A 56-year-old man presented at our institution in March 2017 with altered mental status and diaphoresis, which was believed to be a myocardial infarction. The cardiac workup was negative. However, examination revealed manifestations of hypogonadism and a serum prolactin level of approximately 200 ng/mL. A brain MRI was ordered and revealed a 2 x 2 cm pituitary mass ( Figures 2A, B ). He was diagnosed with a prolactinoma and initiated on cabergoline but experienced gastrointestinal disturbances and was subsequently switched to bromocriptine. The bromocriptine dose was gradually increased to 20mg/day. The tumor size stabilized, and serum prolactin levels decreased ( Figure 3 ).
In December 2020, the patient presented with three days of new-onset diplopia, blurry vision in the left eye, and headache. Physical examination showed a left eye adduction deficit with anisocoria, consistent with left cranial nerve (CN) III palsy. The neurological exam also revealed a subtle left CN VI palsy. His serum prolactin level at admission was 330 ng/mL. A brain MRI showed progression of the mass with suprasellar extension, left cavernous sinus invasion, and evidence of apoplexy ( Figures 2C, D ). Surgical resection was recommended, and the tumor was debulked through a transsphenoidal approach ( Figures 2E, F ). Pathological analysis of the resected tissue showed positive immunohistochemical (IHC) staining for prolactin and PIT-1 and a 30% MIB1/Ki-67 proliferation index with increased mitotic activity and nuclear atypia.
Postoperatively, the patient's CN III palsy improved, and serum prolactin level decreased to 166 ng/mL. The patient was prescribed cabergoline 1 mg twice a week and subsequently underwent adjuvant fractionated radiotherapy (total dose 30 Gy), which was completed 2 months later.
In November 2021, the patient reported significant decrease in vision of the left eye; follow-up MRI revealed progression of the residual tumor with bilateral invasion of the cavernous sinuses and compression of the left optic nerve ( Figures 2G, H ). The serum prolactin was elevated at approximately 500 ng/mL despite an increase in cabergoline dosage. Clinically, his visual acuity was significantly decreased in both eyes, with only light perception in the left eye. He was prescribed two courses of TMZ; however, his vision deteriorated and the tumor continued to grow ( Figures 4A, B ). In January 2022, he underwent a second operation through a transcranial approach and subtotal resection was achieved, decompressing the optic nerves ( Figures 4C, D ). The resected tumor tissue was sent for detailed histopathological and genetic analysis, and the findings are discussed in the section below. Postoperatively, vision partially improved, but then started deteriorating again two months later to complete blindness. Follow-up MRI revealed progression of tumor size, and the serum prolactin level continued to increase (730 ng/mL).
Based on the tumor aggressiveness and resistance to all standardized lines of therapy, a novel approach was explored. The multi-kinase inhibitor, pazopanib, showed promising results in patients with neuroendocrine carcinomas of gastrointestinal, lung, and pancreatic origins. The patient was subsequently started on pazopanib (800 mg daily). His symptoms gradually improved, and after 3 months, there was an improvement in vision in the right eye with partial restoration of visual fields bilaterally. Additionally, serum prolactin decreased to 122 ng/mL, and MRI showed a reduction in tumor size along with a decrease in the cystic and necrotic components of the tumor ( Figures 4E, F ). The patient remained progression-free for six months. However, after 7 months of starting pazopanib treatment, MRI revealed tumor progression ( Figures 4G, H ). Based on PD-L1 positive staining of the tumor tissue ( Figure 5 ), the PD-L1 inhibitor pembrolizumab was added to the patient's treatment regimen, however, the tumor continued to progress. The patient was prescribed a combination therapy of pazopanib and TMZ, yet the tumor still continues to grow.
Histopathological examination of the resected tumor tissue revealed pituitary adenoma with foci of necrosis and hemorrhage. IHC staining was positive for PIT-1 and prolactin but negative for FSH, LH, SF1, GH, TSH, ACTH, and TBX19. IHC results were also strongly positive for PD-L1, MLH1, MSH2, MSH6, and PMS2. The MIB1/Ki-67 proliferation index was 30%, mitotic figures were up to 18 per 10 HPF, and nuclear atypia was moderate to severe. Genome sequencing by microarray analysis of the tumor specimen revealed numerous acquired copy number abnormalities, including focal amplification of chromosome 3q, complex aberrations consistent with chromothripsis in two regions of chromosome 1p, regional loss of chromosome 9p (with a portion of focal homozygous loss breaking within the CDKN2A gene), and regional loss of chromosome 17p (containing the TP53 gene). Other abnormalities detected via microarray analysis included regional chromosomal gain(s) in chromosomes 1, 3, 5, 7, 8, 9, 12, 14q, 16, 17p, 18p, and 19; regional chromosomal loss(es) in chromosomes 1p, 4, 9p, 12p, 17p, 18q, and Yq; and copy neutral loss of heterozygosity in chromosomes 8p, 9p, 13q, 15q, 19p, 20, and 21q ( Figure 6 ). Genomic DNA sequencing also revealed low-level microsatellite instability, low tumor mutational burden, and low (7%) genomic loss of heterozygosity. HLA sequencing detected A*26:01, A*31:01, B*38:01, B*40:01, C*03:04, and C*12:03 genotypes. Details of the methodology of analysis is present in the supplementary material.