Classification of rhabdomyosarcoma and its molecular basis

Abstract

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, has traditionally been classified into embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma (ARMS) for pediatric oncology practice. This review outlines the historical development of classification of childhood RMS and the challenges that have been associated with it, particularly problems with the diagnosis of "solid variant" ARMS and its distinction from ERMS. In addition to differences in clinical presentation and outcome, a number of genetic features underpin separation of ERMS from ARMS. Genetic differences associated with RMS subclassification include the presence of reciprocal translocations and their associated fusions in ARMS, amplification of genes in ARMS and its fusion subsets, chromosomal losses and gains that mostly occur in ERMS, and allelic losses and mutations usually associated with ERMS. Chimeric proteins encoded in most ARMS from the fusion of PAX3 or PAX7 with FOXO1 are expressed, result in a distinct pattern of downstream protein expression, and appear to be the proximate cause of the bad outcome associated with this subtype. A sizeable minority of ARMS lacks these fusions and shares the clinical and biological features of ERMS. A battery of immunohistochemical tests may prove useful in separating ERMS from ARMS and fusion-positive ARMS from fusion-negative ARMS. Because of limitation of predicting outcome solely based on histologic classification, treatment protocols will begin to utilize fusion testing for stratification of affected patients into low-risk, intermediate-risk, and high-risk groups.

1

Histological patterns seen with rhabdomyosarcoma. Embryonal rhabdomyosarcoma (ERMS), containing spindle cells with alternating dense and loose cellularity. B. Alveolar rhabdomyosarcoma (ARMS), showing round cells clustered into nests separated by fibrous septa. Note the periseptal rows and peripheral discohesion. C. Botryoid rhabdomyosarcoma, organized into polypoid structures lined by squamous epithelium with underlying cellular aggregates. D. Pleomorphic rhabdomyosarcoma, composed of differentiating neoplastic myocytes with nuclear enlargement and irregularity. E. Rhabdomyosarcoma containing a densely cellular component resembling ARMS and a less cellular component resembling ERMS. F. ARMS with solid cellular pattern, lacking septa but containing monotonous round cells. G. Sclerosing rhabdomyosarcoma, containing dense bands of collagen. Note the microalveolar pattern H. Anaplastic ERMS containing cells with large hyperchromatic nuclei that contrast with adjacent small cells.

1

Histological patterns seen with rhabdomyosarcoma. Embryonal rhabdomyosarcoma (ERMS), containing spindle cells with alternating dense and loose cellularity. B. Alveolar rhabdomyosarcoma (ARMS), showing round cells clustered into nests separated by fibrous septa. Note the periseptal rows and peripheral discohesion. C. Botryoid rhabdomyosarcoma, organized into polypoid structures lined by squamous epithelium with underlying cellular aggregates. D. Pleomorphic rhabdomyosarcoma, composed of differentiating neoplastic myocytes with nuclear enlargement and irregularity. E. Rhabdomyosarcoma containing a densely cellular component resembling ARMS and a less cellular component resembling ERMS. F. ARMS with solid cellular pattern, lacking septa but containing monotonous round cells. G. Sclerosing rhabdomyosarcoma, containing dense bands of collagen. Note the microalveolar pattern H. Anaplastic ERMS containing cells with large hyperchromatic nuclei that contrast with adjacent small cells.

1

Histological patterns seen with rhabdomyosarcoma. Embryonal rhabdomyosarcoma (ERMS), containing spindle cells with alternating dense and loose cellularity. B. Alveolar rhabdomyosarcoma (ARMS), showing round cells clustered into nests separated by fibrous septa. Note the periseptal rows and peripheral discohesion. C. Botryoid rhabdomyosarcoma, organized into polypoid structures lined by squamous epithelium with underlying cellular aggregates. D. Pleomorphic rhabdomyosarcoma, composed of differentiating neoplastic myocytes with nuclear enlargement and irregularity. E. Rhabdomyosarcoma containing a densely cellular component resembling ARMS and a less cellular component resembling ERMS. F. ARMS with solid cellular pattern, lacking septa but containing monotonous round cells. G. Sclerosing rhabdomyosarcoma, containing dense bands of collagen. Note the microalveolar pattern H. Anaplastic ERMS containing cells with large hyperchromatic nuclei that contrast with adjacent small cells.

1

Histological patterns seen with rhabdomyosarcoma. Embryonal rhabdomyosarcoma (ERMS), containing spindle cells with alternating dense and loose cellularity. B. Alveolar rhabdomyosarcoma (ARMS), showing round cells clustered into nests separated by fibrous septa. Note the periseptal rows and peripheral discohesion. C. Botryoid rhabdomyosarcoma, organized into polypoid structures lined by squamous epithelium with underlying cellular aggregates. D. Pleomorphic rhabdomyosarcoma, composed of differentiating neoplastic myocytes with nuclear enlargement and irregularity. E. Rhabdomyosarcoma containing a densely cellular component resembling ARMS and a less cellular component resembling ERMS. F. ARMS with solid cellular pattern, lacking septa but containing monotonous round cells. G. Sclerosing rhabdomyosarcoma, containing dense bands of collagen. Note the microalveolar pattern H. Anaplastic ERMS containing cells with large hyperchromatic nuclei that contrast with adjacent small cells.

1

Histological patterns seen with rhabdomyosarcoma. Embryonal rhabdomyosarcoma (ERMS), containing spindle cells with alternating dense and loose cellularity. B. Alveolar rhabdomyosarcoma (ARMS), showing round cells clustered into nests separated by fibrous septa. Note the periseptal rows and peripheral discohesion. C. Botryoid rhabdomyosarcoma, organized into polypoid structures lined by squamous epithelium with underlying cellular aggregates. D. Pleomorphic rhabdomyosarcoma, composed of differentiating neoplastic myocytes with nuclear enlargement and irregularity. E. Rhabdomyosarcoma containing a densely cellular component resembling ARMS and a less cellular component resembling ERMS. F. ARMS with solid cellular pattern, lacking septa but containing monotonous round cells. G. Sclerosing rhabdomyosarcoma, containing dense bands of collagen. Note the microalveolar pattern H. Anaplastic ERMS containing cells with large hyperchromatic nuclei that contrast with adjacent small cells.

1

Histological patterns seen with rhabdomyosarcoma. Embryonal rhabdomyosarcoma (ERMS), containing spindle cells with alternating dense and loose cellularity. B. Alveolar rhabdomyosarcoma (ARMS), showing round cells clustered into nests separated by fibrous septa. Note the periseptal rows and peripheral discohesion. C. Botryoid rhabdomyosarcoma, organized into polypoid structures lined by squamous epithelium with underlying cellular aggregates. D. Pleomorphic rhabdomyosarcoma, composed of differentiating neoplastic myocytes with nuclear enlargement and irregularity. E. Rhabdomyosarcoma containing a densely cellular component resembling ARMS and a less cellular component resembling ERMS. F. ARMS with solid cellular pattern, lacking septa but containing monotonous round cells. G. Sclerosing rhabdomyosarcoma, containing dense bands of collagen. Note the microalveolar pattern H. Anaplastic ERMS containing cells with large hyperchromatic nuclei that contrast with adjacent small cells.

1

Histological patterns seen with rhabdomyosarcoma. Embryonal rhabdomyosarcoma (ERMS), containing spindle cells with alternating dense and loose cellularity. B. Alveolar rhabdomyosarcoma (ARMS), showing round cells clustered into nests separated by fibrous septa. Note the periseptal rows and peripheral discohesion. C. Botryoid rhabdomyosarcoma, organized into polypoid structures lined by squamous epithelium with underlying cellular aggregates. D. Pleomorphic rhabdomyosarcoma, composed of differentiating neoplastic myocytes with nuclear enlargement and irregularity. E. Rhabdomyosarcoma containing a densely cellular component resembling ARMS and a less cellular component resembling ERMS. F. ARMS with solid cellular pattern, lacking septa but containing monotonous round cells. G. Sclerosing rhabdomyosarcoma, containing dense bands of collagen. Note the microalveolar pattern H. Anaplastic ERMS containing cells with large hyperchromatic nuclei that contrast with adjacent small cells.

1

Histological patterns seen with rhabdomyosarcoma. Embryonal rhabdomyosarcoma (ERMS), containing spindle cells with alternating dense and loose cellularity. B. Alveolar rhabdomyosarcoma (ARMS), showing round cells clustered into nests separated by fibrous septa. Note the periseptal rows and peripheral discohesion. C. Botryoid rhabdomyosarcoma, organized into polypoid structures lined by squamous epithelium with underlying cellular aggregates. D. Pleomorphic rhabdomyosarcoma, composed of differentiating neoplastic myocytes with nuclear enlargement and irregularity. E. Rhabdomyosarcoma containing a densely cellular component resembling ARMS and a less cellular component resembling ERMS. F. ARMS with solid cellular pattern, lacking septa but containing monotonous round cells. G. Sclerosing rhabdomyosarcoma, containing dense bands of collagen. Note the microalveolar pattern H. Anaplastic ERMS containing cells with large hyperchromatic nuclei that contrast with adjacent small cells.

2.

Cytological details of rhabdomyosarcoma. Embryonal rhabdomyosarcoma (ERMS) with densely cellular focus composed of spindle and polygonal cells with irregular nuclear contours (dense ERMS). B. Alveolar rhabdomyosarcoma composed of monomorphous cells with round, even nuclear contours (solid ARMS). For size comparison, this lymph node metastasis also contains an infiltrate of smaller lymphocytes.

2.

Cytological details of rhabdomyosarcoma. Embryonal rhabdomyosarcoma (ERMS) with densely cellular focus composed of spindle and polygonal cells with irregular nuclear contours (dense ERMS). B. Alveolar rhabdomyosarcoma composed of monomorphous cells with round, even nuclear contours (solid ARMS). For size comparison, this lymph node metastasis also contains an infiltrate of smaller lymphocytes.

3.

Myogenin staining patterns in rhabdomyosarcoma. A. Alveolar rhabdomyosarcoma. Almost all tumor cells strongly express myogenin. B. Embryonal rhabdomyosarcoma. Myogenin expression is seen in a minority of cells.

3.

Myogenin staining patterns in rhabdomyosarcoma. A. Alveolar rhabdomyosarcoma. Almost all tumor cells strongly express myogenin. B. Embryonal rhabdomyosarcoma. Myogenin expression is seen in a minority of cells.