USCAP 2016 – Neuropathology Specialty Evening Conference

Home , Craniopharyngioma, Pituicyte, Pituicytoma

56-year-old female with a recurrent pituitary adenoma

M. Beatriz S. Lopes, MD, PhD Division of Neuropathology Department of Pathology University of Virginia School of Medicine

Immunohistochemical studies

• Immunonegative for pituitary hormones: • GH, PRL, ACTH, βFSH, βLH, βTSH, ɑSU • Immunonegative for transcription factors: • SF-1, Pit-1 SF-1 CHROM S-100

EMA TTF-1 TTF-1 PITUITARY NON-NEUROENDOCRINE TUMOR

CONSISTENT WITH

SPINDLE CELL ONCOCYTOMA WHO 2007

Tumors of the Pituitary and Sellar Region Neuroendocrine Tumors Pituitary Adenoma “Atypical” Adenoma Pituitary Carcinoma Non-Neuroendocrine Tumors Gangliocytoma Pituicytoma Granular Cell Tumor Spindle Cell Oncocytoma Tumors of non-Pituitary Origin Craniopharyngioma Meningioma Chordoma Langerhans Cell Histiocytosis Germ Cell Tumors Metastases WHO 2016

Tumors of the Pituitary and Sellar Region Neuroendocrine Tumors Pituitary Adenoma “Atypical” Adenoma Pituitary Carcinoma Non-Neuroendocrine Tumors Gangliocytoma

TTF-1 Expressing Tumors: Pituicytoma Granular Cell Tumor Spindle Cell Oncocytoma Tumors of non-Pituitary Origin Craniopharyngioma Meningioma Chordoma Langerhans Cell Histiocytosis Germ Cell Tumors Metastases TTF-1 Expressing Pituitary Non-Neuroendocrine Tumors

I. Pituicytoma II. Granular Cell Tumor III. Spindle Cell Oncocytoma

• Similar clinical presentation • Mass effect/compression symptoms • Hypopituitarism • All included in the differential diagnosis of non- functioning pituitary adenoma

TTF-1 Expressing Pituitary Non-Neuroendocrine Tumors

• Most in 4th to 5th decade; slight female predominance • Clinical manifestations of mass-effect (Covington et al., 2011) • Visual disturbances (60%) • Headaches (35%) • Hypogonadism (23.5%) • Fatigue (13.7%) • Amenorrhea (7.8%) • Hyperprolactinemia (25%) – pituitary stalk effect • Radiological findings • Sellar/suprasellar mass, mostly solid • Firmer tumors than pituitary adenomas • Tendency for bleeding during surgery Pituicytomas

• Previous synonyms: “pilocytic astrocytoma of the posterior pituitary and/or infundibulum” or “posterior pituitary astrocytoma” • “Pituicytoma” – description of a sellar region tumor (Liss & Khan, 1958) • Most likely a granular cell tumor of the neurohypophysis • Morphological features similar to pituicyte, a modified glial cell (Bucy,1930) • The pituicytes can be divided into four groups: (1) bipolar, (2) astrocyte-like, (3) triangular, and (4) glomerular. (Liss, 1956) • Bipolar pituicytes: 1A – elongated/oval cells with fibrillary processes; 1B - granular • Brat et at. (2000): definition of a distinctive low-grade, spindle cell neoplasm arising from the pituicytes, the specialized glia of the posterior pituitary and stalk • WHO 2007: recognition as a primary glial neoplasm from the posterior pituitary and infundibulum Pituicytoma Pituicytoma GFAP VIM

S-100 Rich network of intermediate filaments; no neurosecretory granules. Granular Cell Tumor

• Unique neoplasms of the posterior pituitary also suggested to derived from pituicytes • Choristoma, granular cell myoblastoma, granular cell pituicytoma, granular cell schwannoma • Majority are incidental, microscopic “tumorlettes” may be seen in near 10% of autopsies • < than100 symptomatic cases reported

Lopes MB et al., Histology for Pathologists, 3rd Ed Granular Cell Tumor – symptomatic cases Granular Cell Tumor

PAS

Kleinschmidt-Demasters and Lopes. Brain Pathol. 2013 PMID: 23701182 Spindle Cell Oncocytoma

• Spindle Cell Oncocytoma of the Adenohypophysis • Originally described by Roncaroli et al. (2002) as a non-endocrine neoplasm of the adenohypophysis • Clinical presentation and neuroimaging undistinguishable from non- functioning pituitary adenoma • Proposition of a folliculostellate cell (FSC) origin based on similarities of their ultrastructural and immunohistochemical features • Vimentin, EMA, S-100 protein, and Galectin 3 immunoexpression • Cell–cell junctions - desmosomes and intermediate junctions

• WHO 2007: recognition as a pituitary non-neuroendocrine tumor

Spindle Cell Oncocytoma S100 EMA

VIM Galectin 3 Spindle Cell Oncocytoma

Mitochondrial-rich cells with cellular junctions (desmosomes and intermediate junctions); no neurosecretory granules. Thyroid Transcription Factor 1 Expression in Sellar Tumors: A Histogenetic Marker? Lee, Edward; MD, PhD; Tihan, Tarik; MD, PhD; Scheithauer, Bernd; Zhang, Paul; Gonatas, Nicholas

Journal of Neuropathology & Experimental Neurology. 68(5):482-488, May 2009. DOI: 10.1097/NEN.0b013e3181a13fca

FIGURE 2 Thyroid transcription factor 1 (TTF-1) immunoreactivity in pituitary neoplasms. (A) Only one of 21 pituitary adenomas showed TTF-1 immunoreactivity. Note the absence of TTF-1 in most of the cells in this null- cell adenoma. (B) TTF-1 expression is robust in a metastatic adenocarcinoma of lung within the pituitary gland. TTF-1 expression is not detected in the adjacent nonneoplastic pituitary gland. (C, D) Pituicytomas show strong nuclear expression of TTF-1 as determined by immunohistochemistry using antibody clone SPT24. Representative images from Cases 1 and 2 are shown. (E) Pituicytoma with expression of TTF-1 as determined by immunohistochemistry using antibody clone 8G7G3/1. A representative image from Case 3 is shown. A granular cell tumor (F) and a spindle cell oncocytoma (G) show nuclear TTF-1 immunoreactivity using antibody clone SPT24.

4 Lee et al. Thyroid Transcription Factor 1 Expression in Sellar Tumors: A Histogenetic Marker? J Neuropathol Exp Neurol. 68(5):482-488, 2009.

3rd ventricle Adult Human Pituitary

Folliculostellate cells

Pituicytes

Kleinschmidt-Demasters and Lopes. Brain Pathol. 2013 PMID: 23701182 Pituicytoma TTF-1

SCO TTF-1 Marker SCO Pituicytoma GCT (n/N) (n/N) (n/N) GFAP 1/7 3/4 1/3 Vimentin 6/7 4/4 3/3 S100 protein 7/7 4/4 3/3 Olig2 0/7 1/4 0/3 IDH1 (R132H) 0/6 0/4 0/2 NF 0/7 0/4 0/2 Galectin-3 7/7 3/4 0/2 Chromogranin 0/7 0/4 0/3 CD56 5/6 3/4 0/2 EMA 7/7 3/4 1/2 CAM5.2 0/7 0/4 0/2 CD68 2/6 1/4 3/3 Bcl-2 4/6 2/4 0/2 TTF-1 7/7 4/4 3/3

Mete O, Lopes MB, Asa SL. Am J Surg Pathol. 2013 PMID: 23887161 Marker SCO Pituicytoma GCT (n/N) (n/N) (n/N) GFAP 1/7 3/4 1/3 Vimentin 6/7 4/4 3/3 S100 protein 7/7 4/4 3/3 Olig2 0/7 1/4 0/3 IDH1 (R132H) 0/6 0/4 0/2 NF 0/7 0/4 0/2 Galectin-3 7/7 3/4 0/2 Chromogranin 0/7 0/4 0/3 CD56 5/6 3/4 0/2 EMA 7/7 3/4 1/2 CAM5.2 0/7 0/4 0/2 CD68 2/6 1/4 3/3 Bcl-2 4/6 2/4 0/2 TTF-1 7/7 4/4 3/3

Mete O, Lopes MB, Asa SL. Am J Surg Pathol. 2013 PMID: 23887161 Spindle Cell Oncocytomas and Granular Cell Tumors of the Pituitary Are Variants of Pituicytoma. Mete, O; Lopes, MB; Asa, SL Am J Surg Pathol 37(11):1694-1699, 2013.

FIGURE 1 . A-C, Hematoxylin and eosin-stained sections from a case of pituicytoma, granular cell tumor, and spindle cell oncocytoma. D-F, Diffuse and strong TTF-1 expression in pituicytoma, granular cell tumor, and spindle cell oncocytoma, respectively. G-I, Ultrastuctural features of pituicytoma, granular cell tumor, and spindle cell oncocytoma, respectively. The ultrastructural features of pituicytomas, granular cell tumors, and spindle cell oncocytomas revealed morphologic similarities with light (major), granular, and oncocytic pituicytes, respectively. Whereas spindle cell oncocytomas consisted of spindle-shaped or polygonal tumor cells with abundant mitochondria, granular cell tumors were composed of cells with numerous membrane-bound, electron-dense vacuoles consistent with lysosomes. No secretory granules were identified in any of the tumors.

2 Histogenesis of TTF-1 Expressing Pituitary Non-Neuroendocrine Tumors

Pituitary “Ependymomas” = Pituicytomas with Ependymal Differentiation

• About 7 cases described in the literature • Scheithauer et al., 2009 – review of 5 cases and description of an additional case

Histogenesis of TTF-1 Expressing Pituitary Non-Neuroendocrine Tumors

• TTF-1 immunoexpression: • Normal pituicytes • Pituicytomas, Granular Cell Tumors, Spindle Cell Oncocytomas • Five subtypes of pituicytes by EM analysis (Takei et al., 1980) • Normal, dark, granular, oncocytic, ependymal • NORMAL (BIPOLAR) = PITUICYTOMA • EPENDYMAL = PITUICYTOMA WITH EPENDYMAL DIFFERENTIATION • GRANULAR = GRANULAR CELL TUMOR (Liss & Khan, 1958) • ONCOCYTIC = SPINDLE CELL ONCOCYTOMA • WHO 2016 comment: • “Pituicytomas, granular cell tumors of the sellar region, and spindle cell oncocytomas show nuclear expression of TTF-1, suggesting that these three tumors may constitute a spectrum of a single nosological entity.”

Michotte A et al. J Neurol Sci. 2014; 346:362-3.

GFAP TTF-1 Chordoid Gliomas of the Third Ventricle Share TTF-1 Expression With Organum Vasculosum of the Lamina Terminalis. Bielle, et al. Am J Surg Pathol. 2015; 39(7): 948-956

FIGURE 3 . TTF-1 expression in CG3V. TTF-1 immunolabeling of different areas of the same chordoid glioma with the SPT24 clone (A-C) and with the 8G7G3/1 clone (D-F). Signal intensity is high in (A), heterogenous in (B), and weak in (C) with SPT24. Signal intensity is moderate in (D), nonsignificant in (E), and weak in a few cells in (F) with 8G7G3/1.

TTF-1 expressing pituitary non-neuroendocrine tumors and chordoid gliomas do not seem to be related entities TTF-1 Expressing Pituitary Non-Neuroendocrine Tumors - Prognosis

• Most appear to behave in a “benign” fashion • All tumors histologically qualified as WHO grade I • Spindle Cell Oncocytoma – several reported cases of recurrence (Kloub et al., 2005) • Recurrence with higher degree of invasion and proliferative index • Radiation therapy has been recommended • Pituicytoma and Granular Cell Tumors • Reports of regrowth of pituicytomas after subtotal surgical resection • No malignant progression

Take-Home Messages

• TTF-1 Expressing Pituitary Non-Neuroendocrine Tumors • Pituicytoma • Granular Cell Tumor • Spindle Cell Oncocytoma • Clinical manifestations mimic non-functioning adenomas • TTF-1 expression may indicate a common tumorigenesis within a range of morphological tumor subtypes • Alert for surgeons of their high-risk of intra-operative bleeding

References

1. Bielle F, Villa C, Giry M, Bergemer-Fouquet AM, et al. Chordoid gliomas of the third ventricle share TTF-1 expression with organum vasculosum of the lamina terminalis. Am J Surg Pathol. 2015 Jul;39(7):948-56. PubMed PMID: 25786084. 2. Brat DJ, Scheithauer BW, Staugaitis SM, et al. Pituicytoma: a distinctive low-grade glioma of the neurohypophysis. Am J Surg Pathol. 2000 Mar;24(3):362-8. PubMed PMID: 10716149. 3. Cohen-Gadol AA, Pichelmann MA, Link MJ, et al. Granular cell tumor of the sellar and suprasellar region: clinicopathologic study of 11 cases and literature review. Mayo Clin Proc. 2003 May;78(5):567-73. PubMed PMID: 12744543. 4. Covington MF, Chin SS, Osborn AG. Pituicytoma, spindle cell oncocytoma, and granular cell tumor: clarification and meta- analysis of the world literature since 1893. AJNR Am J Neuroradiol. 2011 Dec;32(11):2067-72. PubMed PMID: 21960498. 5. Kleinschmidt-DeMasters BK, Lopes MB. Update on hypophysitis and TTF-1 expressing sellar region masses. Brain Pathol. 2013 Sep;23(5):495-514. PubMed PMID: 23701182. 6. Kloub O, Perry A, Tu PH, Lipper M, Lopes MB. Spindle cell oncocytoma of the adenohypophysis: report of two recurrent cases. Am J Surg Pathol. 2005 Feb;29(2):247-53. PubMed PMID: 15644783. 7. Kwon MJ, Suh YL. Pituicytoma with unusual histological features. Pathol Int. 2011 Oct;61(10):598-602. PubMed PMID: 21951670. 8. Lee EB, Tihan T, Scheithauer BW, Zhang PJ, Gonatas NK. Thyroid transcription factor 1 expression in sellar tumors: a histogenetic marker? J Neuropathol Exp Neurol. 2009 May;68(5):482-8. PubMed PMID: 19525896. 9. Liss L. The cellular elements of the human neurohypophysis; a study with silver carbonate. J Comp Neurol. 1956 Dec;106(2):507-25. PubMed PMID: 13416405. 10. Liss L, Kahn EA. Pituicytoma, tumor of the sella turcica; a clinicopathological study. J Neurosurg. 1958 Sep;15(5):481-8. PubMed PMID:13576191. 11. Mete O, Lopes MB, Asa SL. Spindle cell oncocytomas and granular cell tumors of the pituitary are variants of pituicytoma. Am J Surg Pathol. 2013 Nov;37(11):1694-9. PubMed PMID: 23887161. 12. Michotte A, Van Der Veken J, Huylebrouck M, et al. Expression of thyroid transcription factor 1 in a chordoid glioma. J Neurol Sci. 2014 Nov 15;346(1-2):362-3. PubMed PMID: 25248954. 13. Roncaroli F, Scheithauer BW, Cenacchi G, et al. 'Spindle cell oncocytoma' of the adenohypophysis: a tumor of folliculostellate cells? Am J Surg Pathol. 2002 Aug;26(8):1048-55. PubMed PMID: 12170092. 14. Takei Y, Seyama S, Pearl GS, Tindall GT. Ultrastructural study of the human neurohypophysis. II. Cellular elements of neural parenchyma, the pituicytes. Cell Tissue Res. 1980;205(2):273-87. PubMed PMID: 7188885.