Helen Hatcher
Case history
A 21-year-old man presented to the emergency department with a painful, swollen right foot. He remembered falling over a kerb after drinking alcohol a few weeks previously and had associated the swelling with this. He had no significant medical history prior to this. He had an X-ray and MRI of the right foot (Figs 23.1 and 23.2). A biopsy showed tumour cells arranged in small and large nests surrounded by thin fibrovascular stroma lined by small round blue cells (resembling lymphoma). The structure showed an alveolar growth pattern in small sections of the tumour. Occasional multinucleated giant cells were seen alongside rhabdomyoblasts with small areas of necrosis. Immunohistochemistry showed no staining for CD20, CD45, or HMB45, mild staining for pancytokeratins, and positivity for actin, desmin, and MyoD1.
Fig. 23.1
Fig, 23.2
Questions
1. What do the X-ray (Fig. 23.1) and MRI (Fig. 23.2) show?
2. What does the biopsy indicate?
3. What further tests are needed on the tissue?
4. What further investigations should you do?
Answers
1. What do the X-ray (Fig. 23.1) and MRI (Fig. 23.2) show?
The X-ray shows a soft tissue swelling associated with the fifth metatarsal but no evidence of fracture or bony involvement at that point. The MRI shows the soft tissue lesion between the metatarsal and the skin. There is enhancement of the subcutaneous tissue suggesting involvement of the overlying skin and structure.
2. What does the biopsy indicate?
The biopsy findings are highly suggestive of an aggressive soft tissue sarcoma; immunohistochemistry is suggestive of an alveolar rhabdomyosarcoma (ARMS). Rhabdomyosarcoma is a rare sarcoma of striated muscle with an annual incidence of 1 in 1,000,000. It is the most common childhood soft tissue sarcoma and has a peak incidence in teenagers and young adults. It tends to occur in skeletal structures and can occur anywhere in the body, but common sites include the limbs, the paratesticular region, and the head and neck. It most often presents as a painless lump, often quite rapidly growing, but it can cause pain if it is close to certain structures, for example in the head and neck where compression of adjacent structures can occur. The histological subgroups of rhabdomyosarcoma include embryonal (ERMS; more common in those under 16), alveolar, and pleomorphic (which tends to occur in those over 30). ARMS accounts for approximately 20–30% of all rhabdomyosarcomas. Metastatic disease at diagnosis occurs in 25–30% of patients. The most frequent sites of metastatic spread include the lymph nodes, bone, and bone marrow.
Tumour cells in ARMS are relatively small with scant cytoplasm. They have round regular nuclei with a monotonous chromatin pattern. The cells form aggregates interrupted by fibrovascular septae, and within these aggregates areas of discohesion often form, resulting in spaces that resemble the alveoli of the lung. In some ARMS cases there are few fibrovascular septae, no alveoli-like spaces, and a predominant cellular small round cell population; the term ‘solid variant’ applies to this situation.
In addition to general immunohistochemical markers to identify rhabdomyosarcoma, certain markers aid in the identification of ARMS. Immunostaining for myogenin and MyoD shows different patterns between ARMS and ERMS, such that most cells within an ARMS tumour stain positive whereas fewer cells within an ERMS tumour do so. In addition, based on microarray studies that distinguish fusion-positive ARMS from fusion-negative ERMS, AP2β and p-cadherin were found to be specific markers for the fusion-positive ARMS subtype.
3. What further tests are needed on the tissue?
Further information should be gained by genetic studies using either polymerase chain reaction (PCR) or FISH to look for specific gene rearrangements. ARMS is associated with specific gene rearrangements which give prognostic information. The most common is the PAX3/FOXO1 fusion gene followed by PAX7/FOXO1 (Box 23.1). These fusion genes encode fusion transcription factors with a PAX3 or PAX7DNA-binding domain and FOXO1transactivation domain. Among ARMS tumours, approximately 60% are PAX3/FOXO1-positive, 20% are PAX7/FOXO1-positive, and 20% are fusion negative (Fig. 23.3).
Box 23.1 Molecular cytogenetics in ARMS
♦ t(2;13)(q35;q14)—PAX3/FOXO1 in 60–85%
♦ t(1;13)(p36;q14)—PAX7/FOXO1 in 15–20%
♦ N-myc amplification in 50%
Fig. 23.3 Diagram to show the comparison of wild-type and fusion products associated with the t(2;13) and t(1;13) translocations. The paired box (PB), octapeptide, homeobox (HD), and fork head domain (FD) are indicated as open boxes, and transcriptional domains (DNA-binding domain, DBD; transcriptional activation domain) are shown as solid bars. The vertical dashed line indicates the translocation fusion point.
Reprinted from Atlas Genet Cytogenet Oncol Haematol January 2009; Barr FG. Soft tissue tumors: Alveolar rhabdomyosarcoma by permission of the Atlas.
The PAX7/FOXO1 fusion is often amplified in tumours (70% of PAX7/FOXO1-positive cases) whereas the PAX3/FOXO1 gene fusion is much less frequently amplified in tumours (5% of PAX3/FOXO1-positive cases). Gene amplification appears to be one mechanism for increasing the expression level of the gene fusion in ARMS tumour cells.
4. What further investigations should you do?
He needs further investigation with a CT chest, abdomen, and pelvis, bone scan, and bone marrow examination. Patients with disease at sites at risk of meningeal involvement (e.g. a parameningeal primary) also need an examination of the cerebrospinal fluid.
The CT scan is shown in Fig. 23.4 There was no other disease elsewhere.
Fig. 23.4
Questions
5. What does the CT scan in Fig. 23.4 show?
6. What treatment should he be offered?
7. What are the prognostic factors in ARMS?
Answers
5. What does the CT scan in Fig. 23.4 show?
The CT scan shows a mass close to the left lower lobe bronchus with interstitial shadowing. It indicates metastatic disease to the lungs which places this patient in the high-risk group.
6. What treatment should he be offered?
The optimal treatment involves intensive chemotherapy (in high-risk cases the commonly used regimen is IVADo—ifosfamide, vincristine, actinomycin D, and doxorubicin) followed by radiotherapy and/or surgery tailored to the individual sites of disease and the prognostic group. For localized disease, surgery should be undertaken ideally after four or five cycles of chemotherapy. Radiotherapy is used for high-risk tumours (large, alveolar histology), in cases where surgery is not possible, or in the palliative setting. The tumours are extremely radio- and chemosensitive and an excellent response is often seen to initial chemotherapy but with (in ARMS) a high risk of breakthrough disease or recurrence soon after the completion of treatment. An Italian study has suggested the benefit of a maintenance treatment with 12 cycles of oral cyclophosphamide and intravenous vinorelbine (Casanova et al. 2004), and at the time of writing this is being tested in a European rhabdomyosarcoma trial. At relapse, a number of regimens are used but there is no consensus on the best one. Examples include regimens containing cyclophosphamide/topotecan, irinotecan/temozolamide, or ifosfamide. A phase II European relapse trial is randomizing between vincristine/irinotecan or vincristine/irinotecan/temozolamide ().
7. What are the prognostic factors in ARMS?
Patients with ARMS tumours have a poorer outcome than patients with ERMS tumours. The 4-year failure-free survival rates for patients with localized and metastatic ARMS are 65% and 15%, respectively. Other risk factors that influence the outcome of ARMS include primary site, size of the primary tumour, extent of local spread, and the presence of nodal and distal metastases.
In an analysis of patients from the IRS-IV study, patients with localized PAX3/FOXO1- and PAX7/FOXO1-positive ARMS had comparable outcomes (Sorensen et al. 2002). In contrast, among patients presenting with metastatic disease, those with PAX3/FOXO1-positive tumours had a significantly poorer outcome than those with PAX7/FOXO1-positive tumours (4-year OS of 8% compared with 75%, P = 0.0015).
Further reading
Barr FG. Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma. Oncogene 2001; 20: 5736–5746.
Casanova M, Ferrari A, Bisogno G, et al. Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas: pilot study for the upcoming European Rhabdomyosarcoma Protocol. Cancer 2004; 101: 1664–1671.
Ferrari A, Dileo P, Casanova M, et al. Rhabdomyosarcoma in adults. A retrospective analysis of 171 patients treated at a single institution. Cancer 2003; 98: 571–580.
Gerber NK, Wexler LH, Singer S, et al. Adult rhabdomyosarcoma survival improved with treatment on multimodality protocols. International Journal of Radiation Oncology Biology Physics 2013; 86: 58–63.
Missiaglia E, Williamson D, Chisholm J, et al. PAX3/FOX01 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. Journal of Clinical Oncology2012; 30: 1670–1677.
Sorensen PH, Lynch JC, Qualman SJ, et al. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children’s oncology group. Journal of Clinical Oncology2002; 20: 2672–2679.
Sultan I, Qaddoumi I, Yaser S, et al. Comparing adult and pediatric rhabdomyosarcoma in the surveillance, epidemiology and end results program, 1973 to 2005: an analysis of 2,600 patients. Journal of Clinical Oncology 2009; 27: 3391–3397.