrenal insufficiency. Of note, all cortisol values were AM cortisol with the exception of the preoperative value, which was obtained in the afternoon but was still elevated compared with the reference value. Preoperative secondary hypothyroidism was noted by TSH and free T4 levels, and patient was appropriately started on hormone replacement therapy.

The patient underwent transsphenoidal resection on January 2, 2019 with immediate visual improvement. MRI obtained on postoperative day 1 and at 6 months showed gross total resection (Figure 1). Morning cortisol was 3.6 mg/dL on postoperative day 14, requiring initiation of hydrocortisone for adrenal insufficiency (Table 1). Pathology identified a sparsely granulated corticotroph adenoma with features of malignant transformation. Certain foci showed moderate nuclear staining for p53 and markedly high Ki-67 index (Figure 2). Immunohistochemistry revealed ACTH positivity and loss of expression of MMR proteins MLH1 and PMS2, with intact nuclear staining for MSH2 and MSH6.

FIGURE 2.

Immunohistologic analysis of tumor sample. A, H&E 200× shows typical adenoma with more aggressive component. Focal necrosis is present in the lower left corner. B, H&E 200× shows the pleomorphism and atypia of the more aggressive component. C, H&E 400× shows focal Crook's hyaline changes in the adenoma D, H&E 400× with aggressive component showing increased mitotic activity and presence of apoptotic bodies E, ACTH expressing adenoma (lower part of the slide) on IHC staining. F, Ki-67 IHC staining shows the marked proliferative activity of malignant component (upper right) compared with background adenoma (75%-80%). G, MMR protein MLH1 showing loss of nuclear staining. H, MMR-PMS2 showing loss of nuclear staining. I, MMR-MSH2 showing intact nuclear staining. J, MMR-MSH6 showing intact nuclear staining. IHC, immunohistochemical; MMR, mismatch repair.

Given the elevated Ki67 (75%-80%) and p53 positivity, the patient received 6600 cGy of adjuvant radiation (33 fractions in 2 months). Radiotherapy was tolerated well, but MRI in May 2020 showed newly recurrent tumor. The patient was initiated on 3 cycles of temozolomide; however, post-therapy ACTH was elevated (Table 1), with subsequent tumor progression (Figure 1). Next-generation sequencing performed on the original surgical specimen using the MSK-IMPACT platform identified somatic mutations in MLH1 Y548lfs*9 and TP53 R337C, as well as elevated tumor mutational burden at 8.8 mutations/megabase (Table 2).

TABLE 2.

Tumor Mutation Analysis

Gene	Protein change	Mutation type	Allele frequency
ATM	I1581Sfs*20	FS del	0.64
NF1	I679Dfs*21	FS ins	0.58
TP53	R337C	Missense	0.14
TBX3	L498Cfs*f34	FS del	0.09
MLH1	Y548Ifs*9	FS ins	0.76
AGO2	A603Rfs*71	FS ins	0.6
TBX3	R454C	Missense	0.05
CSDE1	L459Tfs*30	FS ins	0.06
ERG	F445C	Missense	0.46
BCOR	G575D	Missense	0.08

FS del, frameshift deletion; FS ins, frameshift insertion.

Next-generation sequencing using MSK-IMPACT of the patient's tumor sample and a matched normal sample. Notably, the sample demonstrated a MLH1 frameshift insertion mutation, an oncogenic or likely oncogenic mutation. TP53 was also noted to have a missense mutation identified as a recurrent hotspot mutation in a population-scale cohort or tumor samples across various cancer types.

Off-label ipilimumab/nivolumab combination immunotherapy was initiated in August 2020 per ongoing Memorial Sloan Kettering Cancer Center clinical trial NCT04042753 protocol. MRI in September 2020 showed tumor flare but by November 2020 showed marked decrease in the tumor with mild residual sellar enhancement (Figure 1) and complete resolution by February 2021. The patient completed his fourth/final cycle of ipilimumab on February 11, 2020 and his tenth/final nivolumab cycle on April 26, 2021. MRI in November 2021 showed sustained resolution of the tumor (Figure 1). ICI therapy was well tolerated except for eosinophilia requiring prednisone therapy, possibly the result of an ICI-induced autoimmune response.

DISCUSSION

ICIs are well-established, efficacious treatments for various cancers, yet are uncommonly used for APAs and PCs. TMZ remains standard treatment based on a response rate of 40% to 50% in large case series, with 1-year survival as high as 71% with TMZ and radiotherapy.^8,16,17 Treatment options for temozolomide-refractory PC and APAs are limited with poor prognosis. Our patient's tumor was invasive with features of malignant transformation. Classically, this constitutes an APA, but recent literature suggests this may represent in situ PC.¹⁸

CTLA-4 expression in normal pituitary gland and adenoma tissue may result in complement-mediated antipituitary antibodies, making ipilimumab a potential targeted immunotherapy for PC and APA tumor shrinkage. There is heterogenous expression of PD-L1 in pituitary tumors and increased expression in functioning pituitary adenomas compared with nonfunctioning adenomas.¹⁹ Expression of PD-L1 in functioning pituitary tumors with high Ki67 index potentially predicts susceptibility to PD1/PDL1-inhibitors.^20,21 Our patient harbored a mismatch repair deficient (MMRd), hypermutated tumor. Tumors with MMRd and high mutational burden have increased sensitivity to checkpoint inhibitors across cancer, the basis of the tumor agnostic US Food and Drug Administration approval for the PD1 inhibitor, pembrolizumab.^12,22,23

MMRd is defined by defects in key genes (MLH1, MSH2, MHS6, and PMS2) that encode the MMR complex and can be detected using immunohistochemistry.²⁴ Although MMR immunohistochemistry is not a standard procedure, it was performed in this case to further support the tumor's MMRd status. Temozolomide is only cytotoxic in tumors with functional MMR. This patient's MMRd, therefore, predicted his lack of response to temozolomide and subsequent response to checkpoint inhibitors because defective DNA damage repair is hypothesized to generate neoantigens which sensitizes tumors to checkpoint inhibtiors.^25-27

Limitations

A limitation in this case is that follow-up at this time is less than 18 months since ICI therapy initiation and requires longer evaluation for sustained remission. ICI therapy is associated with a myriad of adverse events, including hypophysitis and endocrinopathy (Supplemental Digital Content 2, http://links.lww.com/NEU/D169).^28,29 Our patient tolerated ipilimumab/nivolumab therapy well, with only transient eosinophilia reported. In addition, ICI therapy has not demonstrated blanket effectiveness in treating pituitary tumors. One study demonstrated minimal response to pembrolizumab in a patient with corticotroph-secreting pituitary adenoma with MMRd, although the authors attributed this to hypercortisolemia inducing negative immunomodulatory effects on T-cells.³⁰ Nonetheless, this highlights the need for further evaluation of ICI therapy to establish efficacy and tolerability of adverse effects in treating tumors.

CONCLUSION

Treatment options for refractory APAs and PCs are limited with poor prognosis, especially when TMZ fails. Molecular analysis revealing a loss-of-function MLH1 mutation and elevated tumor mutational burden made our patient a particularly attractive candidate for ICI therapy and introduces a potential screening paradigm for TMZ-refractory tumors. Further studies will be needed to establish ICIs as a mainstream treatment for pituitary APAs or PCs.

Funding

This research was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant No. P30 CA008748.

Disclosures

Dr Lin has institutional support from Bristol Myers Squibb.

Supplemental Digital Content

Supplemental Digital Content 1. Text. Clinical Presentation.

Supplemental Digital Content 2. Text. Discussion.

COMMENTS

In this manuscript, the authors report on a case of an aggressive pituitary adenoma with mismatch repair deficiency and hypermutation which recurred after a thorough resection and a well-dosed radiation. The recurrent tumor did not respond to temozolomide but showed an excellent response to double immune checkpoint inhibition using ipilimumab and nivolumab. As mentioned by the authors, I believe the type of aggressive pituitary adenoma described here is essentially an in-situ pituitary carcinoma, and the phenomenal response to immunotherapy brings hope to an otherwise highly aggressive disease.

While this is a single case report, referenced in this manuscript are several reports of corticotroph adenomas treated with immune checkpoint inhibitors, with variable success. There are also 2 ongoing phase II clinical trials of ipilimumab and nivolumab in patients with aggressive pituitary tumors (NCT04042753) or various rare tumors including pituitary carcinomas (NCT02834013). Of particular similarity to this case, these authors also reported a hypermutant corticotroph pituitary carcinoma which was successfully treated with double immune checkpoint inhibition. These and similar hypermutant cases may form a subgroup of patients with favorable responses to immunotherapy, arguing for more routine sequencing and screening of aggressive pituitary adenomas for hypermutation and mismatch repair deficiency.

Ali Jalali

Houston, Texas, USA

The authors here report a patient with a silent ACTH-producing pituitary adenoma that presented with bilateral cavernous sinus invasion. As the tumor was sparsely granulated and showed of very high KI-67 index of 75% to 80%, fractionated limited-field radiotherapy to 66 Gy was given after gross total resection. The tumor was hypermutated and showed a mismatch repair deficiency on genomic analysis. After recurrence 14 months later, temozolomide was given but was ineffective in stopping tumor progression. The authors then applied double immunotherapy with ipilimumab and nivolumab and achieved a complete response over the ensuing 6 months. This therapy was given empirically, as they did no staining for PD1/PDL1, but a correlation has not been shown between expression of those ligands and treatment response in pituitary tumors. Although the patient tolerated checkpoint inhibition, the follow-up is not long, and we cannot be sure that the patient will remain free of autoimmune effects on extra-pituitary organs. Given the paucity of similar cases we also cannot know how long immunotherapy must be given to maximize long-term tumor control (or indeed, whether long-term control is possible). The results achieved here make a case for using combination checkpoint inhibition for other aggressive pituitary tumors with a similar mutational profile. The failure of temozolomide here was expected given the lack of a functional mismatch repair complex, and one must wonder whether the many treatment failures seen when that drug is applied to invasive pituitary adenomas could be forestalled by using ipilimumab/nivolumab as first-line drug therapy after radiotherapy.

Ian E. McCutcheon

Houston, Texas, USA