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Introduction

The presence of two distinct tumor types in the cranial cavity is rare; therefore, little is known regarding the development and progression of the disease in these cases. Pituitary adenomas comprise ≥90% of sellar masses and 10–15% of all intracranial neoplasm (1). So the coexistence of a pituitary adenoma and other intracranial tumors is not an uncommon finding, but the exact incidence of pituitary adenomas concomitant with other cranial tumors remains unclear. However, numerous reports have described incidences of pituitary adenoma concomitant with other types of cranial cavity tumor, such as meningioma (2–4), medulloblastoma (5), neurinoma (6), craniopharyngioma (7), astrocytoma (8) and glioma (9). While the etiology and underlying mechanisms for the development of these tumors remain unclear, it has been proposed that genomic and endocrine disorders, as well as radiation therapy and embryogenesis, may be important factors (2–11). The majority of pituitary adenomas concomitant with other cranial tumors are diagnosed by MRI or CT, current treatment strategies include the simultaneous or staged resection (12). At present, prolactinoma associated with ependymoma remains a rare finding. The current study describes a rare case of prolactinoma associated with ependymoma in the fourth ventricle.

Case report

Symptoms

A 46-year-old male patient exhibiting impaired vision and dizziness was admitted to the First Hospital of Jilin University (Changchun, China) on March 5, 2010. In 1999, the patient was diagnosed with prolactinoma in the sellar region and underwent surgical resection. In 2001, tumor recurrence was detected, with an hourglass-shaped lesion observed in the sellar region as a low-density signal on T1-weighted magnetic resonance imaging (MRI). Furthermore, upward displacement of the optic chiasm occurred (Fig. 1A) and the tumor was observed to have invaded the cavernous sinus (Fig. 1B). For treatment, the patient underwent transcranial surgery in combination with Gamma Knife therapy (center dose, 45 Gy; peripheral dose, 20 Gy). The patient recovered well; however, tumor recurrence was detected in 2010, as described below.

Figure 1. Magnetic resonance imaging of the pituitary adenoma prior to resection, revealing (A) an hourglass-shaped lesion in the sellar region exhibiting a low-density signal on T1-weighted imaging. In addition, the optic chiasm appears elevated and (B) the tumor has invaded the cavernous sinus.

Presenting clinical symptoms included dizziness with progressive impaired vision. A nervous system examination detected vision in the left and the right eyes of 4.3 and 4.7 diopters, respectively (normal range, 5.0–5.3 diopters). Primary optic atrophy at the fundus and binocular temporal hemianopsia were also observed. Furthermore, an MRI scan detected lesions in the sellar region and fourth ventricle that were associated with a low-density signal on T1-weighted imaging (T1WI) and a relatively high-density signal detected on T2WI, respectively. The lesion volumes were 4.6×4.7×2.3 cm and 3.5×3.5×3.0 cm, respectively. Additionally, the fourth ventricle was observed to expand in response to compression, but was not completely blocked (Fig 2A–D). Hormone levels were detected to be within the normal ranges, with the exception of prolactin at 1,021.40 mIU/l (normal range, 70.81–566.46 mIU/l) and growth hormone at 0.50 ng/ml (normal range, 1.0–5.0 ng/ml). Considering the medical history, MRI and laboratory examination results, the patient was diagnosed with prolactinoma associated with ependymoma in the fourth ventricle.

Figure 2. Magnetic resonance imaging of a pituitary adenoma associated with ependymoma in the fourth ventricle prior to resection. Lesions in the (A) sellar region (4.6×4.7×2.3 cm) and (B) ventricles (3.5×3.5×3.0 cm) were observed as low-density T1-weighted imaging (T1WI) and relatively high-density T2WI signals, respectively. The fourth ventricle expanded in response to compression, but was not completely blocked. (C) and (D) represent enhanced scans of (A) and (B), respectively.

Treatment

Resection of the tumors in the fourth ventricle and the sellar region was conducted in two phases. In phase I, surgical resection of the ependymoma in the fourth ventricle was performed. The tumor was observed to originate from, and to be adhered to, the bottom of the fourth ventricle, with invasion towards the mesopore. The tumor was faint red in color with a moderately tough texture and an abundant blood supply. The tissue was fixed with formalin for 12–48 hours, then following gross examination the tissue was embedded in paraffin and cut to the slides using the cryostat (Leica Biosystems Nussloch GmbH, Wetzlar, Germany). Hematoxylin/eosin (H/E) staining (Leica Biosystems Nussloch GmbH) was used to visualize the tissue architecture and a microscope (CX22, Olympus Corporation, Tokyo, Japan) was used to capture representative images. Pathological examination with H/E staining detected densely arranged tumor cells with certain clusters forming cell masses. The latter were characterized by round or ovoid nuclei, dense chromatin and a slim nucleolus. Together, these observations led to a diagnosis of ependymoma (World Health Organization class II (13); Fig. 3A and B). Following the surgery, the patient recovered well and no complications occurred. Furthermore, postoperative MRI scans demonstrated that the tumor was completely resected and the fourth ventricle was relieved from obstruction (Fig. 4A and B).

Figure 3. Hemotoxylin and eosin staining of the fourth ventricle. (A) Densely arranged tumor cells, some forming cell masses (magnification, x200), (B) exhibiting round or ovoid nuclei, dense chromatin and slim nucleoli (magnification, x400). The tumor was diagnosed as an ependymoma (World Health Organization class II).

Figure 4. (A) Sagittal and (B) axial magnetic resonance imaging scans following resection of the ependymoma.

The second surgical procedure (phase II) to remove a pituitary adenoma in the sellar region was performed 10 days after the phase I surgery. The tumor was observed to be dull red in color, soft in texture and have a relatively abundant blood supply. Based on H/E staining, the tumor cells were observed to be diffusely distributed with minimal extracellular matrix. Additional immunohistochemical assays detected expression of prolactin in the tumor. Together, these characteristics led to a diagnosis of prolactinoma (Fig. 5A and B). Following the surgical procedure, the patient received Gamma Knife therapy and recovered well; the symptoms derived from the mass effects of the tumors improved.

Figure 5. Pathological analysis of lesions that developed in the sellar region. (A) Tumor cells detected by hemotoxylin and eosin staining were diffusely distributed with minimal extracellular matrix. (B) Immunohistochemical assays detected prolactin expression in the in tumor tissues, resulting in a diagnosis of prolactinoma. Magnification, x200.

Discussion

The presence of two different tumor types in the cranial cavity of a single patient is rare (2–6). However, of the cases reported thus far, meningioma associated with glioma is the most frequently described, followed by meningioma associated with pituitary adenoma and neurinoma (13,14). Subsequent to a 1995 study by Love et al (15) that reported a case of pituitary adenoma associated with meningioma, cases of pituitary adenoma associated with medulloblastoma (5), neurinoma (6), craniopharyngioma (7), astrocytoma (8) and glioma (9) have been described. However, to the best of our knowledge, no report has, thus far, described a case of pituitary adenoma associated with an ependymoma in the fourth ventricle. Therefore, the present study of prolactinoma associated with ependymoma in the fourth ventricle represents a unique case.

Similar genetic mutations have been identified in pituitary adenomas and ependymomas, and these mutations appear to be essential in the formation and progression of the two tumor types (10,13). Furthermore, in neurofibroma (type 2), a mutation in NF2, a tumor suppressor gene located at chromosome position 22q12, has been associated with the formation of various intracranial tumors, including meningiomas, gliomas and vestibular schwannomas (16). In addition, Furtado et al (11,15) reported three cases of pituitary adenoma associated with two cases of glioma and one case of meningioma, and demonstrated that these tumors resulted from gene mutations common to both tumor types in each case. However, various gene mutations have been identified in pituitary adenomas and other intracranial tumors, such as gliomas and meningiomas, that have different roles in each tumor type. For example, gene mutations identified in pituitary adenomas include the deletion of segments from chromosomes 1p, 2q, 4, 5, 6, 11q, 12q, 13q and 18q (10,17), and the overexpression of genes on chromosomes 9q, 16p, 17p, 19 and 20q (16,18). Furthermore, there have been a greater number of gain-of-function than loss-of-function mutations associated with pituitary adenomas (10,16,17). In ependymomas, deletion of chromosome 22, and overexpression of genes on chromosomes 1, 6, 7, 9–13, 16, 17, 19 and 20, have been detected (19). Therefore, according to the aforementioned studies, overexpression of genes on chromosomes 17 and 19 may be common genomic disorders associated with pituitary adenomas and ependymomas. However, additional studies are required to clarify this.

Hypotheses regarding the formation of intracranial tumors induced by radiation therapy have been confirmed in specific cases of glioblastoma, meningioma, sarcoma, astroma and ependymoma (20–23). Additionally, there are reports regarding the development of intracranial tumors, such as meningiomas (24,25), primitive neuroectodermal tumors (26), gliomas (20,27) and ependymomas (28) in response to radiation therapy for pituitary adenoma. Similarities between the aforementioned cases have been reviewed (29,30) and include the following: i) The development of secondary tumors within regions exposed to radiation; ii) the formation of secondary tumors following radiation therapy; iii) tissue origin of the primary tumors distinct from the tissue origin of the secondary tumors; iv) pathogenic genes identified in primary tumors differing from those of the secondary tumors; and v) a latency period of secondary tumor development of >5 years. In regard to the present case, we hypothesize that the ependymoma present in the fourth ventricle had a low probability of being induced by the Gamma Knife radiation therapy used to treat the pituitary adenoma, as the radiation was focused on the tumor in the sellar region, which is a considerable distance from the ventricles. As a result, the radiation dose that the fourth ventricle received would be expected to be low. Therefore, it is proposed that induction of the ependymoma in the present case was more likely to be the result of gene mutations in chromosomes 17 and 19 that are common to pituitary adenomas and ependymomas.

Amit et al (6) and Furtado et al (11) have previously speculated that different intracranial tumors may originate from cellular remnants left following embryogenesis. This hypothesis appears to be supported by a case of craniopharyngioma associated with pituitary adenoma and notochordoma reported by Shishkina et al (31). However, the current authors propose that embryogenesis was not involved in the present case, as these two tumors were different in cell origin.

In the clinic, certain cases of pituitary adenoma have been identified to be induced by factors secreted by the pituitary adenoma itself. For example, Curto et al (10) reported a case of pituitary adenoma associated with meningioma and an aneurysm, and demonstrated that growth hormones may have had a role in tumor development. Similarly, Fernandez et al (8) reported a case of pituitary adenoma associated with astroma in which insulin-like growth factor was involved. Somatostatin receptors (32) and epidermal growth factor receptors (33,34) are also expressed in pituitary adenomas and ependymomas, and may have a role in inducing the formation of pituitary adenomas and ependymomas.

In conclusion, the present study reports a rare case of pituitary adenoma associated with ependymoma in the fourth ventricle. Considering the characteristics of the current patient in association with previous case reports involving two tumors within the same cranial cavity, it is proposed that the basis of these disorders includes a genomic and endocrine component.

References