Rhabdomyosarcoma

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Rhabdomyosarcoma
Diagnosis in short

Alveolar rhabdomyosarcoma. H&E stain.

LM +/-rhabdomyoblasts (eccentric nucleus, moderate amount of intensly eosinophilic cytoplasm, striations - not common); alveolar RMS: alveolus-like pattern (classic); embryonal RMS: small round cell tumour
Subtypes embryonal (spindle cell subtype, botryoid), alveolar (translocation-positive, translocation-negative), undifferentiated
LM DDx small round cell tumours - esp. small cell carcinoma and (large cell) lymphomas
IHC desmin (best marker) +ve, actin +ve, myogenin +ve, CD56 +ve (common), synaptophysin -ve/+ve, chromogranin -ve/+ve, cytokeratins -ve/+ve
EM sarcomeric like structures - typically in U-shaped cells
Molecular alveolar RMS (~85% of cases): t(2,13) PAX3/FKHR fusion gene or t(1,13) PAX7/FKHR fusion gene
Site soft tissue - skeletal muscle site (alveolar RMS), non-skeletal muscle site (embryonal RMS)

Clinical history alveolar RMS: young adult or adolescent; embryonal RMS: typically <10 years old
Prevalence not common
Clin. DDx other soft tissue tumours

Rhabdomyosarcoma, often abbreviated RMS, is a malignant tumour of skeletal muscle.

General

Classification

Histologic

  1. Alveolar rhabdomyosarcoma.
    • Usually young adults/adolescents.
    • Early mets common.
    • Usually arises in regions with skeletal muscle.
  2. Embryonal rhabdomyosarcoma.
    • Usual <10 years old.
    • Typically locally invasive.
    • Usually arises in regions without skeletal muscle.

Less common types:[3]

  1. Undifferentiated rhabdomyosarcoma.
  2. Botryoid - may be considered a subtype of embryonal RMS.
  3. Spindle cell - may be considered a subtype of embryonal RMS.

Notes:

  • How to remember the special types BUS: botryoid, undifferentiated, spindle.
  • The above is the international classification. Several classification of RMS exist - see: Classifications of Rhabdomyosarcoma.[4]

Molecular and histologic

  1. Translocation-positive alveolar RMS.
  2. Translocation-negative alveolar RMS.
  3. Embryonal RMS.

Notes:

  • Translocation-negative alveolar RMS shares gene expression profiling characteristics with embryonal RMS -- suggesting these can be grouped together.

Gross

Sarcoma botryoides (embryonal RMS) - distinctive appearance:

Image:

Microscopic

Alveolar rhabdomyosarcoma

Features:[2]

  • Alveolus-like pattern -- key low-power feature.
    • Fibrous septae lined by tumour cells.
      • Cells may "fall-off" the septa, i.e. be detached/scattered in the alveolus-like space.
      • Space between fibrous sepate may be filled with tumour = solid variant of alveolar rhabdomyosarcoma.
  • Rhabdomyoblasts - essentially diagnostic.
    • Eccentric nucleus.
    • Moderate amount of intensly eosinophilic cytoplasm.
    • Striations -- if you're really lucky; these are not common.

Other features:

Notes:

  • Well-differentiated rhabdomyoblasts are uncommon in alveolar RMS.

DDx:

Images

www:

Embryonal rhabdomyosarcoma

Features:[2]

  • Randomly arranged small cells.
  • Myxoid matrix.
  • Strap cells:
    • Tadpole-like morphology.
  • Rhabdomyoblasts - essentially diagnostic.
    • Eccentric nucleus.
    • Moderate amount of intensly eosinophilic cytoplasm.
    • Striations -- if you're really lucky; these are not common.

DDx:

Images:

Subtypes of embryonal RMS

There are two common subtypes of embryonal RMS. Both of them have a better prognosis that embryonal RMS not otherwise specified (NOS).

Common subtypes:

  1. Botryoid subtype (AKA sarcoma botryoides):
    • Gross: Grape-like morphology.
    • Microscopic: Non-proliferating layer deep to the surface ("Cambium layer").
  2. Spindle cell subtype.
    • General: may mimic leiomyosarcoma (complete with vesicular pattern) -- which is not common in the pediatric population.
    • Microscopic: vesicular growth pattern, spindle cells.

Notes:

  • Cambium layer = cellular region deep to epithelial component.[7]
    • Can be thought of as the opposite of a "Grenz zone" -- which is a paucicellular zone between tumour and epithelium.

Anaplasia

Criteria:

  1. Hyperchromatic nuclei with size variation greater or equal to 3x.
  2. Multipolar (atypical) mitotic figures.

Subclassification:

  1. Focal - a few cells.
  2. Diffuse - cluster or sheets of anaplasia.

Notes:

  • Not subtle - can identify at low power.
  • Seen in 10-15% of RMS.
    • More common in older individuals.
  • Poorer prognosis in embryonal RMS.
    • No change in prognosis in alveolar RMS.

IHC

Panel of muscle markers -- DAM:

  • Desmin (best marker).
  • Actin.
  • Myogenin.

For head and neck RMS:[8]

  • CD56 +ve.
  • Synaptophysin -ve/+ve (seen in 12 of 37 cases[8]).
  • Chromogranin A -ve/+ve (seen in 8 of 36 cases[8]).
  • Wide-spectrum cytokeratin -ve/+ve.
  • CAM5.2 -ve/+ve.

For urinary bladder RMS in adults:

  • Myogenin +ve.
  • Desmin +ve.
  • Keratins -ve.[9]
    • Keratin positive tumours are considered rhabdomyosarcomatous sarcomatoid carcinoma or sarcomatoid carcinoma with rhabdomyosarcomatous differentiation.

Subtyping via IHC

PST proposes[2] the following (presumably based on Makawitz et al.[10]):

IHC Translocation positive
alveolar RMS
Embryonal RMS Translocation negative
alveolar RMS
myogenin +ve -- diffuse +ve -- focal +ve -- diffuse
EGFR -ve +ve -ve
P-cadherin +ve -ve -ve
IGF2 -ve +ve +ve

A paper by Wachtel at al.[11] proposes the use of:

  • AP2beta and P-cadherin +ve in translocation positive alveolar RMS, and
  • EGFR and fibrillin-2 +ve in embryonal RMS and translocation negative alveolar RMS.

Electron microscopy

Features:

  • Sarcomeric like structures - usually in "bent" cells; cells that are U-shaped.

Molecular diagnostics

Alveolar rhabdomyosarcoma

Common translocations (~85% of cases):

  • t(1,13).
    • PAX7/FKHR fusion gene.
    • Seen in approx. 15% of cases.
  • t(2,13).[12]
    • PAX3/FKHR fusion gene.
    • Seen in approx. 70% of cases.

Notes:

  • t(1,13) vs. t(2,13) -- t(1,13) usually: younger age, extremity lesion, localized disease, better survival.
  • Several uncommon translocations exist.
  • Important for urinary bladder lesions in adults: the presence of a translocation is more-or-less required for the diagnosis of RMS.[9]
    • It is suggested that keratin negative tumours without molecular testing to corroborate the impression of RMS be referred to as rhabdomyomatous tumours.[9]

Embryonal rhabdomyosarcoma

  • Chromosome 11p loss of heterozygosity.[13]

Note:

  • Not used for diagnosis.

See also

References

  1. Rosenthal, TC.; Kraybill, W. (Aug 1999). "Soft tissue sarcomas: integrating primary care recognition with tertiary care center treatment.". Am Fam Physician 60 (2): 567-72. PMID 10465231.
  2. 2.0 2.1 2.2 2.3 Thorner, Paul S. 14 February 2011. Cite error: Invalid <ref> tag; name "PST14feb11" defined multiple times with different content Cite error: Invalid <ref> tag; name "PST14feb11" defined multiple times with different content Cite error: Invalid <ref> tag; name "PST14feb11" defined multiple times with different content
  3. Hicks, J.; Flaitz, C. (Jul 2002). "Rhabdomyosarcoma of the head and neck in children.". Oral Oncol 38 (5): 450-9. PMID 12110339.
  4. Parham, DM. (May 2001). "Pathologic classification of rhabdomyosarcomas and correlations with molecular studies.". Mod Pathol 14 (5): 506-14. doi:10.1038/modpathol.3880339. PMID 11353062.
  5. Guillou, L.; Coquet, M.; Chaubert, P.; Coindre, JM. (Aug 1998). "Skeletal muscle regeneration mimicking rhabdomyosarcoma: a potential diagnostic pitfall.". Histopathology 33 (2): 136-44. PMID 9762546.
  6. Chen, S.; Wang, S.; Gao, J.; Zhang, S. (May 2010). "[Pleuropulmonary blastoma: a clinicopathological analysis].". Zhongguo Fei Ai Za Zhi 13 (5): 550-3. doi:10.3779/j.issn.1009-3419.2010.05.31. PMID 20677658.
  7. URL: http://www.medilexicon.com/medicaldictionary.php?t=48297. Accessed on: 9 August 2011.
  8. 8.0 8.1 8.2 Bahrami, A.; Gown, AM.; Baird, GS.; Hicks, MJ.; Folpe, AL. (Jul 2008). "Aberrant expression of epithelial and neuroendocrine markers in alveolar rhabdomyosarcoma: a potentially serious diagnostic pitfall.". Mod Pathol 21 (7): 795-806. doi:10.1038/modpathol.2008.86. PMID 18487991.
  9. 9.0 9.1 9.2 Bing, Z.; Zhang, PJ. (2011). "Adult urinary bladder tumors with rhabdomyosarcomatous differentiation: clinical, pathological and immunohistochemical studies.". Diagn Pathol 6: 66. doi:10.1186/1746-1596-6-66. PMID 21762516.
  10. Makawita S, Ho M, Durbin AD, Thorner PS, Malkin D, Somers GR (2009). "Expression of insulin-like growth factor pathway proteins in rhabdomyosarcoma: IGF-2 expression is associated with translocation-negative tumors". Pediatr. Dev. Pathol. 12 (2): 127–35. doi:10.2350/08-05-0477.1. PMID 18788888.
  11. Wachtel M, Runge T, Leuschner I, et al. (February 2006). "Subtype and prognostic classification of rhabdomyosarcoma by immunohistochemistry". J. Clin. Oncol. 24 (5): 816–22. doi:10.1200/JCO.2005.03.4934. PMID 16391296.
  12. URL: http://www.ncbi.nlm.nih.gov/omim/606597. Accessed on: 18 August 2010.
  13. Gallego Melcón, S.; Sánchez de Toledo Codina, J. (Jul 2007). "Molecular biology of rhabdomyosarcoma.". Clin Transl Oncol 9 (7): 415-9. PMID 17652054.