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 Table of Contents  
CASE REPORT
Year : 2022  |  Volume : 14  |  Issue : 1  |  Page : 35-39

Primitive neuroectodermal tumor of maxilla in a 4-year-old child: A rare case report with update on molecular pathogenesis


1 Department of Oral & Maxillofacial Surgery, School of Dental Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
2 Department of Oral Pathology and Microbiology, School of Dental Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
3 Pedodontist, Cosmozone Dental and Implant Clinic, Greater Noida, Uttar Pradesh, India

Date of Submission05-Jan-2021
Date of Acceptance05-Apr-2021
Date of Web Publication31-Dec-2021

Correspondence Address:
Mithilesh Narayan Mishra
Department of Oral Pathology and Microbiology, School of Dental Sciences, Sharda University, Knowledge Park III, Gautam Buddha Nagar, Greater Noida - 201 308, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJDS.IJDS_3_21

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  Abstract 


Primitive neuroectodermal tumor (PNET) belongs to the class of malignant round cell tumor. PNETs show varying degree of neuroectodermal differentiation. They are one of the most common tumors of childhood occurring in bone and also within soft tissues. Light microscopy with the aid of immunohistochemical stains was suitable for the diagnosis. Immunohistochemistry plays a pivotal role in differentiating this tumor entity. The EWSR1-FLI1 fusion is present only in PNET cells and codes for oncogenic protein. In this article, we present a case of maxillary swelling in a 4-year-old girl child who was diagnosed with PNET. We have highlighted the challenges of diagnosing the round cell tumors.

Keywords: Maxilla, nuclear specific enolase, pediatric oncology, primitive neuroectodermal tumor, S-100


How to cite this article:
Patil P, Mishra MN, Chandavarkar V, Patil SP. Primitive neuroectodermal tumor of maxilla in a 4-year-old child: A rare case report with update on molecular pathogenesis. Indian J Dent Sci 2022;14:35-9

How to cite this URL:
Patil P, Mishra MN, Chandavarkar V, Patil SP. Primitive neuroectodermal tumor of maxilla in a 4-year-old child: A rare case report with update on molecular pathogenesis. Indian J Dent Sci [serial online] 2022 [cited 2022 Jan 24];14:35-9. Available from: http://www.ijds.in/text.asp?2022/14/1/35/334523




  Introduction Top


The head-and-neck region exhibits a variety of pediatric tumors varying from simple odontomas to aggressive lymphomas. Etiologies resulting in such lesions may be inflammatory in nature, congenital, benign neoplastic, and malignant in nature. General oral health care professionals and pedodontists are the first to observe such growths. It is imperative that oral health care providers be able to distinguish between normal tissue and lesioned tissue that are manifestations of potentially life-threatening conditions; so that early and prompt referral for appropriate treatment is initiated. The head-and-neck region has a complex anatomy, raising serious concerns for malignancy either because of compression or erosion of adjacent vital structures or due to extreme symptoms such as facial swelling, proptosis, loss of vision, and blockage of the nasal passage.


  Case Report Top


A 4-year-old girl presented with a complaint of a rapidly growing mass in the left side of her upper jaw in the past 3 months. The child belonged to a lower socioeconomic group. There was no history of anorexia, loss of weight, chronic cough, tooth extraction, trauma to the jaws, or bleeding from the oral cavity. On examination, the child was active and playful. Diffuse swelling was noted extra orally on the left cheek region extending from infraorbital margin superiorly till a line drawn horizontally from the corner of the mouth to the ear lobe and from corner of mouth anteriorly to 2 cm in front of the tragus of the ear [Figure 1]. The skin over the swelling was apparently normal; however, anesthesia over the region supplied by the infraorbital nerve was detected. Intraorally, a diffuse, nontender growth was noted measuring 6 cm × 4 cm extending anteroposteriorly from deciduous canine to the maxillary tuberosity. Lesion was extending bucco-palatally and mucosa over the swelling appeared erythematous without any ulceration. The mucosa on the palatal aspect of the lesion was firm in consistency with focal areas of softness [Figure 2]. Left submandibular lymph nodes were palpable, firm, tender, and not fixed. Cervical, axillary, and femoral groups of lymph nodes were not palpable.
Figure 1: Extraoral view of the growth

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Figure 2: Intraoral view of the growth

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A contrast-enhanced computed tomography (CT) scan of the maxilla was obtained which revealed an ill-defined soft-tissue density mass involving the left maxillary sinus approximately measuring 6 cm × 4.2 cm × 4 cm [Figure 3]. The mass exhibited uniform enhancement of contrast media. The lesion had caused bony expansion of the maxillary sinus with erosion of the medial and anterior walls. The mass extended supero-medially into the left orbit and ethmoidal cells, medially into the left nasal cavity, and inferiorly into the body of the maxilla and superior alveolar rim on the left side [Figure 4]. The blood parameters were normal except mild neutrophilia. The systemic evaluation did not report any abnormality.
Figure 3: Computed tomography scan frontal view showing tumor extension

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Figure 4: Computed tomography scan axial view showing the tumor extension

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A provisional diagnosis of juvenile aggressive central giant cell granuloma was made based on the clinical presentation of a rapidly progressing lesion.

Differential diagnosis

The important clinical features in our case are the central location, expansion, and resorptive characteristics of the growth. These features raise suspicion about the growth being inflammatory, congenital, and neoplastic in nature. The painless nature and infraorbital nerve anesthesia are most consistent with a malignant neoplastic process.

Fibrous dysplasia of the maxilla is usually observed in the first three decades of life. It is usually unilateral, commonly found in the posterior maxilla, is painless, and could exhibit proptosis, blindness, or diplopia as consequences of its local spread. However, neurosensory alterations are uncommon and slow growth is its hallmark. The rapid growth and neurosensory disturbance in our case refute the diagnosis of fibrous dysplasia.[1]

Osteosarcoma, the second-most common primary bone malignancy, involves jawbones in only about 5% of cases.[2] Males are more often affected with a mean incidence at 34 years of age. Chondrosarcomas are uncommon tumors arising from cartilage-forming cells. The head-and-neck region accounts for only 5.76% of all the cases of chondrosarcomas. In the head-and-neck region, common sites of involvement are the maxilla, nasal cavity, nasal septum, and mandible. Unlike osteosarcoma, chondrosarcomas usually occur in adulthood, usually in the third to sixth decades of life.[3]

Rhabdomyosarcoma is known to be a malignant neoplasm arising from the skeletal muscle system. The head-and-neck region accounts for 40% of all reported cases. Other known sites of involvement are the genitourinary tract, retroperitoneum, and the extremities. However, the oral cavity represents a very uncommon site of occurrence for this pathology.[4]

Ewing's sarcoma, a primary neoplasm involving the skeletal system, is reported to be the second most common cancer of the bone. Common occurrence is found among Caucasian children,adolescents and young adults. The age of appearance is usually between 5 and 30 years. The mandible is frequently involved as a site of involvement, while the maxilla is a rare site.[5]

Primitive neuroectodermal tumor (PNET) belongs to the Ewing's sarcoma family of tumors and is of neuroectodermal origin. Children and young adults are primarily affected. However, PNETs rarely involve the maxilla. Although it shares a neuroectodermal origin with Ewing's sarcoma, PNET shows more aggressive behavior and metastasizes rapidly.[6],[7]

Diagnosis

The condition was explained to the parent of the child. Written informed consent was obtained from the mother. An incisional biopsy was performed under local anesthesia. Histologically, the tumor was composed of diffuse sheets of small round cells [Figure 5]. Focally, the tumor cells appeared to be forming rosette-like structures. The individual tumor cells had a high nuclear: Cytoplasmic ratio with round-to-oval hyperchromatic nuclei. There was a presence of mitotic activity including atypical mitosis. Areas of focal necrosis were observed [Figure 6]. Immunohistochemistry demonstrated these cells to be diffusely positive for Neuron-specific enolase (NSE) [Figure 7] and focally for S-100 [Figure 8]. Cells were negative for staining with desmin, leukocyte common antigen, chromogranin, and synaptophysin. The histological picture was consistent with PNET. CT of the thorax and abdomen showed no metastasis.
Figure 5: H and E staining (×10) showing sheets of small round cells and focal necrotic areas

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Figure 6: H and E staining (×100) showing round cells with hyperchromatic nuclei and high nuclear: cytoplasmic ratio

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Figure 7: Immunostaining with nuclear-specific enolase

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Figure 8: Immunostaining with S-100 protein

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Management

A treatment plan including chemo-radiotherapy followed by surgical excision was discussed with the parents of the child. The child was referred to a higher pediatric oncology center for further management. Since the child was from the lower socioeconomic strata of the society, an NGO dedicated to cancer took the responsibility for the care.


  Discussion Top


PNETs are considered to be extremely aggressive neoplasms that possess the ability to metastasize widely and rapidly. The pluripotent cells of the neural crest are believed to be the source of PNETs, which are highly malignant, small, and round-cell neoplasms. They belong to Ewing's sarcoma family of tumors (ESFTs) which comprises Ewing's sarcoma, PNET, and Askin's tumor. The first description of PNETs was given by Hart and Earle in 1973. PNET has been reported to occur outside the central nervous system. When it is so located, it is referred to as “peripheral PNET” (pPNET). pPNETs have been identified to occur in many locations of the body, which include the thoracopulmonary and paravertebral regions, pelvis, or extremities.[8]

In ESFTs, most of the cases are associated with translocation t (11; 22) (q24; q12). This fusion of the EWSR1 gene on 22q12 with the FLI1 gene on 11q24 results in a chimeric fusion transcript EWSR1-FLI1. There are two types of translocation sites, i.e. Type 1 (exon 7 of EWS to exon 6 of FLI1) and type 2 (exon 7 of EWS to exon 5 of FLI1). The EWSR1 gene is a part of the TET family of genes. Based on their structure and ability to bind RNA, TET proteins are believed to participate in transcription and RNA processing. The FLI1 gene was spotted as the site of insertion of Friend's murine leukemia virus. FLI1 is expressed in the mesenchymal cells of neural crest origin during embryonal development.[9] The EWSR1-FLI1 chimeric fusion protein is seen only in ESFTs cells and does not exist in any other normal cell of the body. Thus, ESFTs contains a unique protein generated by tumor-specific translocation with a potential for molecular target, but so far nothing has reached the clinics for therapeutic purpose. This could be because EWSR1-FLI1 is a very difficult molecule to be examined directly in vitro due to its poor solubility.

The thoracopulmonary region (46%) is the most commonly involved site for pPNET followed by the head-and-neck (42%) region. Prognosis is generally poor, with survival rates of only 65% for 2 years.[10] This survival rate exists regardless of the type of treatment offered, surgery, radiotherapy, or combined radio-chemotherapy. Primary PNET is a rare occurrence in the maxilla and paranasal sinuses.

The pPNETs generally appear insidiously, assuming large proportions at diagnosis. The most disturbing aspect of these tumors with regard to prognosis is the potential for distant metastases, identified in 20%–25% of newly diagnosed patients, especially those to bone and bone marrow. Lack of availability of immunohistochemistry in the past may have caused the tumor to be under-reported as without such a facility it would be difficult to distinguish pPNET from other round cell tumors.

The current approach to the management of these tumors involves early surgery along with multiple chemotherapies with an aim to treat the residual disease and to prevent metastatic or recurrent disease. Zimmermman et al. had suggested that chemotherapy be utilized as the first-stage treatment with an objective to avoid mutilating surgical procedures and at the same time eliminate chances of intraoperative tumor cell dissemination. The authors recommended that radiotherapy be reserved for those patients in whom surgical excision is not an option due to its position or size and those in whom the tumor has been excised without adequate marginal clearance.

Effective local control of pPNETs requires the establishment of tumor-free surgical margins, keeping in mind its potential for aggressive spread. However, the maxilla being in close proximity to many vital structures does not offer such a scenario. A similar situation was observed in our patient.

NSE is an isoenzyme of the glycolytic enzyme enolase which is neuron cell-specific. It exhibits high specificity for neurons and peripheral neuroendocrine cells. Positive staining for NSE may occur with malignant proliferation and thus can be of value in diagnosis, staging, and treatment of related neuroectodermal tumors.[11] Human cancers commonly exhibit S-100 protein expression in a dysregulated manner. There is an increasing body of evidence to suggest that the biology of most S100 proteins is complex and multifactorial. These proteins have been implicated in active tumor growth and spread by causing cell proliferation, metastasis, angiogenesis, and immune evasion.[12] These two agents together assisted in the differentiation of the tumor type in our patient.


  Conclusion Top


PNET must be considered in the differential diagnosis of small round cell tumors of bone and soft tissue in infants, children, and young adults. The differential diagnosis of small roundcell tumors in the head and neck may include malignant lymphoma, neuroblastoma, leiomyosarcoma, rhabdomyosarcoma, undifferentiated carcinoma, and pPNETEwing sarcoma. Early diagnosis and treatment are vital to improve the survival of young patients, keeping in mind the poor prognosis associated with this type of tumor. Immunohistochemistry plays a vital role in the differentiation of the subtype of small round cell tumors.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Menon S, Venkatswamy S, Ramu V, Banu K, Ehtaih S, Kashyap VM. Craniofacial fibrous dysplasia: Surgery and literature review. Ann Maxillofac Surg 2013;3:66-71.  Back to cited text no. 1
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2.
Prabhusankar K, Karande A, Jerry JJ, Rishal Y. Osteosarcoma of the posterior maxilla. J Int Soc Prev Community Dent 2016;6:S171-4.  Back to cited text no. 2
    
3.
Mahajan AM, Ganvir S, Hazarey V, Mahajan MC. Chondrosarcoma of the maxilla: A case report and review of literature. J Oral Maxillofac Pathol 2013;17:269-73.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
Ananthaneni A, Kuberappa PH, Srinivas GV, Kiresur MA. Alveolar rhabdomyosarcoma of maxilla. J Oral Maxillofac Pathol 2016;20:164.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Jairamdas Nagpal DK, Prabhu PR, Palaskar SJ, Patil S. Ewing's sarcoma of maxilla: A rare case report. J Oral Maxillofac Pathol 2014;18:251-5.  Back to cited text no. 5
    
6.
Rajendran R, Joseph LD, Johnson T, Sneha LM, Scott JX, Srinivasan S. Paediatric peripheral primitive neuroectodermal tumour-A clinico-pathological study from southern India. J Clin Diagn Res 2017;11:C09-12.  Back to cited text no. 6
    
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Ghosh A, Saha S, Pal S, Saha PV, Chattopadhyay S. Peripheral primitive neuroectodermal tumor of head-neck region: Our experience. Indian J Otolaryngol Head Neck Surg 2009;61:235-9.  Back to cited text no. 7
    
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Gao L, Zhu Y, Shi X, Gao Z, Chen X. Peripheral primitive neuroectodermal tumors: A retrospective analysis of 89 cases and literature review. Oncol Lett 2019;18:6885-90.  Back to cited text no. 8
    
9.
Campbell K, Shulman D, Janeway KA, DuBois SG. Comparison of Epidemiology, Clinical Features, and Outcomes of Patients with Reported Ewing Sarcoma and PNET over 40 Years Justifies Current WHO Classification and Treatment Approaches. Sarcoma 2018;2018:1712964.  Back to cited text no. 9
    
10.
Zimmermann T, Blütters-Sawatzki R, Flechsenhar K, Padberg WM. Peripheral primitive neuroectodermal tumor: Challenge for multimodal treatment. World J Surg 2001;25:1367-72.  Back to cited text no. 10
    
11.
Isgrò MA, Bottoni P, Scatena R. Neuron-specific enolase as a biomarker: Biochemical and clinical aspects. Adv Exp Med Biol 2015;867:125-43.  Back to cited text no. 11
    
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Bresnick AR, Weber DJ, Zimmer DB. S100 proteins in cancer. Nat Rev Cancer 2015;15:96-109.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]



 

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