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Table of Contents    
Year : 2020  |  Volume : 68  |  Issue : 5  |  Page : 1175-1182

Clinicopathological Study of Extra-Axial Small Round Cell Tumors of the Cranium

1 Department of Neuropathology, National Institute of Mental Health and Neurosciences [NIMHANS], Bengaluru, Karnataka, India
2 Department of Neurosurgery, National Institute of Mental Health and Neurosciences [NIMHANS], Bengaluru, Karnataka, India

Date of Web Publication27-Oct-2020

Correspondence Address:
Dr. T C Yasha
Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru - 560 029, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.299158

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 » Abstract 

Introduction: The cranium is a host to a variety of neoplasms and includes small round cell tumors (SRCTs) as an important malignant subset. Although SRCTs are histomorphologically similar, they are histogenetically diverse comprising of malignancies of epithelial, hematolymphoid, neuroectodermal, and mesenchymal origin.
Objective: The study aimed to review the clinical and pathological profile of cranial SRCTs.
Materials and Methods: Study is a retrospective review (clinical, imaging, and histopathology) of cranial (extra-axial) SRCTs diagnosed on histology (period: 3.5 years).
Results: Study included 126 cases constituting 1.5% of all intracranial neoplasms and age ranging from 11 months to 82 years (mean: 34.3 years; M:F = 1.46:1). Peripheral primitive neuroectodermal tumors (pPNET-8.2%) was the commonest neoplasm followed by plasmacytoma (14.2%), poorly differentiated carcinomas (13.5%), lymphomas (9.5%), and sarcomas (8.7%). Rare tumors included glioma (undifferentiated) deposits, germ cell tumors, melanoma, neuroendocrine neoplasms, and embryonal tumor. Children constituted one-third of the total with PNETs, embryonal tumors, and round cell sarcomas being the common neoplasms. Elderly patients constituted 14% with plasmacytomas and epithelial neoplasms being common. Three percent of the tumors remained unclassified. Clinical symptomology was location dependent, headache being the commonest followed by visual symptoms. Radiopathological discordance was high (60%).
Conclusion: SRCTs are unusual tumors with a wide spectrum of histogenesis, biology and clinical presentation. Their rarity in cranium, atypical localization, overlapping clinical, and imaging features pose significant difficulty for clinicians, radiologists, and pathologists. A combined algorithmic analysis of the clinical, radiological, and histolopathological findings, supplemented with immunohistochemistry can aid in specific diagnosis which is crucial for optimal management.

Keywords: Cranium, immunohistochemistry, PNET, small round cell tumors
Key Message: A wide variety of round cell tumors of different histogenesis occur in the cranium with overlapping clinical, radiological, and histopathologic features thus demanding additional testing especially immunohistochemistry.

How to cite this article:
Nandeesh B N, Rao S, Sadashiva N, Mahadevan A, Yasha T C, Santosh V. Clinicopathological Study of Extra-Axial Small Round Cell Tumors of the Cranium. Neurol India 2020;68:1175-82

How to cite this URL:
Nandeesh B N, Rao S, Sadashiva N, Mahadevan A, Yasha T C, Santosh V. Clinicopathological Study of Extra-Axial Small Round Cell Tumors of the Cranium. Neurol India [serial online] 2020 [cited 2021 Jul 31];68:1175-82. Available from:

Cranial extra-axial region includes tissues other than brain parenchyma (such as meninges, dura, calvarium, ventricles, choroid plexus, pineal gland, and pituitary gland) and hence is a host to a variety of neoplasms. Small round cell tumors (SRCTs) form an important subset of these cranial extra-axial neoplasms. SRCTs are histogenetically heterogeneous but morphologically similar with small, round, relatively undifferentiated cells and scant cytoplasm.[1] The diagnostic category of SRCTs include diverse malignancies of epithelial, hematolymphoid, neuroectodermal, embryonic, and mesenchymal origin. Because of the diverse tissue origin, the differential diagnosis of SRCTs is complex and continues to be a source of diagnostic difficulty on light microscopy (LM). Their atypical localization and overlapping symptomatology further complicate the diagnosis along with sophisticated biopsy techniques which yield small sized tissue specimen.[2] Early and specific diagnosis is very crucial for an appropriate management as some require only medical line of treatment.[3] Because of these difficulties, the diagnostic workup demands additional testing such as immunohistochemistry (IHC), ultrastructural study, molecular and cytogenetic analysis. However, not all centres are equipped with advanced diagnostic tests and may lack a wide panel of IHC markers. The present study aimed at analyzing the clinicopathological spectrum and immunoprofile of cranial (extra-axial) SRCTs using a set of immune-markers and an algorithm is proposed for the pathological assessment of these neoplasms.

 » Materials and Methods Top

The present study is a retrospective analysis (3.5 years) that included all cranial neoplasms that were extraxial on radiology/surgical evaluation and predominantly had small round cell morphology on LM. The list also included those tumors which were predominantly extra-axial but secondarily infiltrating the brain. However, intraventricular neoplasms were not included. Patients of all the age groups were included in the study irrespective of the type of surgery and size of the sample. The relevant clinical, demographic, and radiological data were noted. Hematoxylin and eosin (H and E) stained sections of all the cases were re-evaluated and a select panel of IHC antibodies [CD45/LCA (the lymphocyte common antigen), CD20, CD3, PanCK, CK7, CK20, CD99, desmin, EMA (epithelial membrane antigen), synaptophysin, chromogranin, GFAP (Glial fibrillary acidic protein), ALK (Anaplastic lymphoma kinase), KI-67, S100, Desmin, SMA, CD34, HMB45, CD68, TdT, Pituitary hormones, CD30, PLAP] was applied using polymer technology on an automated IHC stainer—Ventana. IHC markers were selected based on clinicoradiological and histological differentials. A systematic analysis of the morphology and IHC profile of these neoplasms were performed and were grouped according to the lineage/differentiation and studied.

 » Results Top

The study included a total of 126 cases of SRCTs which constituted nearly 1.5% of all the total cranial neoplasms diagnosed in the department. The age ranged from 11 months to 82 years [Figure 1] with a mean age of 34.3 years and a male to female ratio of 1.46:1. The overall distribution of tumors and across the three major age groups are shown in [Figure 2], [Figure 3], [Figure 4], [Figure 5].
Figure 1: Age group distribution (in percentage) of the patients included in the study

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Figure 2: Histogram showing the distribution of various small round cell tumors across all age

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Figure 3: Histogram showing the distribution of various small round cell tumors in the pediatric age group

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Figure 4: Histogram showing the distribution of various small round cell tumors among middle age group patients

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Figure 5: Histogram showing the distribution of various small round cell tumors among the elderly (>60 yrs) patients

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The most common neoplasm (irrespective of age) in the study was peripheral primitive neuroectodermal (pPNET)/Ewings family of tumors (18.2%) followed by plasmacytoma (14.2%), poorly differentiated carcinomas (metastatic and locally invading, 13.5%), lymphomas (9.5%), and sarcomas (round cell types, 8.7%). The other rare tumors with this (undifferentiated) morphology included neoplastic glioma deposits with small undifferentiated morphology, germ cell tumors, melanoma, neuroendocrine neoplasms, and embryonal tumor deposits.

One-third of all the patients belonged to the pediatric age group with pPNETs, embryonal tumors and round cell sarcomas (RMS) being the common neoplasms in this age group. Elderly patients constituted only 14% with plasmacytomas and epithelial (locally invading and metastasis) neoplasms being the common ones.

While the rest of the patients were middle aged and included neoplasms of diverse origin. The clinical symptom depended on the location with headache being the commonest presentation followed by visual symptoms. The neoplasms exhibited varying and often overlapping radiologic features, hence the radiopathpathological discordance was high (60%). Inspite of using a broad panel IHC markers, a small percentage of cases (2.4%) of the tumors remained unclassified because of complex immunoprofile, an extreme degree of undifferentiation and limitation of the IHC/tissue antigen preservation. Representative microphotographs of some of the neoplasms including the IHC are shown in [Figure 6] and the radiology images of representative cases in [Figure 7].
Figure 6: Showing microphotographs of (a) Peripheral PNET; inset - CD99 IHC, (b) Poorly differentiated carcinoma; inset- Cytokertain IHC, (c) Plasmacytoma; inset - CD138 IHC, (d) Non Hodgkin Lymphoma; inset - CD20 IHC, (e) Langerhan's Cell Histiocytosis; inset- CD1A IHC, (f) Germinoma; inset - PLAP IHC, (g) Olfactory neuroblastoma; inset - Synaptophysin IHC, (h) Undifferentiated sarcoma; inset - Vimentin IHC, (i) Glioma; inset - GFAP IHC, (j) Rhabdomyosarcoma, inset – Desmin IHC, (k) Neuroendocrine carcinoma; inset – synaptophysin IHC, (l) Unclassified tumor

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Figure 7: I: (A) Brain MRI (sinonasal neoplasm) sagittal- contrast enhancing ACF base tumor with a small extension along ethmoidal area to nasal cavity; (B and C) CT- bony defect through which the tumor is extending. II: (A) MRI (A-Axial; B-coronal; C-sagittal) of a contrast enhancing tumor (Myeloid sarcoma) attached to falx; (D) Sagittal T2W- hyperintense lesion with adjacent white matter oedema. III: (A) T2 W axial (midpons)- hyperintense extraaxial lesion (sarcoma) at right CP angle with extension along anterior petrous area; (B) T1W- Heterogenous contrast enhancing lesion. (C) CT- erosion of Ant. petrous bone

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 » Discussion Top

The cranial extra-axial compartment is a host to a variety of neoplasms including many malignant neoplasms as this compartment comprises a broad spectrum of tissue elements including meninges, dura, calvarium, ventricles, choroid plexus, pineal gland, and pituitary gland.[1],[4] SRCTs constitute a small but a very important subset of malignant neoplasms of this region and are composed of patternless sheets of small cells with dense cellularity and high N:C ratio.[5] Hence referred to as small round blue cell tumors because of the scant cytoplasm and closely packed nuclei giving a blue appearance on routine H and E stain. Cytoplasmic abundance roughly correlates with cellular differentiation, which is often modest.[6] Although SRCT comprises round cells that are generally small (double the size of red blood cells), tumors of intermediate size that are round in their configuration are also included. Hence the important neoplasms in the list of SRCT includes Ewing sarcoma/PNET group, Blastomas (neuroblastoma, retinoblastoma ), desmoplastic SRCT, rhabdomyosarcoma, Non-Hodgkin's lymphoma along with small cell carcinoma, poorly differentiated round cell synovial sarcoma, mesenchymal chondrosarcoma, small cell osteosarcoma, small cell malignant peripheral nerve sheath tumor, myeloid sarcoma, malignant melanoma, and other neoplasms with undifferentiated cells.[7] Differential diagnosis of small round cell tumors is particularly difficult due to their undifferentiated or primitive character.[6] The occurrence of these tumors in head and neck is very rare and the occurrence in the cranial region (extra-axial) is much rarer with no comprehensive study available in the literature.[8] However, literature search revealed reports/studies on individual tumor/tumor groups and studies mainly included SRCT of thoraco abdominal region, sinonasal regions or the entire body. A comparation of the findings across these studies are shown in [Table 1].[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21]
Table 1: Comparison of Malignant SRCT in various studies

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A systematic review of these tumors occurring in the cranial region is essential to understand the clinicopathological spectrum of the constituent tumors which would aid in improving our diagnostic and management approach towards these neoplasms. This would especially be of help to pathologists working in a resource limited setting encountering small sized biopsies.

These SRCTs can occur across a wide age as seen in the present study with age ranging from 11 months to 82 years (mean age - 34.3 years; M:F ratio of 1.46:1). A similar wide age range was observed in some of the other studies on SRCT with a comparable mean age and male preponderance.[12],[15] Middle aged patients formed the major group and in a systemic round cell tumor study, the authors noticed a predominance of middle aged patients (44%) and a high male to female ratio of 2.9:1.[16]

In the present study, the Ewing's sarcoma/PNET constituted the commonest (18.3%) neoplasm among the entire tumor list followed by plasmacytoma (14.3%). A similar observation was made in an oncocentre wherein Ewings family of tumors constituted the major bulk of SRCT.[21] This is in contrast to various other studies (whole body and thoraco-abdominal regions) where lymphoma (29.33–54%) formed the commonest neoplasms.[9],[10],[11],[16],[17],[18],[19] However, the second commonest neoplasms in some of these studies was Ewing's sarcoma/PNET.[9],[10],[14],[16],[19] Also in a study by Ashraf MJ et al. on sinonasal SRCT and Deepshikha et al., it was observed that poorly differentiated carcinomas and small cell carcinomas constituted the commonest round cell tumor.[12],[20] This suggests that skull base is not a common site for lymphomatous infiltrate, and non hematolymphoid neoplasms appear to predominate.

However, in the study by Shah SH et al. on pediatric solid tumors, hematolymphoid and solid tumors constituted one third, each, of the total neoplasms with Ewing's sarcoma being the commonest solid neoplasm.[12] A similar observation, wherein Ewing's Sarcoma constituted the commonest neoplasm in the pediatric age group was made in the present study and Deepshikha M et al.[20] This suggests that the cranial extra axial soft tissue is a common conducive site for Ewing's Sarcoma/PNET particularly in children and young adults. The next common pediatric neoplasm observed in the present study was histiocytic neoplasms followed by embryonal tumors and germ cell neoplasms. Similarly rhabdomyosarcoma, neuroblastoma and germ cell neoplasms constituted the second commonest neoplasms in the studies by Shah SH et al., Patel A et al., and Patel MM et al. respectively.[12],[17],[18] Based on these observations, the important cranial SRCTs to be considered in the pediatric age group include Ewing's sarcoma/PNET, histiocytic tumors, embryonal tumors, germ cell tumors and hematolymphoid tumors.

Elderly patients (>60 years) constituted the least common group with plasmacytoma and metastatic poorly differentiated carcinomas being the common ones. Even in the middle aged patients, plasmacytoma constituted the commonest type of neoplasm in this category followed by sinonasal, nasopharyngeal malignancies. In the studies by Das DK et al. and Pity IS et al. carcinomas constituted the second commonest neoplasm among their patients.[11],[13] This suggests that epithelial malignancies and plasmacytic neoplasms dominate the middle and elderly age and can mimic true SRCT as only the poorly differentiated/undifferentiated carcinomas appear as SRCT. [Table 2] summarizes the clinicopathologic features of the round tumors.
Table 2: Summary of Clinicopathologic features of the round tumors based on present study and literature

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Among the clinical symptoms, the headache was the most common presentation (>80%) followed by vomiting (40%), visual disturbances (30%), and cranial nerve related symptoms (30%). Few patients presented with seizures (13%) and other location specific clinical features (Nasal discharge, tinnitus, ear pain, vertigo, swaying, neck pain, weakness). The duration of symptoms at presentation ranged from 8 days to 180 days (mean 2.5 months).

Imaging helped in recognizing the location, extent and involvement of bone (especially CT). However, the radiopathologic discordance was high (60%). This is because the family of SRCT neoplasms included a wide group of neoplastic categories and lacked any specific imaging clues indicative of a specific neoplastic type/subtype. Some of the neoplasms appeared as inflammatory collections on imaging. Most of these neoplasms appeared relatively hyperdense on CT and enhanced well in contrast. MRI wise they appeared to be isodense on T1 and iso to hyperdense on T2 with majority exhibiting good contrast enhancement that was relatively homogeneous and most of the lesions showed white matter edema. Some of the neoplasms especially poorly differentiated carcinomas and melanomas looked iso to hyperdense on CT and MRI showed iso or hyperintensity on T1 images and iso to hypointense on T2 images with contrast enhancement.

A small percentage of tumors may still remain unclassifiable (2.4% in our study) which would need additional studies including molecular genetics. The percentage of these unclassifiable neoplasms on IHC varied across various studies (1.7%–12.5%), depending on the complexity of cases, tumor differentiation, tissue related and technical factors.[9],[11],[12],[13],[17],[20]

IHC plays a major role in modern surgical pathology and is a useful tool to recognize the cell antigen which will guide in identifying and classifying a particular cell/tissue lineage. IHC directed by LM analysis is highly essential for classification/subtyping of SRCTs. Not all centres can afford molecular studies, so we believe that a systematic analysis (algorithmic approach) using a select panel of IHC markers would be of great aid in the diagnostic workup. [Figure 8] shows one such algorithm using a basic panel of IHC markers that can be applied in a resource poor setting. A thorough morphological analysis in correlation with the clinical and radiological findings is fundamental in formulating the differential diagnosis and selection of appropriate IHC markers and their interpretation.[22]
Figure 8: Algorithm for the basic approach on small round cell tumors using IHC

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In conclusion, a wide variety of round cell tumors of different histogenesis occur in the cranium and pose a complex diagnostic challenge with overlapping clinical, radiological, and histopathologic features. Accurate diagnosis of these SRCT necessitates knowledge of clinical, radiological, histomorphological, and immunohistochemical profile. This study is an attempt toward that information and indicates the need for a systematic/multidisciplinary approach in the diagnosis and management. Though IHC is highly essential for these tumors, light microscopic analysis still remains fundamental based on which additional tests can be planned, selected, and applied. The present study provides an algorithm which may be of good assistance in the pathological evaluation of these mystic neoplasms.

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There are no conflicts of interest.

 » References Top

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Ashraf MJ, Beigomi L, Azarpira N, Geramizadeh B, Khademi B, Hakimzadeh A, et al. The small round blue cell tumors of the sinonasal area: Histological and immunohistochemical findings. Iran Red Crescent Med J 2013;15:455-61.  Back to cited text no. 15
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

  [Table 1], [Table 2]


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