Rhabdomyosarcoma
by Ying Gibbens

May 2018

The 2017-2018 Rein in Sarcoma Scholars are each writing a detailed article about a particular sarcoma cancer sub-type.  Ying grew up in a city called Hangzhou in the southeast part of China.  In 2005 she earned a bachelor's degree in molecular biotechnology from the Chinese University of Hong Kong.  Next she earned her PhD degree in molecular biology and genetics at the University of Minnesota.  Ying joined "Be The Match" where she worked as an immunogenetics specialist to match bone marrow donors to patients in need of transplants. In 2014, she went back to the medical school at the University of Minnesota with the hope of becoming a hematology oncologist to help patients defeat cancer.  In her spare time, Ying enjoys biking, museums, and movies with her husband and two sons.

 

Rhabdomyosarcoma in children and adolescents

Introduction

Rhabdomyosarcoma is a type of soft tissue sarcoma most often developing in children and adolescents. It is not common, accounting for only about 7% of all malignancies under the age of 20 years, but it is the most common type of pediatric sarcoma, accounting for about 40% 1, 2 of sarcomas in children. More than half of the cases occur during the first decade of life. There is a slight male predominance (male to female ratio 1.3-1.5). The sarcoma cells are thought to derive from immature cells that are destined to form striated skeletal muscles. However, rhabdomyosarcoma can also be found almost anywhere in the body, including in anatomical locations where striated skeletal muscles are not found such as bladder, prostate, and vagina.

Clinical presentations

Rhabdomyosarcoma is most commonly found in the head and neck region (35-40%), followed by genitourinary tract (~25%), and the extremities (~20%). The clinical signs and symptoms are dictated by the locations of the tumor and thus quite variable. Typically, the tumor presents as a painless mass which can occasionally be associated with swelling and redness of the overlying skin. Fever is usually not present. Classic presentations based on the location of the tumor are briefly discussed below.

Head and neck3:
  • Orbital tumors (inside or near the eye): protrusion of the eye or impaired eye movement.
  • Parameningeal tumors (middle ear, nasal cavity, paranasal sinuses, mastoids): nasal and sinus obstruction, headaches and nerve damage.
Genitourinary tract4:
  • Bladder tumors: urinary obstruction and blood in the urine.
  • Prostate tumors: increased urinary frequency and/or constipation due to tumor compression on bladder and the large bowel.
  • Vaginal tumors: vaginal discharge composed of mucus and blood, a mass protruding from vagina.
Extremities:
  • A mass which is occasionally accompanied by redness and swelling of the overlying skin.

Causes of rhabdomyosarcoma

The etiology and the risk factors associated with rhabdomyosarcoma are largely unknown. Most of the rhabdomyosarcoma cases are believed to be sporadic as there are no obvious inherited patterns. But a few familial syndromes such as neurofibromatosis, Li-Fraumeni, Beckwith-Wiedemann, and Costello syndromes have been associated with a higher incidence of rhabdomyosarcoma5,6,7,8. There are a few preliminary studies showing that radiation exposure during pregnancy, accelerated fetal growth, low socioeconomic status, and recreational drug use during pregnancy may increase the risk of developing rhabdomyosarcoma9,10.

Diagnosis

Definitive diagnosis of rhabdomyosarcoma is made by tissue biopsy11,12. It is recommended to perform diagnostic biopsy at a facility with the expertise in evaluating soft tissue sarcomas to ensure proper tissue processing for accurate diagnosis. Diagnosis of rhabdomyosarcoma requires the visualization of features of the striated skeletal muscle under the light microscope. The pathologist will then sub-categorize it based on the light microscopic findings into four main subtypes: embryonal, alveolar, botryoid and anaplastic. Additionally, the tissue will be stained with fluorescent probes that detect proteins specific to the skeletal muscle cells. Once the diagnosis of rhabdomyosarcoma is made, special molecular biology techniques such as immunohistochemical staining or genetic testing will be used to detect the presence or absence of rearrangement of a gene known as PAX/FOXO1 which is not only diagnostic, it is also prognostic.

Staging

Once the diagnosis is established, a series of tests are done to determine the extent and location of the tumor and any areas of spread. In general, these tests include a CAT scan of the chest abdomen and pelvis or a PET-CT scan of those same areas. If the tumor is in the head and neck area, an MRI of the brain and orbits is usually done and almost all patients have a bone marrow aspirate and biopsy.

Deciding on treatment

There are several staging and grouping systems that are used to categorize rhabdomyosarcoma, inform the appropriate treatment, and predict the prognosis. The Clinical Group (CG) system assigns the patients into four groups, I-IV, based on the extent of surgery and the degree of tumor metastasis at diagnosis13. The TNM staging analyzes the tumor size (T), lymph node involvement (N) and distant metastasis status (M)12.
The size of the tumor can be evaluated by imaging techniques including plain radiographs, CT and MRI. Lymph node involvement can be assessed by biopsy of any suspicious lymph nodes if feasible. To evaluate for distant metastasis, various methods can be used depending on the possible sites of spread. Based on both CG and TNM staging systems as well as the histologic features of the tumor, the patients are stratified into different risk groups that require different treatment strategies14.

By combining stage and group information, the child’s tumor can be categorized into “Risk Groups” based on how aggressive the tumor is. Assigning a risk group helps direct treatment.

Treatment

The treatment for rhabdomyosarcoma has evolved significantly over the last few decades15. At present time, the use of combined modality therapy- surgery, chemo therapy, and radiation therapy- has improved cure rate to over 70%2 overall in the pediatric patients. Some patients can expect a cure rate of over 90%. Specific multimodality treatment protocols have been designed based on the estimated risk of cancer recurrence by the Soft Tissue Sarcoma Committee of the Children’s Oncology Group (COG). The risk of cancer recurrence is calculated based on a number of prognostic factors such as the extent of the surgical resection, the stage of the tumor by the TNM staging system, site of the tumor, age of the patient and etc15.

In general, surgery is used for tumors that can be resected without excessive morbidity, often after several weeks of chemotherapy. Radiotherapy is used in certain locations to prevent a local recurrence. Higher risk groups will be treated with more aggressive regimen in an attempt to achieve remission. The treatment for rhabdomyosarcoma is rapidly evolving and any information regarding the most up-to-date treatment protocols for a specific patient is better obtained from an oncologist who has expertise in treating soft tissue sarcoma.

Summary

Rhabdomyosarcoma is an uncommon pediatric cancer. The clinical presentations are variable depending on the location of the tumor. Most of the rhabdomyosarcoma cases appear to be sporadic, however a few syndromes have been associated with a higher risk of developing this cancer. Definitive diagnosis of rhabdomyosarcoma is made by evaluation of a biopsy. There are four subtypes based on the histology and the molecular characteristics of the tumor: embryonal, botryoid, alveolar and anaplastic rhabdomyosarcoma. MRI is the choice of the imaging modality in initial evaluation of tumor staging along with PET scans and bone marrow evaluations. The treatment for rhabdomyosarcoma is based on the estimated risk of the tumor recurrence based on many prognostic factors, but in general, involves surgery if the tumor can be removed without disability, chemotherapy, and in many cases radiotherapy. The treatment has been constantly evolving and the latest guidelines can be obtained from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group (COG).

References

  1. Branch, P. O., Dagher, R. & Helman, L. Rhabdomyosarcoma: an overview. Oncologist 4, 34–44 (1999).
  2. Punyko, J. A. et al. Long-term survival probabilities for childhood rhabdomyosarcoma: A population-based evaluation. Cancer 103, 1475–1483 (2005).
  3. Reilly, B. K. et al. Rhabdomyosarcoma of the head and neck in children: Review and update. Int. J. Pediatr. Otorhinolaryngol. 79, 1477–1483 (2015).
  4. Bahnson, R. R., Zaontz, M. R., Maizels, M., Shkolnik, A. A. & Firlit, C. F. Ultrasonography and diagnosis of pediatric genitourinary rhabdomyosarcoma. Urology 33, 64–68 (1989).
  5. Hartley, A. L., Birch, J. M., Marsden, H. B., Harris, M. & Blair, V. Neurofibromatosis in children with soft tissue sarcoma. Pediatr. Hematol. Oncol. 5, 7–16 (1988).
  6. Li, F. P. & Fraumeni, J. F. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann. Intern. Med. 71, 747–752 (1969).
  7. DeBaun, M. R. & Tucker, M. a. Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J. Pediatr. 132, 398–400 (1998).
  8. Quezada, E. & Gripp, K. W. Costello syndrome and related disorders. Current Opinion in Pediatrics 19, 636–644 (2007).
  9. Grufferman, S. et al. Environmental factors in the etiology of rhabdomyosarcoma in childhood. J. Natl. Cancer Inst. 68, 107–113 (1982).
  10. Grufferman, S., Schwartz, A. G., Ruymann, F. B. & Maurer, H. M. Parents’ use of cocaine and marijuana and increased risk of rhabdomyosarcoma in their children. Cancer Causes Control 4, 217–224 (1993).
  11. Qualman, S. J. et al. Intergroup rhabdomyosarcoma study: Update for pathologists. Pediatr. Dev. Pathol. 1, 550–561 (1998).
  12. Crist, W. M. et al. Intergroup Rhabdomyosarcoma Study-IV: Results for patients with nonmetastatic disease. J. Clin. Oncol. 19, 3091–3102 (2001).
  13. Crist, W. et al. The Third Intergroup Rhabdomyosarcoma Study. J. Clin. Oncol. 13, 610–630 (1995).
  14. Raney, R. B. et al. Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J. Pediatr. Hematol. Off. J. Am. Soc. Pediatr. Hematol. 23, 215–220 (2001).
  15. Hawkins, D. S., Gupta, A. A. & Rudzinski, E. R. What is new in the biology and treatment of pediatric rhabdomyosarcoma? Current Opinion in Pediatrics 26, 50–56 (2014).