Hit the mark with diffusion-weighted imaging: metastases of rhabdomyosarcoma to the extraocular eye muscles

Background Rhabdomyosarcoma is the most frequent malignant intraorbital tumour in paediatric patients. Differentiation of tumour recurrence or metastases from post-therapeutic signal alteration can be challenging, using standard MR imaging techniques. Diffusion-weighted MRI (DWI) is increasingly considered a helpful supplementary imaging tool for differentiation of orbital masses. Case presentation We report on a 15-year-old female adolescent of Caucasian ethnicity who developed isolated bilateral thickening of extraocular eye muscles about two years after successful multimodal treatment of orbital alveolar rhabdomyosarcoma. Intramuscular restricted diffusion was the first diagnostic indicator suggestive of metastatic disease to the eye muscles. DWI subsequently showed signal changes consistent with tumour progression, complete remission under chemoradiotherapy and tumour recurrence. Conclusions Restricted diffusivity is a strong early indicator of malignancy in orbital tumours. DWI can be the key to correct diagnosis in unusual tumour manifestations and can provide additional diagnostic information beyond standard MRI and PET/CT. Diffusion-weighted MRI is useful for monitoring therapy response and for detecting tumour recurrence.


Background
Rhabdomyosarcoma is the most frequent malignant intraorbital soft tissue tumour in paediatric patients [1]. Primary orbital manifestation is considered to be associated with a relatively good prognosis, while extraorbital extension, the alveolar subtype and orbital relapse are associated with an unfavourable outcome. Classical applications of diffusion-weighted MRI (DWI) include imaging of acute ischaemic insult, cerebral abscess and, more recently, differentiation of tumour entities. Recent studies suggest that DWI holds potential for better differentiation between benign and malignant intraorbital masses [2].

Case presentation
In April 2010, an otherwise healthy 15-year-old girl first presented with acute left-sided protrusio bulbi. MRI revealed an extraconal mass in the left superonasal orbital quadrant with infiltration of the paranasal sinuses and the skull base (Figure 1a). Endonasal biopsy confirmed alveolar rhabdomyosarcoma with PAX3-FKHR-translocation. PET/CT did not show evidence of metastatic spread, and the tumour was staged as T2 N0 M0. Chemotherapy, radiation treatment of the primary tumour and complete tumour resection followed. Five months after completion of treatment, follow-up imaging with PET/CT and MRI detected a solitary bone metastasis in the right femoral neck and two intramammary soft tissue metastases. Tumorous bone marrow infiltration of less than 1% was diagnosed in bone marrow specimen. Multimodal treatment, including chemotherapy, surgical resection of the metastases, local radiation and haploid stem cell therapy achieved complete response.
In early 2012, three months post-therapy, the patient complained about newly occurred double vision. In comparison to numerous preceding MRI studies, a new, though initially very discrete, thickening of the left medial rectus and inferior rectus muscle was observed in the absence of other intraorbital signal alterations (Figure 1b, c). As clinical symptoms aggravated over the ensuing three weeks, we noted progressive bulging of all extraocular left extraocular eye muscles and thickening of the right medial rectus muscle. MRI signal alterations included homogenous T2w signal elevation, increased uptake of contrast media and increasingly restricted diffusivity on follow-up MRI examinations (1.5 Tesla Magnetom Symphony and 3 Tesla Trio, Siemens Medical, Germany, diffusion-weighted single-shot echoplanar SS-EPI imaging with b-values of 0 and 1000 s/mm 2 ; at 1.5 Tesla TR 4600 ms, TE 137 ms, no parallel imaging, at 3 Tesla TR 3300 ms, TE 90 ms, parallel imaging iPAT = 2). Restricted diffusion was indicated by progressively high intralesional signal on DWI at b = 1000 s/mm 2

Conclusions
Rhabdomyosarcoma metastases confined to the extraocular eye muscles constitute a rare clinical entity [3]. In our case, the peculiar intramuscular signal alterations observed in the absence of any other orbital or systemic abnormalities posed a diagnostic problem for standard imaging techniques. As these signal alterations were most pronounced in the medial rectus muscles bilaterally, that is, closest to the primary radiation field, clinical differential diagnosis first considered a sequel of preceding radiotherapy. Furthermore, endocrine orbitopathy and immunoreactions secondary to stem cell transplantation were discussed. SUV (standardised uptake value) quantification on FDG-PET/CT was not found helpful to further clarify the aetiology of muscular swelling, as normal eyes muscles show high physiological FDG uptake and as inflammation could not be ruled out as a cause of increased tracer update in the affected muscles. While findings on standard MRI sequences were initially considered as non-specific, the early finding of restricted diffusion in the affected eye muscles on DWI clearly argued against an inflammatory aetiology (Figure 2 day 20 and 36). According to our own experience with extracranial DWI, inflammatory and oedematous soft tissue lesions present with a relatively stereotypic increase in ADC ranging from 1.4 to 2.6 [4]. ADC values < 1.0 measured in osseous or soft tissue lesions are characteristic of malignant tumours with high cellularity, abscess und some classical findings, such as epidermoid tumours [5]. In the presented case, increasingly high intramuscular signal on DWI at high b-values with corresponding low ADC values was the earliest diagnostic indicator of malignancy.
Some limitations of our study deserve consideration. Firstly, MR imaging at the time of primary diagnosis did not include DWI, so information on diffusivity in the primary tumour is not available. Secondly, some rhabdomyosarcoma may exhibit higher ADC [2,6,7]. While the characteristic low ADC values noted in this study underline a high specificity for malignant tumour, sensitivity for rhabdomyosarcoma in general may be limited to some extent. Thirdly, the series of MRI scans in this case was performed in turns on two MRI scanners. We are aware that this may have caused some degree of variation in longitudinal ADC values. Still, we used scanner hardware of the same manufacturer and similar scan protocols on both platforms. In our experience, other sources of error, such as manual placement of ROI for ADC quantification, account for a much higher degree of variation in ADC data.
In summary, diffusion-weighted MRI is increasingly regarded as a helpful tool in the diagnostic work-up of orbital tumours. Promising current data from the headneck-region show a diagnostic benefit with improved differentiation of malignant and benign neoplasm [6,8]. In a recent study on orbital tumours conducted with DWI at 3 Tesla, sensitivity, specificity and diagnostic accuracy for differentiation of malignant from benign disease were reported as 95%, 91% and 93% [9]. The presented case demonstrates that diffusion-weighted MRI can provide crucial information for establishing the correct diagnosis at an early stage and may prove particularly useful in patients with unusual findings in uncommon localisations. In general, "bright spots" on diffusion-weighted images with corresponding low signal on ADC maps warrant close attention and may likely be the key to correct diagnosis and timely treatment.

Consent
Written informed consent was obtained from the legal guardians of the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Competing interests
All authors declare that they have no competing interests.