Surgical Pathology

Spindle Cell Oncocytoma of the Adenohypophysis

Marc K. Rosenblum
Memorial Sloan-Kettering Cancer Center
New York, NY


Clinical History
This 34 year old man was evaluated for peripheral visual loss and found to have an intrasellar mass. Transphenoidal resection was performed.


Slide 1
This representative section demonstrates a spindle and epithelioid cell neoplasm exhibiting distinct cytoplasmic granularity at the cytologic level.
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Introduction:
A 34 year old man was evaluated for peripheral visual loss and found to have a solid, contrast-enhancing mass in the sella turcica. A transphenoidal resection was performed.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
This intrasellar neoplasm was composed mainly of spindled cells in fascicles or swirls, having a smaller component of epithelioid cell forms.Both cell types exhibited conspicuous cytoplasmic granularity.There were few mitoses.Immunohistochemical assessment demonstrated tumor cell labeling for mitochondrial antigen, EMA,S-100 protein,vimentin,and TTF-1 in the absence of reactivity for GFAP, synaptophysin,chromogranin, any of the adenohypophyseal hormones,AE1/3, CAM 5.2, or thyroglobulin.

Differential Diagnoses:
Principal differential considerations were spindle cell oncocytoma of the adenohypophysis, granular cell tumor of the neurohypophysis,pituicytoma,oncocytic pituitary adenoma, oncocytic glioma,oncocytic meningioma,and intrasellar schwannoma.

Final Diagnosis:
Spindle cell oncocytoma of the adenohypophysis

Case Discussion:
First described by Roncaroli and colleagues in 2002 [1], the spindle cell oncocytoma of the adenohypophysis is a rare neoplasm (constituting <1% of sellar region tumors) that has been reported in adults 26-71 years of age with communicated cases clustering in the 6th and 7th decades [1, 2, 3, 4, 5, 6, 7, 8]. There is not a clear gender predilection. Clinical manifestations commonly reflect impingement on the optic apparatus (visual disturbances), the presence of an expanding intracranial mass (headaches, nausea / vomiting) and pituitary failure (fatigue, weight loss, hypogonadism / impotence). Extension into the nasal cavities has been associated with epistaxis. Laboratory evaluation often demonstrates panhypopituitarism, mild elevation of serum prolactin levels reflecting "stalk effect" in some cases. The neuroradiologic profile is non-specific, spindle cell oncocytomas presenting on CT/MR imaging as solid, non- calcified and contrast enhancing lesions with reported maximal dimensions of 1.5 to 6.5 centimeters. While small examples have been confined to the sella turcica, larger tumors have demonstrated extension to neighboring regions (including the suprasellar compartment, clivus, ethmoid / sphenoid sinuses, nasopharynx and nasal cavity). As implied by the designation accorded this entity, spindled tumor cells dominate the histologic picture. Typically disposed in compact fascicular or swirling array, these are endowed with abundant cytoplasm that is eosinophilic and variably granulated. Nuclei are generally ovoid to more elongated and commonly display vesicular profiles with distinct nucleoli, but may be more densely hyperchromatic in appearance. A moderate level of pleomorphism is often the case, spindle cell oncocytomas occasionally exhibiting bizarre cytologic alterations. Frequently present in addition to spindled forms are granulated cells of epithelioid and polygonal aspect that tend to occur in clusters. Focal lymphohistiocytic infiltration and hemosiderin deposits are common secondary features. Mitotic activity may be apparent but is usually modest (< 1 mitosis per 10 high power fields in most reported cases) and necrosis in primary neurosurgical material has been noted in only select instances. Increased mitotic activity and atypism have been encountered in recurrent examples, as has conspicuous tumor necrosis. Spindle cell oncocytomas of the adenohypophysis emerge from the experience communicated to date as having a fairly characteristic immunoprofile [1, 2, 3, 4, 5, 6, 7, 8], regularly labeling for vimentin, S-100 protein (nuclear and cytoplasmic expression is typical), thyroid transcription factor 1 (TTF- 1) and anti-mitochondrial antibody. Expression of epithelial membrane antigen (EMA) is the rule (this may be membranous as well as cytoplasmic), but is often seen only focally and may be weak or equivocal. Spindle cell oncocytomas are generally immunoreactive for galectin-3 as well and bcl 2 expression has been described. Noteworthy is the consistent failure of spindle cell oncocytomas to express adenohypophyseal hormone antigens of any variety, synaptophysin (a rare case of weak reactivity excepted), chromogranin, neurofilament proteins and cytokeratins (CAM 5.2 and A E 1/3). Cases assessed thus far have proven non- reactive for smooth muscle actin, CD34 and CD68 as well, isolated examples failing to label for A103, tyrosinase, thyroglobulin and neural cell adhesion molecules. MIB-1 / Ki-67 labeling indices ranging from 1-9% have been described on evaluation of primary neurosurgical specimens, with labeling fractions of up to 20 % recorded in recurrences [7]. Ultrastructural studies [1, 2, 4, 5, 7] have confirmed that the cytoplasmic granularity of spindle cell oncocytomas is due to massive accumulation of mitochondria which generally possess lamellar cristae and may manifest pleomorphism. A minority of cases have contained (neuro) secretory-type granules, these being present in limited numbers and only small subsets of tumor cells [4, 5, 7]. An example demonstrating the formation of microfollicular structures similar to those found in the native adenohypophysis has been recorded [4]. Tumor cells may form intercellular junctions, including desmosomes, but this has not been a feature of all studied cases. On the basis of the limited experience (5 cases] communicated originally by Roncaroli et al [1] spindle cell oncocytomas of the adenohypophysis were classified as grade I lesions in the 2007 WHO formulation [9]. All five of the patients included in that initial report underwent gross total tumor resection and all were free of disease 2- 68 (mean=35) months later. Two additional patients were reported as tumor-free 6 months [ case 2 of Dahiya et al [5] ] and 16 years [8] following macroscopically complete resections and a third patient was noted to be alive with stable disease 7 years post-subtotal excision and radiotherapy [case 1 of Dahiya et al [5] ]. With the reporting of additional cases, however, it has become clear that spindle cell oncocytomas of the adenohypophysis may recur and progress (particularly when complete surgical extirpation cannot be achieved). Recurrences have now been recorded in 6 of 14 cases [2, 3, 4, 6, 7], these including examples of late recurrence (13 years) post-gross total resection [2] as well as tumor regrowth within months of subtotal excision [3, 4, 6] and despite adjuvant radiotherapy [3, 7]. Three reported recurrences complicated cases in which only incomplete resection was accomplished, the extent of surgical removal not being recorded in two instances of relapse. While elevated mitotic / MIB-1 labeling activity and necrosis have been documented in some recurrent cases [4, 7], the symptomatic regrowth of spindle cell oncocytomas in the absence of these atypical features has been documented [3, 6]. The characteristic histology and immunophenotype of the spindle cell oncocytoma facilitate its distinction from a variety of lesions that enter the differential diagnosis, these including oncocytic pituitary adenoma / oncocytoma, oncocytic meningioma, granular cell / oncocytic gliomas, intrasellar paraganglioma and schwannoma, metastatic oncocytic endocrine / neuroendocrine neoplasms and ectopic neoplasms of salivary gland and adrenocortical type displaying oncocytic features. We have encountered an oncocytic intrasellar tumor that displayed TTF-1 expression while also expressing thyroglobulin, this lesion occurring in a patient whose subsequent thyroidectomy proved negative for tumor. We would interpret this unique lesion, which occurred in a patient whose subsequent thyroidectomy specimen proved negative for tumor and which ultimately metastasized to the cerebellum, as an ectopic carcinoma of thyroid epithelial type with Hurthle cell features. Two additional entities that may share pathologic attributes (and, as further discussed below, a common histogenesis) with the spindle cell oncocytoma of the adenohypophysis are the granular cell tumor of the neurohypophysis / infundibulum [10] and the pituicytoma [11]. The former is often confined, when small, to the pituitary stalk, but can involve the sella, is generally S- 100 positive, has been shown to express TTF-1 [12] and may harbor spindled components. The granularity of this lesion reflects the accumulation of autophagic vacuoles rather than mitochondria and granular cell tumors of this variety are said to be EMA-negative (though this issue has not been studied in any systematic manner) (10). Even closer in profile is the pituicytoma. Posited to derive from the modified glia ("pituicytes") that populate the neurohypophysis and infundibulum (as are the granular cell tumors of this region), this spindle cell neoplasm does not exhibit cytoplasmic granularity indicative of oncocytic change, usually manifests at least focal / weak GFAP expression and generally fails to express EMA. Pituicytomas, however, like spindle cell oncocytomas, are strongly immunoreactive for vimentin and S-100 protein and regularly express TTF-1 [12]. Furthermore, GFAP expression is not a constant feature of these tumors [13, 14, 15, 16], examples labeling focally for EMA have been described [13, 14], and some cases studied at the ultrastructural level have been characterized by an abundance of mitochondria [13, 15] and the formation of scattered "intermediate" cell junctions [13]. In describing the spindle cell oncocytoma of the adenohypophysis, Roncaroli et al [1] proposed the derivation of this unusual neoplasm from native elements of the anterior pituitary gland known as folliculostellate cells. These may constitute a sustentacular population analogous to that of other endocrine organs, are active in the regulation of secretory activity by hormone-producing adenohypophyseal cells through their elaboration of various cytokines (e.g. interleukin-6 and leukemia inhibitory factor) and growth factors (e.g., vascular endothelial growth factor and basic fibroblast growth factor), and have been forwarded by some observers as adenohypophyseal stem cells (though evidence for this proposition is fragmentary) [17, 18, 19]. Folliculostellate cells express vimentin and S-100 protein, can express EMA and GFAP, fashion desmosomes and intermediate cell junctions and may harbor neurosecretory granules in small numbers (a property adduced in evidence of their potential to generate secretory adenohypophyseal cells). In addition to sharing these features with spindle cell oncocytomas of the adenohypophysis, folliculostellate cells derived from a human pituitary adenoma have been reported to undergo oncocytic change in vitro [20]. A common origin of spindle cell oncocytomas and pituicytomas (as well as pituitary adenomas) from folliculostellate cells or folliculostellate cell-like precursors capable of multidirectional differentiation has also been suggested [16]. Immunoassesment of both fetal and mature human pituitary glands has demonstrated consistent labeling of pituicytes in the neurohypophysis for TTF-1, but has failed to identify TTF-1-expressing cells in the adenohypophysis [12]. In a similar vein, an analysis of human adenohypophyseal tissue could not demonstrate TTF-1 mRNA [21]. Lee et al [12] have suggested that an origin not from differentiated folliculostellate cells but rather from TTF- 1- expressing neuroepithelial precursors that are known to populate the ventral neuroectoderm, that migrate into the developing infundibulum / neurohypophysis and that appear to give rise to pituicytes might link the granular cell tumor, pituicytoma and spindle cell oncocytoma as histogenetic kin. As the cytogenesis of folliculostellate cells remains conjectural, it is conceivable that these, like pituicytes, derive from the ventral neuroectoderm but undergo a repression of TTF-1 expression in the course of differentiation and maturation.

Conclusion(s):
Spindle cell oncocytoma of the adenohypophysis is a relatively recent addition to the roster of sellar region neoplasms that needs to be distinguished from other tumors presenting in this location and that appears amenable to surgical control when completely resectable.

References:
  1. Roncaroli F, Scheithauer BW, Cenacchi G, Horvath E, Kovacs K, Lloyd RV, Abell-Aleff P, Santi M, Yates AJ. 'Spindle cell oncocytoma' of the adenohypophysis: a tumor of folliculostellate cells? Am J Surg Pathol. 2002; 26 (8):1048-55

  2. Borges MT, Lillehei KO, Kleinschmidt-Demasters BK. Spindle cell oncocytoma with late recurrence and unique neuroimaging characteristics due to recurrent subclinical intratumoral bleeding. J Neurooncol. 2010 May 22 [Epub ahead of print]

  3. Borota OC, Scheithauer BW, Fougner SL, Hald JK, Ramm- Pettersen J, Bollerslev J. Spindle cell oncocytoma of the adenohypophysis: report of a case with marked cellular atypia and recurrence despite adjuvant treatment. Clinical Neuropathology 2009; 28(2): 91-95

  4. Coire CI, Horvath E, Smyth HS, Kovacs K. Rapidly recurring folliculostellate cell tumor of the adenohypophysis with the morphology of a spindle cell oncocytoma: case report with electron microscopic studies. Clinical Neuropathology 2009; 28(4): 303-308

  5. Dahiya S, Sarkar C, Hedley-Whyte ET, Sharma MC, Zervas NT, Sridhar E, Louis DN. Spindle cell oncocytoma of the adenohypophysis: report of two cases. Acta Neuropathol. 2005 Jul; 110(1):97-99. Epub 2005 Jun 23

  6. Demssie YN, Joseph J, Dawson T, Roberts G, Carpentier J, Howell S. Recurrent spindle cell oncocytoma of the pituitary, a case report and review of literature. Pituitary. 2009 Feb 25 (Online Pub)

  7. Kloub O, Perry A, Tu PH, Lipper M, Lopes MBS. Spindle cell oncocytoma of the adenohypophysis: Report of two recurrent cases. Am J Surg Pathol 2005; 29: 247-253

  8. Vajtai I, Sahli R, Kappeler A. Spindle cell oncocytoma of the adenohypophysis: report of a case with a 16-year follow-up. Pathol Res Pract. 2006; 202(10):745-50

  9. Fuller GN, Scheithauer BW, Roncaroli F, Wesseling P. Spindle cell oncocytoma of the adenohypophysis. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC, 2007; pp. 245-6

  10. Fuller GN, Wesseling P. Granular cell tumour of the neurohypophysis. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC, 2007; pp. 241-2

  11. Wesseling P, Brat DJ, Fuller GN. Pituitcytoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC, 2007; pp. 243-4

  12. 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; 68 (5):482-8

  13. Brat DJ, Scheithauer BW, Staugaitias SM, et al. Pituicytoma: A distinctive low-grade glioma of the neurohypophysis. Am J Surg Pathol 2000; 24: 362-68

  14. Cenacchi G, Giovenali P, Castrioto C, et al. Pituicytoma: Ultrastructural evidence of a possible origin from folliculo-stellate cells of the adenohypophysis. Ultrastruct Pathol 2001: 25:309-12

  15. Figarella-Branger D, Dufour H, Fernandez C, et al. Pituicytomas, a mis-diagnosed benign tumor of the neurohypophysis: Report of three cases. Acta Neuropathol 2002; 104:313-19

  16. Ulm AJ, Yachnis AT, Brat DJ, et al. Pituicytoma: Report of two cases and clues regarding histogenesis. Neurosurgery 2004: 54:753-7; [discussion 757-8]

  17. de Almeida JP, Sherman JH, Salvatori R, Quiñones- Hinojosa A. Pituitary Stem Cells: Review of the literature and Current Understanding. Neurosurgery. 2010; 67(3):770-80

  18. Horvath E, Kovacs K. Folliculo-stellate cells of the human pituitary: A type of adult stem cell? Ultrastruct Pathol 2002; 26:219-27

  19. Inoue K, Couch EF, Takano K, et al. The structure and function of folliculo-stellate cells in the anterior pituitary gland. Arch Histol Cytol 1999; 62: 205-18

  20. Danila DC, Zhang X, Zhou Y et al. A human pituitary tumor-derived folliculostellate cell line. J Clin Endocrinol Metab 2000; 85: 1180-7

  21. Mantovani G, Corbetta S, Romoli R et al. Absence of throid transcription factor-1 expression in human parathyroid and pituitary glands. Mol Cell Endocrinol 2001; 182: 13-17