Recurrent Macroprolactinoma with Malignant Conversion to Carcinoma with Spinal Metastasis

In contrast to pituitary adenomas, pituitary carcinomas represent a rare malignant neoplasm with a remarkable high mortality. Pituitary carcinomas can arise from any pituitary tumor cell line and are determined to be carcinomas when there is distant metastasis or central nervous system dissemination. In this case vignette, we describe a rare case of malignant prolactinoma with intraspinal metastasis, and we also provide a review of relevant literature and treatment.

EPID-14. EPIDEMIOLOGY OF ADULT PITUITARY TUMORS IN THE U.S. ACCORDING TO THE 2017 WHO CLASSIFICATION OF ENDOCRINOLOGY TUMOURS

INTRODUCTION Among adult intracranial tumors, the pituitary represents a frequent site of origin. We examine their contemporary epidemiology with a particular focus on uncommon pituitary tumor types. METHODS Adult patients presenting with pituitary or sellar tumors between 2004-2017 were identified from the U.S. National Cancer Database (comprising >70% of newly-diagnosed cancers). Their epidemiology was assessed in the context of the 2017 WHO Classification of Endocrine Tumours. RESULTS 12.5% of adult intracranial tumors arose in the pituitary region. 113,352 adults with pituitary tumors were identified. Histopathological diagnosis was obtained in only 59% of cases, in which 93% were pituitary adenomas and 6% were craniopharyngiomas. Among craniopharyngiomas, 71% were adamantinomatous and 29% were papillary, between which there were no differences in age, sex, or tumor size—however, papillary craniopharyngiomas were less common among Black nonHispanic patients (p< 0.001). Among the remaining 1% (n=680) of pituitary tumors, posterior pituitary tumors comprised 21%, chordomas 16%, meningiomas 15%, pituitary carcinomas 11%, GCTs 10%, hematolymphoid 8%, other mesenchymal and stromal 7%, neuronal/paraneuronal 6%, and schwannoma 4%. Meningiomas (84%), mesenchymal/stromal (64%), and neuronal/paraneuronal (64%) tumors displayed a female predominance, whereas GCTs (75%) and pituitary carcinomas (62%) exhibited a male predominance. Age at diagnosis, tumor size, and race/ethnicity varied widely across uncommon tumor types. We further examined the subtypes of uncommon pituitary tumors: for sellar chordomas, 19% were chordoid and none were dedifferentiated; for sellar meningiomas, 94% were grade I; for pituitary GCTs, 79% were pure germinomas; for hematolymphoid, 52% were DLBCL, 11% were plasmacytomas, and 9% were Langerhans cell histiocytosis; for neuronal/paraneuronal, 64% were gangliocytomas; and for mesenchymal tumors, 53% were vascular and 16% were SFTs/HPCs. CONCLUSIONS Using national registry data, we provide a detailed dissection of the epidemiology of adult pituitary tumors, with a particular focus on examining uncommon pituitary tumor types in the context of WHO2017.

A Rare Case of Metastatic Transformation to Pituitary Carcinoma

Background: Pituitary carcinomas are rare and comprise less than 0.5% of pituitary tumors and frequently arise from previously resected and/or radiated infiltrating adenomas.1 Radiation therapy is used to prevent regrowth but does not have significant data supporting improved prognosis.2 True pituitary carcinomas requires the presence of craniospinal and/or systemic metastases. Here, we present a case of benign pituitary adenoma that had progressed to a metastatic tumor and responded to radiation therapy. Clinical Case: Our patient was first diagnosed in 1982 with a pituitary mass after undergoing an MRI due to right eye blindness. He ultimately had a transcranial resection of the tumor and post-operative external radiation to residual tumor. Final pathology was consistent with a nonsecretory tumor. Additionally, he was diagnosed with panhypopituitarism and he was treated accordingly. Due to barriers of patient adherence, only one post-operative MRI was obtained, and he was lost to endocrine follow up. In 2007, he was again referred to endocrinology for new vision loss in the left eye. An MRI revealed a 3.0 x 3.8 x 4.4 cm tumor that compressed the optic chiasm. Additionally, multiple lesions were seen within the dural and leptomeningeal extra-axial areas including the largest left frontal lesion of 2.4 cm and a 1.7 cm lesion posterior to the cord within the foramen magnum. The patient underwent endonasal transsphenoidal resection of the sellar mass and biopsy of the frontal lesion in October 2007. Pathology showed pituitary adenocarcinoma in both the sellar and frontal lesions and immunoperoxidase staining was negative for all hormones. He completed salvage radiation to the sellar and craniospinal lesions in December 2007. MRI scans completed 7 months later showed stable residual pituitary and metastatic lesions. The patient received 6-month MRI screening exams for the first 2 years and then annually thereafter, as well as PET scanning, without significant progression or new metastatic lesions. Conclusion: We present a case of benign pituitary adenoma which transformed following resection to a malignant tumor with metastatic lesions in the brain and spinal cord that was treated with radiation with relative success. Despite the often-aggressive nature of these metastatic tumors, the patient has experienced a successful treatment course with minimal side effects and without progression 13 years after initial treatment of the metastatic pituitary carcinoma.

Pituitary Carcinoma Diagnosis and Survival Improvement, with Affordable Care Act Correlation: A SEER Database Study

Background Pituitary carcinomas are challenging tumors to diagnose and treat due to their rarity and limited data surrounding their etiology. Traditionally, these patients have exhibited poor survival. Over the last several decades, our understanding of pituitary carcinomas has dramatically increased, and there have been recent initiatives to improve patient access to health care, including the Affordable Care Act (ACA). This study investigates whether there were any changes in incidence and treatment outcomes of pituitary carcinoma that correlated with these advances. Methods A retrospective case review was conducted utilizing the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. Those with primary site pituitary tumors with noncontiguous metastases were identified from 1975 to 2016. Demographic data, overall, and cause-specific outcomes were obtained. The data were analyzed using SPSS to generate 5-year Kaplan–Meier curves. Results The incidence of pituitary carcinoma pre- and post-ACA was 0.31 and 2.14 diagnoses/year, respectively. This represents a significant increase (Chi-square, p < 0.00002). In addition, 1-, 2-, and 5-year overall survival of these patients was determined to be 88.2, 74.0, and 66.6% which was significantly improved compared with prior studies. Cause-specific survival of these patients follow similar trends exhibiting 94.1, 79.0, 71.1% after 1, 2, and 5 years, respectively. Conclusion The survival for pituitary carcinoma has improved significantly which signals a change in how practitioners should counsel their patients. There is a significant surge in the number of cases in the post-ACA timeline, which suggests that improving patient access has played a part in wider recognition and treatment initiation for this disease.

Pituitary Carcinoma: Rare Disease with Difficult Diagnosis and Treatment

Although pituitary tumours are common, pituitary carcinomas are very rare. They are defined as adenohypophyseal tumours with metastatic activity within and outside the boundaries of the central nervous system (CNS). They usually spread to the other parts of the body, by the time they are diagnosed. Because so few cases of pituitary carcinoma have been reported worldwide, it is difficult to learn much about them, and it is difficult to diagnose and treat them. Pituitary carcinomas cannot be distinguished from benign pituitary tumours only on the basis of clinical findings and imaging. Presence of metastases is indicative of carcinoma. Many molecular markers for pathogenesis have been proposed, but none so far is a reliable predictor of disease progression or outcome. Treatment for pituitary carcinomas includes surgery, radiotherapy, and chemotherapy. The paucity of reported cases and literature on pituitary carcinomas renders necessary further research into underlying mechanisms, diagnostic findings, and novel molecular targets for therapy.

The Progress of Immunotherapy in Refractory Pituitary Adenomas and Pituitary Carcinomas

Most pituitary adenomas (PAs) are considered benign tumors, but approximately 0.2% can present metastasis and are classified as pituitary carcinomas (PCs). Refractory PAs lie between benign adenomas and true malignant PC and are defined as aggressive-invasive PAs characterized by a high Ki-67 index, rapid growth, frequent recurrence, and resistance to conventional treatments, including temozolomide. It is notoriously difficult to manage refractory PAs and PC because of the limited therapeutic options. As a promising therapeutic approach, cancer immunotherapy has been experimentally used for the treatment of many tumors, including pituitary tumors. The purpose of this review is to report the progress of immunotherapy in pituitary tumors, including refractory PAs and PCs. The tumor immune microenvironment has been recognized as a key contributor to tumorigenesis, progression, and prognosis. One study indicated that the number of CD68+ macrophages was positively correlated with tumor size and Knosp classification grade for tumor invasiveness. The infiltration of CD4+ and CD8+ T cells was relatively scant in these adenomas, but pituitary growth hormone (GH) adenomas exhibited significantly more CD4+ and CD8+ T cells than non-GH adenomas. These results suggest an association of CD68+ macrophage infiltration with an increase in pituitary tumor size and invasiveness. Another study suggested that a lower number of CD8+ lymphocytes is associated with cavernous sinus invasion and resistance to treatment with first-generation somatostatin analogs in acromegaly patients, highlighting a potential role of the tumor immune microenvironment in determining the prognosis of somatotroph pituitary tumors. Preclinical studies have indicated that widely varying degrees of programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) are found among different subtypes. Functional PAs and aggressive PAs express significantly higher levels of PD-L1 and TILs than other subtypes, indicating that PD-1 blockade might be a promising alternative therapy for patients with aggressive PAs. PD-L1 transcript and protein levels were found to be significantly increased in functioning (GH and prolactin-expressing) pituitary tumors compared to nonfunctioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary tumors harbored higher levels of PD-L1 mRNA than recurrent tumors. These findings suggest the possibility of considering checkpoint blockade immunotherapy for functioning pituitary tumors refractory to conventional management. Animal models of Cushing’s disease also demonstrated PD-L1 and TIL expression in cultured tumors and murine models, as well as the effectiveness of checkpoint blockade therapy in reducing the tumor mass, decreasing hormone secretion, and increasing the survival rate. Clinical studies show that immunotherapy may be an effective treatment in patients with pituitary tumors. One corticotroph carcinoma patient showed a significant reduction in hormone levels and shrinkage of the tumor size of primary and metastatic lesions immediately after investigational treatment with ipilimumab and nivolumab. However, another patient with corticotroph adenoma progressed rapidly after four cycles of anti-PD-1 (pembrolizumab) treatment. To date, there are two registered clinical trials of immunotherapy for pituitary tumors. One of them is the phase II clinical trial of nivolumab combined with ipilimumab for patients with aggressive pituitary tumors (NCT04042753). The other one is also a phase II clinical trial of the combination of nivolumab and ipilimumab for rare tumors, including pituitary tumors (NCT02834013). Both clinical trials are in the stage of recruiting patients and have not been completed. In summary, the results from preclinical research and clinical studies indicated that immunotherapy might be a promising alternative therapy for PCs and refractory PAs resistant to conventional treatments. The combination of immunotherapy and radiotherapy or temozolomide may have synergistic effects compared to a single treatment. More preclinical and clinical studies are needed to further indicate the exact efficacy of immunotherapy in pituitary tumors.

Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study

Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region. Symptoms can be debilitating due to hormonal excess and survival is poor. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there has been interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated 4 patients with pituitary carcinoma with pembrolizumab as part of a phase II clinical trial. Two patients (patients 1 and 2) with functioning corticotroph pituitary carcinomas (refractory to surgery, radiotherapy and chemotherapy) had partial radiographic (60% and 32% per Immune-Related Response Evaluation Criteria In Solid Tumors, respectively) and hormonal responses. Patient 1’s response continues 42 months after initiation of pembrolizumab and his tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with MSH2 and MSH6 gene mutations. Patient 2’s tumor after exposure to temozolomide was not sampled, but prior somatic mutational testing was negative. One patient with a non-functioning corticotroph tumor (patient 3) had a best response of stable disease for 4 months. One patient with a prolactin-secreting carcinoma (patient 4) had progressive disease. The latter 2 patients’ tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. Programmed death-ligand 1 staining was negative in all tumors. We report 2 cases of corticotroph pituitary carcinoma responsive to pembrolizumab after prior exposure to alkylating agents. The role of CPIs in treating patients with pituitary carcinoma, the relationship between tumor subtype and response to immunotherapy and mechanisms of hypermutation in this orphan disease require further study.Trial registration number: NCT02721732.