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The role of radiology in childhood rhabdomyosarcoma
Clinical
Radiology
(1999)
54,2-10
Review The Role of Radiology
in Childhood
K. MCHUGH*,
Rhabdomyosarcoma
A. E. BOOTHROYDt
*Radiology Department, Great Ormond Street Hospital for Children, London WClN 3JH and TRadiology Department, Royal Liverpool Children’s Hospital, Alder Hey, Liverpool L12 2AP, UK Received: 13 July 1998 Accepted: 1 September 1998
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children under the age of 15 years, and the third most common extracranial solid tumour after neuroblastoma and Wilms’ tumour [l]. Almost half of all casesare diagnosed in children less than 5 years of age. RMS is a mesenchymal neoplasm accounting for up to 8% of malignancies in childhood [2]. Currently, about 70% of children survive for 5 years or longer - and are probably cured [l]. This compares with an estimated cure rate of only 25% in 1970 [3]. A sustained improvement in survival has equalled the successesachieved in other childhood cancers [l]. Similar improvements have taken place across the different co-operative paediatric oncology groups treating children with RMS. Improved outcome is a result of the use of increasingly effective multimodal therapy, better supportive care and refinements in tumour grouping and staging. Radiology plays a crucial role in the initial staging of children with RMS, in their long-term follow-up and in the assessment of the not infrequent treatment-related complications. The anatomic distribution of RMS is quite different to that observed in adult soft tissue sarcomasin which the majority of tumours arise in the extremities. The location of paediatric RMS by primary site is listed in Table 1. Up to 40% of tumours occur in the head and neck region including the orbits [4,5]. Striking differences in outcome with regard to location of primary sites has been repeatedly documented. In the Third Intergroup Rhabdomyosarcoma Study (IRS) the orbit, head and neck (non-parameningeal), and genitourinary (non-bladder/ prostrate) tumours represented the most prognostically favourable locations [4,6]. Three-year survival for patients with primary tumours located at these sites was estimated to be 94% [4]. Tumours with a less favourable outcome included the parameningeal head and neck sites, the extremities, bladder, prostate and so-called ‘other’ sites. Three-year survival for these particular locations was only 60-70% [4]. Other characteristics important with regard to prognosis include invasive tumours, large tumour size (>5cm) and involvement of locoregional lymph nodes [7]. Correspondenceto: Dr K. McHugh, RadiologyDepartment,Great Ormond
Street Hospital
0009-9260/99/010002+09
for Children, $12.00/O
London
WClN
3JH, UK.
Although systemic multiagent chemotherapy is the mainstay of treatment, controversy still exists as to the appropriate local/ regional management of the primary tumour. Many advocate surgery as the initial approach while others assert that RMS is uniquely radiosensitive, and possibly radiocurable, and that irradiation is optimal [8]. It is well established that in addition to chemotherapy, the majority of children will also need surgery or radiotherapy, or occasionally a combination of both, to achieve local tumour control. The decision regarding resection or irradiation should take into account the TNM stage of the lesion, age of the patient, site of the primary tumour and the likely sequelae of an aggressive surgical procedure or intensive radiation therapy [8].
HISTOLOGIC
AND GENETIC
FEATURES
RMS resembles normal foetal skeletal muscle before innervation at histological examination [9]. Although the term rhabdomyosarcoma suggests a mesenchymal tumour derived from striated muscle, RMS typically arises in sites lacking striated muscle. The two major cell types are embryonal and alveolar, both of which are defined by specific genetic changes. Up to 60% of newly diagnosed casesare classified as embryonal, 20% as alveolar and the remainder as undifferentiated or miscellaneous [l]. The botryoid sub-type of embryonal RMS is described macroscopically by the presence of grape-like polypoid masses and accounts for approximately 5% of cases. Botryoid tumours are found in the mucosa-lined organs of the nasopharynx, genitourinary and gastrointestinal tracts [lo]. These particular tumours rarely metastasize and respond well to current treatment regimens [ 11. An international group of pathologists have recently proposed a new classification for RMS tumours based on a relationship between prognosis and histology: unfavourable (alveolar and undifferentiated tumours), intermediate (the majority of embryonal tumours) and favourable histology (botryoid and spindle-cell variants of embryonal histology) [ Ill. Inherited or somatically acquired genetic changes underlie all forms of cancer. With improved cytogenetic techniques, the 0 1999 The Royal
College
of Radiologists
RADIOLOGY
Table
1 - Primary
site distribution
3
RHABDOMYOSARCOMA
for rbabdomyosarcoma
Site
% of patients
Head and neck orbit parameningeal other Genitourinary Extremity Other (from
IN CHILDHOOD
reference
35 10 10 15 26 19 20 4).
genetic characteristics of RMS are becoming increasingly known. Newer diagnostic techniques use immunohistochemical markers of myogenic differentiation, including antibodies directed towards myoglobin, desmin, actin, and the MyoDl gene product [12]. Embryonal and alveolar tumours can be distinguished by structural chromosomal changes. For example, while embryonal tumours lack tumour-specific translocations, the alveolar histiotype is characterized by a rearrangement of chromosomes 2 and 13, the t(2;13) (q35:q14) in which the PAX3 gene within band 2q35 is fused to the FKHR gene within band 13q14 (1). Unlike some other childhood malignancies, RMS tumours are not associated with a raised serological marker e.g. alpha-foeto protein, which can be measured at diagnosis and used during follow-up to prompt further imaging if there is a later rise in the marker levels. Mutations of the p53 gene are seen in asmany as 50% of caseswith either alveolar or embryonal histiotype and have been linked to the Li-Fraumeni syndrome which includes RMS and other soft tissue sarcomas u31. CLINICAL
STAGING
Staging of RMS has proved problematic because until recently the various co-operative paediatric oncology groups have used different staging systems. The only pre-treatment staging system in use is the TNM system used by the Intemational Society of Paediatric Oncology (SIOP) [14]. The North American IRS grouping system takes into account a primary method of treatment i.e. surgery, and as such is a post-surgical staging system [14]. The extent of the initial surgery may however vary with the surgeon or the overall management philosophy in an institution - with differing approaches to possible mutilating surgery or the late effects of radiation therapy. Using the IRS grouping, therefore, there can be significant variability with regard to the initial extent of disease [14]. Furthermore, incorporating surgery into the staging assumes that the surgical procedure itself carries prognostic value, which has not to date been proven. Increased use of and reliance on imaging techniques, in particular computed tomography (CT) and magnetic resonance imaging (MRI), should now facilitate a better assessmentof tumour extent at diagnosis and consequently be associated with fewer disparities between studies [14]. This also applies to the demonstration of contemporaneous regional lymph node enlargement (and presumed tumour involvement).
Fig. 1 - Ultrasound showing a small paratesticular an 1 l-year-old boy who presented with inguinal
RhLS mass (calipers) adenopathy.
in
It should be noted that the major difference between the pretreatment staging of childhood RMS and the more standard TNM staging systems utilized for many adult cancers, is the incorporation of anatomic site of origin into the staging process [4]. The improvements in survival between the IRS II and IRS III studies also emphasize the impact that changes in technology, particularly radiology, used in the clinical evaluation of tumours, and changes in treatment strategies may have on the prognostic value of staging criteria [4]. In addition to the clinical and radiological extent of the tumour, other factors namely histology and the site of origin of the mass lesion also have an impact on prognosis.
IMAGING RECOMMENDATIONS At presentation imaging of the primary site should be performed by CT or MRI, both with intravenous contrast administration, with measurements of the tumour recorded in, at least, the two largest diameters [15]. A volume estimation calculated from the maximum sagittal, coronal and axial diameters is favoured by many investigators. In general, there is little to choose in terms of accuracy of diagnosis or tumour bulk estimation between CT and MRI. Where available MRI, due to its multiplanar capability, better lesion characterization, and lack of ionizing radiation is preferable. MRI is particularly recommended for limb, pelvic and paraspinal masses. CT is probably superior to MRI in the evaluation of possible bone erosion and abdominal lymphadenopathy. Occasionally ultrasound may be the imaging modality of choice, e.g. in the initial staging and assessmentof local disease in paratesticular RMS (Fig. 1). It is generally advisable to follow-up treatment response with. the same imaging technique (CT or MRI) particularly when accurate measurements are required whichever imaging modality is used it is important to re-assessthe tumour using the same parameters. This is particularly true of MR such that the same planes and sequences should be used where possible. Imaging of the primary site should include examination of the regional lymph nodes. For example, it is mandatory that the pelvic lymph nodes are examined in cases of paratesticular and lower limb tumours. Up to 14% of children with RMS will have metastatic
4
CLINICAL
RADIOLOGY
Fig. 2 - Coronal unenhanced Tl image showing a large left parapharyngeal RMS tumour extending superiorly through the cavernous sinus (arrow).
@I
(b)
Fig. 3 - (a) Sagittal Tl-weighted MRI in a four-year old girl demonstrates a large nasopharyngeal tumour with intracranial extension directly through the sphenoid bone. (b) Axial image revealing marked tumour enhancement after gadolinium administration,
Fig. 4 - Parameningeal RMS. (a) Bone and (b) soft-tissue windows after contrast enhancement showing destruction of the petrous apex and mastoid air cells on the right, with variable enhancement of the tumour mass (arrow).
RADIOLOGY
IN CHILDHOOD
RHABDOMYOSARCOMA
5
Fig. 5 - A 5-year-old girl with an orbital RMS. &enhanced CT reveals a predominantly extraconal mass arising superolaterally in the right orbit (arrow).
Fig. 6 - Contrast enhanced CT demonstrating a massive chest wall RMS tumour which extended through the neck to the level to the level of the mandible in a l-day-old newborn male.
disease (clinical stage 4) at presentation [6]. Even if chest radiographs are clear it is always advisable to perform chest CT to assessfor pulmonary metastases. Chest CT can be positive for metastasesin at least 8% of patients at diagnosis including patients with negative chest radiographs [ 161.In addition, spiral CT has been shown to be superior to conventional CT in the detection of lung nodules [17]. The case for routine Tc99mMDP bone scintigraphy at diagnosis is less clear-cut with only 4% of isotope studies being positive for skeletal metastases [16]. In addition, not all skeletal metastases are evident on bone scans [ 181. To reduce the trauma to the child and the overall costs of staging it may be advisable to limit bone scintigraphy to patients with unfavourable histology or bone pain, but currently most RMS imaging protocols include routine radionuclide bone scanning at diagnosis. In the European SIOP studies, a clinical complete response to chemotherapy is defined as disappearance of all signs of tumour based on both clinical and imaging evidence [15]. A partial remission is defined as greater than or equal to 50% decrease in tumour area, without appearance of new areas of
Fig. 7 - Two biliary RMS lesions. (a) Transverse T2-weighted MRI in an eight-year-old boy defines the large hyperintense, septated intrahepatic mass, (b) Enhanced CT in a l-year-old male again showing tumour heterogeneity with extension to the porta of an exophytic component of the mass.
disease. Progressive disease is defined as an increase greater than or equal to 25% in tumour area, or the appearance of new areasof disease[ 151. Tumour volume measurementsare written into many oncology protocols (often without radiological input) but, due to the wide variation in tumour shape, accurate estimations of tumour volume are very difficult to achieve. Similarly, percentage tumour bulk decrease is difficult to quantify. It is our opinion that until such time as accurate and easily reproducible three-dimensional volume measurement packages become widely available with CT and MR scanners, maximum tumour diameter measurements in two or three planes should suffice at the initial and follow-up examinations of paediatric oncology patients. Such simple diameter measurements are much less prone to interobserver variability and error.
ANATOMIC
LOCATION
RMS of the head and neck grow insidiously and often invade
6
CLINICAL
RADIOLOGY
Fig. 8 - Abdominal CT study after intravenous contrast in a three-year-old boy showing a large central abdominal RMS with marked ascites and peritoneal seedlings of tumour (arrow).
the intracranial space through the numerous foramina leading to the brain (Fig. 2). MRI is ideally suited with coronal and sagittal imaging to assessfor intracranial extension (Fig. 3). These tumours typically have a loose stromal network and high overall water content resulting in high signal intensity on long
Fig. 9 - Sagittal
Tl images
demonstrating
a large prostatic
RMS
(arrow)
TIUTE images. The masses also are typically isointense or nearly isointense to muscle on Tl weighted (short TR/short TE) images [5]. Consequently, they are easily distinguished from benign lesions in the head and neck of children, e.g. branchial cleft or thyroglossal duct cysts, which are frequently of lower intensity than muscle on short TR images. Specific parameningeal sites include the nasal cavity, paranasal sinuses, pterygoid fossa, nasopharynx and the middle ear (Fig. 4). Tumours at these locations tend to be large and invasive [S]. Orbital turnouts with intracranial invasion or bone destruction for practical purposes are treated as parameningeal disease. As surgery is often not feasible, all parameningeal tumours merit early irradiation. From the information provided by imaging, the radiotherapist will include the full margins of the tumour plus a 2-3 cm margin [5]. Orbital tumours generally are non-invasive and confined to the bony orbit (Fig. 5). Tumour mass at presentation is commonly of similar size to the globe and the mass may be intraconal or extraconal [ 191. Within the orbit the superonasal quadrant is the most common location [19]. Regional lymph node extension is rare, believed to be due to a paucity of orbital lymphatics. Excellent survival rates in excessof 90% have been reported [S]. Even for a site as favourable as the orbit, chemotherapy is generally not sufficient in terms of local control, event-free or overall survival [8]. Despite varied
inferior
to an empty
bladder.
Note a catheter
traverses
the urethra.
RADIOLOGY
IN CHILDHOOD
(b) Fig. 10 - Limb RMS manifesting (a) as intermediate signal intensity on coronal Tl images (arrow) and (b) heterogenously hyperintense on axial T2 images, adjacent to the lateral aspect of the distal femoral metaphysis and epiphysis. No bone destruction is evident.
long-term sequelae of local irradiation, combined radiation therapy and chemotherapy provide an excellent outcome and a good quality of life. When examining the orbit with MRI, fat saturation techniques to reduce signal from normal orbital fat are recommended.
RHABDOMYOSARCOMA
7
RMS tumours arising in the thorax or abdomen are unusual (Fig. 6). A few reports exist of RMS arising from congenital cystic lesions of the lung including cystic adenomatoid malformation [20]. It has even been suggested that, because of the risk of malignant degeneration, an asymptomatic pulmonary cyst in a child should be resected, unless radiographic evidence can show it to be acquired [20,21]. Although RMS is the most common tumour of the biliary tree in children, it is rare accounting for only 1% of all RMS tumours or approximately 0.04% of all paediatric cancers [22]. Ultrasound (US) typically reveals biliary dilatation and an intraductal mass [22]. Associated portal vein thrombosis has not as yet been described [23]. When a large hepatic tumour is found in a child, a biliaty origin may be difficult to prove as intraductal growth may not always be obvious (Fig. 7). The tumour may in fact arise from the intraor extrahepatic bile ducts, the gallbladder or cystic duct, a choledochal cyst or the liver parenchyma [22]. Extension into the duodenum is not uncommon. Involvement of both right and left hepatic ducts need not be a contraindication to surgery and complete excision does not appear to be a prerequisite for longterm survival [22]. Operability may thus be a different concept for biliary RMS than for other malignant liver tumours in which complete excision is probably essential. While US and CT or MRI will clearly show tumour extent, direct visualization of the biliary tree with percutaneous transhepatic cholangiography will frequently also be necessary.Bizarre filling defects corresponding to ductal tumour can be seen [22]. Metastases to the liver or the peritoneal surfaces including the omentum and mesentery are also common (Fig. 8). Intraperitoneal metastatic disease can occur at initial presentation or later relapse of tumour in approximately 11% of children with RMS [24]. Genitourinary RMS accounts for a quarter of all childhood RMS casesand RMS is the most common malignant neoplasm of the pelvis in children. Tumours in the bladder and prostate have generally a worse prognosis than other sites, e.g. the vagina. Prostatic tumours commonly spread laterally to the periurethal tissues, posteriorly to the perivesical tissues with frequent bladder base invasion (Fig. 9). Tumour extension can also occur superiorly and anteriorly to the bladder into the retropubic space of Retzius [25]. Although MRI is recommended for all pelvic tumours, it is not without pitfalls. Gadolinium enhancement can lead to layered contrast in the bladder with confusing paramagnetic effects and is probably best avoided. Oedema after radiotherapy suggesting an increase in tumour sizecan lead to discrepanciesbetween the CT or MRI findings and surgical or biopsy results [26]. CT has been reported to be incorrect in the assessment of residual disease in around 20% of cases [27]. Nevertheless, MRI in the coronal and sagittal planes, particularly Tl weighted sequences with urine hypointense on Tl within the bladder, can give useful information on which to base clinical decisions. On T2weighted sequences urine in the bladder can obscure hyperintense bladder wall tumour tissue. The goal of therapy for bladder or bladder/prostate RMS is now survival with an intact and functioning bladder 1261. Paratesticular RMS has been applied to primary tumours arising in the spermatic cord, testis, epididymis, and penis. Paratesticular tumours account for 7% of RMS and 12% of childhood scrotal tumours [28]. Ultrasound is the primary modality to initially investigate scrotal disease in general. It
8
CLINICAL
RADIOLOGY
BIOPSY
- RADIOLOGICALLY-GUIDED SURGICAL?
OR
This is a controversial area; the requirements of the pathologist for adequate tissue to make the diagnosis must be balanced against a desire to be minimally invasive for the patient’s benefit. Whilst a needle biopsy is capable of providing adequate diagnostic tissue including full immunohistochemistry, difficulties may be encountered if the tumour proves to be heterogeneous or if insufficient tissue is provided for biological studies [30]. Although many centres favour open surgical biopsy, a 14G or 16G cutting needle usually gives adequate cores of tissue for paediatric biopsies. With either US or CT guidance the non-cystic and non-necrotic parts of the tumour mass and large vessels may be easily avoided, thus improving the diagnostic yield and reducing the risk from percutaneous biopsies. Close co-operation with the local histopathology department is, of course, sensible. Fine needle aspiration cytology is not recommended. Current guidelines allow for flexibility, particularly if the child is considered to be too sick to undergo open biopsy [31]. In such circumstances it is reasonable to perform a guided needle biopsy (preferably more than two cores of tissue) and only proceed to surgery if there is inadequate sampling.
COMPLICATIONS
Fig. 11 - Long-term sequelae of irradiation. This patient had undergone radiotherapy 13 years previously for a large pelvic tumour. As well as radiation damage to the lower pole of the kidneys, there is undergrowth of the lumbar spine and iliac blades, an osteochondroma arising from the right pubic ramus and bilateral slipped upper femoral epiphyses.
is noteworthy that a paratesticular RMS lesion may show hyperaemia and increased diastolic llow on colour doppler sonography which may mimic infection [29]. Tumours in a paratesticular location are associated with a good outcome although the 5-year survival is significantly diminished in patients aged 10 years or older or by retroperitoneal lymph node involvement [28]. All these patients merit high quality abdominal CT studies, after the administration of oral and intravenous contrast. Complications of retroperitoneal lymph node dissection such as intestinal obstruction, loss of ejaculatory function and leg lymphoedema have resulted in an increasing reliance on CT to detect involved abdominal nodes, and a trend away from retroperitoneal dissection in patients with paratesticular disease. MRI is particularly good for evaluating tumours arising in the limbs (Fig. 10). Multiplanar imaging for assessment of tumour extent, neurovascular encasement and bone marrow involvement and the higher inherent contrast resolution of MRI over CT make MRI the modality of choice when available. Fat suppressedsequencesin a coronal plane can easily demonstrate tumour supero-inferior extent and regional lymphadenopathy. Regional lymph node involvement is more frequent in extremity tumours than tumours at other sites [7].
OF TREATMENT
The spectrum of abnormalities detected in patients treated for childhood cancer has broadened with the use of new and more intensive therapies, more sensitive imaging modalities, notably MRI, and improvements in long-term survival with an unfortunate increased risk of a second malignancy [32]. Multimodal treatment plans have improved survival rates in patients with RMS; however, this successhas exacted a toll. In the first IRS study, 90% of patients with primary orbital tumours developed cataracts, 61% orbital hypoplasia and 61% growth retardation. All of these were attributable to local irradiation [33]. Bowel obstruction (12%) haemorrhagic cystitis (33%) and an increase in follicle stimulating hormone (54%) were apparent in 84 patients who underwent treatment for paratestitular RMS [34]. Of 109 patients treated for bladder/prostate tumours 50% lost their bladders, 10% had growth retardation and 29% had abnormal findings on renal imaging [35]. A recent study has reported venoocclusive disease of the liver occurring in 10 patients treated with the VAC regimen (vincristine, Actinomycin D, cyclophosphamide) of IRS IV [36]. The toxic death rate in various IRS trials has ranged from 5 to 12% with sepsis accounting for most fatalities [6]. Many iatrogenic bone changes can be identified radiologically. These include changes secondary to radiotherapy such as radiation osteitis, impairment of bone growth including injury to the epiphyseal plate. osteonecrosis, medullary infarction and osteochondromas [32]. Many of these changes can be seen in Fig. 11. Chemotherapeutic agents can also lead to specific osseous problems such as isosfamide-induced rickets. The increased use of MRI has allowed for the evaluation of bone marrow changes. Interpretation of the paediatric bone marrow is complicated by normal age-related changes in the
RADIOLOGY
IN CHILDHOOD
distribution of haematopoietic and fatty marrow. A knowledge of the normal conversion pattern from red to yellow marrow throughout the skeleton is necessary before ascribing marrow heterogeneity or lack of typical fatty marrow on Tl-weighted images as being due to metastatic disease [38]. Conversely, patients who have undergone radiotherapy have a resulting increase in marrow signal on TlW images due to the conversion of haemopoeitic to fatty marrow. These changes slowly regress indicating marrow recovery [39]. Soft tissue changes are also demonstrable following radiotherapy. The size and shape of the high signal intensity region on T2W MR images conforms to the irradiated volume and is secondary to oedema and fibrosis [32]. Radiological abnormalities may be found in patients with associated clinical changes in skin and soft tissues [40]. Some children who survive their primary disease will suffer the devastation of a second malignant neoplasm. The risk of this continues to increase with time. Such tumours are seen most frequently in children initially treated for retinoblastoma, Hodgkin disease, Ewing sarcoma, rhabdomyosarcoma and Wilms’ tumour where alkylating agents and radiotherapy have been used in combination [32].
chemotherapy regimens will inevitably lead to greater reliance on MRI in evaluating RMS tumours in all parts of the body at diagnosis, follow-up and suspected relapse. Acknowledgements. We would like to thank Heather Liverpool, Paula Colarinha, Lisbon, Jon Pritchard and Anthony London, for their help and comments on this manuscript.
McDowell, Michalski,
REFERENCES
THE FUTURE
Treatment for RMS has grown more intensive. Therapy with recombinant human granulocyte colony-stimulating factor (G-CSF) is being assessed as a means to reduce severe neutropenia and allow increasing intensity of the chemotherapy treatment [ 11.Reconversion from fatty to haemopoietic marrow due to G-CSF use can be demonstrated on MRI and this should be borne in mind before diagnosing recurrent disease or marrow metastases on follow-up MRI examinations [41]. Hyperfractionated radiation is also being evaluated to control local tumour growth whilst reducing the late effects on somatic growth [42]. Despite improved results with increasing drug and radiation doses further improvements may be achieved with tumour specific agents. Current studies are testing the therapeutic value of antisense oligonucleotides and ribozymes in RMS cell lines and xenografts carrying the t(2: 13), the chromosomal translocation responsible for PAX3-FKHR fusion. This fusion gene is particularly associated with alveolar RMS [43,44]. Uptake of thallium-201 (201TI) chloride and technetium99m methoxyisobutyllisonitrile (99mTc-sestamibi) have been reported in a number of tumours including RMS. Tumour uptake of these agents reflects perfusion and cellular viability and may be used to evaluate tumour response to chemotherapy. Tracer uptake of TI-201 correlates with mmour viability [4.5]. RMS expression of the P-glycoprotein gene and its association with multidrug resistance is currently of uncertain significance [46]. Uptake of 99mTc-sestamibi in tumours is considered to be inversely related to the P-glycoprotein expression, such that it may be applicable as a tool to demonstrate the P-glycoprotein status of a tumour and to predict the likely chemotherapy effect. Finally, MRI is and will no doubt remain the single most useful technique for the diagnosis and follow-up of RMS. Faster scanning sequences and the more widespread availability of MRI machines in addition to more intensive
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11
12
13 14
15
16
17
18
19 20
21
Pappo AS, Shapiro DN, Crist WM. Rhabdomyosarcoma, biology and treatment. Pediatric Oncology 1997;44:953-971. Gilles R, Cauanet D, Sigal R et al. Head and neck rhabdomyosarcomas in children: value of clinical and CT findings in the detection of locoregional relapses. Clinical Radiology 1994;49:412-415. Crist WM, Kun LE. Common solid turnouts of childhood. New England Journal of Medicine 1991;324:461-471. Lawrence W Jr, Anderson JR, Gehan EA et al. Pretreatment TNM staging of childhood rhabdomyosarcoma. A report of the Intergroup Rhabdomyosarcoma Study group. Cancer 1997;80:1165-1170. Yousem DM, Lexa FJ, Bilaniuk LT, Zimmerman RI. Rhabdomyosatcomas in the head and neck: MR imaging evaluation. Radiology 1990;177:683-686. Crist W, Gehan EA, Ragab AH et al. The Third Intergroup Rhabdomyosarcoma Study. Journal ofClinical Oncology 1995;13(3):610-630. Rodary C, Gehan EA, Flamant F et al. Prognostic factors in 951 nonmetastatic rhabdomyosarcoma in children: a report from the international Rhabdomyosarcoma Workshop. Medical and Pediatric Oncology 1991;19:89-95. Donaldson SS, Anderson J. Factors that influence treatment decisions in childhood rhabdomyosarcoma. Radiology 1997;203:17-22. Horn RC, Enterline HT. Rhabdomyosarcoma: a clinicopathological study and classification of 39 cases. Cancer 1958;11:181-199. Tsokos M. The diagnosis and classification of childhood rhabdomyosarcoma: a new classification scheme related to prognosis. Archives of Pathology and Laboratory Medicine 1992;116:847-855. Newton WA, Gehan EA, Webber BL et al. Classification of Rhabdomyosarcomas and related sarcomas: pathologic aspects and proposal for a new classification - an Intergroup Rhabdomyosarcoma study. Cancer 1995;76:1073-1084. Agrons GA, Wagner BJ, Lonergan GJ et al. Genitourinary rhabdomyosarcoma in children: radiologic-pathologic correlation. Radiographics 1997;17:919-937. Li FP, Fraumeni JR, Mulvihill JJ. A cancer family syndrome in twenty four kindreds. Cancer Research 1993;53:5108-5112. Rodary C, Flamant F, Donaldson SS. An attempt to use a common staging system in rhabdomyosarcoma: A report of an International Workshop initiated by the International Society of Pediatric Oncology (SIOP). Medical and Pediatric Oncology 1989;17:210-215. International Society of Paediatric Oncology. MMT 95 Study for rhabdomyosarcoma and other malignant soft tissue tumours of childhood, 1995. McHugh K, Horton D, McDowell H. The role of chest CT and bone scintigraphy at initial diagnosis in patients with rhabdomyosarcomas. Soft Tissue Sarcome Group meeting, Stuttgart, 1997. Remy-Jardin M, Renny J, Giraud et al. Pulmonary nodules: detection with thick-section spiral CT vesus conventional CT. Radiology 1993;187:513-520. Quddus FF, Espinola D, Kramer SS, Leventhal BG. Comparison between x-ray and bone scan detection on bone metastases in patients with rhabdomyosarcoma. Medical and Pediatric Oncology 1983;11:125-129. Sohaib SA, Moseley I, Wright JE. Orbital rhabdomyosarcoma - the radiological characteristics. Clinical Radiology 1998;53:357-362, McDermott VGM, MacKenzie S, Hendry GMA. Case report: primary intrathoracic rhabdomyosarcoma: a rare childhood malignancy. British .Ioumal ofRadiology 1993;66:937-941. Weinburg AG, Currarino G, Moore GC Votteler TP. Mesenchymal neoplasia and congenital pulmonary cysts. Pediatric Radiology 1980;9:179-182.
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CLINICAL
22 Roebuck D, Yang WT, Lam WWM, Stanley P. Hepatobiliary rhabdomyosarcoma in children: diagnostic radiology. Pediattic Radiology 1998;28:101-108. 23 Geoffray A, Couanet D, Montagne JP et al. Ultrasonography and computed tomography for diagnosis and follow-up of biliary tract rhabdomyosarcomas in children. Pediuttic Radiology 1987;17: 127-131. 24 Chung CJ, Fordham L, Little S etal. Intraperitoneal rhabdomyosarcoma in children: incidence and imaging characteristics on CT. American Journal of Roentgenology 1998;170:1385-1387. 25 Levin T, Berdon WE, Ruzal-Shapiro C et al. Three pediatric patients with extension of prostatic embryonal rhabdomyosarcoma anterior to the bladder into the space of Retzius. Pediatric Radiology 1992;22:200-202. 26 Heyn R, Newton WA, Beverly Raney R et al. Preservation of the bladder in patients with rhabdomyosarcoma. Journal ofClinical Oncology 1997;15:69-75. 27 Atra A, Ward HC, Aitken K, et al. Conservative surgery in multimode1 therapy for pelvic rhabdomyosarcoma in children. British Journal of Cancer 1994;70:1004-1008. 28 Wiener ES, Lawrence W, Hays D et al. Retroperitoneal node biopsy in paratesticular rhabdomyosarcoma. Journal of Pediatric Surgery 1994;29:171-178. 29 Wood A, Dewbury KC, Case report: paratesticular rhabdomyosarcoma - colour doppler appearances. Clinical Radiology 1995;50: 130-131. 30 Jennings PE, Donald JJ, Coral A, Lees WR. Ultrasound guided core biopsy. Lancet 1989;8651:1369-1371. 31 Biopsy of Paediatric Solid Tumours. UKCCSG Surgical Working Group, 1995. 32 Fletcher BD. Effects of paediatric cancer therapy on the musculoskeletal system. Pediatric Radiology 1997;27:623-636. 33 Heyn R, Ragab A, Raney RB. Late effects of therapy in orbital rhabdomyosarcoma in children. A report of the Intergroup Rhabdomyosarcoma Study. Cancer 1986;57:1738-1743. 34 Heyn R, Raney RB, Hays DM. Late effects of therapy in patients with paratesticular rhabdomyosarcoma. Journal of Clinical Oncology 1992;10:614-623. 35 Raney B, Heyn R, Hays D. Sequelae of treatment in 109 patients followed for five to fifteen years after diagnosis of sarcoma of the bladder and prostate. Cancer 1993;71:2387-2394.
RADIOLOGY 36 Ortega JA, Donaldson SS, Ivy SP, et al. Venoocclusive disease of the liver after chemotherapy with vincristine, actinomysin D and cyclophosphamide for the treatment of rhabdomyosarcoma. A report of the Intergroup Rhabdomyosarcoma Study Group. Cancer 1997;79:24352439. 37 Burk CD, Restaino I, Kaplan BS Meadows AT. Ifosfamide-induced renal tubular dysfunction and rickets in children with Wilms’ tumour. Journal of Paediatrics 1990;117:331-335. 38 Waitches G, Zawin JK, Poznanski AK. Sequence and rate of bone marrow conversion in the femora of children as seen on MR imaging: are accepted standards accurate? American Journal of Roentgenology 1994;162:1399-1406. 39 Cavenagh EC, Weinberger E, Shaw DWN White KS, Geyer JR. Haemopoietic marrow regeneration in paediatric patients undergoing spinal irradiation: MR depiction. American Journal of Neuroradiology 1995;16:461-467. 40 Sovik E, Levi AH, Tveit KM. Post irradiation changes in the pelvic wall. Findings on MR. Actu Radiologica 1993;34:573-576. 41 Ryan SP, Weinberger E, White KS et al. MR imaging of bone marrow in children with osteosarcoma: effect of granulocyte colonystimulating factor. American Journal of Roentgenology 1995;165:915-920. 42 Donaldson SS, Asmar L, Breneman .I. Hyperfractionated radiation in children with rhabdomyosarcoma. International Journal of Radiation Oncology Biology and Physics 1995;32:903-911. 43 Potter PM, Shapiro D, Dias P, Houghton P. Ribozyme-mediated cleavage of a fusion transcript specifically expressed in alveolar rhabdomyosarcoma. Proceedings of the Annual Meeting American Association of Cancer Research 1994;35:530. 44 Shapiro DN, Jones BG, Shapiro LH. Antisense-mediated reduction in insulin-like growth factor-l receptor expression suppresses the malignant phenotype of a human alveolar rhabdomyosarcoma. Journal of Clinical Investigation 1994;94:1235-1242. 45 Maini CL, Tofani A, Sciuto R et al. Thallium-201 scintigraphy and chemotherapeutic response in rhabdomyosarcoma. Clinical Nuclear Medicine 1994;19:607-610. 46 Chan HS, DeBoer G, Haddad G et al. Multidrng resistance in pediatric malignancies. Hematology and Oncology Clinics of North America 1995;9:275-318.
Radiology
(1999)
54,2-10
Review The Role of Radiology
in Childhood
K. MCHUGH*,
Rhabdomyosarcoma
A. E. BOOTHROYDt
*Radiology Department, Great Ormond Street Hospital for Children, London WClN 3JH and TRadiology Department, Royal Liverpool Children’s Hospital, Alder Hey, Liverpool L12 2AP, UK Received: 13 July 1998 Accepted: 1 September 1998
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children under the age of 15 years, and the third most common extracranial solid tumour after neuroblastoma and Wilms’ tumour [l]. Almost half of all casesare diagnosed in children less than 5 years of age. RMS is a mesenchymal neoplasm accounting for up to 8% of malignancies in childhood [2]. Currently, about 70% of children survive for 5 years or longer - and are probably cured [l]. This compares with an estimated cure rate of only 25% in 1970 [3]. A sustained improvement in survival has equalled the successesachieved in other childhood cancers [l]. Similar improvements have taken place across the different co-operative paediatric oncology groups treating children with RMS. Improved outcome is a result of the use of increasingly effective multimodal therapy, better supportive care and refinements in tumour grouping and staging. Radiology plays a crucial role in the initial staging of children with RMS, in their long-term follow-up and in the assessment of the not infrequent treatment-related complications. The anatomic distribution of RMS is quite different to that observed in adult soft tissue sarcomasin which the majority of tumours arise in the extremities. The location of paediatric RMS by primary site is listed in Table 1. Up to 40% of tumours occur in the head and neck region including the orbits [4,5]. Striking differences in outcome with regard to location of primary sites has been repeatedly documented. In the Third Intergroup Rhabdomyosarcoma Study (IRS) the orbit, head and neck (non-parameningeal), and genitourinary (non-bladder/ prostrate) tumours represented the most prognostically favourable locations [4,6]. Three-year survival for patients with primary tumours located at these sites was estimated to be 94% [4]. Tumours with a less favourable outcome included the parameningeal head and neck sites, the extremities, bladder, prostate and so-called ‘other’ sites. Three-year survival for these particular locations was only 60-70% [4]. Other characteristics important with regard to prognosis include invasive tumours, large tumour size (>5cm) and involvement of locoregional lymph nodes [7]. Correspondenceto: Dr K. McHugh, RadiologyDepartment,Great Ormond
Street Hospital
0009-9260/99/010002+09
for Children, $12.00/O
London
WClN
3JH, UK.
Although systemic multiagent chemotherapy is the mainstay of treatment, controversy still exists as to the appropriate local/ regional management of the primary tumour. Many advocate surgery as the initial approach while others assert that RMS is uniquely radiosensitive, and possibly radiocurable, and that irradiation is optimal [8]. It is well established that in addition to chemotherapy, the majority of children will also need surgery or radiotherapy, or occasionally a combination of both, to achieve local tumour control. The decision regarding resection or irradiation should take into account the TNM stage of the lesion, age of the patient, site of the primary tumour and the likely sequelae of an aggressive surgical procedure or intensive radiation therapy [8].
HISTOLOGIC
AND GENETIC
FEATURES
RMS resembles normal foetal skeletal muscle before innervation at histological examination [9]. Although the term rhabdomyosarcoma suggests a mesenchymal tumour derived from striated muscle, RMS typically arises in sites lacking striated muscle. The two major cell types are embryonal and alveolar, both of which are defined by specific genetic changes. Up to 60% of newly diagnosed casesare classified as embryonal, 20% as alveolar and the remainder as undifferentiated or miscellaneous [l]. The botryoid sub-type of embryonal RMS is described macroscopically by the presence of grape-like polypoid masses and accounts for approximately 5% of cases. Botryoid tumours are found in the mucosa-lined organs of the nasopharynx, genitourinary and gastrointestinal tracts [lo]. These particular tumours rarely metastasize and respond well to current treatment regimens [ 11. An international group of pathologists have recently proposed a new classification for RMS tumours based on a relationship between prognosis and histology: unfavourable (alveolar and undifferentiated tumours), intermediate (the majority of embryonal tumours) and favourable histology (botryoid and spindle-cell variants of embryonal histology) [ Ill. Inherited or somatically acquired genetic changes underlie all forms of cancer. With improved cytogenetic techniques, the 0 1999 The Royal
College
of Radiologists
RADIOLOGY
Table
1 - Primary
site distribution
3
RHABDOMYOSARCOMA
for rbabdomyosarcoma
Site
% of patients
Head and neck orbit parameningeal other Genitourinary Extremity Other (from
IN CHILDHOOD
reference
35 10 10 15 26 19 20 4).
genetic characteristics of RMS are becoming increasingly known. Newer diagnostic techniques use immunohistochemical markers of myogenic differentiation, including antibodies directed towards myoglobin, desmin, actin, and the MyoDl gene product [12]. Embryonal and alveolar tumours can be distinguished by structural chromosomal changes. For example, while embryonal tumours lack tumour-specific translocations, the alveolar histiotype is characterized by a rearrangement of chromosomes 2 and 13, the t(2;13) (q35:q14) in which the PAX3 gene within band 2q35 is fused to the FKHR gene within band 13q14 (1). Unlike some other childhood malignancies, RMS tumours are not associated with a raised serological marker e.g. alpha-foeto protein, which can be measured at diagnosis and used during follow-up to prompt further imaging if there is a later rise in the marker levels. Mutations of the p53 gene are seen in asmany as 50% of caseswith either alveolar or embryonal histiotype and have been linked to the Li-Fraumeni syndrome which includes RMS and other soft tissue sarcomas u31. CLINICAL
STAGING
Staging of RMS has proved problematic because until recently the various co-operative paediatric oncology groups have used different staging systems. The only pre-treatment staging system in use is the TNM system used by the Intemational Society of Paediatric Oncology (SIOP) [14]. The North American IRS grouping system takes into account a primary method of treatment i.e. surgery, and as such is a post-surgical staging system [14]. The extent of the initial surgery may however vary with the surgeon or the overall management philosophy in an institution - with differing approaches to possible mutilating surgery or the late effects of radiation therapy. Using the IRS grouping, therefore, there can be significant variability with regard to the initial extent of disease [14]. Furthermore, incorporating surgery into the staging assumes that the surgical procedure itself carries prognostic value, which has not to date been proven. Increased use of and reliance on imaging techniques, in particular computed tomography (CT) and magnetic resonance imaging (MRI), should now facilitate a better assessmentof tumour extent at diagnosis and consequently be associated with fewer disparities between studies [14]. This also applies to the demonstration of contemporaneous regional lymph node enlargement (and presumed tumour involvement).
Fig. 1 - Ultrasound showing a small paratesticular an 1 l-year-old boy who presented with inguinal
RhLS mass (calipers) adenopathy.
in
It should be noted that the major difference between the pretreatment staging of childhood RMS and the more standard TNM staging systems utilized for many adult cancers, is the incorporation of anatomic site of origin into the staging process [4]. The improvements in survival between the IRS II and IRS III studies also emphasize the impact that changes in technology, particularly radiology, used in the clinical evaluation of tumours, and changes in treatment strategies may have on the prognostic value of staging criteria [4]. In addition to the clinical and radiological extent of the tumour, other factors namely histology and the site of origin of the mass lesion also have an impact on prognosis.
IMAGING RECOMMENDATIONS At presentation imaging of the primary site should be performed by CT or MRI, both with intravenous contrast administration, with measurements of the tumour recorded in, at least, the two largest diameters [15]. A volume estimation calculated from the maximum sagittal, coronal and axial diameters is favoured by many investigators. In general, there is little to choose in terms of accuracy of diagnosis or tumour bulk estimation between CT and MRI. Where available MRI, due to its multiplanar capability, better lesion characterization, and lack of ionizing radiation is preferable. MRI is particularly recommended for limb, pelvic and paraspinal masses. CT is probably superior to MRI in the evaluation of possible bone erosion and abdominal lymphadenopathy. Occasionally ultrasound may be the imaging modality of choice, e.g. in the initial staging and assessmentof local disease in paratesticular RMS (Fig. 1). It is generally advisable to follow-up treatment response with. the same imaging technique (CT or MRI) particularly when accurate measurements are required whichever imaging modality is used it is important to re-assessthe tumour using the same parameters. This is particularly true of MR such that the same planes and sequences should be used where possible. Imaging of the primary site should include examination of the regional lymph nodes. For example, it is mandatory that the pelvic lymph nodes are examined in cases of paratesticular and lower limb tumours. Up to 14% of children with RMS will have metastatic
4
CLINICAL
RADIOLOGY
Fig. 2 - Coronal unenhanced Tl image showing a large left parapharyngeal RMS tumour extending superiorly through the cavernous sinus (arrow).
@I
(b)
Fig. 3 - (a) Sagittal Tl-weighted MRI in a four-year old girl demonstrates a large nasopharyngeal tumour with intracranial extension directly through the sphenoid bone. (b) Axial image revealing marked tumour enhancement after gadolinium administration,
Fig. 4 - Parameningeal RMS. (a) Bone and (b) soft-tissue windows after contrast enhancement showing destruction of the petrous apex and mastoid air cells on the right, with variable enhancement of the tumour mass (arrow).
RADIOLOGY
IN CHILDHOOD
RHABDOMYOSARCOMA
5
Fig. 5 - A 5-year-old girl with an orbital RMS. &enhanced CT reveals a predominantly extraconal mass arising superolaterally in the right orbit (arrow).
Fig. 6 - Contrast enhanced CT demonstrating a massive chest wall RMS tumour which extended through the neck to the level to the level of the mandible in a l-day-old newborn male.
disease (clinical stage 4) at presentation [6]. Even if chest radiographs are clear it is always advisable to perform chest CT to assessfor pulmonary metastases. Chest CT can be positive for metastasesin at least 8% of patients at diagnosis including patients with negative chest radiographs [ 161.In addition, spiral CT has been shown to be superior to conventional CT in the detection of lung nodules [17]. The case for routine Tc99mMDP bone scintigraphy at diagnosis is less clear-cut with only 4% of isotope studies being positive for skeletal metastases [16]. In addition, not all skeletal metastases are evident on bone scans [ 181. To reduce the trauma to the child and the overall costs of staging it may be advisable to limit bone scintigraphy to patients with unfavourable histology or bone pain, but currently most RMS imaging protocols include routine radionuclide bone scanning at diagnosis. In the European SIOP studies, a clinical complete response to chemotherapy is defined as disappearance of all signs of tumour based on both clinical and imaging evidence [15]. A partial remission is defined as greater than or equal to 50% decrease in tumour area, without appearance of new areas of
Fig. 7 - Two biliary RMS lesions. (a) Transverse T2-weighted MRI in an eight-year-old boy defines the large hyperintense, septated intrahepatic mass, (b) Enhanced CT in a l-year-old male again showing tumour heterogeneity with extension to the porta of an exophytic component of the mass.
disease. Progressive disease is defined as an increase greater than or equal to 25% in tumour area, or the appearance of new areasof disease[ 151. Tumour volume measurementsare written into many oncology protocols (often without radiological input) but, due to the wide variation in tumour shape, accurate estimations of tumour volume are very difficult to achieve. Similarly, percentage tumour bulk decrease is difficult to quantify. It is our opinion that until such time as accurate and easily reproducible three-dimensional volume measurement packages become widely available with CT and MR scanners, maximum tumour diameter measurements in two or three planes should suffice at the initial and follow-up examinations of paediatric oncology patients. Such simple diameter measurements are much less prone to interobserver variability and error.
ANATOMIC
LOCATION
RMS of the head and neck grow insidiously and often invade
6
CLINICAL
RADIOLOGY
Fig. 8 - Abdominal CT study after intravenous contrast in a three-year-old boy showing a large central abdominal RMS with marked ascites and peritoneal seedlings of tumour (arrow).
the intracranial space through the numerous foramina leading to the brain (Fig. 2). MRI is ideally suited with coronal and sagittal imaging to assessfor intracranial extension (Fig. 3). These tumours typically have a loose stromal network and high overall water content resulting in high signal intensity on long
Fig. 9 - Sagittal
Tl images
demonstrating
a large prostatic
RMS
(arrow)
TIUTE images. The masses also are typically isointense or nearly isointense to muscle on Tl weighted (short TR/short TE) images [5]. Consequently, they are easily distinguished from benign lesions in the head and neck of children, e.g. branchial cleft or thyroglossal duct cysts, which are frequently of lower intensity than muscle on short TR images. Specific parameningeal sites include the nasal cavity, paranasal sinuses, pterygoid fossa, nasopharynx and the middle ear (Fig. 4). Tumours at these locations tend to be large and invasive [S]. Orbital turnouts with intracranial invasion or bone destruction for practical purposes are treated as parameningeal disease. As surgery is often not feasible, all parameningeal tumours merit early irradiation. From the information provided by imaging, the radiotherapist will include the full margins of the tumour plus a 2-3 cm margin [5]. Orbital tumours generally are non-invasive and confined to the bony orbit (Fig. 5). Tumour mass at presentation is commonly of similar size to the globe and the mass may be intraconal or extraconal [ 191. Within the orbit the superonasal quadrant is the most common location [19]. Regional lymph node extension is rare, believed to be due to a paucity of orbital lymphatics. Excellent survival rates in excessof 90% have been reported [S]. Even for a site as favourable as the orbit, chemotherapy is generally not sufficient in terms of local control, event-free or overall survival [8]. Despite varied
inferior
to an empty
bladder.
Note a catheter
traverses
the urethra.
RADIOLOGY
IN CHILDHOOD
(b) Fig. 10 - Limb RMS manifesting (a) as intermediate signal intensity on coronal Tl images (arrow) and (b) heterogenously hyperintense on axial T2 images, adjacent to the lateral aspect of the distal femoral metaphysis and epiphysis. No bone destruction is evident.
long-term sequelae of local irradiation, combined radiation therapy and chemotherapy provide an excellent outcome and a good quality of life. When examining the orbit with MRI, fat saturation techniques to reduce signal from normal orbital fat are recommended.
RHABDOMYOSARCOMA
7
RMS tumours arising in the thorax or abdomen are unusual (Fig. 6). A few reports exist of RMS arising from congenital cystic lesions of the lung including cystic adenomatoid malformation [20]. It has even been suggested that, because of the risk of malignant degeneration, an asymptomatic pulmonary cyst in a child should be resected, unless radiographic evidence can show it to be acquired [20,21]. Although RMS is the most common tumour of the biliary tree in children, it is rare accounting for only 1% of all RMS tumours or approximately 0.04% of all paediatric cancers [22]. Ultrasound (US) typically reveals biliary dilatation and an intraductal mass [22]. Associated portal vein thrombosis has not as yet been described [23]. When a large hepatic tumour is found in a child, a biliaty origin may be difficult to prove as intraductal growth may not always be obvious (Fig. 7). The tumour may in fact arise from the intraor extrahepatic bile ducts, the gallbladder or cystic duct, a choledochal cyst or the liver parenchyma [22]. Extension into the duodenum is not uncommon. Involvement of both right and left hepatic ducts need not be a contraindication to surgery and complete excision does not appear to be a prerequisite for longterm survival [22]. Operability may thus be a different concept for biliary RMS than for other malignant liver tumours in which complete excision is probably essential. While US and CT or MRI will clearly show tumour extent, direct visualization of the biliary tree with percutaneous transhepatic cholangiography will frequently also be necessary.Bizarre filling defects corresponding to ductal tumour can be seen [22]. Metastases to the liver or the peritoneal surfaces including the omentum and mesentery are also common (Fig. 8). Intraperitoneal metastatic disease can occur at initial presentation or later relapse of tumour in approximately 11% of children with RMS [24]. Genitourinary RMS accounts for a quarter of all childhood RMS casesand RMS is the most common malignant neoplasm of the pelvis in children. Tumours in the bladder and prostate have generally a worse prognosis than other sites, e.g. the vagina. Prostatic tumours commonly spread laterally to the periurethal tissues, posteriorly to the perivesical tissues with frequent bladder base invasion (Fig. 9). Tumour extension can also occur superiorly and anteriorly to the bladder into the retropubic space of Retzius [25]. Although MRI is recommended for all pelvic tumours, it is not without pitfalls. Gadolinium enhancement can lead to layered contrast in the bladder with confusing paramagnetic effects and is probably best avoided. Oedema after radiotherapy suggesting an increase in tumour sizecan lead to discrepanciesbetween the CT or MRI findings and surgical or biopsy results [26]. CT has been reported to be incorrect in the assessment of residual disease in around 20% of cases [27]. Nevertheless, MRI in the coronal and sagittal planes, particularly Tl weighted sequences with urine hypointense on Tl within the bladder, can give useful information on which to base clinical decisions. On T2weighted sequences urine in the bladder can obscure hyperintense bladder wall tumour tissue. The goal of therapy for bladder or bladder/prostate RMS is now survival with an intact and functioning bladder 1261. Paratesticular RMS has been applied to primary tumours arising in the spermatic cord, testis, epididymis, and penis. Paratesticular tumours account for 7% of RMS and 12% of childhood scrotal tumours [28]. Ultrasound is the primary modality to initially investigate scrotal disease in general. It
8
CLINICAL
RADIOLOGY
BIOPSY
- RADIOLOGICALLY-GUIDED SURGICAL?
OR
This is a controversial area; the requirements of the pathologist for adequate tissue to make the diagnosis must be balanced against a desire to be minimally invasive for the patient’s benefit. Whilst a needle biopsy is capable of providing adequate diagnostic tissue including full immunohistochemistry, difficulties may be encountered if the tumour proves to be heterogeneous or if insufficient tissue is provided for biological studies [30]. Although many centres favour open surgical biopsy, a 14G or 16G cutting needle usually gives adequate cores of tissue for paediatric biopsies. With either US or CT guidance the non-cystic and non-necrotic parts of the tumour mass and large vessels may be easily avoided, thus improving the diagnostic yield and reducing the risk from percutaneous biopsies. Close co-operation with the local histopathology department is, of course, sensible. Fine needle aspiration cytology is not recommended. Current guidelines allow for flexibility, particularly if the child is considered to be too sick to undergo open biopsy [31]. In such circumstances it is reasonable to perform a guided needle biopsy (preferably more than two cores of tissue) and only proceed to surgery if there is inadequate sampling.
COMPLICATIONS
Fig. 11 - Long-term sequelae of irradiation. This patient had undergone radiotherapy 13 years previously for a large pelvic tumour. As well as radiation damage to the lower pole of the kidneys, there is undergrowth of the lumbar spine and iliac blades, an osteochondroma arising from the right pubic ramus and bilateral slipped upper femoral epiphyses.
is noteworthy that a paratesticular RMS lesion may show hyperaemia and increased diastolic llow on colour doppler sonography which may mimic infection [29]. Tumours in a paratesticular location are associated with a good outcome although the 5-year survival is significantly diminished in patients aged 10 years or older or by retroperitoneal lymph node involvement [28]. All these patients merit high quality abdominal CT studies, after the administration of oral and intravenous contrast. Complications of retroperitoneal lymph node dissection such as intestinal obstruction, loss of ejaculatory function and leg lymphoedema have resulted in an increasing reliance on CT to detect involved abdominal nodes, and a trend away from retroperitoneal dissection in patients with paratesticular disease. MRI is particularly good for evaluating tumours arising in the limbs (Fig. 10). Multiplanar imaging for assessment of tumour extent, neurovascular encasement and bone marrow involvement and the higher inherent contrast resolution of MRI over CT make MRI the modality of choice when available. Fat suppressedsequencesin a coronal plane can easily demonstrate tumour supero-inferior extent and regional lymphadenopathy. Regional lymph node involvement is more frequent in extremity tumours than tumours at other sites [7].
OF TREATMENT
The spectrum of abnormalities detected in patients treated for childhood cancer has broadened with the use of new and more intensive therapies, more sensitive imaging modalities, notably MRI, and improvements in long-term survival with an unfortunate increased risk of a second malignancy [32]. Multimodal treatment plans have improved survival rates in patients with RMS; however, this successhas exacted a toll. In the first IRS study, 90% of patients with primary orbital tumours developed cataracts, 61% orbital hypoplasia and 61% growth retardation. All of these were attributable to local irradiation [33]. Bowel obstruction (12%) haemorrhagic cystitis (33%) and an increase in follicle stimulating hormone (54%) were apparent in 84 patients who underwent treatment for paratestitular RMS [34]. Of 109 patients treated for bladder/prostate tumours 50% lost their bladders, 10% had growth retardation and 29% had abnormal findings on renal imaging [35]. A recent study has reported venoocclusive disease of the liver occurring in 10 patients treated with the VAC regimen (vincristine, Actinomycin D, cyclophosphamide) of IRS IV [36]. The toxic death rate in various IRS trials has ranged from 5 to 12% with sepsis accounting for most fatalities [6]. Many iatrogenic bone changes can be identified radiologically. These include changes secondary to radiotherapy such as radiation osteitis, impairment of bone growth including injury to the epiphyseal plate. osteonecrosis, medullary infarction and osteochondromas [32]. Many of these changes can be seen in Fig. 11. Chemotherapeutic agents can also lead to specific osseous problems such as isosfamide-induced rickets. The increased use of MRI has allowed for the evaluation of bone marrow changes. Interpretation of the paediatric bone marrow is complicated by normal age-related changes in the
RADIOLOGY
IN CHILDHOOD
distribution of haematopoietic and fatty marrow. A knowledge of the normal conversion pattern from red to yellow marrow throughout the skeleton is necessary before ascribing marrow heterogeneity or lack of typical fatty marrow on Tl-weighted images as being due to metastatic disease [38]. Conversely, patients who have undergone radiotherapy have a resulting increase in marrow signal on TlW images due to the conversion of haemopoeitic to fatty marrow. These changes slowly regress indicating marrow recovery [39]. Soft tissue changes are also demonstrable following radiotherapy. The size and shape of the high signal intensity region on T2W MR images conforms to the irradiated volume and is secondary to oedema and fibrosis [32]. Radiological abnormalities may be found in patients with associated clinical changes in skin and soft tissues [40]. Some children who survive their primary disease will suffer the devastation of a second malignant neoplasm. The risk of this continues to increase with time. Such tumours are seen most frequently in children initially treated for retinoblastoma, Hodgkin disease, Ewing sarcoma, rhabdomyosarcoma and Wilms’ tumour where alkylating agents and radiotherapy have been used in combination [32].
chemotherapy regimens will inevitably lead to greater reliance on MRI in evaluating RMS tumours in all parts of the body at diagnosis, follow-up and suspected relapse. Acknowledgements. We would like to thank Heather Liverpool, Paula Colarinha, Lisbon, Jon Pritchard and Anthony London, for their help and comments on this manuscript.
McDowell, Michalski,
REFERENCES
THE FUTURE
Treatment for RMS has grown more intensive. Therapy with recombinant human granulocyte colony-stimulating factor (G-CSF) is being assessed as a means to reduce severe neutropenia and allow increasing intensity of the chemotherapy treatment [ 11.Reconversion from fatty to haemopoietic marrow due to G-CSF use can be demonstrated on MRI and this should be borne in mind before diagnosing recurrent disease or marrow metastases on follow-up MRI examinations [41]. Hyperfractionated radiation is also being evaluated to control local tumour growth whilst reducing the late effects on somatic growth [42]. Despite improved results with increasing drug and radiation doses further improvements may be achieved with tumour specific agents. Current studies are testing the therapeutic value of antisense oligonucleotides and ribozymes in RMS cell lines and xenografts carrying the t(2: 13), the chromosomal translocation responsible for PAX3-FKHR fusion. This fusion gene is particularly associated with alveolar RMS [43,44]. Uptake of thallium-201 (201TI) chloride and technetium99m methoxyisobutyllisonitrile (99mTc-sestamibi) have been reported in a number of tumours including RMS. Tumour uptake of these agents reflects perfusion and cellular viability and may be used to evaluate tumour response to chemotherapy. Tracer uptake of TI-201 correlates with mmour viability [4.5]. RMS expression of the P-glycoprotein gene and its association with multidrug resistance is currently of uncertain significance [46]. Uptake of 99mTc-sestamibi in tumours is considered to be inversely related to the P-glycoprotein expression, such that it may be applicable as a tool to demonstrate the P-glycoprotein status of a tumour and to predict the likely chemotherapy effect. Finally, MRI is and will no doubt remain the single most useful technique for the diagnosis and follow-up of RMS. Faster scanning sequences and the more widespread availability of MRI machines in addition to more intensive
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Pappo AS, Shapiro DN, Crist WM. Rhabdomyosarcoma, biology and treatment. Pediatric Oncology 1997;44:953-971. Gilles R, Cauanet D, Sigal R et al. Head and neck rhabdomyosarcomas in children: value of clinical and CT findings in the detection of locoregional relapses. Clinical Radiology 1994;49:412-415. Crist WM, Kun LE. Common solid turnouts of childhood. New England Journal of Medicine 1991;324:461-471. Lawrence W Jr, Anderson JR, Gehan EA et al. Pretreatment TNM staging of childhood rhabdomyosarcoma. A report of the Intergroup Rhabdomyosarcoma Study group. Cancer 1997;80:1165-1170. Yousem DM, Lexa FJ, Bilaniuk LT, Zimmerman RI. Rhabdomyosatcomas in the head and neck: MR imaging evaluation. Radiology 1990;177:683-686. Crist W, Gehan EA, Ragab AH et al. The Third Intergroup Rhabdomyosarcoma Study. Journal ofClinical Oncology 1995;13(3):610-630. Rodary C, Gehan EA, Flamant F et al. Prognostic factors in 951 nonmetastatic rhabdomyosarcoma in children: a report from the international Rhabdomyosarcoma Workshop. Medical and Pediatric Oncology 1991;19:89-95. Donaldson SS, Anderson J. Factors that influence treatment decisions in childhood rhabdomyosarcoma. Radiology 1997;203:17-22. Horn RC, Enterline HT. Rhabdomyosarcoma: a clinicopathological study and classification of 39 cases. Cancer 1958;11:181-199. Tsokos M. The diagnosis and classification of childhood rhabdomyosarcoma: a new classification scheme related to prognosis. Archives of Pathology and Laboratory Medicine 1992;116:847-855. Newton WA, Gehan EA, Webber BL et al. Classification of Rhabdomyosarcomas and related sarcomas: pathologic aspects and proposal for a new classification - an Intergroup Rhabdomyosarcoma study. Cancer 1995;76:1073-1084. Agrons GA, Wagner BJ, Lonergan GJ et al. Genitourinary rhabdomyosarcoma in children: radiologic-pathologic correlation. Radiographics 1997;17:919-937. Li FP, Fraumeni JR, Mulvihill JJ. A cancer family syndrome in twenty four kindreds. Cancer Research 1993;53:5108-5112. Rodary C, Flamant F, Donaldson SS. An attempt to use a common staging system in rhabdomyosarcoma: A report of an International Workshop initiated by the International Society of Pediatric Oncology (SIOP). Medical and Pediatric Oncology 1989;17:210-215. International Society of Paediatric Oncology. MMT 95 Study for rhabdomyosarcoma and other malignant soft tissue tumours of childhood, 1995. McHugh K, Horton D, McDowell H. The role of chest CT and bone scintigraphy at initial diagnosis in patients with rhabdomyosarcomas. Soft Tissue Sarcome Group meeting, Stuttgart, 1997. Remy-Jardin M, Renny J, Giraud et al. Pulmonary nodules: detection with thick-section spiral CT vesus conventional CT. Radiology 1993;187:513-520. Quddus FF, Espinola D, Kramer SS, Leventhal BG. Comparison between x-ray and bone scan detection on bone metastases in patients with rhabdomyosarcoma. Medical and Pediatric Oncology 1983;11:125-129. Sohaib SA, Moseley I, Wright JE. Orbital rhabdomyosarcoma - the radiological characteristics. Clinical Radiology 1998;53:357-362, McDermott VGM, MacKenzie S, Hendry GMA. Case report: primary intrathoracic rhabdomyosarcoma: a rare childhood malignancy. British .Ioumal ofRadiology 1993;66:937-941. Weinburg AG, Currarino G, Moore GC Votteler TP. Mesenchymal neoplasia and congenital pulmonary cysts. Pediatric Radiology 1980;9:179-182.
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22 Roebuck D, Yang WT, Lam WWM, Stanley P. Hepatobiliary rhabdomyosarcoma in children: diagnostic radiology. Pediattic Radiology 1998;28:101-108. 23 Geoffray A, Couanet D, Montagne JP et al. Ultrasonography and computed tomography for diagnosis and follow-up of biliary tract rhabdomyosarcomas in children. Pediuttic Radiology 1987;17: 127-131. 24 Chung CJ, Fordham L, Little S etal. Intraperitoneal rhabdomyosarcoma in children: incidence and imaging characteristics on CT. American Journal of Roentgenology 1998;170:1385-1387. 25 Levin T, Berdon WE, Ruzal-Shapiro C et al. Three pediatric patients with extension of prostatic embryonal rhabdomyosarcoma anterior to the bladder into the space of Retzius. Pediatric Radiology 1992;22:200-202. 26 Heyn R, Newton WA, Beverly Raney R et al. Preservation of the bladder in patients with rhabdomyosarcoma. Journal ofClinical Oncology 1997;15:69-75. 27 Atra A, Ward HC, Aitken K, et al. Conservative surgery in multimode1 therapy for pelvic rhabdomyosarcoma in children. British Journal of Cancer 1994;70:1004-1008. 28 Wiener ES, Lawrence W, Hays D et al. Retroperitoneal node biopsy in paratesticular rhabdomyosarcoma. Journal of Pediatric Surgery 1994;29:171-178. 29 Wood A, Dewbury KC, Case report: paratesticular rhabdomyosarcoma - colour doppler appearances. Clinical Radiology 1995;50: 130-131. 30 Jennings PE, Donald JJ, Coral A, Lees WR. Ultrasound guided core biopsy. Lancet 1989;8651:1369-1371. 31 Biopsy of Paediatric Solid Tumours. UKCCSG Surgical Working Group, 1995. 32 Fletcher BD. Effects of paediatric cancer therapy on the musculoskeletal system. Pediatric Radiology 1997;27:623-636. 33 Heyn R, Ragab A, Raney RB. Late effects of therapy in orbital rhabdomyosarcoma in children. A report of the Intergroup Rhabdomyosarcoma Study. Cancer 1986;57:1738-1743. 34 Heyn R, Raney RB, Hays DM. Late effects of therapy in patients with paratesticular rhabdomyosarcoma. Journal of Clinical Oncology 1992;10:614-623. 35 Raney B, Heyn R, Hays D. Sequelae of treatment in 109 patients followed for five to fifteen years after diagnosis of sarcoma of the bladder and prostate. Cancer 1993;71:2387-2394.
RADIOLOGY 36 Ortega JA, Donaldson SS, Ivy SP, et al. Venoocclusive disease of the liver after chemotherapy with vincristine, actinomysin D and cyclophosphamide for the treatment of rhabdomyosarcoma. A report of the Intergroup Rhabdomyosarcoma Study Group. Cancer 1997;79:24352439. 37 Burk CD, Restaino I, Kaplan BS Meadows AT. Ifosfamide-induced renal tubular dysfunction and rickets in children with Wilms’ tumour. Journal of Paediatrics 1990;117:331-335. 38 Waitches G, Zawin JK, Poznanski AK. Sequence and rate of bone marrow conversion in the femora of children as seen on MR imaging: are accepted standards accurate? American Journal of Roentgenology 1994;162:1399-1406. 39 Cavenagh EC, Weinberger E, Shaw DWN White KS, Geyer JR. Haemopoietic marrow regeneration in paediatric patients undergoing spinal irradiation: MR depiction. American Journal of Neuroradiology 1995;16:461-467. 40 Sovik E, Levi AH, Tveit KM. Post irradiation changes in the pelvic wall. Findings on MR. Actu Radiologica 1993;34:573-576. 41 Ryan SP, Weinberger E, White KS et al. MR imaging of bone marrow in children with osteosarcoma: effect of granulocyte colonystimulating factor. American Journal of Roentgenology 1995;165:915-920. 42 Donaldson SS, Asmar L, Breneman .I. Hyperfractionated radiation in children with rhabdomyosarcoma. International Journal of Radiation Oncology Biology and Physics 1995;32:903-911. 43 Potter PM, Shapiro D, Dias P, Houghton P. Ribozyme-mediated cleavage of a fusion transcript specifically expressed in alveolar rhabdomyosarcoma. Proceedings of the Annual Meeting American Association of Cancer Research 1994;35:530. 44 Shapiro DN, Jones BG, Shapiro LH. Antisense-mediated reduction in insulin-like growth factor-l receptor expression suppresses the malignant phenotype of a human alveolar rhabdomyosarcoma. Journal of Clinical Investigation 1994;94:1235-1242. 45 Maini CL, Tofani A, Sciuto R et al. Thallium-201 scintigraphy and chemotherapeutic response in rhabdomyosarcoma. Clinical Nuclear Medicine 1994;19:607-610. 46 Chan HS, DeBoer G, Haddad G et al. Multidrng resistance in pediatric malignancies. Hematology and Oncology Clinics of North America 1995;9:275-318.