Alveolar rhabdomyosarcoma with treatment-induced cytodifferentiation
Rhabdomyosarcomas are a group of soft tissue tumors that predominantly affect children and are characterized by some degree of skeletal muscle differentiation. They can be classified by their histologic features into several subtypes which carry prognostic significance. Variants with superior prognosis include botryoid and spindle cell rhabdomyosarcoma, both of which are considered variants of embryonal rhabdomyosarcoma. The group of tumors with intermediate prognosis is comprised of embryonal rhabdomyosarcomas (ERMS), and the poor prognosis category includes alveolar (ARMS) and undifferentiated variants and rhabdomyosarcomas with diffuse anaplasia (1-3).
ERMS is histologically characterized by alternating areas of dense, compact cellularity and loose, myxoid areas. Tumor cell appearance can range from stellate cells with amphophilic cytoplasm and central oval nuclei to differentiated cells with brightly eosinophilic cytoplasm, multinucleation and cytoplasmic cross striations. Typical ARMS consists of primitive cells that are arranged in clusters and nests surrounded by fibrovascular septa. Tumor cells align the septa in a picket fence-like fashion, whereas central cell clusters show some loss of cohesion and appear to float in the alveolus (1-3).
The tumor presented here provided some diagnostic challenges. In the initial biopsy, a diagnosis of rhabdomyosarcoma could be rendered confidently based on the immunohistochemical staining pattern with strong nuclear myogenin positivity and scattered positivity for desmin and HHF-35 (muscle specific actin). However, determination of the subtype was more difficult as the biopsy material consisted solely of patternless sheets of primitive cells with minimal myoblastic differentiation. The two variants that were considered in the differential diagnosis included a cellular ERMS and the solid variant of ARMS (3, 4). The latter variant is composed of similar cells as the typical variant of ARMS but lacks the fibrovascular septa (1-3). Because of the morphologically similar appearance, densely cellular areas of ERMS may be indistinguishable from solid ARMS, particularly in small samples. This diagnostic problem may be resolved by identification of one of the translocations associated with ARMS. Both the t(1;13) translocation (PAX7/FKHR) and the more common t(2;13) translocation (PAX3/FKHR) have been found in cases of solid ARMS (4). In our case, a PAX7/FKHR fusion transcript has been identified by RT-PCR, establishing a diagnosis of ARMS. This diagnosis was supported by the strong immunoreactivity for myogenin, as ARMS usually exhibit more extensive staining than ERMS (5).
Microscopic examination of the resection specimen revealed a very heterogeneous appearance. In some areas, the tumor showed similar features as the biopsy specimen and even exhibited focally a more classical alveolar growth pattern. In addition, numerous more differentiated rhabdomyoblastic cells were present with round or elongated shape, multinucleation and focal cytoplasmic striations. This degree of differentiation is typically not a feature of ARMS. The phenomenon of cytodifferentiation has been previously recognized as therapy-induced change (6, 7). Cytodifferentiation is a more frequent and prominent occurrence in botryoid and non-botryoid ERMS than in ARMS (6, 7). As seen in our case, areas of cytodifferentiation can sometimes intermingle with undifferentiated areas, a feature which is more commonly seen in ARMS than ERMS (6). Cytodifferentiation might be associated with longer survival and more favorable outcome, but evidence is still lacking that it is an independent prognostic marker.
Contributed by Julia Kofler, MD and Sarangarajan Ranganathan, MD