A Nose Bleed Reveals Rhabdomyosarcoma’s Seed

Abstract

Embryonal rhabdomyosarcoma is the malignant mesenchymal proliferation of undifferentiated skeletal muscle. It is the most common soft tissue tumour found in children. Head and neck location accounts for 40% of the cases with the most common variants being of embryonal Nasopharyngeal RMS is a type of parameningeal RMS (arising from tissues adjacent to the meninges) having propensity for CNS and known for having a poorer prognosis, early recurrence, rapid growth and invasion to adjacent structures. Other types of RMS include orbital and non-orbital/non-parameningeal.

Here, we encountered a rare case of a 5 year old boy presenting with complaints of epistaxis. On anterior rhinoscopy of the nose, no apparent mass could be visualised. However, on oral examination, a right sided oropharyngeal bulge was noted. Clinical evidence was corroborated radiologically with MRI neck findings which suggested a hyperintense lesion with heterogeneous enhancement in the region of right side of nasopharynx extending laterally into parapharyngeal region and carotid space, encasing the right internal carotid artery with narrowing of nasopharyngeal airway. Hence, biopsy was taken from the nasopharynx and a diagnosis of embryonal rhabdomyosarcoma - botryoid type was made which was confirmed with IHC markers.

Introduction

Embryonal rhabdomyosarcoma is the malignant mesenchymal proliferation of undifferentiated skeletal muscle. It is the most common soft tissue sarcoma found in paediatric age group. Head and neck location accounts for 40% of the cases with the most common variants being of embryonal and alveolar histology [1]. Most common site of presentation in head and neck location is orbit, followed by nasopharynx (10–15%) [2]. Not much is known about the etiology, however recent studies have suggested environmental exposure and germline genetic mutations to be important factors contributing to its malignancy [3]. Based on location, head and neck RMS can be orbital, parameningeal or non-orbital/non-parameningeal. Based on histology, as per WHO (2020 classification), there are four subtypes - embryonal, alveolar, pleomorphic and spindle cell/sclerosing. It does not separate the botryoid subtype [4]. According to the International Classification of Rhabdomyosarcoma, it is classified as superior risk group (botryoid type and spindle cell type), intermediate risk group (embryonal type) and unfavourable risk group (alveolar type) [5]. At chromosomal level, translocations between PAX3 or PAX7 and FOXO1 genes result in fusion genes which is now a strong prognostic factor for risk stratification and is hence included in treatment protocols [3]. Multiple case reports have shown that head and neck RMS usually present with non-specific ENT symptoms like, foreign body sensation in nose, nose block, nasal discharge, mouth breathing, snoring, throat pain, symptoms of OSA, disturbed sleep, upper airway obstruction [6] and a variety of other common ENT symptoms which can easily be misdiagnosed and hence a critical diagnosis is delayed.

Case Report

A five year old boy presented to ENT OPD with complaints of epistaxis as informed by the father. This was the third episode that he had 1 week back. The first two episodes being 2 years and 4 months back respectively. Each episode was preceded by a high grade fever and extreme weakness following which the child had nose bleed from the right nostril. The bleed was scanty in quantity, could be easily wiped off with a tissue, containing fresh blood and no clots, lasting less than 5 s. The parents gave a positive history of nose picking by the child and there was no history of trauma to the nose specifically or face. No specific triggering factors could be identified by the parents. The child had no complaints of nasal block or nasal discharge. No history of mouth breathing or snoring was given by the parents. There was no history of usage of topical corticosteroids. Parents gave no history suggestive of allergy, atopy or recurrent URTI. There was no history of disturbance of smell. However, parents were concerned about the decreasing appetite of the child and apathy to even junk food which led to significant malaise and failure to gain weight as appropriate for his age, weighing just 12.5 kg at the age of 5. For the past one week, his parents also started noticing a significant change in the child’s voice. No other complaints could be elicited from the parents.

A detailed family history was taken and history of bleeding dyscrasias and history of malignancies in the family were ruled out. The child is the second born out of a non-consanguineous family. Mother had no exposure to radiation during the antenatal period. Birth history and postnatal period were uneventful. Child has been immunised appropriately for his age. Patient was taken to a local hospital by the parents for the above mentioned complaints where he was admitted and evaluated for the same and an MRI neck with contrast was done which suggested a 4.8 × 4.8 × 3.7 cm hyperintense lesion with heterogeneous enhancement in the region of right side of nasopharynx extending laterally into parapharyngeal region and carotid space, encasing the right internal carotid artery with narrowing of nasopharyngeal airway (as visualised in Fig. 1), considering the possibility of nasopharyngeal angiofibroma. HPE correlation was advised for which the patient was referred out.

Fig. 1.

MRI images showing the lesion in the nasopharynx, extending into the Infratemporal fossa, Pterygopalatine fossa and parapharyngeal space

Upon presentation at our tertiary medical centre, the above history was taken and the following examination findings were noted - on anterior rhinoscopy, no apparent mass could be visualised. On oral cavity and oropharyngeal examination, a bulge was noted in the soft palate as well as the right tonsillar fossa and right lateral pharyngeal wall (Fig. 2A). A direct nasal endoscopy was done which showed a reddish mass in the right nasal cavity and nasopharynx (Fig. 2B). Interventional radiology reference was given and advice sought in view of need for embolisation and to review the outside MRI films and give his expert opinion on the same. Opinion suggested the presence of solid components in the lesion giving a sarcoma like appearance. Hence, based on the MRI reports and the clinical findings, the patient was planned and taken up for nasopharyngeal biopsy under general anaesthesia after anaesthesia and paediatrics fitness. Intraoperative and postoperative periods were uneventful. Intraoperative findings showed a reddish mass in the right nasal cavity and nasopharynx from which biopsy was taken and sent for HPE. Microscopic examination revealed nasal mucosa lined by respiratory epithelium and underlying proliferation of tumor cells with subepithelial accentuation (cambium layer) as seen in Fig. 3A. The tumor cells were predominantly round to oval with high N: C ratio, hyperchromatic nuclei and scanty cytoplasm arranged in sheets. Foci of spindled tumor cells embedded in myxoid stroma were noted (Fig. 3B and C). Initial differential diagnoses included small round blue cell tumour and embryonal RMS which were distinguished using IHC markers. The following IHC markers were found to be strongly positive - Desmin and CD56 while patchy positivity was seen for CD99 and WT-1 (Fig. 3D and F). Cyclin D1 and Synaptophysin were found to be negative (Fig. 3E). The above histopathological and immunohistochemical features were compatible with the diagnosis of Embryonal Rhabdomyosarcoma- Botryoid variant. Further IHC evaluation with Myogenin/MyoD1 was recommended for confirmation, however not done. Reference to paediatric haemato-oncology was given with the above histopathological report for further plan of management and were advised to undergo a PET CT scan to know the spread of the disease, cerebrospinal fluid analysis and a bone marrow aspiration biopsy. PET CT (as illustrated in Figs. 4 and 5) showed a mildly heterogeneous soft tissue mass lesion 5.8 × 3.5 × 4.6 cm involving the right nasopharyngeal wall, anteriorly eroding the right medial pterygoid plate and mildly displacing the right lateral pterygoid plate with loss of flat planes of pterygoid process, reaching up to posterior choana, completely obstructing on the right side and partially obstructing the left side causing resultant fullness in right nasal cavity and right maxillary sinus. Medially, it was noted as an exophytic and lobulated growth into the nasopharyngeal cavity with evidence of mild narrowing of lumen and posteriorly, abutting the vertebrae but without any bony infiltration. Right laterally, it was extending into the right carotid space, displacing and encasing the right carotid artery, right IJV could not be visualised separately with displacement of right lateral pterygoid muscle. Superiorly, loss of fat planes was noted with the base of skull but no intracranial extension seen, however, involvement of adenoid region noted crossing the midline. Bilateral tonsillar enlargement also noted with multiple bilateral cervical level II, level III, level VI B lymph nodes, likely metastasis. Multiple bone marrow lesions noted involving manubrium, multiple cervical and dorsolumbar vertebrae, sacrum, multiple bilateral pelvic bones and bilateral femurs - highly suggestive of metastasis. A single tiny ground glass nodule noted in the right lung lower lobe lateral segment but too small to be characterised. As per the pathology, the patient was categorised under the Very High Risk group - subgroup II - with nodes positive. Patient was planned for chemoport insertion, bone marrow aspiration biopsy and CSF analysis after anaesthesia clearance and started on neoadjuvant chemotherapy as per EpSSG protocol IVADo regimen which constitutes of 4 cycles of Ifosfamide, Vincristine, Actinomycin D and Doxorubicin (with constant watch for pancytopenia and any relevant organ dysfunction) over 12 weeks with an interval of 3 weeks between the courses after which plan is to re-evaluate the patient in view of the possibility of a debulking surgery and going forward, to resume chemotherapy with or without radiotherapy based on the prior response and resolution. As suggested by the paediatric oncologist, the prognosis is dismal given the occurrence of bony metastasis.

Fig. 2.

(A) Intraoral picture visualising the bulge in the right side of oropharynx (B) Mass visualised in the right nasal cavity and nasopharynx during doing Diagnostic Nasal Endoscopy

Fig. 3.

(A, B, C, D, E, F) – Microscopic images of the biopsied tissue showing low power view of nasal mucosa with tumor cells forming Cambium layer (subepithelial hypercellularity), sheets of dyscohesive small round blue cells with high N: C ratio, hyperchromatic nuclei and scant cytoplasm and tumor cells showing diffuse positivity for Desmin (D), and CD56 (F) and negativity for Synaptophysin (E)

Fig. 4.

PET CT images showing the lesion involving the right nasopharyngeal wall, eroding the right medial pterygoid plate and displacing the right lateral pterygoid plate, reaching up to posterior choana, occluding the right nasal cavity and right maxillary sinus completely. Medially growing into the nasopharyngeal cavity with narrowing of lumen and posteriorly, abutting the vertebrae without any bony infiltration. Right laterally, it was extending into the right carotid space, displacing and encasing the right carotid artery, right IJV could not be visualised separately with displacement of right lateral pterygoid muscle. Superiorly, loss of fat planes was noted with the base of skull

Fig. 5.

PET CT images showing the lesion involving the right nasopharyngeal wall, eroding the right medial pterygoid plate and displacing the right lateral pterygoid plate, reaching up to posterior choana, occluding the right nasal cavity and right maxillary sinus completely. Medially growing into the nasopharyngeal cavity with narrowing of lumen and posteriorly, abutting the vertebrae without any bony infiltration. Right laterally, it was extending into the right carotid space, displacing and encasing the right carotid artery, right IJV could not be visualised separately with displacement of right lateral pterygoid muscle. Superiorly, loss of fat planes was noted with the base of skull

Discussion

Nasopharyngeal RMS account for an incidence of 4.4–4.5 per 1 million children and is the most common paediatric soft tissue sarcoma with parameningeal RMS variant carrying a poorer prognosis due to its risk for skull base and intracranial extension [7]. Among the few cases that have presented around the world, here we have a brief discussion about their clinical presentation, diagnosis and management to get a holistic approach to such cases.

In July 2019, a 9 month old boy presented with a slow growing mass over the right dorsum of nose which initially appeared like a nasal dermoid or neuroglial heterotopia. MRI revealed a right para midline extranasal mass attached to a fibrous stalk extending intracranially through the foramen cecum which was removed surgically without any intraoperative or postoperative complications. Post surgery histopathology and IHC correlation revealed the tumour to be an embryological RMS following which oncology workup was done including whole body PET/CT, bone marrow aspiration and biopsy, lumbar puncture and CT with contrast. Considering the extremely young age of the patient with a developing brain, only surgical resection and intensified chemotherapy was given to the patient. Patient was doing well at his 11 month follow up post chemotherapy conclusion [7].

Similarly, a case report from 2021 shows how an embryonal RMS presented as a blocked nose in a 7 year old boy and was initially treated as adenoiditis with steroids and antibiotics until the child later ended up in stridor and drooling in supine position following which a thorough workup was done and the CT revealed a right sided nasopharyngeal mass extending into the parapharyngeal space, skull base and soft palate with mass effect on nearby structures. Initial differential diagnoses included nasopharyngeal carcinoma, dermoid cyst and rhabdomyosarcoma which was confirmed by biopsy followed by histopathological examination and immunohistochemistry. Due to the extent of the tumour, surgical resection of tumour was deferred and the patient was started on vincristine and dactinomycin. Patient was on the road to recovery at his one year follow up [8].

Another literature from 2015 shows a similar presentation of a 4 year old boy with sinus and nasal congestion. On examination, an enlarged right tonsil was noted with anterior cervical lymphadenopathy. However there were no other complaints and total leukocyte counts were within normal limits. Initial trial of an antibiotic course was given however there was no resolution which prompted further investigations and CT was done which revealed a soft tissue enhancement in posterior pharynx and right peritonsillar area without any focal collection of fluid. Hence, biopsy was taken and revealed to be alveolar RMS. MRI showed extent from skull base to epiglottis. Patient was started on chemoradiotherapy and post 5 years has no evidence of recurrence [9].

All patients diagnosed with RMS are assumed to have distant metastatic spread by the time of diagnosis and require a multifaceted approach including chemotherapy, radiotherapy and surgery. Considering the extremely niche location of the head and neck spaces of RMS, a debulking surgical approach is not always an option and in those cases, only chemoradiotherapy can be proceeded with.

Currently, surgery stands as the foremost treatment of choice for RMS patients with the aim of radical resection of tumour with suitable margins which is preceded/followed by chemo/radiotherapy. In cases where surgery is not feasible due to the extent of spread, radical radiotherapy is considered as the next modality. Radiotherapy is recommended for all patients and the number of cycles is determined specifically for patient to patient. If the tumour involves the base of skull or cranial nerves, RT can be started only in the 12th week of treatment, provided that it follows a promptly initiated chemotherapy. In patients without metastases, neoadjuvant and adjuvant chemotherapy together have helped in the achievement of 60–90% 5 year survival rate. Some common paediatric chemotherapy agents used are a combination of ifosfamide, vincristine, actinomycin D, doxorubicin and dacarbazine [10]. Post CTRT complications of head and neck paediatric RMS include pituitary dysfunction, hypo/hyperthyroidism, hearing impairment and change in dental and craniofacial structure [11].

Hence, it is suggested that after the completion of the treatment course, patients should be under observation and regular follow up by physical examination and imaging (CT/MRI), also to watch out for recurrence or residual disease.

Conclusion

The above case reports go on to show that the presentation of nasopharyngeal rhabdomyosarcoma can be extremely varied and non-specific. No particular symptom can prompt a clinical practitioner to consider malignancy as the primary diagnosis. However, unilaterality (of symptoms and examination findings) and failure of resolution of symptoms after multiple courses of antibiotics may hint on a potential malignant cause and can be considered a differential diagnosis to investigate and rule out or to diagnose and start early management of this disease.

Funding

This study did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Declarations

Ethics Approval

This study has been carried out in compliance with the ethical standards after obtaining Institutional Ethics Committee Approval (Manipal Academy of higher Education- Kasturba Medical College, Mangalore).

Informed Consent

I hereby give my consent for images or other clinical information relating to my case to be reported in a medical publication. I understand that my name and initials will not be published and that efforts will be made to conceal my identity, but that anonymity cannot be guaranteed. I understand that the material may be published in a journal, web site or other form of publication. As a result, I understand the material may be seen by the general public. I understand that the material may be included in medical books.

Conflict of Interest

Nil.