Rhabdomyosarcoma in children – current pathologic and molecular classification

Introduction

Rhabdomyosarcoma (RMS) is the most common malignant solid tumour in children after neuroblastoma and nephroblastoma (Wilms tumour). This tumour accounts for 5% to 10% of all childhood tumours [1, 2, 3, 4, 5]. For all soft tissue sarcomas, RMS accounts for 19% of such cases in adults and 45% of cases in children. Rhabdomyosarcoma is the most common soft tissue malignant neoplasm in the latter age group. Rhabdomyosarcoma is derived from primary mesenchymal cells that show skeletal muscle differentiation. It was first described by Weber in 1854. About 90% of all RMS presentations are in individuals under 25 years of age, and almost 70% are in children under 10 years of age [1, 2, 3, 6]. The most common RMS location is in the head and neck region (35-40%), followed by the urogenital system, extremities, and torso [1, 2, 3, 6, 7].

Rhabdomyosarcoma aetiology and pathogenesis

The predisposing factors for the development of soft tissue sarcoma are unknown. Increased RMS morbidity is observed in individuals with genetic syndromes predisposing to carcinogenesis, such as Li-Fraumeni syndrome, Gardner syndrome, neurofibromatosis type I, and Beckwith-Wiedemann syndrome. The common co-occurrence of RMS with defects of the central nervous system, urogenital, gastrointestinal, and circulatory systems, and melanocytic nevi has been reported [3, 5, 8, 9, 10, 11, 12].

Nomenclature and pathologic classification

In formerly used pathologic classifications, RMS was divided into two main types: alveolar and embryonal [3, 5, 7, 13]. The embryonal type includes the botryoides and spindle cell subtypes. However, in the current WHO classification (World Health Organisation; WHO 2013) [14], four histological RMS types are recognised and classified as follows:
1. Embryonal rhabdomyosarcoma:
a. botryoides variant,
b. anaplastic variant.
2. Alveolar rhabdomyosarcoma:
a. solid variant,
b. anaplastic variant.
3. Pleomorphic rhabdomyosarcoma.
4. Spindle cell/sclerosing rhabdomyosarcoma.
It should be noted that pleomorphic RMS occurs most commonly in adults, but rare cases have been observed in children [14].
The College of American Pathology (CAP) classification of skeletal muscle-derived tumours also recognises ectomesenchymoma as part of this group of malignant neoplasms. Ectomesenchymoma is a neoplasm consisting of rhabdomyoblasts resembling the myosarcoma of both embryonal and alveolar type, with a distinctly higher presence of ERMS elements observed. The histology of the tumour also shows the presence of ganglion cells and foci of neuroblastomatous dedifferentiation. The current WHO classification of soft tissue and bone tumours places ectomesenchymoma in the same group with neurogenic neoplasms [14].
The American group of physicians specialising in RMS, “Children’s Oncology Group (COG)”, distinguishes the classical and solid ARMS variant, and typical, botryoid, spindle cell, sclerosing, dense, and epithelioid ERMS. Additionally, rare mixed-type RMS is listed. The rhabdomyosarcoma, not otherwise specified (RMS-NOS) category is restricted to tumours that are small and showing sampling or fixation artefact, or are necrotic, making a specific classification impossible [15].

Pathologic appearance of rhabdomyosarcoma

Rhabdomyosarcoma diagnosis should be based not only on the histopathological appearance but also on the immunohistochemical and molecular profiles. The histology of RMS shows cellular elements that are related to the structures resembling the cells of developing striated muscle (Fig. 1). Rhabdomyoblasts with a diverse level of atypia are the key cells in RMS diagnosis. The highly differentiated rhabdomyoblast is a round or oval cell that contains abundant acidophilic granular or fibrillar cytoplasm, with eccentric or centrally-located circular nuclei. Binucleation is commonly noted. Occasional large nucleoli are visible within nuclei [16] (Fig. 2). Vacuoles containing glycogen are sometimes visible in the cytoplasm. Rhabdomyoblasts can take many different forms –ribbon or tadpole-like, appearing similar to tennis rackets or spiders (Fig. 3). In less than 30% of diagnosed RMS, rhabdomyoblasts with distinct striations are observed. Detection of such a characteristic RMS cytological feature is difficult using standard haematoxylin and eosin staining. The striations can be easily visualised using a tricolour histochemical staining method, such as phosphotungstic acid haematoxylin (PTAH) (Fig. 4). However, most of the tumours are composed of less differentiated or undifferentiated rhabdomyoblasts with scant cytoplasm, and round or oval nuclei. The cellular edges of such myoblasts are star shaped. Sometimes RMS cells fuse and generate polynuclear cells that resemble multinucleated giant cells (Fig. 5) [17].

Embryonal rhabdomyosarcoma

The microscopic appearance of embryonal rhabdomyosarcoma (ERMS) shows rhabdomyoblasts of heterogeneous appearance. Undeveloped, round cells with a hyperchromatic nucleus and basophilic cytoplasm are common in low-cell-density regions embedded in a myxoid submucosa. High-cell-concentration regions are present around vessels and are organised in characteristic perivascular thickenings (Fig. 6). In association with poorly differentiated cells, better differentiated rhabdomyoblasts showing acidophilic cytoplasm, sometimes with cross-striation, are commonly observed. Overall, ERMS histology resembles a combination of the stages of the embryonal development of striated muscle: from the small, round, undifferentiated cells, through tadpole-like cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts (Fig. 7).

Embryonal rhabdomyosarcoma – botryoid variant

In the botryoid variant of ERMS, a so-called compact cambium layer (appearance analogous to the layer of plant cells that are present between xylem and phloem and cause the thickening of the plant) can be seen. These cells form the group of densely packed undifferentiated neoplastic cells just under the epithelium. The more hypocellular and mucoid areas of the neoplasm are observed under this layer (Figs. 8, 9).

Embryonal rhabdomyosarcoma – anaplastic variant

The anaplastic variant of ERMS is composed of large, anaplastic rhabdomyoblasts with hyperchromatic nuclei. These cells are often present as single cells between rhabdomyoblasts with various types of atypia (Fig. 10). They are highly polymorphous and contain a small amount of cytoplasm. This last characteristic is distinct from the pleomorphic type, where cells often contain abundant acidophilic cytoplasm. Atypical mitotic figures are also present.

Alveolar rhabdomyosarcoma

The alveolar RMS (ARMS) is characterised by the presence of poorly differentiated rhabdomyoblasts, which are slightly larger than the undifferentiated cells in ERMS. These cells are characterised by scant cytoplasm and large nuclei (Fig. 11). The histology of ARMS also shows differentiated rhabdomyoblasts with abundant acidophilic cytoplasm and characteristic neoplastic multinucleated giant cells. The neoplastic cells cover the thick strands of connective tissue with regressive changes in the form of sclerosis. The neoplastic cells aggregate in areas at the edges of fibrous septa to which the rhabdomyoblasts adhere in a single layer. In the central portion of such lesion, the cells lose this connection, undergoing necrosis and degeneration. Such foci can resemble a pulmonary alveolar structure (Figs. 12, 13).

Alveolar rhabdomyosarcoma – solid variant

In this variant of the tumour, the neoplastic cells have no connective tissue submucosa, and rhabdomyoblasts are present in various stages of differentiation forming extensive lobular structures. The cytological features of the cells are the same as in the classic form [14] (Fig. 14).
The WHO classification of bone and soft tissue tumours additionally lists rare ARMS variants without detailed characteristics including mixed alveolar and embryonal rhabdomyosarcoma and anaplastic alveolar rhabdomyosarcoma [14].

Pleomorphic rhabdomyosarcoma

Pleomorphic rhabdomyosarcoma is composed of the following cells: polymorphic, spindle, and multinucleated giant cells with abundant acidophilic cytoplasm. Sometimes cells with bizarre atypia are haphazardly arranged in the connective tissue submucosa (Fig. 15). Highly differentiated striated rhabdomyoblasts are rarely observed.

Spindle cell/sclerosing rhabdomyosarcoma

The spindle-cell variant is characterised by extensive histologic heterogeneity. Cells can be ribbon-shaped, embedded in sclerotic submucosa, or can form fascicular or elongated interwoven arrangements composing a so-called herring-bone pattern (Figs. 16, 17). The sclerosing subtype rarely occurs in children [18]. There is evidence that suggests a different biology and prognosis for the spindle-cell RMS subtype in children in comparison with ERMS [19]. Therefore, distinguishing between these two RMS groups is of crucial importance (Table I) [20, 21].

Immunohistochemical diagnostics

The diversity in RMS morphology often leads to significant difficulty in correct diagnosis. Therefore, utilisation of integrated diagnostic methods, including immunohistochemical and molecular methods, is necessary.
The use of immunohistochemical methods for RMS diagnosis in order to identify rhabdomyoblasts is a routine procedure. In cases of less differentiated tumours, the easiest method to detect rhabdomyoblastic differentiation of the sarcoma is the demonstration of expression of MyoD1 protein and myogenin (Myf4) (Figs. 18, 19). Positive nuclear staining in both markers is an important diagnostic criterion for RMS and is the gold standard in differential diagnosis with other neoplasms.
Furthermore, MyoD1 and myogenin have additional practical significance for distinguishing the ARMS from other RMS subtypes. Myogenin expression obtained in more than 50% of the neoplastic cells is highly suggestive of a diagnosis of ARMS [22, 23, 24]. Myogenin and MyoD1 are useful for distinguishing the classical ARMS and sclerosing RMS. Myogenin expression in sclerosing RMS is weak and focal, and in the case of ARMS, strong and diffuse. In contrast, the MyoD1 expression is strong and diffuse in sclerosing RMS. ARMS, however, exhibits variable MyoD1 expression [15]. Cytoplasmic expression of vimentin and desmin can be observed in poor or undifferentiated cells (Fig. 20), and expression of muscle actin and myoglobin, in differentiated rhabdomyoblasts.
Recently the importance of novel immunohistochemical markers as prognostic factors for RMS has been reported. Among others, the role of p53, bcl-2, MDR-1, and MIB1 (Ki67) expression is highlighted. The DNA ploidy status in cerralion with the clinical course of RMS was also analysed – hyperdiploid ERMS tumours showing a more favourable prognosis [25, 26].
Expression of other proteins evaluated the use of immunohistochemical techniques such as AP2i and P-cadherin appeared to be a selective ARMS marker. On the other hand, the expression of epidermal growth factor receptor (EGFR) and fibrillin-2 are characteristic for ERMS. EGFR and fibrillin-2 expression are correlated with the favourable course of the disease, while the presence of AP2i and P-cadherin is associated with a poor prognosis [27].

Differential diagnosis

The differential diagnosis with other tumours showing small cells with round and spindled configurations is based not only on the morphology of the cells but, above all, also on additional tests, particularly immunophenotyping [21] (Tables II, III). Various neoplasms can exhibit differentiation towards skeletal muscle, which can additionally hamper obtaining a correct diagnosis [28, 29, 30]. The differential diagnosis in this group of tumours includes: malignant Triton tumour, spindle cell carcinomas, sarcomatoid carcinomas, melanoma, liposarcoma, malignant teratoma, teratocarcinosarcoma, salivary carcinosarcoma, anaplastic thyroid carcinoma, nephroblastoma, and some tumours of the central nervous system.

Molecular diagnostics

The traditional clinical and pathological parameters are sometimes not sufficient to adequately define the clinical course and prognosis. Additionally, determining the RMS subtype is not always possible based on the pathologic examination alone. Hence, much recent attention has been devoted to the molecular distinctions of rhabdomyosarcoma. The analyses of cytogenetic changes have shown their usefulness in distinguishing subtypes of RMS. The most common translocations that are selectively characteristic for ARMS are t(2;13)(q35;q14) and t(1;13)(p36;q14), which lead to the generation of fusion genes, PAX3 (2q35) or PAX7 (1p36), respectively, with the gene encoding fork-head-region transcription factor – foxo1 (previous name fkhr) (13q14) [31]. The translocations mentioned above are present, respectively, in 56% to 85%, and 6% to 10% of all ARMS-type tumours, and these are either not observed or are only occasionally present in ERMS [31, 32]. Preliminary data shows that ARMS tumours with a PAX7/FKHR translocation exhibit a less aggressive course of disease in comparison with tumours having PAX3/FKHR translocation. However, ERMS-type tumours show changes in a number of chromosome pairs – 2, 7, 8, 11, 12, 13, and 20 – in as much as 25% to 50% of cases. The loss of 9 and 10 chromosome pairs is described in 20% to 30% of cases. Genome amplification is another change observed relatively often in RMS – in as many as 16% to 56% of tumours. In case of ERMS, the amplification covers the 12q13-q15 region, and in the case of ARMS it involves the 1p36 (PAX7-FOXO1), 2p24 (MYCN),12q13-q14, 13q14 (PAX7-FOXO1), and 13q31 (MIR17HG, encoding miR-17-92 microRNA) regions. RMS-type tumours also show relatively common loss of heterozygosity of the region located on chromosome 11p15.5 [33, 34].
Analysis of gene mutations have shown their common occurrence in RMS, potentially indicating their contribution in neoplastic pathogenesis. As many as 28% of ERMS tumours are found to have point mutations in KRAS, TP53, FGFR4, EGRF, PIK3CA, CTNNB1, CDKN2A, BRAF, and PTPN11 genes, indicating frequent occurrence in this tumour [33, 34]. However, in ARMS tumours these mutations occur only occasionally. Mutation of the MyoD1 – myogenic differentiation 1 – gene was observed in the spindle-cell subtype localised in head and neck and limb regions. This mutation is present in the DNA-binding element of the MyoD1 transcription factor, which leads to the generation of a protein product acting as a MYC oncogene. The mutation in MyoD1 is assosiated with poor prognosis [33, 34]. Although chemotherapy remains the primary treatment for child patients, the identification of point mutations in the previously mentioned genes may in the future be a useful diagnostic element in the targeted therapy of RMS. These therapies offer a new approach to increase the efficacy of RMS treatment. The most important of these are those blocking the signalling pathways of the epidermal growth factor receptor (EGFR, HER-1, ERBB1), which is a member of the group of tyrosine kinase receptors, consisting of three additional receptors that are similar in structure:
EGFR2/HER2/HER-2-NEU/ERBB2, EGFR3/HER-3/ERBB3, and ERBB4/HER4. Phosphorylated tyrosine kinase stimulates intracellular signal transduction by a cascade of other pathways such as RAS-RAF-MEK-MAPK-PI3K-AKT-JAK-STAT, which regulate processes of proliferation, apoptosis, and angiogenesis. Others are those that participate in the mTOR pathway distorting the integration of signals from proteins such as PI3K, AKT, and PTEN. This pathway harmonises with other IGF1-R-PI3K/AKT-mTOR and MAPK pathways.
The summary of molecular changes in RMS and possible targeted therapies can be seen in Table IV.

Clinico-surgical-pathologic classification

All types of RMS should be accepted as high-grade sarcomas [35]. The exception is pleomorphic RMS in adults, for which the grading system was established by Fédération Nationale des Centres de Lutte Contre le Cancer/American Joint Committee on Cancer (FNCLCC/AJCC). This system is based on the analysis of the histological type, the mitotic activity, and the level of necrosis in the tumour tissue [36]. The Paediatric Oncology Group (POG) introduced its own system for assessment of the malignancy level based on the histological type, presence, and amount of necrosis, and mitotic activity. However, the POG system does not apply in the case of RMS, where the most important prognostic factor is the histological type [37]. The present pathologic description of RMS is based on the CWS 2002, 2006, and RMS guidance 2014 European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) programs and includes the so-called polymorphous RMS in children and adolescents within the ERMS type. ERMS and its variants together with spindle-cell RMS are accepted as a favourable pathology, while ARMS with its solid variant is accepted as an unfavourable pathology. This classification is significant for the evaluation of the clinical stage.

The clinical stage of rhabdomyosarcomas

The most important aspect to determine the risk of tumour recurrence is clinical staging. For this purpose, the stage of disease defined before initiation of treatment (TNM Pretreatment Staging Classification), the surgical-pathologic group (IRS Clinical Group Classification), and histologic type of the neoplasm are taken into account. The neoplasm stage before treatment depends on tumour localisation, the extent of infiltration, lymph node involvement, and the presence of distant metastases. The surgical-pathologic group results from the level of the tumour resection completeness. Current prognostic classification of RMS in children (according to CWS-guidance Version 1.6.1. from 24.05.2014) combining all the classifications mentioned above is presented in Table V.
In summary, the current RMS classifications are based not only on the morphological but also on the immunohistochemical image. Further molecular classification should be considered in the future. The development of molecular diagnostics gives the opportunity not only to confirm the RMS diagnosis, but also to monitor residual disease during treatment and, more importantly, offers the possibility for the application of targeted therapy.

Part of the pathology slide photography is published thanks to the kindness and consent of Professor G. Petur Nielsen. These photographs are part of his archival collection.
The authors declare no conflict of interest.

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Address for correspondence

Ireneusz Dziuba
Pathology Department
University Hospital of Lord’s Transfiguration
Szamarzewskiego 82/84
60-569 Poznan, Poland
e-mail: mmid@wp.pl