Introduction
When to suspect rhabdomyosarcoma
Patient 1 was a previously healthy 6-year-old boy, who presented to the general practitioner with a persistent swelling of his left eye 4 weeks after minor trauma, accompanied by complaints of progressive visual impairment over the preceding week. On physical examination, a palpable swelling of the left upper eyelid with severe ptosis was evident. There were no signs of infection. Because of the unknown origin of the swelling and progressive visual impairment, the general practitioner referred him to an ophthalmologist. An outside magnetic resonance imaging (MRI) study showed a solid mass in the upper quadrant of the left orbit. Computed tomography of the orbit showed no osseous erosion. A surgical incisional biopsy was performed at the referring hospital. |
The patient was referred to a paediatric oncology centre and discussed with a multidisciplinary team. MRI was repeated after the biopsy and showed a mass of 3.1 × 2.7 cm in the upper quadrant with involvement of the surrounding eye muscles (superior and lateral rectus muscles and levator palpebrae superioris muscle) and the lacrimal gland (Fig. 3). No signs of osseous or optic nerve involvement were seen. There was minor compression of the eye bulb. The mass showed enhancement after gadolinium administration and a hyperintense T2 signal. Diffusion-weighted imaging showed increased diffusion restriction. Diffuse swelling and oedema of the eyelid were seen due to the biopsy. No suspicious local lymph nodes were seen. Taken together, clinical and radiological signs were suspicious of an orbital malignancy, possibly a rhabdomyosarcoma. Potential other diagnoses included lymphoma, leukaemia and Langerhans cell histiocytosis. |
Histomorphology showed an embryonal rhabdomyosarcoma; as expected with this type of histomorphology, molecular analysis showed no fusion in PAX-FOXO1. |
Patient 2, a girl age 14 years at presentation, felt a small perianal mass and subsequently a slightly enlarged lymph node in her left groin. A month later she visited her general practitioner and was referred to the local hospital. On physical examination, a firm perianal mass measuring 8 × 3 cm and an enlarged firm, ipsilateral inguinal lymph node of 3 × 2 cm were found. There were no signs of infection and neither mass was painful. |
An outside MRI, where the groin was not within the field of view, showed a well-demarcated left-sided perianal mass with homogeneous contrast enhancement (Fig. 4). On the coronal short tau inversion recovery (STIR) images, diffuse foci of high signal intensity, in keeping with bone metastases, were visible (Fig. 5). Ultrasound (US) showed a lymph node in the left groin of 1.5 × 2.5 cm, which, due to its short axis of 15 mm, was considered pathologic in line with the RECIST 1.1 criterion. Moreover, on US, a second pathologic enlarged lymph node was seen along the left iliac vein (Fig. 6). |
With the findings of a solid soft tissue mass and pathologic enlarged lymph nodes, the differential diagnosis was a rhabdomyosarcoma or an adult-type soft tissue sarcoma. The girl was referred to a paediatric oncology expert centre, where after discussion with the multidisciplinary team the most likely diagnosis was felt to be rhabdomyosarcoma. An incisional biopsy of the primary mass and an excision biopsy of the lymph node in the groin were performed by a paediatric surgeon. Histomorphology showed an alveolar rhabdomyosarcoma, PAX3-FOXO1 fusion positive, with a tumour-positive lymph node. |
Region | Definition | |
---|---|---|
Extremities | Upper extremity | Axillary, brachial, epitrochlear, infraclavicular nodes |
Lower extremity | Inguinal, femoral, popliteal nodes | |
Genito urinary | Bladder/prostate | Pelvic (hypogastric, obturator, iliac, peri-vesical, pelvic, sacral, presacral nodes) (note: para-aortic nodes are distant nodes) |
Cervix | Pelvic (hypogastric, obturator, iliac, peri-vesical, pelvic, sacral, presacral nodes) (note: para-aortic nodes are distant nodes) | |
Uterus | Pelvic, retroperitoneal nodes at renal vessels or below | |
Paratesticular/gonadal | Ipsilateral pelvic, retroperitoneal nodes at renal vessels or below (inguinal if the scrotum is involved) | |
Vagina | Retroperitoneal, pelvic nodes at or below common iliac vessels, inguinal nodes | |
Vulva | Inguinal nodes | |
Head and neck | Head/neck | Ipsilateral parotid, occipital and cervical nodes (all levels). Tumours close to the midline may show bilateral metastases (plural) and retropharyngeal nodes may be involved in parameningeal tumours |
Orbit/eyelid/cheek/external ear/temporal region | Parotid, ipsilateral jugular, pre-auricular, cervical nodes | |
Trunk | Intrathoracic | Internal mammary, mediastinal nodes |
Retroperitoneum/pelvis | Pelvic, retroperitoneal nodes | |
Intra-abdominal | Sub diaphragmatic, intra-abdominal, iliac lymph nodes; according to site | |
Abdominal wall | Inguinal, femoral nodes | |
Chest wall | Axillary, internal mammary, infraclavicular nodes | |
Other | Biliary/liver | Porta hepatis nodes |
Perianal, perineal | Inguinal, pelvic nodes; may be bilateral |
Biopsy
Pathology
Staging and risk stratification
Patient 1 |
For risk stratification, whole body fluorodeoxyglucose-positron emission tomography FDG-PET/CT was performed, which showed no regional or distant metastases. Chest CT showed a small (<0.5 cm) subpleural lesion (Fig. 10). Because of its size, the nodule was classified as an indeterminate pulmonary nodule. |
Bone marrow trephines and punctures showed no bone marrow infiltration. |
This patient with embryonal rhabdomyosarcoma, fusion negative, IRS post-surgical stage group III, no nodal involvement, favourable site, size and age, was staged as standard risk, EpSSG RMS 2005 treatment group C. |
Patient 2 |
For risk stratification SPECT/CT was performed, which at that time was standard of care. This showed diffuse bone marrow uptake in keeping with bone metastases. Chest CT showed no pulmonary metastases. |
Surgical biopsy of the lymph node in the left groin and bone marrow trephines and punctures showed metastatic disease. |
This patient was treated according to the metastatic guidelines, part of the EpSSG RMS 2005 protocol. |
Nodal involvement
Metastatic disease
Risk groups
Risk group | Sub-group | FOXO1 fusion status | Post surgical stage | Site | Node stage | Size and age |
---|---|---|---|---|---|---|
Low risk | A | Negative | I | Any | N0 | Both favourable |
Standard risk | B | Negative | I | Any | N0 | One or both unfavourable |
C | Negative | II, III | Favourable | N0 | Any | |
High risk | D | Negative | II, III | Unfavourable | N0 | Any |
E | Negative | II, III | Any | N1 | Any | |
F | Positive | I, II, III | Any | N | Any | |
Very high risk | G | Positive | II, III | Any | N1 | Any |
H | Any | IV | Any | Any | Any |
Treatment
Patient 1 |
The patient was started on chemotherapy which consisted of nine cycles of IVA (ifosfamide, vincristine and actinomycin-D) as defined in the EpSSG RMS 2005 protocol. After three cycles, the tumour response was assessed using magnetic resonance imaging. The primary tumour showed volume reduction, a decreased signal intensity on T2 and less restricted diffusion (Fig. 11). Complete surgical resection was not feasible due to the location of the tumour (with involvement of essential eye muscles and the lacrimal gland). As there had been no progressive disease, the planned treatment of chemotherapy and local therapy continued. |
Proton therapy was given as local therapy (36 Gy in 1.8 Gy fractions, plus a boost of 9.0 Gy in 1.8 Gy fractions) starting in parallel with chemotherapy cycle five. During this therapy, chemotherapy was continued with ifosfamide and vincristine but without actinomycin-D due to its photosensitising properties. |
Patient 2 |
The patient was included in the BERNIE study [50]. Induction therapy consisted of nine cycles of chemotherapy, comprising four cycles of IVADo (ifosfamide, vincristine, actinomycin-D and doxorubicin), followed by five cycles of IVA. Patients were randomised to receive (experimental arm) or not receive (control arm) bevacizumab. Maintenance chemotherapy comprised 12 cycles of low-dose cyclophosphamide and vinorelbine, with or without bevacizumab. The patient was randomised to the standard arm, without bevacizumab. |
After three courses, the primary tumour showed a partial response (Fig. 12) while the bone metastases showed complete response. As there was no progressive disease, the planned treatment of chemotherapy and local therapy continued. Local treatment consisted of brachytherapy (55 Gy—44 pulses of 1.25 Gy) of the primary tumour followed by photon radiotherapy of the groin and iliac lymph nodes, with a total dose of 45 Gy. |
Chemotherapy
Surgery
Radiotherapy
Brachytherapy
Response assessment and follow up
Patient 1 |
After completion of therapy, further volume reduction of the residual tumour was evident on MRI. An increase in soft tissue oedema was seen due to recent proton therapy. During follow-up, the residual tumour remained stable. |
Seven months after the end of treatment, the tumour showed progression on follow-up imaging. MRI showed tumour growth with diffusion restriction (Fig. 13). No signs of intracranial extension were seen. |
Due to suspicion of relapse, a FDG-PET/CT was performed, which showed no distant metastases. A biopsy was performed that showed embryonal rhabdomyosarcoma cells. |
Relapse therapy was started with VIT chemotherapy (vincristine, irinotecan and temozolomide) [63]. After two courses, the tumour showed stable volume and a loss of diffusion restriction. |
The patient was discussed by a multidisciplinary team and it was decided that the tumour residue was resectable, making the patient eligible for salvage AMORE procedure including exenteration of the orbit followed by brachytherapy. |
Follow-up MRIs have been performed every 3 months and there are no signs of relapse to date. |
Patient 2 |
Almost 17 months after achieving complete remission, the patient presented with a new pelvic skeletal metastasis on MRI (Fig. 14). FDG-PET-CT showed multiple skeletal metastases (Fig. 15). This recurrence indicated a very poor prognosis, nevertheless the patient and her parents opted for potentially curative second-line chemotherapy. This treatment was based on the COG protocol D9802 and consisted of nine courses of a combination of irinotecan and vincristine alternating with vincristine, actinomycin-D and cyclophosphamide (VAC). |
Thirty-one months after the initial diagnosis, the patient succumbed to her disease. |
1-dimensional assessment (RECIST 1.1) | 3-dimensional volumetric assessment | |
---|---|---|
CR: complete remission | 100% decrease | 100% decrease |
PR: partial remission | ≥30%, but <100% decrease | ≥66%, but <100% decrease |
SD: stable disease | Neither PR nor PD | Neither PR nor PD |
PD: progressive disease | ≥20% increase | ≥73% increase |