The patient is a 69-year old man who presented with an enlarged lymph node in the left axilla. A core biopsy was performed.
Histological sections show a high grade sarcomatous neoplasm within a variably myxoid stroma. The tumor is composed of spindle and focally pleomorphic cells arranges in intersecting fascicles. Tumor cells show hyperchromatic fusiform nuclei, with moderate nuclear pleomorphism and high mitotic activity. Focal areas of rhabdomyoblastic differentiation, with more abundant eosinophilic cytoplasm, are also noted.
Immunohistochemical stains for cytokeratin (AE1/AE3), EMA, S-100, Melan-A, TTF-1, CD45, SMA, CD34, and nyoglobin are negative. Desmin is positive, and myogenin is focally positive. MyoD1 is focally positive, while CDK4 and MDM2 are negative. H3K27me3 expression is at least partially retained.
DIAGNOSIS: EMBRYONAL RHABDOSARCOMA
Rhabdomyosarcoma (RMS) is a primitive malignant soft tissue sarcoma arising from myogenic progenitors that have lost their capability to differentiate into skeletal muscle. Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma and accounts for up to 10% of all solid tumors in children.
The World Health Organization classifies rhabdosarcoma into several histologic subtypes, which have prognostic implications. Major categories include embryonal, alveolar, spindle cell/sclerosing and pleomorphic types. With the exception of the latter, rhabdomyosarcoma is uncommon in adults.
Embryonal RMS (ERMS) is the most common subtype of rhabdomyosarcoma; it is most common in children and accounts for less than 20% of all cases of RMS in adults. Despite having a skeletal muscle derivation, rhabdosarcoma may arise away from the skeletal muscle and originate in visceral organs, mucosa of the bladder and vagina, skin and central nervous system. The most common sites of origin for embryonal RMS are head and neck and genitourinary tract.
On microscopy, ERMS consists of small round blue cells with a subset of polygonal and spindle cells, embedded in a variable amount of myxoid stroma. Because the rhabdomyoblasts may display varying degrees of differentiation, the immunohistochemical studies confirming the myogenic derivation of the tumor are key to establishing correct diagnosis. Differential diagnosis of a high grade sarcomatoid neoplasm, such as in our case include a high grade malignant peripheral nerve sheath tumor with rhabdomyosarcomatous component (Triton tumor) and a dedifferentiated liposarcoma with divergent rhabdomyosarcoma. Because ERMS may demonstrate aberrant staining with a variety of markers, including cytokeratin, CD99, S100 neurofilaments, and CD20, these findings must be interpreted in a context of a panel of markers. Work-up of any small round blue cell tumor should include desmin, muscle-specific actin, myogenin, and MyoD1. Combined nuclear expression of the early myogenic transcriptional factors myogenin and MyoD1 has the highest sensitivity and specificity for RMS.
The prognosis of ERMS has markedly improved in the recent years with the use of multimodality treatment that utilizes surgery and chemoradiation. Unraveling its molecular mechanisms may help to identify potential targets for the molecular therapy in the future.
Embryonal rhabdomyosarcomas may result from sporadic or inherited mutations. Most ERMS cases have complex karyotypes with gains of chromosomes 2, 8, and 13 and allelic loss of 11p15. Recent genetic studies have suggested that reduced levels of H3K27me3 levels at the regulatory locus for the differentiation of the ERMS cells may play a crucial role in the pathogenesis of this cancer. Amplification of MDM2 gene has also been suggested as a mechanism in the development of RMS.
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