Journal of Cancer Research and Practice 5 (2018) 47e52

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Journal of Cancer Research and Practice

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Original Article The impact of pituicytoma on hormone secretary function

* Ting-Wei Chang a, Shih-Ming Jung b, Hung-Yi Lai a, , Chi-Cheng Chuang a, Peng-Wei Hsu a, Chen-Nen Chang a, Kuo-Chen Wei a a Departments of Neurosurgery, Chang Gung Memorial Hospital and Chang Gung University at Linko, Taiwan b Departments of Pathology, Chang Gung Memorial Hospital and Chang Gung University at Linko, Taiwan article info abstract

Article history: Background: Pituicytes are glial cells supporting hypothalamic axons in the posterior pituitary gland. Received 23 August 2017 Pituicytoma arises from pituicytes, and is currently classified as a World Health Organization grade I Received in revised form central nervous system tumor. Clinically, some patients with pituicytoma are misdiagnosed with func- 14 December 2017 tioning before surgical interventions and pathological examinations. This study was Accepted 18 December 2017 designed to investigate the correlation between pituicytoma and abnormal hormone function. Available online 20 December 2017 Methods: The records of patients who underwent pituitary surgery at Linkou Chang Gung Memorial Hospital between 2000 and 2016 were reviewed. Patients with a pathological diagnosis of pituicytoma Keywords: Pituicytoma were included. Among these patients, those with inadequate data and/or specimens were excluded. Pituitary gland Clinical information including presenting symptoms, serum hormone level, neuroimages, and results of Abnormal hormone secretion pathological examinations including hematoxylin and eosin stains and immunohistochemical stains Pituitary adenoma were collected for analysis. Immunohistochemical stain Results: Between 2000 and 2016, eight patients were pathologically diagnosed with pituicytoma. Two patients were excluded due to missing data and/or specimens. Among the six remaining patients, five presented with hormone changes. The immunohistochemical stains of pituicytoma confirmed no secretory function; however, the surrounding pituitary glandular tissue showed positive results responsible for clinical hormone changes. Conclusions: Pituicytoma had a negative endocrine secretory function in this study. However, pituicy- toma was associated with hyperactivity of the surrounding pituitary glandular tissue, which resulted in clinically abnormal hormone secretion. The diagnosis of pituicytoma before a thorough pathological examination is difficult when the patients present with hormone dysfunction. Therefore, maximum resection of the pituitary tumor is necessary to make the diagnosis of pituicytoma and to exclude pi- tuitary adenoma. © 2018 Taiwan Oncology Society. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction . Occasionally, a pituicytoma is found accidentally during autopsy4; pituicytoma-induced spontaneous suprasellar Pituicytoma is a low-grade glioma that arises from pituicytes in hemorrhage has also been reported.5 Hormone changes in patients the neurohypophysis, which are mostly located in the posterior with pituicytoma are unusual, and are mostly triggered by a tumor- lobe of the pituitary or pituitary stalk.1 Pituicytoma is rare and related mass effect (e.g., hypopituitarism and hormone suppres- usually occurs during adulthood, with a slightly higher incidence sion).6 However, at our institute, we determined that most patients among males.2 Clinically, pituicytoma can be easily misdiagnosed with pituicytoma also presented with elevated hormone levels. as nonfunctioning pituitary adenoma due to a mass effect,3 and its These patients were considered to have a functioning pituitary symptoms include headaches, visual field defects, and adenoma before pathological diagnosis. A review of the English literature revealed only two case reports of pituicytoma with hor- mone elevation, and in both cases the patients presented with 7 8 * Cushing disease. , These reports also provided some indication of Corresponding author. Departments of Neurosurgery, Chang Gung Memorial fi Hospital, No.5, Fuxing St., Guishan Dist., Taoyuan City 333, Taiwan. hormone elevation, but lacked suf cient pathological and immu- E-mail address: [email protected] (H.-Y. Lai). nohistochemical (IHC) examinations to confirm this phenomenon. Peer review under responsibility of Taiwan Oncology Society. https://doi.org/10.1016/j.jcrpr.2017.12.002 2311-3006/© 2018 Taiwan Oncology Society. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). 48 T.-W. Chang et al. / Journal of Cancer Research and Practice 5 (2018) 47e52

It is unclear whether pituicytoma influences endocrine secretory /- þ þþ þ function or whether it can cause a normal pituitary gland to reach þ

hypersecretory status, In addition, no previous study has analyzed /------coexisting pituicytoma and functioning pituitary adenoma tu- -- - þþ þþ þ þ mors. Therefore, this study was designed to elucidate the rela- þ /- /- tionship between pituicytoma and hormone dysfunction. - -- 2. Materials and methods gland/pituitary adenoma The records of patients who underwent surgical resection for þþ þþþ þ þ þþ þ þþþþþþ þþ þþþþ þþþ þþþþ pituitary tumors at Chang Gung Memorial Hospital in Linkou, Taiwan between 2000 and 2016 were reviewed. Patients who received a pathological diagnosis of pituicytoma were included in - - - - - the present study, and those with insufficient clinical laboratory - data or images and a lack of specimens for study were excluded. þ þ þ þ þ Clinical data were collected, including the patients' presenting þ symptoms and laboratory data from before and after surgery. tissue tissue tissue tissue tissue NF Cytokeratin ADH ACTH PRL GH LH TSH FSH Peritumoral tissue Tumor location was identified by examining computed tomogra- - Peritumoral 2 phy and magnetic resonance images, and tumor size was deter- þ

mined as the linear measurement of the maximum tumor /- - Peritumoral þ þ - dimension in the coronal, sagittal, and axial planes. The diagnoses were confirmed by a neuropathologist who conducted a micro- - - - Peritumoral scopic examination of hematoxylin and eosin (H/E) and IHC staining results. Specifically, the IHC stains revealed the presence of vimentin, S-100 protein, thyroid transcription factor 1 (TTF-1), /- - - - Peritumoral fi /- - -- synaptophysin, epithelial membrane antigen (EMA), glial brillary - - - - Peritumoral acidic protein (GFAP), B-cell lymphoma 2 protein (BCL-2), neuro- filaments (NFs), cytokeratin, and the neuroendocrine markers of adrenocorticotropic hormone (ACTH), (PRL), growth Vimentin Synaptophysin EMA GFAP BCL-

hormone (GH), luteinizing hormone (LH), thyroid-stimulating S- 100 hormone (TSH), follicle-stimulating hormone (FSH), and antidi- þþþ þþþ þ þþþ þ þþþ N/A (not enough specimen) þþþ þ þþþ þ þ IHC study of pituicytomas IHC study of normal pituitary uretic hormone (ADH). TTF- 1 g/dL.

3. Results m 23 e During the study period, 1532 pituitary surgeries were per- none none none bleeding; pneumocra-nium none formed at the Chang Gung Memorial Hospital Linko Medical complications Center using either the transsphenoidal approach or transcranial approach, and eight patients (0.52%) received a pathological 270 - none 43.3 105.3 - none 10.26 months diagnosis of pituicytoma. Two of the eight patients were excluded due to a lack of viable specimens for the IHC study. The six 252 ng/mL; cortisol, 5 - Cortisol 7.1 - Prolactin fi Cortisol 28.74 remaining patients included one man and ve women with a e

mean age of 39.3 years (range: 21e53 years) (Table 1). All of the , negative. patients' lesions were located in the sella turcica without extra- - - IGH-1 - -Cortisol 14.37 Prolactin - Prolactin N/A N/A N/A Tumor bed Prolactin 47.8 Cortisol 11.81 Post-op serum hormone Post-op sellar extension, and had a maximum diameter on a single plane 1-3 days 2 weeks 3 ranging from 4 to 11.9 mm. One patient presented with bitemporal hemianopia, and the other five all presented with hormone 617 31.7 44.43 Prolactin 0.6 hormone change 118.4 30.22 changes, including hyperprolactinemia and galactorrhea (one Serum hormone change , weak positive; 29.2 ng/mL; IGF-1, 94 e patient), hypoprolactinemia (one patient), (one pa- / tient), and Cushing disease that was diagnosed using the dexa- þ ) methasone suppression test (two patients). All of the patients 3 8.7 x 11.9 x 7.5 IGH-1 6 x 6.7 x 8 Prolactin 5.7 x 5.8 x 4.5 Cortisol 3.9 x x7.3 x 10.8 10.2 x 9.5 x 3.7 No 4 x 4 x 2.5 Prolactin 6.5 x 6.5 x 7.6 Cortisol underwent tumor resection surgeries, and the specimens sent for Tumor size (mm , positive; pathological examinations included tumors and surrounding pi- þ

tuitary gland tissue. One patient (#7) suffered from post-operative oor tumor bed bleeding and pneumocranium. The other seven pa- fl intermedia Left pars intermedia intermedia nervosa Left paramedian sella Left pars intermedia paramedian pars distalis tients had smooth recovery courses and were negative for dia- location betes insipidus, cerebrospinal fluid leakage, central nervous

system infection, visual field change, and panhypopituitarism , strong positive;

(Table 1). þþ Pathological studies revealed pituicytoma in all six cases. These hemianopsia, unsteady gait headache tumors appeared as spindle cells with abundant fibrillar cyto- lactation plasms, whereas normal pituitary gland cells are round and oval cells with sinusoids (Fig. 1). IHC staining of the pituicytomas showed positive results for vimentin and S-100 protein, nuclear Age Sex Presentation Tumor #4 46 M Acromegaly Left pars #3 26 F Bitemporal #5 53 F Cushing disease Left pars #8 35 F Cushing disease N/A N/A N/A N/A N/A N/A none N/A (not enough specimen) #2 21 F Amenorrhea Left pars #7 55 M Dizziness and #1 39 F nonpuerperal #6 51 F Cushing disease Right Patient #7 and #8 were excluded because they did not have enough specimens for IHC study. Table 1 Topography of the eight patients received a pathological diagnosis of pituicytoma. Notes: #, patient number; F,Serum female; hormone M, units male; and N/A, normal not ranges: applicable. prolactin, 2.8 * staining for TTF-1, positive results for NFs in the peritumoral Mark for IHC stains: T.-W. Chang et al. / Journal of Cancer Research and Practice 5 (2018) 47e52 49

Fig. 1. H/E and IHC staining of specimens from patient #2. (a) H/E staining showed short-spindle cells (left side; arrow) and round and oval cells with sinusoids (right side; asterisk). (bed) Positive results for TTF-1, vimentin, and S-100 protein were observed (left side), suggesting pituicytoma. (e) Positive results for ADH were found around the pituicytoma cells. (fek) Pituitary gland cells (right side) were strongly positive for PRL and FSH, weakly positive for LH, GH, and ACTH, and negative for TSH. tissue, and various results for synaptophysin, EMA, GFAP, and BCL-2 3.1. Illustrative case (patient #1) (Table 1). The surrounding glandular tissue showed normal pitui- tary gland morphologies. Staining of pituicytoma cells revealed 3.1.1. Clinical presentation negative results for all neuroendocrine markers except for ADH A 39-year-old women presented with nonpuerperal lactation (which was positive in peritumoral tissue) (Fig. 1). However, for 3 months. A neurological examination revealed normal cranial staining of normal pituitary gland cells was strongly positive for nerve function, full muscle power, and no gait disturbance. How- various markers in different patients. Specifically, patient #1 with ever, laboratory data indicated hyperprolactinemia (118.4 ng/mL), hyperprolactinemia showed strongly positive staining for PRL, LH, and neuroimaging showed a nodular lesion at the left pars inter- and ACTH; patient #2 with hypoprolactinemia showed strongly media region (4 4 2mm3)(Fig. 2). She was diagnosed with pi- positive staining for PRL and FSH; patient #3 with no clinical hor- tuitary prolactinoma and was treated with agonists for 1 mone dysfunction showed strongly positive staining for PRL and month. However, because of her intolerance to the side effects of LH; patient #4 with acromegaly showed strongly positive staining this medical treatment, surgical treatment was suggested. for GH; and patients #5e6 with Cushing disease showed strongly positive staining for ACTH (Table 1).

Fig. 2. T1-weighted magnetic resonance images of patient #1 with contrast. (a) Coronal view and (b) sagittal view showing a 4-mm non-enhancing hypointense lesion located at the left paramedian sella turcica (white arrow). 50 T.-W. Chang et al. / Journal of Cancer Research and Practice 5 (2018) 47e52

3.1.2. Surgery and postoperative course positive for FSH, GH, and TSH (Fig. 5). The patient then underwent endoscopic transsphenoidal pitui- tary tumor surgery in our hospital. The margin of the nodular lesion was not clearly defined by gross inspection during the operation, 4. Discussion and partial gland tissue removal was performed in the peritumoral Pituicytomas are rare and benign tumors that originate from region. The procedure was completed smoothly without perioper- 1 ative complications, and no postoperative cerebrospinal fluid pituicytes in the neurohypophysis and pituitary stalk. Pituicytes fi are glial cells that support hypothalamic axons in the posterior leakage, , or visual eld defects were observed. 2 Her serum prolactin level decreased to 47.8 ng/mL on the third day pituitary gland, which produces vasopressin and oxytocin. The fi after surgery, and her symptoms of galactorrhea disappeared. rst case of pituicytoma was reported by Scothorne in 1955, who described the mass as a glioma in the posterior lobe.9 However, the term “pituicytoma” was not introduced until 2000, when Brat et al. 3.1.3. Pathological examination reported nine cases of low-grade glioma in the neurohypophysis.1 A microscopic examination following H/E staining revealed two Pituicytoma was initially defined as a pituitary astrocytoma, pos- types of cells: pituitary glandular cells (identified as round or oval terior lobe glioma, choristoma, and infundibuloma, before being cells flanked by vascular sinusoids, Fig. 3a) and pituicytoma cells classified as a separate grade I tumor in 2007 according to the (identified as a storiform arrangement of bipolar spindle cells with World Health Organization's classification of central nervous sys- abundant fibrillary cytoplasms without vacuoles or granulation, tem tumors.10,11 Fig. 3b). IHC staining of the pituicytoma cells showed positive re- Only 81 cases of pituicytoma have been recognized in the sults for vimentin, S-100 protein, and BCL-2, nuclear staining for literature since it was first described in 1955, most of which are TTF-1 (Fig. 4), and negative results for synaptophysin, EMA, GFAP, detailed in case reports and small case series.2 The most common and cytokeratin. In addition, the peritumoral tissue showed posi- symptoms of pituicytoma include visual field disorders (56.4%),2 tive staining for NFs (Fig. 4). The pituicytoma cells were also headaches (43.6%),2 hypopituitarism (21.8%),2 dizziness negative for all neuroendocrine markers, whereas the glandular (7.7%),3,12,13 and epilepsy (3.8%)14 16; a spontaneous tumor hem- cells were strongly positive for PRL, LH, and ACTH, and weakly orrhage was also documented in one case report.5 These clinical

Fig. 3. H/E stain of the specimens from patient #1 showing two types of cells. (a) Round and oval cells (asterisk) flanked by vascular sinusoids. (b) Bipolar spindle cells (arrow) with storiform arrangement, with abundant fibrillar cytoplasm and without vacuoles or granulation.

Fig. 4. IHC staining of spindle cells from the tumor from patient #1. (a) Nuclear staining of TTF-1. (bec) Positive results for S-100 protein and vimentin, suggesting a diagnosis of pituicytoma. (d) Positive ADH results in the peritumoral tissue. T.-W. Chang et al. / Journal of Cancer Research and Practice 5 (2018) 47e52 51

Fig. 5. IHC staining of pituitary gland cells from patient #1. (aec) Strongly positive staining for PRL, LH, and ACTH markers; (def) weakly positive staining for FSH, GH, and TSH markers; and (g) negative results for ADH markers. symptoms are typically caused by a mass effect, and are induced in microenvironment of their pituitary glands, thus inducing the hy- the same way as those of parapituitary tumors. For example, optic peractivity of pituitary gland cells. chiasm compression causes visual field defects, hypophysis Pituitary adenomas originate from pituitary gland cells and compression causes headaches and hypopituitarism, and infun- exhibit a wide range of hormonal and proliferative behaviors. The dibular compression causes hypothalamic dopamine delivery dis- pathogenesis of pituitary adenoma is unknown, although some e order (i.e., the pituitary stalk effect). However, hormone depression genetic diseases have been associated with pituitary adenoma.19 21 in patients with pituicytoma is an unusual presentation,6 and No previous study has described pituitary adenoma being induced hormone elevation is even more unusual. There have been only two by other tumors, although pituitary adenomas can occur in case reports of patients with pituicytoma who also presented with conjunction with other sellar tumors, such as Rathke cleft cysts, hormone elevation: one was a 2012 report by Schmalisch et al. that craniopharyngioma, colloid cysts, arachnoid cysts, epidermoid described a patient with pituicytoma and a presentation of Cushing cysts, and intrasellar Schwannoma, as well as with other ,7 and the other was a 2016 report by Guo et al. that adenomas.22 There is only one reported case of synchronous pitu- described a case of pituicytoma coexisting with corticotroph hy- itary adenoma and pituicytoma, which was described by Marian perplasia.8 Despite their unusual findings, neither group conducted et al., in 2016.23 The patient presented with a 6-month history of a complete IHC study of both the tumor and normal pituitary gland increasing visual impairment and headaches, however no symp- cells. We hypothesize three possible mechanisms for the occur- toms of endocrine dysfunction were noted and no association be- rence of hormone elevation in patients with pituicytoma: first, tween the two tumors was disclosed following a histopathological pituicytoma may have a neuroendocrine secretory function; sec- examination and DNA methylation profiling.23 In this study, no co- ond, pituicytoma can stimulate the over-secretion of normal pitu- existing adenoma was found in thorough pathological examina- itary glands; and third, there is coexisting pituitary adenoma. tions. However, whether a co-existing adenoma was responsible for Despite its rarity, five of the six patients with pituicytomas in the the hormone dysfunction is uncertain, giving the fact that these present study presented with hormone changes, and four of them patients had only partial removal of pituitary gland tissue. had the specific syndromes of hormone elevation (including non- In the present study, the patients' symptoms at presentation puerperal lactation, acromegaly, and Cushing disease) that were mostly hormone changes. Of note, the sizes of their tumors mimicked functioning pituitary tumors. Notably, our IHC analyses were relatively small (4e11.9 mm in diameter), and significant showed negative results for neuroendocrine markers within serum hormone improvements were observed immediately after pituicytoma cells in all of the cases, which suggests that pituicy- surgery. However, serum hormone relapse was observed in two of toma has no neuroendocrine secretory function and does not the patients during follow-up (patient #1 and #6 in Table 1), for directly contribute to hormone changes. which there are two possible explanations: either the coexisting Endocrine disorders related to sellar and parasellar tumors pituitary adenoma was not resected, or the residual pituicytoma other than pituitary adenomas usually present with hypopituita- cells induced local irritation and triggered the recurrence. In both rism, which results from mass-effect-related pituitary gland cell cases, it is clear that resection was insufficient. Because pituicytoma suppression and decreased local circulation.2 In this study, most of is a benign tumor, the goal of surgical treatment is to reduce the the patients presented with hyperactive neuroendocrine secretion, mass effect causing clinical symptoms rather than total tumor and the IHC staining results also indicated a specific hormone removal,2 however this response appears to be inadequate for pa- change in the normal pituitary glands surrounding the tumor. For tients with pituicytoma and predominant hormone elevation. instance, strongly positive staining for PRL, GH, and ACTH was Therefore, we suggest the following. First, the tumor should be noted in the patients with hyperprolactinemia, acromegaly, and resected as thoroughly as possible. Second, a thorough pathological Cushing disease, respectively. This evidence of the hyperactivity of examination should be performed on specimens of the tumor to normal glandular secretions suggests that a mass effect is not the confirm the existence or absence of adenoma. Finally, a complete only pathophysiological explanation for the influence of pituicy- IHC study should be conducted to determine the status of the pi- toma on neuroendocrine function. Notably, changes in the regional tuitary gland. microenvironment can be induced by gliomas and result in various In this paper, we describe rare cases of pituicytoma presenting clinical symptoms; for example, researchers have found that with elevations in hormone levels, and postulate the pathophysi- epileptic seizures can be induced by supratentorial low-grade gli- ology of pituicytoma and hormone dysfunction. However, the as- omas.17,18 In our patients, pituicytomas may have changed the sociation between pituicytes and the gland 52 T.-W. 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