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|Year : 2021 | Volume
| Issue : 5 | Page : 1153-1164
Pineal Parenchymal Tumor of Intermediate Differentiation (PPTID) and Papillary Tumor of Pineal Region (PTPR): A Review
Nishanth Sadashiva1, Harsh Deora1, Kirit Arumalla1, Shilpa Rao2, Jitender Saini3, Dhaval Shukla1, Vani Santosh2
1 Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
2 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
3 Department of Neuroradiology and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
|Date of Submission||14-Oct-2020|
|Date of Decision||01-Jul-2021|
|Date of Acceptance||06-Jul-2021|
|Date of Web Publication||30-Oct-2021|
Associate Professor, Neurosurgery, National Institute of Mental Health and Neurosciences, Bengaluru - 560 029, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Pineal parenchymal tumors account for less than 0.3% of all CNS tumors and “Pineal parenchymal tumor of intermediate differentiation” (PPTID; World Health Organization (WHO) grades II and III) exhibit intermediary differentiation and prognosis. However “Papillary tumor of the pineal region” (PTPR; WHO grades II and III) is a distinct entity.
Objectives: This combination of rarity and apparent similarity often leads to perplexity regarding the treatment and prognosis among neurosurgeons. In this review, we have tried to elucidate the differences in clinical as well as treatment modalities and outcomes of these two entities.
Methods: We used the PubMed Database to search for all relevant articles using the keywords “pineal parenchymal tumor of intermediate differentiation” and “Papillary tumor of the pineal region.” Articles having details regarding demographic and clinical variables along with treatment and outcomes were chosen for this study. Full text of these articles was analyzed, and data tabulated.
Results: A total of 25 articles for PPTID and 45 for PTPR were found suitable for inclusion in this study. The studies were either case reports or small retrospective series with only one systemic review for each pathology. Despite the poor quality of data, some trends were apparent. Surgical resection offered a survival benefit in both pathologies. Radiotherapy was effective in increasing the survival in PPTID, while there was little to no effect in PPTR. Chemotherapy was not found to be beneficial in either.
Conclusion: Both of these tumors have moderate growth rate and potential for malignant behavior. This continuum of characteristics makes their optimal treatment strategy difficult and confusing. The discussion on comprehensive literature review should give information for neurosurgeons to decide on optimal treatment strategies.
Keywords: Papillary tumor of the pineal region, pineal parenchymal tumors, pineal parenchymal tumor of intermediate differentiation, prognosis
Key Message: Currently, there is lack of clear understanding about basic clinical, treatment and prognostic differences between PPTID and PTPR. It is a combination of rarity and apparent similarity. We did literature review to form a coherent opinion of effective strategies.
|How to cite this article:|
Sadashiva N, Deora H, Arumalla K, Rao S, Saini J, Shukla D, Santosh V. Pineal Parenchymal Tumor of Intermediate Differentiation (PPTID) and Papillary Tumor of Pineal Region (PTPR): A Review. Neurol India 2021;69:1153-64
|How to cite this URL:|
Sadashiva N, Deora H, Arumalla K, Rao S, Saini J, Shukla D, Santosh V. Pineal Parenchymal Tumor of Intermediate Differentiation (PPTID) and Papillary Tumor of Pineal Region (PTPR): A Review. Neurol India [serial online] 2021 [cited 2021 Dec 7];69:1153-64. Available from: https://www.neurologyindia.com/text.asp?2021/69/5/1153/329550
The tumors of pineal region comprise a heterogeneous spectrum including the pineal parenchymal tumors (PPT) and papillary tumor of pineal region (PTPR). The PPT can be of different histopathological grades, pinealocytoma (PC, Grade I), pineal parenchymal tumor of intermediate differentiation (PPTID) (Grade II or III) and pinealoblastoma (PB, Grade IV). There is lack of complete understanding about actual prognosis and need for adjuvant treatment in the intermediate grade neoplasms, namely, PPTID and PTPR. It is a combination of rarity and apparent similarity. Though histopathologically they are distinct, many reports have combined these entities in their analysis and many neurosurgeons seem to have no clear idea differentiating these two entities.
The criteria to differentiate these entities, especially between World Health Organization (WHO) grades II and III of both PPTID and PTPR can be nebulous and hence decision making difficult.,,, It does not help that both of these entities were introduced recently.,,,, While the first six cases of PTPR were described by Jouvet et al. in 2003, with only two prior case reports before that,, PPTID was defined as a distinct entity by Schild et al. in 1993 and categorized by the WHO in 2000 as PPT with an intermediate prognosis between PC and PB. It was regarded as an intermediate- grade tumor and subdivided into WHO grade II or III.
Treatment of PPTID and PTPR has always been varied. So, we conducted a literature review of all these cases and form a coherent opinion of effective strategies for these cases. Most of these cases have either been case reports or small series.
| » Methods|| |
A Pubmed/Medline search was conducted using the MESH keywords “Pineal parenchymal tumors,” “Papillary tumor of the pineal region,” and all reported cases and series were collected, and relevant details extracted from the same. Data was extracted concerning the type of study, the number of cases, follow-up duration, the primary treatment offered, details of adjuvant therapy, overall survival (OS), and recurrence rates where relevant. All data was then tabulated and reviewed. Cases showing relevant information on treatment modalities and its effect on outcomes and survival were only included.
| » Results|| |
For PPTID, a total of 89 results were found on PubMed (until March 2020) of which 25 articles were found relevant [Figure 1]. 134 results for PPTR were found on the PubMed database (until March 2020), and after duplicates removal, a total of 45 studies were found to be relevant [Figure 2]. Variable from the 25 studies for PPTID [Table 1],,,,,,,,,,,,,,,,,,,,,, and 45 articles of PPTR [Table 2],,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, were tabulated and used. Most of these series were either retrospective cases series or case reports along with a single systematic review for each pathology. The primary treatment modality in almost all cases was either surgery or biopsy followed by adjuvant radiotherapy; however, differences were clear. Radiotherapy was effective in increasing the progression-free survival (PFS) or OS in cases of PPTID, while there was little to no effect in cases with PPTR. Chemotherapy was uniformly proven to be of minimal to no benefit in either pathology. OS in PPTID ranged from 16 to 80 months, while in cases of PPTR, it was 3 to 13 years. Gross total resection of the tumor in either pathology conferred the highest rate of OS. Recurrence rates were higher in PPTR (38–80%) as compared to PPTID (9–50%), perhaps due to the higher rates of metastasis and poorer rates of resections.
|Figure 1: Flow diagram showing search strategy and study selection in pineal parenchymal tumor with intermediate differentiation (PPTID)|
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|Figure 2: Flow diagram showing search strategy and study selection in papillary tumor of pineal region (PTPR)|
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|Table 1: Results of all the reported pineal parenchymal tumor with intermediate differentiation (PPTID) reported in literature, the details of treatment, and outcome are enlisted|
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|Table 2: Results of all the reported papillary tumor of pineal region (PTPR) reported in literature, the details of treatment, and outcome are enlisted|
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| » Discussion|| |
Pineal region is one of the most complex areas of the brain to deal with and it can harbor wide variety of tumors. Tumors in this region constitute only 1.2% of all the CNS tumors. Pineal region tumors have been categorized to: Germ cell tumors, PTPR, PPT, glial cell tumors, and miscellaneous tumors. Though historically surgical management was fraught with complications, over the past 40 years, there is significant advancement in safety and efficacy of surgical resection. Securing a histological diagnosis is fundamental in decision making and to distinguish among the many diverse histological subtypes of tumors in this region.
The 2000 and 2007 WHO classifications added two intermediate grade neoplasms to the classification of pineal region tumors. The PPTID (WHO grade II/III) was the intermediate grade between the PCs and PBs and the PTPR (WHO grade II/III). For both these neoplasms, precise grading to either grade II or III was not defined leading to much confusion and heterogeneity. Much of this confusion can be attributed to closely resembling nomenclature as well as similar grading with lack of definition in their subclassifications. It is not uncommon for neurosurgeons to be uncertain about prognosis and need of adjuvant therapy when either of these entities has been reported by pathologists. With this problem in mind, we have tried to differentiate these entities in all aspects from clinical presentation, radiology, surgery, outcomes, and need of adjuvant therapies.
Clinical features: A systemic review of PPTIDs found that the median age at presentation was 33 years, though recent studies have reported cases at much elder age groups., It has been reported that there is a slight female preponderance (1:1.6). Similarly, a systematic review and analysis on PTPR found that the median age being 33.0 ± 15.3 yrs, with a slightly higher proportion of male patients (53.2%). The clinical features at presentation include headaches, ataxia, visual disturbances and perinaud's syndrome with almost similar frequencies.,
PPTIDs are usually infiltrating T1-heterogeneously hypointense, T2-heterogeneously iso to hyperintense, showing strong heterogeneous contrast enhancement and in many cases having cystic foci [Figure 3]. In contrast, PTPR are well-circumscribed masses and tend to be larger than other pineal tumors characterized by a partially cystic tumor with heterogeneous enhancement. They can be either iso or hyper on T1 images and are heterogeneously hyperintense on T2-weighted images, [Figure 4]. Image patterns on diffusion-weighted image and spectroscopy have not been established to differentiate these tumors.
|Figure 3: Illustrative patient with Pineal parenchymal Tumor with Intermediate Differentiation. 24year old male with headaches, Magnetic Resonance Imaging (MRI) (a) T2 Weighted axial Images showing heterogeneously Hyperintense mass in the posterior third ventricle with hydrocephalus, (b) Lesion is heterogeneously enhancing on post gadolinium T1 sagittal images. Patient underwent Supracerebellar Infratentorial approach and excision of lesion. (c and d) showed corresponding MRI images done 3 months after surgery showing complete excision of lesion|
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|Figure 4: Illustrative patient with Papillary Tumor of Pineal Region (PTPR) in a 6year old girl with severe headaches. (a and b) Show Magnetic Resonance Imaging (MRI) with lesion in posterior third ventricle enhancing heterogeneously and avidly on T1 post gadolinium contrast sequences taken in axial and sagittal planes. Patient underwent endoscopic third ventriculostomy and biopsy. Three months later the lesion had grown in size as shown in images (c and d). patient underwent supracerebellar infratentorial approach and resection of tumor. Images e and f show MRI done 2months after surgery showing residue for which focal radiotherapy was advised|
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PPTs originate from pineocytes, endocrine cells of the pineal gland which secrete melatonin and regulate circadian rhythm. PPTIDs are composed of round cells with vesicular chromatin, inconspicuous nucleoli, and scanty to moderate amount of clear-to-eosinophilic cytoplasm; they may have moderate to highly cellularity with mild to moderate nuclear atypia. Mitotic figures are present and are more common in grade III than grade II tumors. Morphological subtype, mitotic index, and positivity of neurofilament have been used to differentiate PPTID. Morphologically, PPTID are divided into (1) lobulated pattern, endocrine-like and high vascularity, (2) diffuse growth pattern, similar to oligodendroglioma/neurocytoma, and (3) transitional type with areas of lobulated and diffuse growth patterns, associated with areas of pineocytomatous rosettes.
Jouvet et al., divided PPTIDs to low-grade (WHO II): with lobulated, transitional or diffuse subtype patterns having high expression of neurofilament (similar to PC), 0–5 mitoses per 10 HPF and moderate MIB-1 labeling indices, and high-grade (WHO III): without pineocytomatous rosettes, more than six mitoses/10 HPF, or less than six mitoses/10 HPF but negative for neurofilament and higher MIB-1 indices., MIB labeling indices are higher in PPTID (8–11.8%) compared to a PC (1.6%), but lower than PB (24–27%). Though neuronal differentiation has been claimed to be associated with better outcome, the same has not been reproduced in other studies., Interestingly, pleomorphism may be present in lower and intermediate grade lesions and are not used in grading. On immunohistochemistry (IHC), they reveal strong and diffuse synaptophysin positivity; focal chromogranin-A and NFP reaction is seen occasionally. GFAP and S100 are expressed in interstitial cells. ASMT-positive cells are significantly more numerous in PPTIDs than in pinealoblastomas., [Figure 5] illustrates the histopathological picture in case depicted in [Figure 3].
|Figure 5: Pathology photomicrographs of case depicted in [Figure 3] showing lobules of round tumor cells displaying fine chromatin and mild atypia (a, H and E, ×200). Tumor cells are diffusely synaptophysin positive (b, immunoperoxidase, ×100) and GFAP negative (c, imunoperoxidase, ×100) with moderate proliferation (d, MIB-1, immunoperoxidase, ×100). A diagnosis of pineal parenchymal tumor with intermediate differentiation (PPTID) was made|
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In contrast, PTPR originates from a distinct ependymal cell of the subcommissural organ, which has a unique papillary architecture associated with particular histological and immunohistochemical features. They are epithelial-like neoplasm arranged in two major architectural patterns, papillary and solid. Papillary areas exhibit broad fibrovascular cores, sometimes containing multiple capillaries that impart a pseudoangiomatous aspect to the tumor. These vessels are lined by a multilayered cuboidal or columnar epithelium with pale eosinophilic cytoplasm, arranged in perivascular pseudorosettes. In solid regions of the tumor, clearing or vacuolation of the cytoplasm may occur, often containing an acidophilic intracytoplasmic structure that is periodic acid–Schiff positive. The cells have round-to-oval nuclei situated toward the basal pole and a small nucleolus may be present. IHC plays an essential role in diagnosis, low-molecular-weight cytokeratins being the trademark of PTPR, with particularly strong reactivity to CK18. S100, NCAM, neuron-specific enolase, and transthyretin are frequent. PTPR is usually negative for GFAP, synaptophysin, chromogranin, and neural antigens, although focal, weak staining may be observed. Tumor cells exhibit features of ependymal, secretory, and neuroendocrine cells. [Figure 6] illustrates the histopathological picture in case depicted in [Figure 4].
|Figure 6: Pathology photomicrographs of case depicted in [Figure 4] showing cellular tumor composed of cells arranged in papillae (a, H and E, ×100), which are diffusely positive for cytokeratin (b, immunoperoxidase, ×100); negative for GFAP (c, immunoperoxidase, ×100). A diagnosis of papillary tumor of pineal region (PTPR) was made. GFAP = glial fibrillary acidic protein|
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Surgical options: The role of surgical resection in the treatment of pineal region tumors has grown markedly over the last few decades due to enlightened appreciation of the value of accurate tissue diagnosis combined with improved microsurgical techniques. Since Horsely through Oppenheim and Krause, Dandy followed by Stein, there has been an increased knowledge on surgical approaches. The past 15 years has demonstrated the epitome of microsurgical mastery with morbidity and mortality rates ranging between 1–20 and 0–10%, respectively, and rates of gross total resection (GTR) between 49 and 91%. The tumors of pineal region can be approached by infratentorial supracerebellar approach, occipital transtentorial approach, transcallosal interhemispheric approach, or transcortical transventricular approach. For majority of lesions, a supracerebellar infratentorial approach was preferred.,,, Other procedures which can be considered if only biopsy is thought of are endoscopic tissue biopsy with third ventriculostomy and stereotactic needle biopsy.
In a systematic review of PPTIDs by Mallick et al. in 2016 including 127 patients from 29 studies, it was found that gross total or near total resection was reported in 32 cases (25.2%), subtotal resection or debulking was reported in 50 cases (31.9%), biopsy only was possible in 40 cases (31.7%), and 1 patient had diagnosis in autopsy. The median OS was 14 years with 3- and 5-year OS being 91 and 84.1%, respectively. Interestingly, the extent of surgical excision had no impact on OS. Some reports indicate that PPTID can be treated with surgery alone in whatever extent possible, but a few others studies have described PPTIDs as tumors with cerebrospinal fluid (CSF) dissemination and recommend postoperative adjuvant therapy.,, Considering the heterogeneity of PPTID compared to other pineal region tumors, an open procedure was reported to be optimal to obtain sufficient amount of tumor for accurate diagnosis and for distinguishing PPTID from PC and PB. Many studies have shown better prognosis with greater extent of resection.,,, Keeping this evidence in mind several guidelines have recommended resection of lesion.
When it comes to PTPR, a systematic review and analysis by Yamaki et al., in 2019, including 177 patients from 71 studies, most patients underwent surgical resection (82.0%) and GTR was achieved on 71.4%. Three-year survival rate was 83.5%. Attempt at surgical resection (82.0%), compared to biopsy, was associated with increased survival at 36 months. However, the extent of resection did not affect outcomes. This study demonstrated local recurrence in 57.6%. Tumor size was the only independent variable associated with recurrence. However, survival was not influenced by recurrence. So the authors recommended maximum safe surgical resection to ameliorate response to adjuvant treatments and improve survival rate. Other studies have also shown that wider resection is associated with a better prognosis.,,,,
Whenever there is concurrent hydrocephalus, endoscopic third ventriculostomy and biopsy are increasingly used in management of the pineal region tumors. It is proved to be safe and is associated with higher biopsy results. The purpose of biopsy is to exclude lesions like germinoma, which can be managed with radiotherapy. After management of hydrocephalus and biopsy, the patient can be planned for surgical excision or adjuvant therapy. Ventriculoperitoneal shunt procedures are discouraged.
Adjuvant treatment: In their systematic review of PPTIDs by Mallick et al., they found that use of adjuvant radiation was found to be associated with better OS, though information on the radiation treatment was available in less than half of the reviewed patients. The indications of adjuvant treatment varied widely depending on local practice. So, one-third patients who underwent a gross total excision received adjuvant radiation and many did not receive adjuvant radiation even after subtotal resection. The authors concluded that it is advisable to give adjuvant radiotherapy for less than GTR and local radiation may be preferred over craniospinal irradiation. Though there is some evidence that adjuvant radiation treatment provides better local and spinal control in patients with PPTID,,,, there are no clear consensus, however, for the role of radiotherapy., Literature regarding role of radiosurgery is nonuniform with inclusion of primary and adjuvant treatment as well as inclusion of PC and PB in their analysis.,,, Though focal radiation seems to be a valid approach in adjuvant treatment, there are rare reports of delayed CSF seeding which needs to be kept in mind and warrants periodic CSF cytology and craniospinal irradiation whenever necessary., The role of chemotherapy still remains an area of conflict but may be tried in patients with recurrent disease or those with CSF. Some studies have shown success of radio-chemotherapy after biopsy., A combination of platinum plus etoposide would be the preferred regimen. Kang et al., in 2016, reviewed role multidisciplinary management (surgical resection and radiochemotherapy) in 160 patients with PPTID and only 30 of them received some kind of chemotherapy. Very few cases had a long follow-up more than 5 years, and the role of chemotherapy as an adjuvant therapy has still to be confirmed.
In cases of PTPR, the systematic review by Yamaki et al. did not show any effect of either RT or CT on outcomes. Typically, 56% showed local recurrence in follow-up. In their study, Fauchon et al. RT and CT did not confer any survival benefit in the treatment of the PTPR. Distant dissemination is described through cerebral spinal fluid and has been reported to have worse prognosis.,
Survival and Outcome: Fauchon et al. (2000) in their multicenter analysis of 76 consecutive patients with PPT reported that there were 27 grade II and 20 grade III tumors. The reported 5-year survival rates of these tumors are 74% for WHO grade II PPTID and 39% for WHO grade III PPTID. Event-free survival was 96 and 42%, respectively. In a systematic review by Mallick et al., including 127 patients from 29 studies, median PFS of the entire cohort was 5.17 years. Estimated 3- and 5-year PFS was 63.4 and 52.2%, respectively. Median OS was 14 years with 3- and 5-year OS, 91 and 84.1%, respectively. Female patients and use of adjuvant radiation were found to be associated with better OS. However, age, extent of surgery, or use of adjuvant chemotherapy had no significant impact on OS. Of the 24 patients who had recurrence, 62.5% experienced spinal or leptomeningeal recurrence, while 37.5% had local recurrence only. This result shows us the importance of CSF cytology as a part of workup as well as follow-up. In a study by Yu et al. on 27 cases of PPTIDs, the progression-free rates at 3 and 5 years were 77.8 and 74.1%, respectively. Longer PFS demonstrated significant association with GTR, adjuvant therapy, mitotic count (<3/10 HPFs), and Ki67 LI (<5). Similar results of correlation of prognosis with proliferative activity by counting mitosis or by the Ki-67 LI using IHC has been showed.,,
For PTPR, Fevre-Montange et al. in 2006 did a retrospective multicenter study of 31 cases. They were the first to systematically address prognosis of PTPR, which was a newly evolving tumor entity then. In their univariate analysis, GTR was the only clinical factor that tended to be associated with OS and recurrence, but statistical significance was not achieved. However, multivariate analysis was not possible in their data. They had described this as tumor with frequent local recurrence and rare spinal dissemination. Fauchon et al. did a multicenter retrospective study in 2013 including 44 patients. OS was 84.5% after 2 years and 71.6% after 10 years. Median PFS was 58.1 months. GTR and younger age were associated with a longer OS; radiotherapy and chemotherapy had no significant impact. Rate of recurrence was 58% at 5 years and >70% at 6 years. GTR, RT, and CT had no significant effect on PFS. They emphasized the importance of GTR in PTPR due to high incidence of local recurrence. Poulgrain et al., in 2011 published two case reports and did a literature review of 70 published cases PTPR till then. The mean and median follow-up period was 52 and 30.5 months, respectively. In total, 50% had developed recurrences, most of which were local. Four patients had CSF dissemination. In total, 18% suffered two or more recurrences, three of which had three or more. Five-year and 10-year OS rates were 73.8 and 61.5% respectively. In total, 5-year estimate for PFS is 34.5%, with a 10-year estimate of 8.6%. Recently, Yamaki et al. 2019 did a systemic review of 177 patients with PTPR in 77 articles. Three year after diagnosis, 83.5% of the patients were alive and 60.0% had good functional outcomes (GOS 4 or 5) were observed in the last follow-up. In total, 56.8% had recurred after a median 29 months. The 36-month survival rate was 83.5%. On univariate analysis, larger tumors were associated with decreased 3-year survival and surgical resection was associated with increased survival. However, the extent of resection did not affect outcomes. Typically, RT (44%), CT (10.3%), and radiosurgery (10.8%) did not improve survival. Local recurrence had occurred in 57.6%. After multivariate analysis, tumor size and surgical treatment were associated with survival. [Table 3] lists some fundamental differences between PPTID and PTPR.
|Table 3: A comparative table showing fundamental differences between pineal parenchymal tumor with intermediate differentiation (PPTID) and papillary tumor of pineal region (PTPR)|
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| » Conclusion|| |
Overall, the clinical picture of both these entities can be similar, presenting with obstructive hydrocephalus causing headache and ataxia. On imaging though, there are some points like heterogeneous T2 intensity to distinguish these two tumors, though not very specific. Both pathologies are to be managed with maximum safe surgical decompression as possible. With the available evidence, it is prudent to attempt maximum safe resection followed by focal radiotherapy/radiosurgery for the residue if present. Chemotherapy should be reserved for cases with unresponsive and progressive recurrences. When it comes to PTPRs, with the available evidence, the recommendation should be to attempt GTR. The literature is very heterogeneous regarding adjuvant therapy, but there is high proportion of local recurrence. This should prompt us to individually consider focal RT/radiosurgery only if there is a focal residue or regrowth.
PPTID – Pineal parenchymal tumor of intermediate differentiation
PTPR – papillary tumor of pineal region
CNS – Central nervous system
PC – Pinealocytoma
PB – Pinealoblastoma
HPF – High-power field
IHC – Immunohistochemistry
OS – Overall survival
PFA – Progression-free survival
GTR – Gross total resection
CSF – Cerebrospinal fluid
RT – Radiotherapy
CT – Chemotherapy
All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
For this type of study, formal consent is not required.
- The criteria to differentiate these entities, especially between WHO grades II and III of both PPTID and PTPR, can be nebulous and hence decision making difficult.
- We did a review of all PPTID and PTPR articles having details regarding demographic and clinical variables along with treatment and outcomes.
- Both pathologies are to be managed with maximum safe surgical decompression as possible. The literature is very heterogeneous regarding adjuvant therapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3]