Pituitary DOI 10.1007/s11102-014-0568-7
Pituicytomas and spindle cell oncocytomas: modern case series from the University of California, San Francisco Corinna C. Zygourakis • John D. Rolston • Han S. Lee • Carlene Partow • Sandeep Kunwar Manish K. Aghi
•
Ó Springer Science+Business Media New York 2014
Abstract Purpose Pituicytomas and spindle cell oncocytomas (SCOs) are extremely rare neoplasms of the sellar and suprasellar region that can often mimic pituitary adenomas. To date, there are relatively few cases of pituicytomas and SCOs reported; and most of these are small case series. Methods In this paper, we provide a retrospective review of the treatment, imaging characteristics, post-operative course, and histopathology of five cases of pituicytomas and two SCOs treated at the University of California, San
C. C. Zygourakis J. D. Rolston S. Kunwar M. K. Aghi (&) Department of Neurological Surgery, University of California at San Francisco, 505 Parnassus Avenue, Rm 779M, San Francisco, CA 94143-0112, USA e-mail: [email protected] H. S. Lee Neuropathology Division, Department of Anatomic Pathology, University of California at San Francisco, San Francisco, CA, USA C. Partow Johns Hopkins University, Baltimore, MD, USA M. K. Aghi Brain Tumor Research Center, University of California at San Francisco, 505 Parnassus Avenue, Rm 779M, San Francisco, CA 94143-0112, USA M. K. Aghi Center for Minimally Invasive Skull Base Surgery, University of California at San Francisco, 505 Parnassus Avenue, Rm 779M, San Francisco, CA 94143-0112, USA M. K. Aghi Maydan Family Endowed Faculty, University of California at San Francisco, 505 Parnassus Avenue, Rm 779M, San Francisco, CA 94143-0112, USA
Francisco (UCSF) over a 10-year period from 2003 to 2013. Results We find that pituicytomas and SCOs present similarly to pituitary adenomas, and look identical on CT or MR imaging. We histopathologically confirmed all pituicytomas with a combination of hematoxylin and eosin morphology and immunohistochemical positivity for vimentin and S100; SCOs stain for anti-mitochondrial antigen and endothelial membrane antigen. We observe positive thyroid transcription factor 1 (TTF1) immunohistochemistry in both cases of SCO, as well as in both of the cases of pituicytoma in which TTF1 staining was available. Conclusions This represents the largest single-institution case series of pituicytomas and SCOs to date, and also includes the first description of the management of a pregnant female with SCO. Our findings are consistent with the idea of common histogenesis for pituicytomas and SCOs, and also raise the possibility of more aggressive growth in SCOs as compared to pituicytomas. Keywords Pituicytoma Spindle cell oncocytoma Pituitary Tumor
Introduction Pituicytomas and spindle cell oncocytomas (SCOs) are extremely rare neoplasms of the sellar and suprasellar region. The former are solid, well-circumscribed glial neoplasms that arise from the pituicytes of the posterior pituitary gland (neurohypophysis) or infundibulum [1, 2]. Referred to as ‘‘posterior pituitary astrocytomas’’ or ‘‘infundibulomas’’ in the past, pituicytomas are World Health Organization (WHO) grade I tumors composed of elongated, bipolar spindle cells that generally stain positive for
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vimentin, S100 protein, thyroid transcription factor 1 (TTF1), and to a variable degree, glial fibrillary acidic protein (GFAP) [1]. They are curable with gross total resection, often via an endoscopic endonasal transsphenoidal approach [3]. Pituicytomas are usually diagnosed in adults (mean age of diagnosis = 50.3 years old [4]), although they have been reported in children as young as seven [5]. They are found with equal distribution in males and females [4]. Patients most often present with vision impairment and headache, as well as hypopituitarism, fatigue, and decreased libido [4], as would be expected based on the location of these lesions. To date, only approximately 70 cases of pituicytomas have been reported, consisting of very small case series [6– 33]. The largest case series is a report of nine cases of pituicytomas seen in consultation at either Johns Hopkins or Mayo Clinic between 1991 and 1999 [34]. The most recent pituicytoma series describes just three cases, although it also provides a comprehensive literature review of every published pituicytoma case [3]. Like pituicytomas, SCOs are rare, WHO grade I spindle cell lesions. These tumors were originally hypothesized to arise from folliculostellate cells of the anterior pituitary gland (adenohypophysis [35]); however, recent studies suggest origin from pituicytes [36]. Their oncocytic cytoplasm contains numerous mitochondria that are seen ultrastructurally and results in positive staining for antimitochondrial antibody (AMA), in addition to S100, TTF1 and epithelial membrane antigen (EMA) [1, 2]. They were first described by Roncaroli et al. [35] in a five patient case study, and only approximately twenty cases have been reported to date [37–43]. They usually present in adults, and clinical symptoms are similar to those of patients with pituictyomas [37]. Since these reports, SCO has been formally codified in the WHO in 2007 as a distinct entity [1, 2]. This paper provides a comprehensive review of the presentation, treatment and pathology of five cases of pituicytomas and two SCOs treated at the University of California, San Francisco (UCSF) over a 10-year period from 2003 to 2013. This represents the largest singleinstitution case series to date, and also includes the first description of the management of a pregnant female with spindle cell oncocytoma.
Methods A retrospective review was performed of all patients undergoing surgery for resection of a histopathologically confirmed pituicytoma or spindle cell oncocytoma at the UCSF Medical center between 2003 and 2013. Identifying patient characteristics, including name, diagnosis, and
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tumor location were prospectively collected in these databases for all consenting patients undergoing neurosurgical evaluation at UCSF; this occurred in accordance with the Committee for Human Research (IRB #11-05901). The medical records, radiographic imaging, pathology reports, and operative notes for each of these patients were reviewed. Data collected included: patient demographics, preoperative symptoms, surgical approach, tumor location, histopathology, extent of resection, postoperative symptoms, adjuvant therapy, tumor recurrence, and years of follow-up. All histopathologic stains, including immunohistochemistry, were performed at the UCSF Anatomic Pathology histology laboratory as part of routine neuropathologic diagnosis, with the exception of TTF1. TTF1 immunohistochemistry was performed retrospectively on cases with available tissue blocks, also at the UCSF Anatomic Pathology laboratory. Pituicytoma: case 1 Our first case is a classic presentation of pituicytoma. A 33 year-old female presented with many years of headaches, galactorrhea, and menstrual irregularities. Magnetic resonance imaging (MRI) revealed a T1 hyperintense, intermediate T2 signal 5 9 5 9 2 mm mass in the midline between the anterior and posterior pituitary lobes. The pituitary stalk was midline, and the optic chiasm was normal. This was initially thought to be a prolactinoma by a referring physician, and the patient was treated with cabergoline, with no response. She also received dexamethasone treatment with no effect. She was then referred to UCSF, at which point all pituitary hormonal function was found to be normal. The patient went to the operating room for an endonasal transsphenoidal microscopic resection of this lesion. In the operating room, the lesion was white, firm, and fibrous—characteristics that are very unusual for a pituitary adenoma. There was a distinct plane between the tumor and the posterior pituitary lobe, and the surgeon achieved a gross total resection. Pathological analysis showed a haphazard arrangement of delicate spindled cells with fibrillary processes, and immunohistochemical stains for vimentin, S-100 and GFAP were positive, confirming the diagnosis of pituicytoma. Post-operatively, the patient required thyroid hormone replacement, but her pituitary function otherwise remained intact. MRI follow-up at 2 years showed no evidence of recurrent disease. Pituicytoma: case 2 In our second case, a 71 year-old male presented with decreased libido and hypernatremia. He was found to have panhypopituitarism, and imaging revealed a 20 9 20 x
Pituitary
Fig. 1 Radiographic features of pituicytomas and spindle cell oncocytomas. Pituicytoma (case 2): a T1 post-contrast MRI, sagittal view of large enhancing sellar mass with suprasellar extension, whose pathology revealed pituicytoma. b T1 post-contrast coronal MRI of same lesion. Spindle cell oncocytoma. (case 3): c T1 post-contrast
sagittal MRI showing sellar lesion with suprasellar extension. The superior margin of this spindle cell oncocytoma contacts the bilateral A1 segments of the anterior cerebral artery. d T1 post-contrast coronal MRI view of the same lesion, showing displacement of the optic chiasm
20 mm sellar mass with suprasellar expansion (Fig. 1). He went to the operating room for a transsphenoidal resection of a presumed pituitary macroadenoma. Upon opening the dura, the surgeon noted that the normal pituitary gland was thickened and displaced anteriorly. There was a clear demarcation between the anterior pituitary lobe and the tumor itself, which was pale grey and very firm. The tumor was extremely vascular, with several large blood vessels— all characteristics that are more consistent with a pituicytoma, as opposed to a pituitary adenoma. A gross total resection was achieved, and confirmed on post-operative imaging. Pathologic diagnosis revealed a pituicytoma, with positive immunohistochemical staining for S100, vimentin, and TTF1 (see Fig. 2). Post-operatively, the patient did well and was discharged home on hydrocortef, synthroid, and testosterone replacement. He was followed with serial MRI scans, which showed no evidence of recurrent disease until 6 years later. At this
point, he was found to have a 6 mm recurrent nodule, which increased in size to 1.2 cm over the next 2 years. Here therefore elected to undergo gamma knife radiotherapy to the recurrent tumor. He did well afterwards and remained neurologically stable at last follow-up. Spine cell oncocytoma: case 3 Our third case is an extremely unusual case of spindle cell oncocytoma, which is, to our knowledge, the first description of this tumor in a pregnant female. A 31 yearold female, 36-weeks pregnant, presented with 4 weeks of blurry peripheral vision, worsening particularly over several days. She was seen at an outside hospital, where a CT scan showed a hyperintense sellar and suprasellar lesion; she also had a prolactin level of 55 and was started on bromocriptine. Five days later, she presented to UCSF, where she was found to have a very dense bitemporal
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Fig. 2 Histopathology of pituicytoma (case 2). a H&E histology at medium power (9200 magnification, bar = 50 lm). b H&E histology at high power (b 9400, bar = 20 lm). c Immunohistochemistry
for Thyroid Transcription Factor-1 (TTF1) showing positively stained nuclei (9400, bar = 20 lm)
hemianopsia, and was able to read fine print only in the very center of her vision. A non-contrast MRI revealed a 2.2 cm sellar lesion with significant suprasellar extension and displacement of the optic chiasm rostrally. Given the patient’s rapid visual loss, immediate intervention was recommended. The patient opted for induction of labor, followed by transsphenoidal surgery soon after vaginal delivery. She had an initial biopsy, followed by a subtotal resection 2 days later. Following the transsphenoidal resection, the patient had immediate improvement in her vision, and she was able to count fingers in all four visual quadrants. She experienced transient post-operative diabetes insipidus, which resolved with desmopressin treatment, but she did require dexamethasone and thyroid replacement. At six-month follow-up, MRI showed a stable size of the residual neoplasm. Routine hematoxylin and eosin (H&E) histopathology revealed a spindle cell neoplasm composed predominantly of cells with small, oval nuclei and ample eosinophilic cytoplasm, arranged in interlacing compact fascicles or groups (see Fig. 3a, b). The neoplastic cells were positive by immunohistochemistry for TTF1 and AMA (see Fig. 3c, d), with patchy EMA positivity. The combination of H&E morphology and immunohistochemical stains, in particular AMA, is diagnostic of spindle cell oncocytoma. In
addition, synaptophysin, chromogranin, S-100 and GFAP stains were negative, further arguing against a pituitary adenoma or pituicytoma. Of note, estrogen and progesterone receptor stains were also negative. As such, the tumor was not likely to be hormone responsive. MIB-1 labeling showed a low proliferative index (\5 %).
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Results Our UCSF experience includes five pituicytomas and two SCOs (see Table 1). Among the pituicytomas, there are three males and two females. This is consistent with the roughly equal gender distribution in the published literature [4]. Our average age is 52.8 years old, ranging from 33 to 71. Pituicytoma patients presented with vision loss, headaches, and pan-hypopituitarism, as would be expected given the tumor’s location. The majority of the pituicytomas were located in the sella, although one tumor also extended into the supra-sellar region. All patients were treated with transsphenoidal resections, and a gross total resection was achieved in four out of five cases. Tumor recurrence occurred in two out of the five cases, one in which a sub-total resection was performed initially. These findings are consistent with the known benign behavior of
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Fig. 3 Histopathology of spindle cell oncocytoma (case 3). a H&E histology at medium power (9200 magnification, bar = 50 lm). b H&E histology at high power (9400 bar = 20 lm). c Immunohistochemistry for thyroid transcription factor-1 (TTF1) showing
positive nuclei (c 9 400, bar = 20 lm). d Immunohistochemistry for anti-mitochondrial antigen (AMA) showing positive granular pattern of cytoplasmic staining (d 9 400, bar = 20 lm)
pituicytomas. All of our pituicytomas (for which we have immunohistochemical data) stained positive for vimentin and S-100, with variable positivity for GFAP (one out of four), and showed morphologic features suggesting the presence of glial fibrillary cytoplasm. This is consistent with the pathologic description of pituicytomas [34, 44]. We also retrospectively stained for TTF1, in cases for which a tissue block was still available, and both cases showed positive staining (see Fig. 2c; Table 1). Both of our cases of SCOs presented in adults (ages 31 and 53), as has been described previously in the literature. One patient presented with visual loss due to a large 2.2 cm lesion compressing the optic apparatus, while the other presented with headaches from a smaller 7 mm lesion. Both patients were treated with transsphenoidal subtotal resections and neither have had a recurrence on short-term follow-up. Pathologically, the typical morphology of interlacing compact fascicles of eosinophilic spindled cells was present (Fig. 3a, b). Both tumors were positive for mitochondrial accumulation (positive AMA) and EMA, but were heterogeneous in terms of S100 and GFAP immunostaining (Table 1). The evidence of mitochondrial accumulation and EMA positivity confirmed the diagnoses of SCO. Of note, both cases showed variable but positive staining for TTF1 (see Fig. 3c; Table 1). Neither patient
received adjuvant chemotherapy.
therapy,
such
as
radiation
or
Discussion Pituicytomas and SCOs are very rare pituitary tumors, with only 70 cases of pituicytomas and 20 cases of SCOs reported in the literature thus far. Although the term ‘‘pituicytoma’’ is found in papers dating back to 1958, it was not until 2007 that this was formally defined by the WHO as a distinct pathologic entity. Similarly, SCOs were first described by Roncaroli et al. [35] in a 2002 case series, but were only recognized by WHO in 2007 [1, 2]. Our study brings an additional five new pituicytoma and two unique SCO cases. The total number of pituicytomas and SCOs remains incredibly small, reflecting both the rarity of these diseases and the difficulty in identifying them. Short of pathological analysis, there is no way to differentiate these tumors from the far more common pituitary adenomas. Both pituicytomas and SCOs usually present in adults, with average presentation in the 50s for both tumor types. The most frequent presenting symptoms are headaches, hormonal symptoms, or visual loss, occurring in 67, 50, and 50 % of our patients, respectively, similar to those
123
123
M
F
M
M
F
F
F
54
48
71
58
33
31
53
Headache
Visual field cut, headache
Headache, lactation
Visual field cut, weight loss, fatigue
Weight gain, decrease libido, hyper-natremia
Vision loss, headache
N/A
Preop Sx
Type 2 DM
Prolac 55
Pan-hypopit
Pan-hypopit
Pan-hypopit
Normal
N/A
Pre-op endo
Same
Transient DI
Pan-hypopit
Pan-hypopit
Pan-hypopit
Pan-hypopit, DI
N/A
Post-op endo
Sellar ? supra-sellar
Sellar ? supra-sellar
Sellar
Sellar ? supra-sellar
Sellar
Sellar
Sellar
Loc
7 mm
2 cm
5 mm
3 cm
2 cm
2 cm
1 cm
Size
Bx
STR
GTR
GTR
GTR
STR
GTR
EOR
SCO
SCO
Pit
Pit
Pit
Pit
Pit
Path
TTF1?
GFAP?
S100?
EMA?
Anti-mitochondrial Ab?
GFAPTTF1?
S100-
EMA?
Anti-mitochondrial Ab?
GFAP-
S100?
Vimentin?
GFAP?
S100?
Vimentin?
TTF1?
GFAP-
S100?
Vimentin?
TTF1?
S100? GFAP-
Vimentin?
IHC
2 mos
6 mos
2 yrs
5 yrs
No
No
No
No
Yes Yes
7 yrs
N/A
N/A
8 yrs
Rec
F/U
Pit pituicytoma, SCO spindle cell oncocytoma, M male, F female. Sx symptoms, Endo endocrine, Pan-hypopit pan-hypopituitarism, Prolac prolactin, DM diabetes mellitus. Loc location, EOR extent of resection, GTR gross total resection, STR subtotal resection, Bx biopsy. Yrs years, mos months, N/A not available. IHC immunohistochemistry, F/U follow-up, Rec recurrence
Note that all patients underwent transsphenoidal surgical approaches
Sex
Age
Table 1 Pituicytomas and spindle cell oncocytomas—summary of patient characteristics, pathology, and outcome
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Pituitary
of other pituitary tumors. There are currently no unique characteristics on MRI or CT that can separate these tumors from the far more common pituitary adenomas. Imaging reveals T1 hypo- or isointense lesions that are homogeneously contrast enhancing, similar to pituitary adenomas. And the range of lesion sizes that we encountered (average = 16 mm, range = 5–30 mm) was quite comparable to that of adenomas. These lesions are usually sellar, with occasional suprasellar extension or invasion into the sinus. Interestingly, while one recent study suggests that pituicytomas are often suprasellar [3], four out of five of our pituicytomas were purely sellar without any suprasellar extension, and only one of our pituicytomas extended into the suprasellar region. Both of our SCOs had suprasellar extension. Similarly, in a meta-analysis, Covington et al. [4] had noted that SCOs uniformly show both intrasellar and suprasellar components, while pituicytomas were often purely intrasellar or suprasellar. Not knowing the pathology in advance, however, does not appear to affect treatment of pituicytomas and SCOs. The most common treatment in the literature, and the treatment for all of the patients in our series, is transsphenoidal resection. Only a few craniotomies are reported [45]. The goal is gross total resection, identical to the goal for most pituitary adenomas. Unlike most adenomas, these tumors are often vascular and firm and intimately attached to normal structures like the infundibulum or posterior lobe, making them difficult to resect completely. Interestingly, in our experience, we found a distinct plane between pituicytomas and the pituitary gland, making surgical resection of these tumors easier than for SCOs. We achieved a gross total resection in four out of five pituicytomas, while both SCOs were found to be more invasive, with less distinct planes separating them from the pituitary gland. As a result, both SCOs could only be subtotally resected. The infiltrative growth that we note clinically among our cases of SCO correlates with the radiologic observation of infiltrative growth among all cases of SCOs seen in one study [4]. Transient postoperative diabetes insipidus occurred in 16.6 % of our patients; permanent diabetes insipidus in 16.6 % of patients. Although neither of our SCO patients received adjuvant therapy, there are reports of radiation use in at least two SCO cases, but no strong evidence supporting its efficacy [45]. Follow-up is very limited across patients with SCO, but recurrences have occurred in at least 7 of the 22, even in patients where gross total resection was achieved. Spindle cell oncocytoma was originally suggested to arise from folliculostellate cells of the anterior pituitary [35]. This hypothesis was based on a common immunohistochemical phenotype including positive EMA, S100, vimentin and galectin-3, as well as the ultrastructural finding of desmosomes in SCOs. However, recent studies
have also demonstrated that normal pituicytes of the neurapophysis, pituicytomas, SCOs and granular cell tumors all share expression of the TTF1 gene [36, 46, 47]. In addition, ultrastructural studies of the neurohypophysis have suggested the existence of different classes or forms of pituicytes, including both ‘‘oncocytic pituicytes’’ and ‘‘granular pituicytes’’ [47–49]. These observations have led to the hypothesis that the pathologic entities of pituicytoma, spindle cell oncocytoma and granular cell tumor show common histogenesis and are all derived from pituicytes [36]. Hence, a key distinguishing feature of SCOs from pituicytoma, increased mitochondria, may simply represent a known morphologic variation of pituicytes. Similarly, in our cases, we observe positive TTF1 immunohistochemistry in both cases of SCO as well as in both of the cases of pituicytoma in which TTF1 staining was available. As such, the findings in our study are consistent with the idea of common histogenesis. However, our clinical findings raise the possibility of more aggressive growth in SCOs as compared to pituicytomas, given the presence of infiltrative growth seen with SCOs and not pituicytomas, as well as the suprasellar extension seen among the tumors. Given the limited number of SCO cases described in our report, further studies are necessary to confirm this observation.
Conclusion In summary, we review the presentation, treatment and pathology of five cases of pituicytomas and two SCOs treated at UCSF over a 10-year period. Although a few past studies report a larger number of patients (up to 9 pituicytomas, 5 SCOs), ours is the largest case series with patients from a single institution. All patients were similarly managed by two surgeons (M.K.A., S.K), and histopathological evaluations were done in the same laboratory. Furthermore, we include the first description of the management of a pregnant female with spindle cell oncocytoma. We conclude that pituicytomas and SCOs present similarly to pituitary adenomas, and look identical on CT or MR imaging. We believe that the best surgical approach for these lesions is the transsphenoidal approach, with gross total resection as the goal. Our data is too limited to draw conclusions about whether adjuvant therapy plays a role in the treatment of tumor recurrence. We histopathologically confirmed all pituicytomas with a combination of H&E morphology and immunohistochemical positivity for vimentin and S100; SCOs stain for AMA and EMA. We observe positive TTF1 immunohistochemistry in both cases of SCO, as well as in both of the cases of pituicytoma for which TTF1 staining was available, supporting a common histogenesis for these two entities. And finally,
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although we have a limited number of patients, we find that SCOs are more invasive and harder to completely resect than pituicytomas. Conflict of interest The authors declare that they have no conflict of interest, that this research was not sponsored by an organization, and that the authors have no financial relationship with any organization relevant to this research.
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of two cases. Folia Neuropathologica/Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences 48:175–184 Vajtai I, Sahli R, Kappeler A (2006) Spindle cell oncocytoma of the adenohypophysis: report of a case with a 16-year follow-up. Pathol Res Pract 202:745–750 Dahiya S, Sarkar C, Hedley-Whyte ET, Sharma MC, Zervas NT, Sridhar E, Louis DN (2005) Spindle cell oncocytoma of the adenohypophysis: report of two cases. Acta Neuropathol 110:97–99 Kloub O, Perry A, Tu PH, Lipper M, Lopes MB (2005) Spindle cell oncocytoma of the adenohypophysis: report of two recurrent cases. Am J Surg Pathol 29:247–253 Louis DNOH, Wiestler OD, Cavenee WK, Burger PC, Jouvet A (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109
45. Singh G, Agarwal S, Sharma MC, Suri V, Sarkar C, Garg A, Kale SS (2012) Spindle cell oncocytoma of the adenohypophysis: report of a rare case and review of literature. Clin Neurol Neurosurg 114:267–271 46. Lee EB, Tihan T, Scheithauer BW, Zhang PJ, Gonatas NK (2009) Thyroid transcription factor 1 expression in sellar tumors: a histogenetic marker? J Neuropathol Exp Neurol 68:482–488 47. Kleinschmidt-DeMasters BK, Lopes MB (2013) Update on hypophysitis and TTF-1 expressing sellar region masses. Brain Pathol 23:495–514 48. Takei Y, Seyama S, Pearl GS, Tindall GT (1980) Ultrastructural study of the human neurohypophysis. II. Cellular elements of neural parenchyma, the pituicytes. Cell Tissue Res 205:273–287 49. Scheithauer BW, Horvath E, Kovacs K (1992) Ultrastructure of the neurohypophysis. Microsc Res Tech 20:177–186
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Pituicytomas and spindle cell oncocytomas: modern case series from the University of California, San Francisco Corinna C. Zygourakis • John D. Rolston • Han S. Lee • Carlene Partow • Sandeep Kunwar Manish K. Aghi
•
Ó Springer Science+Business Media New York 2014
Abstract Purpose Pituicytomas and spindle cell oncocytomas (SCOs) are extremely rare neoplasms of the sellar and suprasellar region that can often mimic pituitary adenomas. To date, there are relatively few cases of pituicytomas and SCOs reported; and most of these are small case series. Methods In this paper, we provide a retrospective review of the treatment, imaging characteristics, post-operative course, and histopathology of five cases of pituicytomas and two SCOs treated at the University of California, San
C. C. Zygourakis J. D. Rolston S. Kunwar M. K. Aghi (&) Department of Neurological Surgery, University of California at San Francisco, 505 Parnassus Avenue, Rm 779M, San Francisco, CA 94143-0112, USA e-mail: [email protected] H. S. Lee Neuropathology Division, Department of Anatomic Pathology, University of California at San Francisco, San Francisco, CA, USA C. Partow Johns Hopkins University, Baltimore, MD, USA M. K. Aghi Brain Tumor Research Center, University of California at San Francisco, 505 Parnassus Avenue, Rm 779M, San Francisco, CA 94143-0112, USA M. K. Aghi Center for Minimally Invasive Skull Base Surgery, University of California at San Francisco, 505 Parnassus Avenue, Rm 779M, San Francisco, CA 94143-0112, USA M. K. Aghi Maydan Family Endowed Faculty, University of California at San Francisco, 505 Parnassus Avenue, Rm 779M, San Francisco, CA 94143-0112, USA
Francisco (UCSF) over a 10-year period from 2003 to 2013. Results We find that pituicytomas and SCOs present similarly to pituitary adenomas, and look identical on CT or MR imaging. We histopathologically confirmed all pituicytomas with a combination of hematoxylin and eosin morphology and immunohistochemical positivity for vimentin and S100; SCOs stain for anti-mitochondrial antigen and endothelial membrane antigen. We observe positive thyroid transcription factor 1 (TTF1) immunohistochemistry in both cases of SCO, as well as in both of the cases of pituicytoma in which TTF1 staining was available. Conclusions This represents the largest single-institution case series of pituicytomas and SCOs to date, and also includes the first description of the management of a pregnant female with SCO. Our findings are consistent with the idea of common histogenesis for pituicytomas and SCOs, and also raise the possibility of more aggressive growth in SCOs as compared to pituicytomas. Keywords Pituicytoma Spindle cell oncocytoma Pituitary Tumor
Introduction Pituicytomas and spindle cell oncocytomas (SCOs) are extremely rare neoplasms of the sellar and suprasellar region. The former are solid, well-circumscribed glial neoplasms that arise from the pituicytes of the posterior pituitary gland (neurohypophysis) or infundibulum [1, 2]. Referred to as ‘‘posterior pituitary astrocytomas’’ or ‘‘infundibulomas’’ in the past, pituicytomas are World Health Organization (WHO) grade I tumors composed of elongated, bipolar spindle cells that generally stain positive for
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vimentin, S100 protein, thyroid transcription factor 1 (TTF1), and to a variable degree, glial fibrillary acidic protein (GFAP) [1]. They are curable with gross total resection, often via an endoscopic endonasal transsphenoidal approach [3]. Pituicytomas are usually diagnosed in adults (mean age of diagnosis = 50.3 years old [4]), although they have been reported in children as young as seven [5]. They are found with equal distribution in males and females [4]. Patients most often present with vision impairment and headache, as well as hypopituitarism, fatigue, and decreased libido [4], as would be expected based on the location of these lesions. To date, only approximately 70 cases of pituicytomas have been reported, consisting of very small case series [6– 33]. The largest case series is a report of nine cases of pituicytomas seen in consultation at either Johns Hopkins or Mayo Clinic between 1991 and 1999 [34]. The most recent pituicytoma series describes just three cases, although it also provides a comprehensive literature review of every published pituicytoma case [3]. Like pituicytomas, SCOs are rare, WHO grade I spindle cell lesions. These tumors were originally hypothesized to arise from folliculostellate cells of the anterior pituitary gland (adenohypophysis [35]); however, recent studies suggest origin from pituicytes [36]. Their oncocytic cytoplasm contains numerous mitochondria that are seen ultrastructurally and results in positive staining for antimitochondrial antibody (AMA), in addition to S100, TTF1 and epithelial membrane antigen (EMA) [1, 2]. They were first described by Roncaroli et al. [35] in a five patient case study, and only approximately twenty cases have been reported to date [37–43]. They usually present in adults, and clinical symptoms are similar to those of patients with pituictyomas [37]. Since these reports, SCO has been formally codified in the WHO in 2007 as a distinct entity [1, 2]. This paper provides a comprehensive review of the presentation, treatment and pathology of five cases of pituicytomas and two SCOs treated at the University of California, San Francisco (UCSF) over a 10-year period from 2003 to 2013. This represents the largest singleinstitution case series to date, and also includes the first description of the management of a pregnant female with spindle cell oncocytoma.
Methods A retrospective review was performed of all patients undergoing surgery for resection of a histopathologically confirmed pituicytoma or spindle cell oncocytoma at the UCSF Medical center between 2003 and 2013. Identifying patient characteristics, including name, diagnosis, and
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tumor location were prospectively collected in these databases for all consenting patients undergoing neurosurgical evaluation at UCSF; this occurred in accordance with the Committee for Human Research (IRB #11-05901). The medical records, radiographic imaging, pathology reports, and operative notes for each of these patients were reviewed. Data collected included: patient demographics, preoperative symptoms, surgical approach, tumor location, histopathology, extent of resection, postoperative symptoms, adjuvant therapy, tumor recurrence, and years of follow-up. All histopathologic stains, including immunohistochemistry, were performed at the UCSF Anatomic Pathology histology laboratory as part of routine neuropathologic diagnosis, with the exception of TTF1. TTF1 immunohistochemistry was performed retrospectively on cases with available tissue blocks, also at the UCSF Anatomic Pathology laboratory. Pituicytoma: case 1 Our first case is a classic presentation of pituicytoma. A 33 year-old female presented with many years of headaches, galactorrhea, and menstrual irregularities. Magnetic resonance imaging (MRI) revealed a T1 hyperintense, intermediate T2 signal 5 9 5 9 2 mm mass in the midline between the anterior and posterior pituitary lobes. The pituitary stalk was midline, and the optic chiasm was normal. This was initially thought to be a prolactinoma by a referring physician, and the patient was treated with cabergoline, with no response. She also received dexamethasone treatment with no effect. She was then referred to UCSF, at which point all pituitary hormonal function was found to be normal. The patient went to the operating room for an endonasal transsphenoidal microscopic resection of this lesion. In the operating room, the lesion was white, firm, and fibrous—characteristics that are very unusual for a pituitary adenoma. There was a distinct plane between the tumor and the posterior pituitary lobe, and the surgeon achieved a gross total resection. Pathological analysis showed a haphazard arrangement of delicate spindled cells with fibrillary processes, and immunohistochemical stains for vimentin, S-100 and GFAP were positive, confirming the diagnosis of pituicytoma. Post-operatively, the patient required thyroid hormone replacement, but her pituitary function otherwise remained intact. MRI follow-up at 2 years showed no evidence of recurrent disease. Pituicytoma: case 2 In our second case, a 71 year-old male presented with decreased libido and hypernatremia. He was found to have panhypopituitarism, and imaging revealed a 20 9 20 x
Pituitary
Fig. 1 Radiographic features of pituicytomas and spindle cell oncocytomas. Pituicytoma (case 2): a T1 post-contrast MRI, sagittal view of large enhancing sellar mass with suprasellar extension, whose pathology revealed pituicytoma. b T1 post-contrast coronal MRI of same lesion. Spindle cell oncocytoma. (case 3): c T1 post-contrast
sagittal MRI showing sellar lesion with suprasellar extension. The superior margin of this spindle cell oncocytoma contacts the bilateral A1 segments of the anterior cerebral artery. d T1 post-contrast coronal MRI view of the same lesion, showing displacement of the optic chiasm
20 mm sellar mass with suprasellar expansion (Fig. 1). He went to the operating room for a transsphenoidal resection of a presumed pituitary macroadenoma. Upon opening the dura, the surgeon noted that the normal pituitary gland was thickened and displaced anteriorly. There was a clear demarcation between the anterior pituitary lobe and the tumor itself, which was pale grey and very firm. The tumor was extremely vascular, with several large blood vessels— all characteristics that are more consistent with a pituicytoma, as opposed to a pituitary adenoma. A gross total resection was achieved, and confirmed on post-operative imaging. Pathologic diagnosis revealed a pituicytoma, with positive immunohistochemical staining for S100, vimentin, and TTF1 (see Fig. 2). Post-operatively, the patient did well and was discharged home on hydrocortef, synthroid, and testosterone replacement. He was followed with serial MRI scans, which showed no evidence of recurrent disease until 6 years later. At this
point, he was found to have a 6 mm recurrent nodule, which increased in size to 1.2 cm over the next 2 years. Here therefore elected to undergo gamma knife radiotherapy to the recurrent tumor. He did well afterwards and remained neurologically stable at last follow-up. Spine cell oncocytoma: case 3 Our third case is an extremely unusual case of spindle cell oncocytoma, which is, to our knowledge, the first description of this tumor in a pregnant female. A 31 yearold female, 36-weeks pregnant, presented with 4 weeks of blurry peripheral vision, worsening particularly over several days. She was seen at an outside hospital, where a CT scan showed a hyperintense sellar and suprasellar lesion; she also had a prolactin level of 55 and was started on bromocriptine. Five days later, she presented to UCSF, where she was found to have a very dense bitemporal
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Fig. 2 Histopathology of pituicytoma (case 2). a H&E histology at medium power (9200 magnification, bar = 50 lm). b H&E histology at high power (b 9400, bar = 20 lm). c Immunohistochemistry
for Thyroid Transcription Factor-1 (TTF1) showing positively stained nuclei (9400, bar = 20 lm)
hemianopsia, and was able to read fine print only in the very center of her vision. A non-contrast MRI revealed a 2.2 cm sellar lesion with significant suprasellar extension and displacement of the optic chiasm rostrally. Given the patient’s rapid visual loss, immediate intervention was recommended. The patient opted for induction of labor, followed by transsphenoidal surgery soon after vaginal delivery. She had an initial biopsy, followed by a subtotal resection 2 days later. Following the transsphenoidal resection, the patient had immediate improvement in her vision, and she was able to count fingers in all four visual quadrants. She experienced transient post-operative diabetes insipidus, which resolved with desmopressin treatment, but she did require dexamethasone and thyroid replacement. At six-month follow-up, MRI showed a stable size of the residual neoplasm. Routine hematoxylin and eosin (H&E) histopathology revealed a spindle cell neoplasm composed predominantly of cells with small, oval nuclei and ample eosinophilic cytoplasm, arranged in interlacing compact fascicles or groups (see Fig. 3a, b). The neoplastic cells were positive by immunohistochemistry for TTF1 and AMA (see Fig. 3c, d), with patchy EMA positivity. The combination of H&E morphology and immunohistochemical stains, in particular AMA, is diagnostic of spindle cell oncocytoma. In
addition, synaptophysin, chromogranin, S-100 and GFAP stains were negative, further arguing against a pituitary adenoma or pituicytoma. Of note, estrogen and progesterone receptor stains were also negative. As such, the tumor was not likely to be hormone responsive. MIB-1 labeling showed a low proliferative index (\5 %).
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Results Our UCSF experience includes five pituicytomas and two SCOs (see Table 1). Among the pituicytomas, there are three males and two females. This is consistent with the roughly equal gender distribution in the published literature [4]. Our average age is 52.8 years old, ranging from 33 to 71. Pituicytoma patients presented with vision loss, headaches, and pan-hypopituitarism, as would be expected given the tumor’s location. The majority of the pituicytomas were located in the sella, although one tumor also extended into the supra-sellar region. All patients were treated with transsphenoidal resections, and a gross total resection was achieved in four out of five cases. Tumor recurrence occurred in two out of the five cases, one in which a sub-total resection was performed initially. These findings are consistent with the known benign behavior of
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Fig. 3 Histopathology of spindle cell oncocytoma (case 3). a H&E histology at medium power (9200 magnification, bar = 50 lm). b H&E histology at high power (9400 bar = 20 lm). c Immunohistochemistry for thyroid transcription factor-1 (TTF1) showing
positive nuclei (c 9 400, bar = 20 lm). d Immunohistochemistry for anti-mitochondrial antigen (AMA) showing positive granular pattern of cytoplasmic staining (d 9 400, bar = 20 lm)
pituicytomas. All of our pituicytomas (for which we have immunohistochemical data) stained positive for vimentin and S-100, with variable positivity for GFAP (one out of four), and showed morphologic features suggesting the presence of glial fibrillary cytoplasm. This is consistent with the pathologic description of pituicytomas [34, 44]. We also retrospectively stained for TTF1, in cases for which a tissue block was still available, and both cases showed positive staining (see Fig. 2c; Table 1). Both of our cases of SCOs presented in adults (ages 31 and 53), as has been described previously in the literature. One patient presented with visual loss due to a large 2.2 cm lesion compressing the optic apparatus, while the other presented with headaches from a smaller 7 mm lesion. Both patients were treated with transsphenoidal subtotal resections and neither have had a recurrence on short-term follow-up. Pathologically, the typical morphology of interlacing compact fascicles of eosinophilic spindled cells was present (Fig. 3a, b). Both tumors were positive for mitochondrial accumulation (positive AMA) and EMA, but were heterogeneous in terms of S100 and GFAP immunostaining (Table 1). The evidence of mitochondrial accumulation and EMA positivity confirmed the diagnoses of SCO. Of note, both cases showed variable but positive staining for TTF1 (see Fig. 3c; Table 1). Neither patient
received adjuvant chemotherapy.
therapy,
such
as
radiation
or
Discussion Pituicytomas and SCOs are very rare pituitary tumors, with only 70 cases of pituicytomas and 20 cases of SCOs reported in the literature thus far. Although the term ‘‘pituicytoma’’ is found in papers dating back to 1958, it was not until 2007 that this was formally defined by the WHO as a distinct pathologic entity. Similarly, SCOs were first described by Roncaroli et al. [35] in a 2002 case series, but were only recognized by WHO in 2007 [1, 2]. Our study brings an additional five new pituicytoma and two unique SCO cases. The total number of pituicytomas and SCOs remains incredibly small, reflecting both the rarity of these diseases and the difficulty in identifying them. Short of pathological analysis, there is no way to differentiate these tumors from the far more common pituitary adenomas. Both pituicytomas and SCOs usually present in adults, with average presentation in the 50s for both tumor types. The most frequent presenting symptoms are headaches, hormonal symptoms, or visual loss, occurring in 67, 50, and 50 % of our patients, respectively, similar to those
123
123
M
F
M
M
F
F
F
54
48
71
58
33
31
53
Headache
Visual field cut, headache
Headache, lactation
Visual field cut, weight loss, fatigue
Weight gain, decrease libido, hyper-natremia
Vision loss, headache
N/A
Preop Sx
Type 2 DM
Prolac 55
Pan-hypopit
Pan-hypopit
Pan-hypopit
Normal
N/A
Pre-op endo
Same
Transient DI
Pan-hypopit
Pan-hypopit
Pan-hypopit
Pan-hypopit, DI
N/A
Post-op endo
Sellar ? supra-sellar
Sellar ? supra-sellar
Sellar
Sellar ? supra-sellar
Sellar
Sellar
Sellar
Loc
7 mm
2 cm
5 mm
3 cm
2 cm
2 cm
1 cm
Size
Bx
STR
GTR
GTR
GTR
STR
GTR
EOR
SCO
SCO
Pit
Pit
Pit
Pit
Pit
Path
TTF1?
GFAP?
S100?
EMA?
Anti-mitochondrial Ab?
GFAPTTF1?
S100-
EMA?
Anti-mitochondrial Ab?
GFAP-
S100?
Vimentin?
GFAP?
S100?
Vimentin?
TTF1?
GFAP-
S100?
Vimentin?
TTF1?
S100? GFAP-
Vimentin?
IHC
2 mos
6 mos
2 yrs
5 yrs
No
No
No
No
Yes Yes
7 yrs
N/A
N/A
8 yrs
Rec
F/U
Pit pituicytoma, SCO spindle cell oncocytoma, M male, F female. Sx symptoms, Endo endocrine, Pan-hypopit pan-hypopituitarism, Prolac prolactin, DM diabetes mellitus. Loc location, EOR extent of resection, GTR gross total resection, STR subtotal resection, Bx biopsy. Yrs years, mos months, N/A not available. IHC immunohistochemistry, F/U follow-up, Rec recurrence
Note that all patients underwent transsphenoidal surgical approaches
Sex
Age
Table 1 Pituicytomas and spindle cell oncocytomas—summary of patient characteristics, pathology, and outcome
Pituitary
Pituitary
of other pituitary tumors. There are currently no unique characteristics on MRI or CT that can separate these tumors from the far more common pituitary adenomas. Imaging reveals T1 hypo- or isointense lesions that are homogeneously contrast enhancing, similar to pituitary adenomas. And the range of lesion sizes that we encountered (average = 16 mm, range = 5–30 mm) was quite comparable to that of adenomas. These lesions are usually sellar, with occasional suprasellar extension or invasion into the sinus. Interestingly, while one recent study suggests that pituicytomas are often suprasellar [3], four out of five of our pituicytomas were purely sellar without any suprasellar extension, and only one of our pituicytomas extended into the suprasellar region. Both of our SCOs had suprasellar extension. Similarly, in a meta-analysis, Covington et al. [4] had noted that SCOs uniformly show both intrasellar and suprasellar components, while pituicytomas were often purely intrasellar or suprasellar. Not knowing the pathology in advance, however, does not appear to affect treatment of pituicytomas and SCOs. The most common treatment in the literature, and the treatment for all of the patients in our series, is transsphenoidal resection. Only a few craniotomies are reported [45]. The goal is gross total resection, identical to the goal for most pituitary adenomas. Unlike most adenomas, these tumors are often vascular and firm and intimately attached to normal structures like the infundibulum or posterior lobe, making them difficult to resect completely. Interestingly, in our experience, we found a distinct plane between pituicytomas and the pituitary gland, making surgical resection of these tumors easier than for SCOs. We achieved a gross total resection in four out of five pituicytomas, while both SCOs were found to be more invasive, with less distinct planes separating them from the pituitary gland. As a result, both SCOs could only be subtotally resected. The infiltrative growth that we note clinically among our cases of SCO correlates with the radiologic observation of infiltrative growth among all cases of SCOs seen in one study [4]. Transient postoperative diabetes insipidus occurred in 16.6 % of our patients; permanent diabetes insipidus in 16.6 % of patients. Although neither of our SCO patients received adjuvant therapy, there are reports of radiation use in at least two SCO cases, but no strong evidence supporting its efficacy [45]. Follow-up is very limited across patients with SCO, but recurrences have occurred in at least 7 of the 22, even in patients where gross total resection was achieved. Spindle cell oncocytoma was originally suggested to arise from folliculostellate cells of the anterior pituitary [35]. This hypothesis was based on a common immunohistochemical phenotype including positive EMA, S100, vimentin and galectin-3, as well as the ultrastructural finding of desmosomes in SCOs. However, recent studies
have also demonstrated that normal pituicytes of the neurapophysis, pituicytomas, SCOs and granular cell tumors all share expression of the TTF1 gene [36, 46, 47]. In addition, ultrastructural studies of the neurohypophysis have suggested the existence of different classes or forms of pituicytes, including both ‘‘oncocytic pituicytes’’ and ‘‘granular pituicytes’’ [47–49]. These observations have led to the hypothesis that the pathologic entities of pituicytoma, spindle cell oncocytoma and granular cell tumor show common histogenesis and are all derived from pituicytes [36]. Hence, a key distinguishing feature of SCOs from pituicytoma, increased mitochondria, may simply represent a known morphologic variation of pituicytes. Similarly, in our cases, we observe positive TTF1 immunohistochemistry in both cases of SCO as well as in both of the cases of pituicytoma in which TTF1 staining was available. As such, the findings in our study are consistent with the idea of common histogenesis. However, our clinical findings raise the possibility of more aggressive growth in SCOs as compared to pituicytomas, given the presence of infiltrative growth seen with SCOs and not pituicytomas, as well as the suprasellar extension seen among the tumors. Given the limited number of SCO cases described in our report, further studies are necessary to confirm this observation.
Conclusion In summary, we review the presentation, treatment and pathology of five cases of pituicytomas and two SCOs treated at UCSF over a 10-year period. Although a few past studies report a larger number of patients (up to 9 pituicytomas, 5 SCOs), ours is the largest case series with patients from a single institution. All patients were similarly managed by two surgeons (M.K.A., S.K), and histopathological evaluations were done in the same laboratory. Furthermore, we include the first description of the management of a pregnant female with spindle cell oncocytoma. We conclude that pituicytomas and SCOs present similarly to pituitary adenomas, and look identical on CT or MR imaging. We believe that the best surgical approach for these lesions is the transsphenoidal approach, with gross total resection as the goal. Our data is too limited to draw conclusions about whether adjuvant therapy plays a role in the treatment of tumor recurrence. We histopathologically confirmed all pituicytomas with a combination of H&E morphology and immunohistochemical positivity for vimentin and S100; SCOs stain for AMA and EMA. We observe positive TTF1 immunohistochemistry in both cases of SCO, as well as in both of the cases of pituicytoma for which TTF1 staining was available, supporting a common histogenesis for these two entities. And finally,
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although we have a limited number of patients, we find that SCOs are more invasive and harder to completely resect than pituicytomas. Conflict of interest The authors declare that they have no conflict of interest, that this research was not sponsored by an organization, and that the authors have no financial relationship with any organization relevant to this research.
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