—  SHORT COURSE #52  —

Soft Tissue Tumors in Children and Adolescents:
A Morphologic Pattern Oriented Approach with Molecular and Genetic Correlations

Section 9 - Malignant Rhabdoid Tumor

Cheryl M. Coffin, M.D.
David M. Parham, M.D.


Clinical History:
A 6-month old girl presented with intermittent seizures and multiple skin nodules located on her back, near the paraspinal region. The lesions were freely moveable and well-circumscribed, and they appeared to be primarily situated within the subcutaneous fat. An excisional biopsy was performed, and following the diagnosis, MRI and CT scanning was performed of the abdomen and head. This revealed a paraventricular tumor located near the left parietal lobe. The lesion was isointense with grey matter had areas of apparent necrosis, cystic degeneration, and associated edema. Post-contrast images showed variable enhancement of the tumor. The lesion was excised but rapidly regrew with spinal cord metastases, and the child expired four months after the initial diagnosis.

Discussion and Differential Diagnosis:
This is an example of an extrarenal rhabdoid tumor. The discussion will focus on the diagnosis of rhabdoid tumor, its distinction from the variety of other lesions that contain rhabdoid elements, and its molecular features that may be useful in confirmatory studies.

Sections are taken from the brain tumor. They consist of curettings of tumor with meninges and Gelfoam packing material. There is extensive necrosis and hemorrhage with areas of acute inflammation. The tumor comprises sheets of round cells with eccentric oval nuclei, distinct cell borders, and moderate to abundant eosinophilic cytoplasm. The nuclei contain clear chromatin and prominent central nucleoli. The cytoplasm in some cells contains a rounded pink inclusion body with hyaline features. Mitoses are not prominent. Immunohistochemical stains for keratin, EMA, and vimentin revealed strong positivity, particularly in the inclusions. Stains for GFAP and myogenin were negative. Cytogenetic testing on tumor tissue revealed 45,XX,-22.

Rhabdoid tumors were first recognized as an entity by Beckwith and Palmer, when they compared the cytohistologic features and clinical outcome of a large cohort of childhood renal tumors accrued in the first National Wilms Tumor Study. They recognized that three histologic subgroups had a poor outcome, independent of tumor stage. These included the rhabdomyosarcomatoid, clear cell, and anaplastic varieties of Wilms tumor. Further studies indicated that only the anaplastic subtype should be considered a form of Wilms tumor, and the rhabdomyosarcomoid variety came be known as the rhabdoid tumor.

Infants comprised the principle patient population affected by renal rhabdoid tumors, and case reports soon appeared of similar lesions arising in extrarenal sites, including liver, thorax, soft tissues, skin, and brain. Many cases have been described in older patients, even elderly ones, but careful analyses revealed that cells with rhabdoid cytology could be found in a variety of carcinomas and sarcomas. Rhabdoid features are now recognized in some melanomas, colon and bladder carcinomas, epithelioid and desmoplastic small cell sarcomas, epithelioid malignant peripheral nerve sheath tumors, rhabdomyosarcomas, neuroendocrine carcinomas, and even some benign tumors such as meningioma and salivary gland adenoma. It is important to distinguish "true" rhabdoid tumors from their mimickers, as these are aggressive neoplasms that rarely respond to chemotherapy. Apparent rhabdoid tumors arising in older children or adults are particularly suspect.

Unusual features of rhabdoid tumors include their occasional presentation as skin lesions, prior to discovery of a large primary tumor elsewhere. At times this is masked by another cutaneous tumor such as hemangioma. Another unusual feature is the co-existence of visceral tumors and CNS tumors. The latter were originally called "teratoid-rhabdoid tumor", because they also have features of central PNET or a mixture of PNET and rhabdoid features.

Immunohistochemical stains can be useful in diagnosis of rhabdoid tumors, which characteristically display co-expression of vimentin and keratin. Neuroectodermal antigens such as synaptophysin, CD99, and NSE are also frequently positive. At times confusing results and expression of numerous markers may be seen, however. Of particular note is that myogenin stains should be negative, excluding rhabdomyosarcoma, but desmin stains may be positive on occasion. Electron microscopy may be helpful in diagnosis and typically shows intracytoplasmic whorls of intermediate filaments that comprise the cytoplasmic inclusion. These whorls often contain entrapped organelles. Depending on sampling, inclusions may not easily be found. Ultrastucture can help to exclude rhabdoid tumor mimics, although at times the inclusions turn out to be masses of tonofilaments or non-filamentous structures such as cytoplasmic lumens.

The identification of deletions on chromosome 22q11.2 has proven to be an excellent method for confirmation of a diagnosis of rhabdoid tumor. Other entities resembling rhabdoid tumor usually do not show this anomaly. A tumor suppressor gene known by a variety of names, including INI1, hSNF5, or SMARCB1, appears to be the key gene that is mutated or deleted in these tumors, whether they arise in the brain, kidney, or other locations. Interphase FISH has been used to demonstrate INI1 mutations and confirm the diagnosis of rhabdoid tumor. CNS tumors frequently show monosomy 22 with standard cytogenetics. Immunohistochemistry for INI1 can be used for ancillary diagnosis, as allelic loss results in negative immunostains in rhabdoid tumors, whereas other tumors are generally positive. Of note is that choroid plexus tumors may have similar genetic abnormalities, suggesting a linkage between the two neoplasms. Recently, loss of INI1 staining has been described in epithelioid sarcoma, further muddying the distinction between these neoplasms and rhabdoid tumors. Constitutional INI1 mutations can be inherited and lead to a cancer predisposition syndrome; some of these constitituation mutations appear to affect a second unidentified gene other than INI1. Mutation of INI1 may be acquired in composite tumors, although they are generally immunostain-positive.

Regardless of location, the diagnosis of rhabdoid tumor is a dreaded one for pediatric oncologists, as these are extremely aggressive neoplasms and the affected patients have a dismal outlook. Low stage lesions that are completely excised have the best prognosis.

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