Alveolar rhabdomyosarcoma metastatic to the brain

Abstract

Alveolar rhabdomyosarcoma (ARMS) has a predilection for the peripheral extremities, and brain metastases are rare, with only a few cases reported after the initial diagnosis. We present a 22-year-old male patient with a right orbital-ethmoidal ARMS who presented with a recurrence to the brain 1 year after the initial diagnosis. He was referred to our institution due to acute neurological deterioration. A brain MRI was performed, showing an enhancing bilateral parafalcine lesion centred about the bilateral cingulate gyri with extension into the corpus callosum. The patient was taken to the operating room for a stereotactic biopsy under general anaesthesia, which was compatible with metastatic ARMS. Our case is exceedingly rare, considering the initial diagnosis of an orbital/ethmoidal ARMS, its subsequent metastasis to the brain and its clinical sequelae after a biopsy. Prognosis after cerebral metastatic ARMS is dismal, with most patients expiring due to central nervous system metastatic disease.

Background

Rhabdomyosarcoma (RMS) is a highly malignant neoplasm of skeletal muscle first described by Weber in 1854.¹ RMS can be divided into three histological types: embryonal, alveolar and pleomorphic, with a rare sclerotic variant and an aggressive botryoid rare variant.^{1 2} Embryonal is the most common type, with 60% of cases, and alveolar the second most common with 20% of cases.² RMS can be associated with hereditary syndromes such as neurofibromatosis type 1, Noonan, Li-Fraumeni, Beckwith-Wiedemann and Costello.²

RMS has a male to female predominance of 1.3:1. It most commonly affects the head and neck region, genitourinary tract and the extremities. Most of these tumours occur in the first decade of life. Only 10% of RMS occurs at the orbit.³ Less than 25% of RMS cases have distant metastases at the time of diagnosis, typically to lung, bone, bone marrow, omentum and pleura. Alveolar rhabdomyosarcoma (ARMS) has a predilection for the peripheral extremities.³ ARMS metastases to the orbit are extremely rare and occur through haematogenous spread.^{4 5} Brain metastases are rare for ARMS, with only a few cases reported after the initial diagnosis.^6–10 We present a patient with a right orbital-ethmoidal ARMS with extension to the nasal cavity that presented with a recurrence to the brain 1 year after the initial diagnosis.

Case presentation

A 22-year-old male patient, diagnosed 15 months prior with a right orbital-ethmoidal ARMS, was referred to our institution due to acute neurological deterioration. Before the first intervention, the initial brain MRI showed an enhancing lesion centred in the right ethmoidal air cells with extension into the right nasal cavity and medial extraconal, conal and intraconal orbit (figure 1). There was no radiological evidence of parenchymal or leptomeningeal involvement. At that time, he was treated with surgery, chemotherapy and radiotherapy. He had an uneventful course for the following 15 months.

Figure 1.

Initial sinonasal tumour with orbital extension at first diagnosis. Brain MRI shows an enhancing lesion demonstrating restricted diffusion centred at the right ethmoid air cells with extension into the right nasal cavity and right medial orbit (medial extraconal, conal and intraconal compartments). (A) T2-weighted coronal image, (B) T1-weighted axial image, (C) T1-weighted post-contrast axial image, (D) diffusion-weighted imaging sequence and (E) apparent diffusion coefficient image.

The day before our second and current intervention evaluation, he developed multiple episodes of tonic-clonic seizures. The physical examination revealed an intubated acutely ill patient with a Glasgow Coma Scale (GCS) of 7. Pupils were equal and reactive to light, eyes open to painful stimuli and withdrawal from pain from all four extremities. The patient was admitted to the neurosurgery intensive care unit. Further history from the parents revealed chronic headaches and lower extremity weakness for the last month.

Investigations

Head CT scan performed at an outside hospital demonstrated bilateral intracranial parafalcine lesion with no recurrent sinonasal/orbital tumour. A brain MRI was performed, showing a bilateral parafalcine lesion with an enhancing meningeal component as well as juxtacortical involvement extending to the bilateral cingulate gyri and corpus callosum, which demonstrates restricted diffusion with no corresponding contrast enhancement (figure 2).

Figure 2.

Intracranial metastasis. Brain MRI shows a bilateral parafalcine lesion with an enhancing meningeal component as well as juxtacortical involvement extending to the bilateral cingulate gyri and corpus callosum, which demonstrates restricted diffusion with no corresponding contrast enhancement. (A) T1-weighted post-contrast axial image, (B) T1-weighted post-contrast sagittal image, (C) T1-weighted post-contrast coronal image, (D) diffusion-weighted imaging sequence and (E) apparent diffusion coefficient image.

Treatment

The patient was taken to the operating room for a right frontal burr hole approach stereotactic biopsy under general anaesthesia. There were no intraoperative complications. After the biopsy, the neurological examination showed a GCS of 3 without brainstem reflexes except for some respiratory effort. An immediate post-biopsy non-enhanced axial head CT shows a small amount of right frontal parafalcine pneumocephalus related to the biopsy tract (figure 3). It showed diffuse cerebral oedema with cerebral herniation and no haematoma or hydrocephalus. He was returned to the neurosurgical intensive care unit for antioedema and supportive measures. Electroencephalography, the next day, confirmed the diagnosis of brain death.

Figure 3.

Immediate post-biopsy head CT scan. Non-enhanced head CT scan in the axial plane shows a small amount of right frontal parafalcine pneumocephalus related to the biopsy tract.

Outcome and follow-up

Histopathological examination of brain samples showed a nesting pattern of discohesive undifferentiated RMS cells separated by a thin fibrovascular septa, with brain tissue background (figure 4). Immunohistochemistry studies performed for desmin had strong nuclei immunopositivity of tumour cells, myogenin had diffuse nuclei immunopositivity of tumour cells, and actin was focally positive in tumour cells. Synaptophysin, chromogranin, CK-pankeratin, ALK1, napsin A and TTF1 were negative in tumour cells. The Ki67 was positive for 50% of tumour cells. Examination was consistent with an ARMS recurrence, with brain infiltration.

Figure 4.

(A) H&E stain (×10) showing groups of discohesive cells, separated by a thin fibrovascular septa with brain tissue background. (B) Desmin (×20) showing a strong nuclear immunopositivity of tumour cells. (C) Myogenin (×20) showing diffuse nuclear positivity. (D) CK-pankeratin (×10) showing strong immunopositivity of some glial cells, but negative in tumour cells.

Discussion

RMS is a highly malignant tumour. Over the past 30 years, head and neck RMS incidence has been increasing approximately 1.16% per year; however, the 5-year survival has not statistically changed.³ Due to its life-threatening nature, rapid diagnosis and treatment is essential. Early diagnosis can pose a challenge. Several patients present with metastases on initial diagnosis, and those with two or fewer metastatic sites and embryonal histology have a better prognosis.¹¹

Metastases of orbital RMS are usually by haematogenous spread due to scarce lymphatics.^{4 5 12} Lung, bone and bone marrow are the most common locations. An orbital RMS can present with pain, visual loss and signs of sinusitis.¹² There are few cases reported in the literature where RMS presents with cranial recurrency. The first symptom in our patient that indicated the possibility of recurrence was headaches, followed by weakness and acute neurological deterioration. On head CT scan, RMS appears isodense to muscle, homogeneous and well circumscribed. RMS is typically T1-weighted isointense to muscle and T2-weighted hyperintense with evidence of restricted diffusion on brain MRI.

Our case is exceedingly rare, considering the initial diagnosis of an orbital ARMS, its subsequent metastasis to the brain and its clinical sequelae after a biopsy. The final pathological diagnosis was positive for ARMS recurrence. A genetic study in our patient was not performed. Approximately 80% of ARMS present two different chromosomal translocations.^13–15 The most common one is translocation t(2;13)(q35;q14), which fuses the PAX3 gene located on chromosome 2 (regulate transcription during early neuromuscular development) with the FKHR gene located on chromosome 13 (a member of the forkhead family of transcription factors). The less frequent translocation is t(1;13)(p36;q14), which fuses with the PAX7 gene located on chromosome 1 with FKHR. Patients with tumours expressing the PAX7-FKHR fusion are younger, with lesions frequently of the extremities, suggesting a distinct clinical phenotype associated with more prolonged event-free survival and a better prognosis.^{1 2} These translocations generate novel transcription factors that stimulate proliferation, induce angiogenesis and inhibit apoptosis.

Orbital RMS recurrence occurs in 17% of cases, with 8% of these to distant sites.¹² While embryonal and alveolar RMS has a 5-year survival of 94% and 74%, respectively, the overall survival of metastatic RMS is less than 5%.¹² The ARMS tends to produce early metastases via the bloodstream and lymphatics with common locations in the lymph nodes, lung, pleura, pancreas, bone, heart, adrenals, testes, liver, kidney and spleen; however, brain metastases are extremely rare. To our knowledge, our case is the 10th case of ARMS that later presented with a parenchymal brain metastasis. In the first case reported, the autopsy showed a brain metastasis from a forearm ARMS diagnosed 4 years prior.⁶ Four cases were reported by the group in St. Jude Hospital arising from primary tumours in the pterygoid fossa, chest wall, gluteus and pelvis diagnosed between 6 and 55 months prior.⁷ Two of those cases were in stage/clinical group IV (metastatic disease at diagnosis/initial presentation) with bone marrow metastases. In the sixth case reported, the patient died 1 day after undergoing a brain biopsy from an original haematogenous/lymphatic ARMS diagnosed 16 months prior.⁸ A seventh case was reported in a patient with a shoulder ARMS that approximately 4 months later (5 cycles of chemotherapy) was found with a pituitary metastasis.⁹ This patient was stage IV with lung and bone metastases at the time of the original diagnosis. A large RMS series from the Memorial Sloan Kettering Cancer Center reported two cases with brain parenchymal metastasis without leptomeningeal involvement from a primary tumour in the buttock diagnosed 12 months prior in one case, and the paraspinal area diagnosed 21 months prior in the other case who was stage IV.¹⁰ The same centre reported 14 patients with ARMS with leptomeningeal metastases, 6 of them with a combination of leptomeningeal and parenchymal metastases. From the previous nine reported cases, five of them who were in stage IV could have had brain metastasis during the initial diagnosis but could have been missed as no brain studies were performed given the absence of neurological symptoms. Table 1 summarises all previously published cases. Our case is the first case of an orbital/paranasal sinus ARMS, who later developed metastasis to the brain. We do not clearly explain the patient’s sudden deterioration as there was no haemorrhage at the biopsy site. However, the patient could have had seizures during the procedure as he was under anaesthesia, and this may have produced increased intracranial pressure with subsequent herniation. The sudden death of our patient after a brain biopsy may caution other surgeons about this unfortunate outcome. Patiroglu et al reported a similar biopsy outcome in his patient.⁸ Occasional reports of primary brain and cerebellum RMS had been described.^16–24 However, only four primary brain parenchymal ARMS had been reported in the literature.^25–28

Table 1.

Published ARMS cases which later presented with parenchymal brain metastasis

Authors	Year	Sex	Age	Primary site	Initial Mets	Brain Mets	Time to brain Mets	Group	Initial Tx	Brain Tx	Outcome
Kleinert et al6	1985	F	10 years	Forearm	LN	Frontal	48 months	IV	S, C, R	None	Dead
Parasuraman et al7	1999	F	18 years	Gluteus	BM	Frontal	12 months (median)	IV	C	R, C	Dead (28 days)
Parasuraman et al7	1999	F	6 years	Pelvis	LN, BM	Parietal	12 months (median)	IV	C	C	Dead (21 days)
Parasuraman et al7	1999	F	10 years	Pterygoid fossa	None	Brain	12 months (median)	III	C, R	Steroid	Dead (10 days)
Parasuraman et al7	1999	F	14 years	Chest wall	Ribs	Parietal	12 months (median)	IV	B, C, R	S, C, R	Dead (15 months)
Patiroglu et al8	2014	M	14 years	LN	Multiple LN	Brain	16 months	IV	C	B	Dead (1 day)
Ismail et al9	2014	M	17 years	Shoulder	Lung, bone	Pituitary	4 months	IV	C	B, R, C	Dead (2 months)
De et al10	2018	M	1 year	Buttock	None	Bbrain	12 months	III	C	R	Dead (11 months)
De et al10	2018	F	4 years	Paraspinal	Yes (n/s)	Brain	21 months	IV	C	B, R, C	Dead (50 months)
Rodriguez et al (current)	2021	M	21 years	Orbital ethmoidal	None	Cingulate gyrus/CC	15 months	III	S, C, R	B	Dead (1 day)

Intergroup Rhabdomyosarcoma Group classification (IV—metastatic disease at diagnosis, III—gross residual tumour after biopsy or surgery).

B, biopsy; BM, bone marrow; C, chemotherapy; CC, corpus callosum; LN, lymph node; Mets, metastasis; NS, not specified; R, radiotherapy; S, surgery; Tx, treatment.

The combination of vincristine, adriamycin and cyclophosphamide is the accepted standard of care for metastatic ARMS.³ Radiotherapy had also been given in some cases. However, the literature is lacking randomised clinical trials that delineate the best combination modality. Prompt and aggressive chemotherapy carries the best prognosis. For brain metastasis, directed radiotherapy and/or whole-brain radiotherapy is the principal treatment modality.¹⁰ Chemotherapy is occasionally added. The central nervous system involvement of RMS carries a negative prognostic factor but is better in those patients where it is found at the time of diagnosis.²⁹ The median survival after a leptomeningeal or parenchymal brain relapse is 5 months.¹⁰ Prognosis after cerebral metastatic ARMS is dismal, with most patients expiring due to central nervous system metastatic disease.¹⁰ It is essential to recognise the signs and symptoms of ARMS recurrence. The literature on managing these patients is limited due to the low quantity of reported cases and can prove challenging.

Learning points.

• Orbital/ethmoid alveolar rhabdomyosarcoma (ARMS) brain metastasis is a rare event.

• Late brain metastases from ARMS is a rare event.

• Prognosis for ARMS with brain metastasis is dismal.

• Due to limited reported cases in the literature, there is much to understand about this tumour’s behaviour and management.

• Our case will add some understanding of this disease and the critical management of brain metastasis.