Infra-Tentorial Brain Tumors – Biological Behavior during First Post-Operative Year – SKIMS, Kashmir Experience

Background: To observe the biological behavior like residual disease, progression, recurrence, disabilities, mortality, event free survival (EFS) etc., of histologically different infra-tentorial tumors of in the rst postoperative year. Methods: The histopathological records of 410 infra-tentorial tumors out of 589 patients were compared with their clinical outcome up to rst postoperative-year in a single-centre, amounting to regional epidemiological-value. In this observational study, retrospectively postoperative records of 589 infra-tentorial tumors of brain from Nov., 1990 to Dec., 2010 (20 years) were retrieved, scrutinized and compiled. The post-operative records of 410 patients with proved histopathological-examination results were included. Statistical law of Variance was applied where-ever necessary. Results: The 63.2% of 410 operated infra-tentorial tumors were males while females predominated in meningiomas and pineoblastomas. About 31.7% infra-tentorial or posterior fossa tumours were children (below-18yrs.). About 54.1% cases were histologically malignant. The residual-tumors comprised 40.2% and symptoms of disease-progression occurred in 10.9%. The tumor recurrence occurred in 14.3% while 6.0% patients developed severe-disability. The overall mortality was 11.4% up to rst post-operative year with 18.9% in malignant patients. The rst-one-year event-free-survival (EFS) for all the patients was 66.0%. While the patients with malignancies had rst-one-year EFS of 47.7%, the histologically benign group had 87.7%. Conclusion: The rst one-year postoperative biological behavior like EFS of histologically benign and some tumors both astrocytomas, ependymomas


Background
The triad of anatomically tight-spaced infra-tentorial intra-cranial-space or posterior fossa of brain, presence of biologically active tumor and obstructive hydrocephalus are the predictors of the worse outcome in the infra-tentorial space tumors. The infra-tentorial space of the cranial cavity, limited by the tentorium above, also called posterior fossa, has much smaller space than the rest of the cranial cavity.
However the contents of such a comparably small space are several types of motor and sensory tracts and a number of vital nuclei and reticular formation for the systemic body functions and consciousness in the form of midbrain, pons and medulla. Also packed are cranial nerves, vascular network with large venous sinuses, changing volume of CSF in the ventricle and cisterns and prominently visible cerebellar parenchyma with nuclei and peduncles. Most of the times, the infra-tentorial space or the posterior fossa tumors present themselves as an acute emergencies following the compression of the brainstem either due to the increase in tumor size, edema, bleed or obstruction to CSF pathways and herniation. The surgical debulking, to relieve the pressure on the brainstem, though full of risks, is indispensable mode of management. However in such a small space, the intra-operative complications and postoperative disease progression owing to residual or recurrence of the lesion worsens the surgical outcome. In 1930 an account of 61 patients of infra-tentorial space tumors of brain was published by the most cherished neurosurgeon of the world, Cushing H, claiming fatal outcome in almost all [1]. The present study outlines the biological behavior of different histologically subtypes in the rst postoperative year.

Materials And Methods
Literally of epidemiological value, this observational study took into account the records of those patients who were treated in the past and did not need to identify themselves to the researchers. Since the study was mainly compilation of surgical and histopathological records wherein neither IRB/Ethical approval nor patient consent was required, it provided an epidemiological data about the disease and a particular population because the population group is mainly ethnic and non-migratory. It bene ted medical and community health census directly. It was conducted on all operated patients of infra-tentorial space tumors of brain admitted from Nov., 1990 to Dec., 2010 (20 years) in the division of Neurosurgery. The neurosurgical patients are managed with a standard and uniform protocol. Retrospectively records of all the 589 patients of infra-tentorial space tumors of brain were retrieved from the les in the Medical Records Department, Operation Theatre Register, Out-patient Department les, referral clinics and followup les of the supportive departments like medical and radiation oncology, pathology etc., of this tertiary healthcare facility. The information about the patient's bio-data, history, examination, basic routine biochemical and hematological investigations, all the imaging (CT, MRI), surgical-procedures, intraoperative (frozen/crush) histopathological reports, nal histopathological examination reports, postoperative follow-up notes and imaging records (CT, MRI) up to the rst one-year of only 410 patients were available and were included and recorded. The data was analyzed, compiled and conclusions drawn. The statistical law of Variance was applied where ever necessary.

Results
Results of the study revealed a male-predominance of 63.2% (259/410) cases in overall infra-tentorial space tumors with M/F-ratio of 1.7:1.0. (Table 1). About 31.7% (130/410) of all the infra-tentorial space tumors of brain were found in the children (age=18 yrs. & below). The most commonly occurring infratentorial space tumors in children were medulloblastomas (Fig. 1), more of a classical variety, 84.7% (61/72). However various tumors like schwannomas 2.9% (3/102) and meningiomas 2.6% (1/38) were uncommonly found in children while metastases not at all. The results revealed that the vestibular schwannoma at the rate of 23.9% (98/410) was the most occurring individual infra-tentorial space tumor.

Discussion
The present study on the biological behavior of infra-tentorial space brain tumors in the rst postoperative year observed that 31.7% patients were children ( [4]. The present study observed 50% residual tumors in trigeminal schwannomas and 23.4% in vestibular schwannomas. About 2.9% schwannomas were found in children. Roberti et.al, 2001, wrote that a hundred and sixty one patients of infra-tentorial space meningiomas were operated over a period of 9 years with residual tumors found in 43% patients; progression of disease and recurrence in 13.7% and mortality was found in 2.5% patients [5]. The researchers in 2012 showed postoperative results of 64 patients of infra-tentorial space meningiomas, where recurrence occurred in 15.6% patients, severe neurological de cits in 33%, hydrocephalus in 43.75% patients and mortality in 3.2% [6]. Hakuba et.al, reported 17% mortality and severe neurological de cits in 83% patients in radical excision of clival meningiomas of infra-tentorial space [7]. Couldwell et.al, studied 40 males and 69 females, a male female ratio of 1:1.7, with infra-tentorial space (petro-clival) meningiomas postoperatively in which gross total excision was achieved in 69% of the patients, 13% had recurrence or progression of disease [8]. Louis et.al, reported a 5-year progression-free survival of approximately 50% [9]. The present analysis showed almost similar results. Hemangioblastomas are uncommon highly vascular, well-circumscibed, less than 3% of all CNS tumors, mostly (7.5%) in adult cerebellum and brainstem [10]. The present study found an incidence of 6.8% for hemangioblastomas, including two sisters in a family. Research found an Event Free Survival (EFS) of 85.7% in the rst-postoperative year. Dermoid cysts represent a rare clinical entity that accounts for 0.1-0.7% of all brain tumors [11]. This study observed that the dermoids comprised 3.6% of all the infra-tentorial space tumors of the brain. The EFS of dermoids was 100% in the rst postoperative year. Epidermoids, also known as cholesteatomas, are pearly tumors and account for approximately 0.1% of all intracranial tumors growing by the desquamation of the cyst wall and accumulation of keratin and cholesterol [12]. Zakrzewski et.al, studied 216 children with infra-tentorial space tumors below 18 th year of age, which depicted male/female ratio of 1.35:1.00. The commonest tumor was pilocytic astrocytoma -41.5%; medulloblastoma -34.5%; ependymomas -13% and mixed neuronal-glial tumors -5.5% [13]. Muzmdar D et.al, in 2011, presented 154 patients (age<18 years) of Medulloblastoma (Fig. 1) noting 92.2% (142 cases) had classical medulloblastoma, 5.1% (8 cases) had desmoplastic variant. The 5-year and 10-year progression free survival rate was 73% and 41% respectively for average risk disease while for high risk disease, it was 34% [14]. Rutka 1997 noted that medulloblastomas are intracranial childhood neoplasm, accounting for 25% of all childhood tumors [15]. Also Bloom & Bessell in 1990 showed that medulloblastomas in adults account for < 1% of all adult brain tumors [16]. Chan et.al, in 2000 found in a study that the recurrence rate for medulloblastomas in adults is approximately 50% to 60%. The median time-to-tumor progression (TTP) and recurrence is approximately 30 months after treatment [17]. In present study medulloblastomas ( Fig. 4 & 5) were found in 17.5% patients mostly (84.7%) in children. The postoperative residual tumor was found in 43.0% and recurrence in 19.4%. A mortality of 30.5% occurred in the rst-postoperative year. Djalilian and Hall (1998) reported that 53% patients in a study had grade IV malignant cerebellar gliomas and 47% had anaplastic grade III astrocytomas [18]. The present study observed that 11.4% infra-tentorial space tumorss had high-grade anaplastic and glioblastoma type of malignant cerebellar astrocytomas. The postoperative residual tumor was found in 70.2% and a EFS of 31.9% in rst-postoperative year was observed with a mortality of 2.1%. Witt et.al, 2011 reported that the posterior fossa ependymomas comprise two distinct molecular entities, ependymoma posterior fossa A (EPN PFA) and ependymoma posterior fossa B (EPN PFB), with differentiable gene expression pro les [19]. In present study ependymoma of the 4 th ventricle (Fig. 4) had residual tumors in 41.8% and recurrence in 11.6%. The EFS of 51.1% and a mortality of 6.9% were found in rst postoperative-year. Desai et.al, 2001, reported that the pilocytic cerebellar astrocytomas comprise 25% of all infra-tentorial space tumors in children [20]. Following up 104 children with cerebellar juvenile pilocytic astrocytomas reported high rate of recurrence or progression and often follow an inexorable course of progression, despite therapy [23]. All brainstem gliomas in present study had postoperative residual lesions and 37.5% had progression of disease and 56.2% recurrence. The severe disability in the brainstem gliomas, like pontine gliomas (Fig. 5), in present study, was more often linked to the long survival, motor dysfunction, decubitus ulcers and respiratory system infections caused by the early involvement of lower cranial nerves and the long tracts by these low-grade tumors. These had a mortality of 43.7% and an EFS of 31.2%. Sunderland et.al, 2016 reported that overall 80% patients underwent gross total resection (GTR), 14 % subtotal resection (STR) and 6 % underwent biopsy of metastatic infratentorial space contents (Fig. 1). The median overall survival (OS) was 6.00 months. The 28 day mortality was 7.6 % (n = 7) with a peri-operative morbidity of 22.8 % (n = 21) [24]. Zhang et.al, 2012 observed that the most common primary site of malignancy for brain metastasis was lung (20-40 %) followed by breast (5-17 %) and melanoma (7-11 %) with renal, colorectal and gynecological cancers making up the majority of the remaining [25]. The present series of 410 infra-tentorial space brain tumors also consisted of 2.1% patients of metastatic deposits, mostly from primaries like carcinoma lung, carcinoma breast, renal cell carcinoma and malignant melanoma. Tate et.al., in 2012 suggested an increase in survival of pineoblastomas ( Fig. 6) with increasing degrees of resection by observing 5-year survival rate of 84% for patients who underwent gross total resection versus 53% for patients who underwent subtotal resection and 29% for patients who underwent debulking [26]. Pineoblastomas in this study comprised 1.7% of all infra-tentorial space tumors while 57.1% of these were children. Roberti et.al., 2001 reported 5% malignant meningiomas in a study of 161 patients [5]. However, Wang et.al. 2016, reported that about 51% patients experienced recurrences. The relapse free survival at 12 months was 84.3% and at 5 years was 57.8% [27]. Of 410 infra-tentorial space brain tumors presently, 0.97% had malignant meningiomas (WHO grade-III), mostly rhabdoid and anaplastic, which formed 10.6% of all infra-tentorial space tumors with a recurrence of 100% and mortality of 75.0%.

Conclusion
The present study of biological behavior of infra-tentorial space tumors during st postoperative year in children and adults in an ethnic population is of the value of regional epidemiology value. Given the aggressive biological behavior, the histologically proven malignant lesions in infra-tentorial space have all the opportunities to harm the vitality of infra-tentorial space structures and lead to catastrophic outcome pre, intra and postoperatively.

Declarations
Disclosure of Funds: There is nothing to disclose about the funding. No funds used for the study.
No author of this study had any nancial support from anywhere and there is no industrial a liation of any author, no grants and no interest whatsoever. ii).        Pilocytic Astrocytoma Cerebellum is depicted by the CT scan, MR images and intra-operative photographs in sitting position. The histological microphotograph shows cerebellar pilocytic astrocytoma (Hematoxylin & Eosin X200).

Figure 5
Metastatic lesion in right cerebellar lobe revealed on CT, MR and intra-operative images.