Neuro-Ophthalmic Manifestations of Pituitary Carcinoma

Clinical Correspondence Neuro-Ophthalmic Manifestations of Pituitary Carcinoma Emily A. Chang, BS, Ravi Shah, MD, Stacy V. Smith, MD, Ama Sadaka, MD, Juan Ortiz Gomez, MD, Patricia Chevez-Barrios, MD, Andrew G. Lee, MD P ituitary carcinomas are rare, representing 0.1%-0.2% of pituitary neoplasms (1). The only true diagnostic criterion for carcinoma is metastatic spread, making it difficult to differentiate pituitary adenoma from carcinoma. However, certain features may suggest this as a more aggressive pituitary lesion. These include histologic features of "atypical" cells within a pituitary adenoma, rapid recurrence or progression of disease, and the development of metastatic lesions in a patient with a presumed benign pituitary tumor. We describe 2 patients who demonstrate the prolonged latency period between the diagnosis of pituitary adenoma and pituitary carcinoma. A 54-year-old woman presented with bitemporal hemianopia and headache. Neuroimaging demonstrated a suprasellar mass, and transsphenoidal resection revealed a typical pituitary adenoma. Five years later, MRI showed residual tumor growth, and she underwent stereotactic radiosurgery. Serial neuroimaging studies remained stable. The patient was asymptomatic for 13 years when repeat MRI showed tumor recurrence with extension to the paranasal sinuses. She underwent repeat surgical resection, but histopathology now showed features of "atypical pituitary adenoma," including larger than usual cells with prominent nucleoli, scattered mitotic figures, rare positive nuclei for p53, and an MIB-1 antibody labeling index of 9.1%. The patient received a postoperative radiotherapy. Two years later, MRI revealed extension of the tumor into the right orbit. Positron emission tomography (PET) demonstrated metastatic lesions in the neck, chest, lung, and several lymph nodes. On neuro-ophthalmic examination, visual acuity was 20/20 in both eyes, but there was Baylor College of Medicine (EC, RS, PCB, AGL), Houston, Texas; Department of Ophthalmology (SVS, AS, PCB, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Department of Pathology (JOG, PCB), Houston Methodist Hospital, Houston, Texas; Departments of Ophthalmology, Neurology, and Neurosurgery (PCB, AGL), Weill Cornell Medicine, New York City, New York; Section of Ophthalmology (AGL), UT MD Anderson Cancer Center, Houston, Texas; Department of Ophthalmology (AGL), Baylor College of Medicine, Houston, Texas; Department of Ophthalmology (AGL), University of Iowa, Iowa City, Iowa; and Department of Ophthalmology (AGL), University of Texas Medical Branch, Galveston, Texas. The authors report no conflicts of interest. Address correspondence to Andrew G. Lee, MD, Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street, Suite 450, Houston, Texas 77030; E-mail: [e-mail] Chang et al: J Neuro-Ophthalmol 2018; 38: 339-341 a right relative afferent pupillary defect and mild diffuse depression of the right visual field. There was a slight limitation to elevation of the right eye, and the remainder of the examination was unremarkable. Right frontotemporal craniotomy coupled with multiple lymph node biopsies showed synaptophysin-positive pituitary cells negative for all hormone markers, including prolactin, adrenocorticotropic hormone (ACTH), growth hormone, thyroid-stimulating hormone, follicle-stimulating hormone, and luteinizing hormone. Scattered nuclei were p53 positive, the MIB-1 labeling index was 24.2%, and lymph node dissection revealed 4 mitoses per 10 highpower fields (Fig. 1). Together, the morphologic features, immunophenotype, and nodal metastases supported the diagnosis of pituitary carcinoma. After surgery, visual acuity was 20/25 in the right eye and 20/20 in the left eye. There was a right relative afferent pupillary defect. Extraocular motility revealed a moderate limitation of elevation and abduction of the right eye. The patient received additional boost radiotherapy to the tumor bed and right neck nodal metastatic lesions and was administered systemic chemotherapy with temozolomide and capecitabine. She has remained stable clinically and radiographically for 3 years after the diagnosis FIG. 1. Pituitary tumor. There is extensive necrosis of the pituitary adenoma with fragments of bone (hematoxylin & eosin, ·20). Inset shows areas of the viable tumor with atypical cells containing pleomorphic nuclei and occasional mitoses (arrow). These findings associated with lymph node involvement are consistent with pituitary carcinoma. 339 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. A. Initial postcontrast axial T1 MRI reveals a suprasellar mass (arrow). B. Initial pituitary biopsy specimen reveals bland monomorphic nuclei with eosinophilic cytoplasm (hematoxylin & eosin, ·400). C. Biopsy of recurrent pituitary tumor demonstrates atypical cells with large pleomorphic nuclei (arrow) (hematoxylin & eosin, ·400). Upper inset, few tumor cells are positive for adrenocorticotropic hormone (ACTH) by immunochemistry (ACTH, ·400). Lower inset, the MIB-1 index proliferation rate is 30% (MIB-1, ·400). of metastatic pituitary carcinoma and 15 years after the discovery of her pituitary adenoma. A 36-year-old man experienced decreased vision and on examination was found to have a bitemporal hemianopia. MRI revealed a suprasellar mass (Fig. 2A), which was resected through the transsphenoidal approach and proved to be an ACTH-positive pituitary adenoma. Although neuroendocrine-appearing cells showed focal nuclear pleomorphism, no mitotic figures were identified (Fig. 2B). One year later, the patient required second craniotomy followed by boost stereotactic radiosurgery for suprasellar extension of the lesion, but there was still no evidence of pituitary carcinoma on tissue biopsy. The patient remained stable for 2 more years until a liver mass was found on evaluation for abdominal pain. Biopsy of the lesion revealed a synaptophysin-positive neuroendocrine carcinoma that was morphologically similar to the previous pituitary pathology but revealed higher MIB-1 positivity rates (10% vs the original 3%), consistent with metastatic pituitary carcinoma. Full-body PET confirmed liver involvement, for which he received fractionated radiosurgery. PET also identified extension of the neoplasm into the right orbit, which ultimately required orbital exenteration as the right eye became blind and painful. Two years later, the patient again noted worsening of vision in his left eye. Visual acuity was 20/30 in the left eye, eye movements were intact, the left visual field demonstrated a stable temporal hemianopic defect, and the left optic nerve was pale. MRI showed an increase in the size of the suprasellar mass, and the patient underwent craniotomy for tumor debulking. Pathology revealed pituitary carcinoma with an extensive area of necrosis and an MIB-1 index of 30%, although p53 staining remained negative (Fig. 2C). Seven years after the original diagnosis, visual acuity in the left eye was 20/20, and both the examination findings and MRI results were stable. 340 The defining clinical characteristic of pituitary carcinoma is evidence of metastasis, believed to occur via hematogenous spread through the venous circulation (2). Pituitary carcinomas are most commonly ACTH- or prolactin-secreting tumors (42% and 33% of cases, respectively) and rarely null-cell carcinomas (12% of cases) (2). Recent reports have documented a mean survival time of 31 months, a slight improvement from 24 months reported in the past (3,4). To our knowledge, our patients are among the longest survivors of pituitary carcinoma in the ophthalmic literature. With the continual implementation of newer treatment modalities such as temozolomide, this trend should continue to improve. Currently, pituitary carcinomas are believed to arise from large adenomas through the accumulation over time of chromosomal abnormalities (5). Although the characterization of histopathological markers of pituitary carcinomas continues to evolve, there is still no pathognomonic biomarker pattern. However, attempts have been made to revise the histological criteria differentiating atypical from typical pituitary adenomas. These include setting cutoff values in 4 parameters: threshold values for p53 ($2%), mitotic index ($2 mitoses within 10 high-power fields), MIB-1 index ($4%), and Ki-67-labeling index $4% (6). Treatment of pituitary carcinomas consists of surgical resection, pharmacotherapy, radiation therapy, and more recently, newer chemotherapeutics. Most notably, temozolomide, originally approved for treatment of refractory glioblastoma multiforme, was adapted in 2006 to treat aggressive pituitary tumors and pituitary carcinomas, with an initial response rate of 50%-60% (7,8). Ji et al (9) noted a 56.2% 5-year survival in patients treated with temozolomide. Pituitary carcinomas sensitive to temozolomide characteristically have methylation of the O6-alkylguanine DNA alkyltransferase-encoding gene and upregulation of MSH6, a mismatch repair protein (10). Other treatments include cyclohexyl-chloroethyl-nitrosourea combined with 5-fluorouracil, which have been used in the treatment of Chang et al: J Neuro-Ophthalmol 2018; 38: 339-341 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence certain pituitary carcinoma subtypes (7). Bevacizumab, an anti-vascular endothelial growth factor antibody, has been shown to inhibit the angiogenesis of pituitary carcinomas, thus inhibiting their growth (10). 6. REFERENCES 1. Pichard C, Gerber S, Laloi M, Kujas M, Clemenceau S, Ponvert D, Bruckert E, Turpin G. Pituitary carcinoma: report of an exceptional case and review of the literature. J Endocrinol Invest. 2002;25:65-72. 2. Ragel BT, Couldwell WT. Pituitary carcinoma: a review of the literature. Neurosurg Focus. 2004;16:E7. 3. Kamiya-Matsuoka C, Cachia D, Waguespack SG, Crane CH, Mahajan A, Brown PD, Nam JY, McCutcheon IE, Penas-Prado M. Radiotherapy with concurrent temozolomide for the management of extraneural metastases in pituitary carcinoma. Pituitary. 2016;19:415-421. 4. Pernicone PJ, Scheithauer BW, Sebo TJ, Kovacs KT, Horvath E, Young WF Jr, Lloyd RV, Davis DH, Guthrie BL, Schoene WC. Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer. 1997;79:804-812. 5. Kaltsas GA, Nomikos P, Kontogeorgos G, Buchfelder M, Grossman AB. Clinical review: diagnosis and management of Chang et al: J Neuro-Ophthalmol 2018; 38: 339-341 7. 8. 9. 10. pituitary carcinomas. J Clin Endocrinol Metab. 2005;90:3089- 3099. Miermeister CP, Petersenn S, Buchfelder M, Fahlbusch R, Lüdecke DK, Hölsken A, Bergmann M, Knappe HU, Hans VH, Flitsch J, Saeger W, Buslei R. Histological criteria for atypical pituitary adenomas-data from the German pituitary adenoma registry suggests modifications. Acta Neuropathol Commun. 2015;3:50. Heaney AP. Pituitary carcinoma: difficult diagnosis and treatment. J Clin Endocrinol Metab. 2011;96:3649-3660. Lasolle H, Cortet C, Castinetti F, Cloix L, Caron P, Delemer B, Desailloud R, Jublanc C, Lebrun-Frenay C, Sadoul JL, Taillandier L, Batisse-Lignier M, Bonnet F, Bourcigaux N, Bresson D, Chabre O, Chanson P, Garcia C, Haissaguerre M, Reznik Y, Borot S, Villa C, Vasilievic A, Gaillard S, Jouanneau E, Assié G, Raverot G. Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas. Eur J Endocrinol. 2017;176:769-777. Ji Y, Vogel RI, Lou E. Temozolomide treatment of pituitary carcinomas and atypical adenomas: systematic review of case reports. Neurooncol Pract. 2016;3:188-195. Yang Z, Zhang T, Gao H. Genetic aspects of pituitary carcinoma: a systematic review. Medicine (Baltimore). 2016;95:e5268. 341 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.