Magnitude of Neurogenic Tumor Burden in Pediatric Population: A Tertiary Care Center Study.

OBJECTIVE: Progress in the diagnosis and treatment of childhood neoplasm in the past few decades is one of the most gratifying achievements in the field of oncology. This study was aimed to ascertain the burden (incidence and prevalence) and histopathologic features of neurogenic tumors occurring in the pediatric population.
MATERIALS AND METHODS: The study evaluated a total of 492 cases of pediatric tumors over a period of 8 years from 2007 to 2015, including patients of 0-12 years of age group; attending the out-patients and in-patients Department of Pediatrics and Pediatric Surgery at Jawaharlal Nehru Medical College, AMU, Aligarh, with the complaints of tumor or tumor associated sign and symptoms. Clinical profile, hematological and histopathological examination along with immunohistochemical analysis were implicated to attain a conclusive diagnosis. RESULT: Out of 492 pediatric tumor cases, 255 (52%) cases were benign and 237 (48%) cases were malignant. Neurogenic tumor (brain tumors) comprised 49 (10%) of the total case, being most common malignant solid neoplasm and second most common (next to leukemia) overall malignancy, constituting 49/237 (21%) cases. Astrocytoma 22/49 (45%) cases were the most common type brain tumor followed by medulloblastoma 15/49 (31%), ependymoma 9/49 (18%), and craniopharyngioma 3/49 (6%).
CONCLUSION: Effective management of pediatric neurogenic tumor is a multipronged approach involving effort of good Pediatric neurosurgeon, Pathologist and a host of Oncology specialists with insight into childhood neoplasms.

INTRODUCTION

Cancer incidence prevailing in children and adolescents is rare with extremely variable biological behavior as compared to those occurring in adults.[12] About 148,000 cancers were estimated to occur around the year 2008 in pediatric population between 0 and 14 years in the underdeveloped regions;[3] however, in India, cancer is constitutes the 9th common cause for the deaths among children between 5 and 14 years of age.[4] Neoplasms arising in the nervous system constitute second most common childhood malignancy following leukemia,[5] comprising about 35% of all childhood malignancies being major cause of cancer-related deaths in children.[6] Pediatric central nervous system (CNS) neoplasms has a remarkable divergent biological behavior from those of adult brain tumors with different sites of origin, clinical presentation, tendency to disseminate early, and histological features. Due to sparse data collection and monetary resources, information on the demographic profiles of these pediatric tumors in the developing world is underestimated. Till date, we lack a published database on the demographic profile of pediatric brain tumors in India, which is undoubtedly a burdensome task. This study, therefore, aims to profile the hospital-based prevalence of pediatric CNS malignancies taking into account the latest WHO classification.[7] Low-grade gliomas (WHO I and II) are the frequent pediatric brain tumor that includes cerebellar pilocytic astrocytomas occurring more commonly, preceding supratentorial diffuse fibrillary astrocytomas. Medulloblastoma being second and ependymomas as the third most common tumor followed by craniopharyngioma, occupying the fourth place. Current studies have suggested the activation of the RAS/RAF/MEK pathway involved in the tumorigenesis of astrocytic tumors.

MATERIALS AND METHODS

A retrospective and prospective study of childhood tumors was commenced during period from 2007 to 2015, evaluating a total of 492 cases of pediatric tumors, including patients of 0–12 years age group, attending the out-patients and in-patients Department of Paediatrics and Paediatric Surgery at Jawaharlal Nehru Medical College, AMU, Aligarh, with the complaints of tumor or tumor associated sign and symptoms. Clinical profile, hematological and histopathological examination along with immunohistochemical analysis were implicated to attain a conclusive diagnosis. The profile of childhood brain tumors was studied focusing on the nature of lesion (benign vs. malignant), site of involvement, age and sex. The material for this study was obtained from fresh sections of paraffin blocks of different cases which were stained with H and E stains, and relevant special stain along with the immunostains. The cases were diagnosed and categorized according to the most recent WHO classification prevailing at the time of diagnosis.

RESULT

Diagnosis was mainly established by amalgamating symptomatology at presentation, finding of radiological imaging, and histopathological examination. Out of 492 pediatric tumor cases, 255 (52%) cases were benign and 237 (48%) cases were malignant. Neurogenic tumor (brain tumors) comprised 49 (10%) of the total case, being most common malignant solid neoplasm and second most common (next to leukemia) overall malignancy, constituting 49/237 (21%) cases. The mean age of the patients was 7.7 years and M:F ratio was 1.2:1. Astrocytoma 22/49 (45%) cases were the most common type brain tumor followed by medulloblastoma 15/49 (31%), ependymoma 9/49 (18%), and craniopharyngioma 3/49 (6%). Cerebellum was found to be the most common site followed by cerebral hemispheres and ventricles. Predominance of infratentorial tumors was observed in 1–10 years of age group, while supratentorial tumors were common within 1st year of life and after 10 years of age. Raised intracranial pressure (headache and vomiting) and disturbed gait were among the most common symptom observed.

DISCUSSION

In developing countries like India, due to the lack of complete registration of newly diagnosed cases with local cancer registries, the exact tumor burden of such diseases goes unnoticed and is underestimated. Hospital-based prevalence data, therefore, form the basis for estimating the disease load. These data are essential for ascertaining the required health-care infrastructure in the management of these diseases, and for assessing geographical differences in their molecular and genetic profiles.

Brain tumor accounted for 49/492 (10%) of the total tumor cases and 49/237 (21%) of all malignancies. Brain tumors accounted to be the second most common malignancy in our study; Arora et al.[8] and Kaatsch[9] reported brain tumors being 22%–25% and 20% of pediatric neoplasm, respectively, almost comparable with our study, while Jabeen et al.[10] reported a lower incidence of only 3.7%. We observed a predominance of infratentorial tumors in 1–10 years age group and that of supratentorial tumors within 1st year of life and after 10 years of age, a finding concordant to that seen by Shankar[11] in his study. Topographically, the cerebellum was found to be the most common site followed by cerebral hemispheres. Medulloblastomas and most of the pilocytic astrocytomas, which comprise the major histological entities, were frequently found occupying the cerebellum. Astrocytoma 22/49 (45%) accounted a maximum of total brain tumors followed by medulloblastoma and ependymoma similar to that observed by Jain et al.[5] and Shah et al.[12] Most of the patients presented with symptoms of increased intracranial tension (headache and vomiting). The patients with medulloblastoma had ataxia and gait disturbances as well. The histologic type of astrocytoma seen in this study were pilocytic astrocytoma and diffuse astrocytoma, pilocytic astrocytoma being the most common variant. Similar histologic types were reported by Shankar.[11] Rosenthal fibers were seen in only one case of astrocytoma, while none showed eosinophilic granular bodies in our study. Medulloblastoma accounted for 15/49 (31%) of all brain tumors, which varied from the study of Friedman et al., 1991 (20%–25%).[13] On histopathology, medulloblastoma showed small round tumor cells forming Homer Wright rosettes at places. Ependymoma accounted for 9/49 (18%) of total tumor cases being 3rd most common brain tumor as observed by Alexiou et al.[14] in his study on ependymomas in childhood. Recent advancement in neurosurgery, radiotherapy, and chemotherapy has brought a outstanding progress in the management and treatment of pediatric brain tumors over the past decades. Although survival and cure rates have improved gradually, the treatment-related morbidity still remains high with significant long-term sequelae.

Astrocytoma (22 cases)

Accounted for 45% of all brain tumors. There were 12 cases of pilocytic and 8 cases of fibrillary (diffuse) astrocytoma. The mean age was 7.2 years and M:F ratio was 1:1. The pilocytic astrocytoma was located in cerebellum while diffuse type were situated in cereberal hemisphere. On histopathology, pilocytic astrocytoma showed spindle to oval tumor cells in a dense fibrillary matrix with few rosenthal fibers seen. The diffuse type astrocytoma showed increase in number of glial cell nuclei with mild nuclear pleomorphism, in a fibrillary background formed by intervening astrocytic processes [Figure 1], positive for glial fibrillary acid protein [Figure 2]. Even with an excellent overall survival for these patients, the management of pediatric astrocytoma remains a difficult task. As most of these tumors has and indolent course of progression, the treatment must not be worse than the disease. The therapy should aim to dispense a long-term survival with only few long-term sequelae. Although complete resection is able to bestow cure to many children, still a handful of cases exist where it is not possible.[15] Front-line chemotherapy regime combining cisplatin plus etoposide are being evaluated for the risk-benefit ratio with unresectable low-grade gliomas.

Figure 1

Diffuse fibrillary astrocytoma: Showing lack of cellular cohesion and conspicuous cytoplasmic processes (H and E, ×400)

Figure 2

Glial fibrillary acid protein positivity of cytoplasmic processes in diffuse fibrillary astrocytoma (H and E, ×400)

Medulloblastoma (15 cases)

Accounted for 30% of all brain tumors which was higher as compared to study done by Gaur et al.[1] Out of these 2 cases showed cystic change, one case was of neuroblastic medulloblastoma. All the cases were located in cerebellum. Mean age of occurrence was found to be 7.6 years. Males were affected more than female 1.7:1. On histopathology, sheets of small round to oval cells with scant amount of cytoplasm and hyperchromatic nucleus was seen along with the formation of pseudorosettes and true rosettes with occasional mitotic figures, molding were seen at few places [Figure 3]. Multipronged approach combining surgery, radiation and chemotherapy remains the cornerstone for the treatment of medulloblastoma, as these tumors gives an excellent response to radiation and chemotherapy subsequent to surgical resection.[16] However, the age, histology, tumor stage, and type of surgery are the major determinant of prognosis.

Figure 3

Medulloblastoma: Showing Homer Wright Rosettes; consisting tumor cell nuclei disposed in circular fashion about tangled cytoplasmic processes and around blood vessel forming pseudorossetes (H and E, ×400)

Ependymoma (9 cases)

Accounted for 18% of all pediatric brain tumors occupying the position of the third most common brain tumor similar to the result of a large meta-analysis performed by Rickert and Paulus.[17] All of the cases were located in fourth ventricle. Mean age of occurrence was 8.5 years. It was found to be equal in both the sexes. On histopathology, tumor section showed tumor cells with round to ovoid nucleus and granular cytoplasm forming pseudorosettes [Figure 4]. Intracranial ependymomas commonly occupies the posterior fossa, however their biological and clinical behaviors varies according to their location.[18] Better survival is often observed in patients with supratentorial ependymomas as compared to those present in posterior fossa because total resection is frequently achieved in cases of supratentorial ependymomas.[19] Duration of symptoms before the diagnosis affects the prognosis and tumors with indolent course tend to have a better prognosis. Increased epidermal growth factor receptor expression has been associated with adverse prognosis as it plays a pivotal role in tumor proliferation, while P-53 and bcl-2 expression corresponds to tumor aggressiveness.[14]

Figure 4

Ependymoma: The ependymal tumors cells forming true and pseudorosettes (H and E, ×100)

Craniopharyngioma (3 cases)

Accounted for 6% of all brain tumors in our study similar to what observed by Reddy et al.[20] Craniopharyngiomas are rare non-glial tumor, commonly in children between ages 5 and 15, representing 6%–9% of all brain tumors in this age group.[20] These are typically located in or above the sella turcica. Compression of adjacent neural structures bring about the symptoms. Slow growth and insidious onset of the symptoms, often delays the diagnosis of these tumors. Craniopharyngiomas occur in two histological subtypes, adamantinomatous form that is the most common pediatric variant which was encountered in the present study as well, on other form is papillary type, found almost exclusively in adults. The pediatric form arises from the epithelial remnants of the craniophayngeal duct or Rathke's pouch, an embryologic structure that develops into the anterior pituitary. Grossly, these tumors shows solid as well as cystic components, often calcified on imaging. The cyst fluid is dark, oily, and rich in lipids with birefringent cholesterol crystals. Although histologically benign, they have a high recurrence rate after treatment. Treatment includes conservative surgery as subtotal resection or biopsy only to gross total resection followed by subsequent radiotherapy.

CONCLUSIONS

The population-based studies are required to study the demographics and to determine the burden of malignancies among pediatric patients in India

Hospital-based studies have a major role to play in estimating the disease load in a particular geographical region and subsequent planning of health-care infrastructure toward the disease

Effective management of pediatric neurogenic tumor is a multipronged approach involving effort of good Pediatric Neurosurgeon, Pathologist and a host of oncology specialists with insight into childhood neoplasms.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.