Papillary Tumor of the Pineal Region: A Case Report and Literature Review

: Pineal tumors of the pineal region (PTPR) are rare neuroepithelial tumors of the central nervous system, and their clinical features often lack specificity, so it is always difficult to make a definite diagnosis before surgery


Introduction
Pineal parenchymal tumors are neuroepithelial tumors originating from the epithelial and mesenchymal cells of the pineal region and account for less than 1% of all primitive central nervous system (CNS) tumors and 15% to 30% of pineal tumors [1][2]. These tumors are uncommon, and among them, papillary tumors of the pineal region (PTPR) are even rarer, with an incidence of approximately 1% in adult intracranial tumors [3]. As a neuroepithelial tumor, papillary tumors of the pineal region were originally described by Jouvet et al. in 2003 [4] and were included in the 2007 World Health Organization (WHO) classification of tumors of the central nervous system [5]. PTPRs are characterized by a combination of papillary structures and solid regions with morphological features of epithelial-like cells and strong immunoreactivity to cytokeratin [6]. However, the pathogenesis of PTPRs has not been fully elucidated, and some studies prompt the possibility of an association with the loss of chromosome 10 and the gain of chromosomes 4 and 9 [7][8], where the genetic alterations of PTEN have been described [9]. Epidemiological data on these rare tumors are limited, and the published reports suggest that they can occur in both children and adults without gender preference [10]. Notably, the limited prognostic data indicate a high frequency of local recurrence of PTPRs and the possibility of spinal dissemination [11]. Moreover, surgical resection and the increased mitotic and proliferative indices were strongly correlated with the prognosis of PTPRs [12].

Clinical Information
The patient, a 21-year-old male, was admitted to the hospital with intermittent dizziness, headache, and vomiting for approximately 2 months. There was neither an obvious trigger nor an abnormal family history, and no enlargement of superficial lymph nodes was noted during the physical examination. After admission and completion of ancillary examination such as hematology and imaging, the results showed that the concentration of Ferritin (558.02 ng/ml) was elevated and the concentration of β-human chorionic gonadotropin (β-HCG) was normal (0.26 mIU/ml). The cranial CT and MRI showed an occupying lesion in the pineal region, occlusion of the midbrain aqueduct, fluid in the superior ventricular system, and demyelinating changes in the white matter of the cerebrum around the bilateral ventricles and of the cerebrum in the hemi-oval center ( Figure 1); in addition, cranial vascular CTA showed bilateral embryonic posterior cerebral arteries and a small A1 segment of the left anterior cerebral artery. After discussion, the patient was preoperatively diagnosed with a germ cell tumor, and the tumor was subsequently removed from the posterior ventricle under the microscope. Intraoperatively, the tumor was observed to be located in the posterior part of the third ventricles, grayish red in color, soft, adherent to the surrounding tissues, and rich in blood supply, and the midbrain conduit was opened after the lesion was removed. Postoperative histopathological examination clarified that the patient was diagnosed with PTPR.
The patient was discharged from the hospital after finishing postoperative combination chemotherapy and was in good general condition with normal laboratory parameters. We advised him to review regularly at the outpatient clinic, and the last telephone follow-up was in February 2023 (Table 1). Until February 2023, the tumor markers were normal and MRI did not show any evidence of recurrence.

Histological and Immunohistochemical Characteristics
After adequate fixation with 10% neutral formalin, the tissue appeared off-white or gray-red, with moderate hardness, and a size of approximately 2.0 × 2.0 × 2.3 cm. Microscopically, the tumor tissue was mainly composed of cuboidal or columnar epithelial-like cells with clear cytological boundaries. The cytoplasm was eosinophilic and partially translucent, and the nuclei were round to ovoid, with obvious heterogeneity and speckled chromatin. However, defined nuclear fission images are less commonly seen. Equally significantly, the tumor tissue was principally arranged in a papillary, micropapillary, or solid lamellar pattern, with locally visible pseudo-rose nodes, as well as invasion of the brain parenchyma ( Figure 2). Ki-67 (5%) (Figure 3).
The patient was eventually diagnosed with a papillary tumor in the pineal region (WHO grade II to III).

Discussion
The biological and clinical behavior of PTPR is alterable. Most of them correspond to WHO grade II and the more aggressive ones may correspond to grade III, but no usable histological grading criteria have been proposed to define them precisely [5,13]. At the time of presentation, patients experience the highest frequency of elevated intracranial pressure, while other symptoms are relatively common, including Parinox syndrome, ataxia, and isolated diplopia [14]. Radiographically, PTPRs generally show clear boundaries, mild lobulation, focal cystic lesions, and enhanced heterogeneity of the mass, usually accompanied by obstructive hydrocephalus [15][16]. They seem to be difficult to distinguish from other intracranial tumors, especially pineocytomas [15,17]. Nevertheless, a portion of previous PTPR-related reports described high signal in non-contrast T1-weighted sequences [18][19], which may be a result of the high concentration of secreted material in the small cystic spaces and may contribute to the diagnosis of PTPR [20]. In contrast, no hyperintensity signal was found in other cases [21][22], including ours, suggesting a difference in radiographic presentation among the lesions.
It is well known that PTPRs is characterized by papillary formations and an epithelial growth pattern [10]. These epithelial-like tumor cells are chiefly cuboidal and columnar with eosinophilic or somewhat hyaline cytoplasm. Besides, this solid tumor usually exhibits ventricular tubular-like differentiation, with blood vessels frequently covered by large, pale-to-eosinophilic columnar cell layers in papillary areas. Further immunohistochemistry demonstrates that these tumor cells are strongly reactive to cytokeratin, specifically to cytokeratin 18 (CK18) [23] as well as varying degrees of expression of neuron-specific enolase (NSE), wave proteins, glial pro-fibrillary acidic protein (GFAP), and S-100. The diagnosis of this tumor is always complex due to its similarity to other primary or secondary papillary lesions in the pineal region, including pineal parenchymal tumors, papillary ependymoma, choroid plexus papillomas, germ cell tumors with papillary features, and metastatic papillary carcinoma [24].
The clinical course of PTPRs is often complicated by frequent local recurrences, leading to a continuing controversy about the optimal treatment of PTPRs. Whether surgery, radiation, or chemotherapy is applied individually or combinedly, research has revealed that PTPR is unavoidably prone to recurrence [23]. However, a large study showed that chemotherapy did not seem to affect overall survival (OS) or progression-free survival (PFS) [11]. Currently, the definitive treatment for patients with PTPRs involves mainly surgical resection in combination with radiotherapy [9]. Unfortunately, the outcome of these patients remains poor and even fatal, with a 5-year OS of 73% and a 10-year of 58% [25]. Therefore, what we still need is to continue exploring new potential therapeutic targets to prolong PFS.