An 11-year-old African American boy presented to his pediatrician with bilateral neck swelling, difficulty swallowing, decreasing appetite, and right shoulder pain that had lasted for 3 months. The patient's mother informed the doctor that he had lost 2 kg in the past month. On physical examination, the boy had marked restriction of neck movement in all directions and bulky, bilateral cervical lymphadenopathy mainly localized in the posterior occipital region. Both lungs were clear, and there were no palpable lymph nodes in the supraclavicular or axillary areas. An examination of the oropharynx revealed an edematous and swollen pharyngeal wall with a slight deviation of the soft palate toward the right side. Laboratory investigations performed at that time showed a white blood cell count of 6.9 × 103/μL, a hemoglobin level of 15 g/dL, and an erythrocyte sedimentation rate of 6 mm/h. A computed tomography scan of the neck showed an irregular soft tissue mass in the posterior oropharynx and multiple ring-enhancing lesions, likely necrotic lymph nodes, along the posterior cervical chain. Magnetic resonance imaging showed that the lesion had invaded the clivus, the left petrous apex, the occipital bones, and the C1 to C2 vertebral bodies (Figure 1). Abdominal sonography did not show any renal mass lesions.
A biopsy of the enlarged neck lymph nodes showed a metastatic neoplasm that was replacing the entire lymph node. The neoplasm was formed by diffuse sheets of markedly pleomorphic malignant cells with interspersed mature lymphocytes. Nucleomegaly, eccentric nuclei, prominent nucleoli, and numerous mitotic figures were noted in the neoplastic cells (Figure 2; hematoxylin-eosin, original magnification ×400). The cytoplasm was eosinophilic and abundant with occasional perinuclear eosinophilic inclusions. Immunohistochemical stains showed strong positivity for pan-cytokeratin (Figure 3; pan-cytokeratin, original magnification ×250) and vimentin, whereas negative staining was seen with S100, leukocyte common antigen, desmin, smooth muscle actin, HHF-35, placental alkaline phosphatase, CD30, CD31, lysozyme, CD34, and anaplastic lymphoma kinase. Electron microscopy demonstrated numerous paranuclear whorls of closely packed arrays of intermediate filaments (Figure 4). The patient was administered appropriate chemotherapeutic agents.
What is your diagnosis?
Pathologic Diagnosis: Metastatic Malignant Extrarenal Rhabdoid Tumor
Rhabdoid tumor is a controversial entity whose very existence as a separate neoplasm has been called into question. This neoplasm usually shows a wide spectrum of histologic, immunophenotypic, and cytogenetic findings. Despite regional and lineage diversity, tumors with a rhabdoid phenotype are almost always rapidly fatal. This entity was first described in 1978 and was at first thought to be a “rhabdomyosarcomatoid variant of Wilms' tumor.”1 However, the absence of muscle differentiation led Haas et al2 to introduce the term “rhabdoid tumor of the kidney” in 1981. Subsequently, this neoplasm was defined as a distinct clinicopathologic entity different from Wilms tumor. Also, neoplasms with a histologic appearance similar to those arising in the kidney have been described in several extrarenal anatomic sites. These malignant extrarenal rhabdoid tumors (MERTs) have been seen over a broader range of patient ages and anatomic locations, but they share considerable morphologic and biologic similarities with their renal counterparts. Also, “composite” extrarenal tumors with identifiable “parent” neoplasms admixed with MERTs have been observed in numerous locations.3 Different locations of MERTs include the central nervous system, soft tissue, skin, urogenital tract, lung, heart, liver, thymus, and lacrimal gland. They are usually characterized by a high incidence of metastatic disease and a resistance to chemotherapy.
Histopathologically, MERTs are characterized by noncohesive single cells, clusters, and/or sheets of large malignant cells with abundant glassy or eosinophilic cytoplasm. The neoplastic cells typically have an eccentric vesicular nucleus and an extremely large nucleolus. The cytoplasm usually contains eosinophilic and periodic acid–Schiff-positive hyaline inclusions or globules. Histologic similarities between rhabdoid tumor and epithelioid sarcoma have been described,4 and some authors have suggested that the distinction between these 2 neoplasms is clinical rather than pathologic. Also, MERTs should be differentiated from melanomas, carcinomas, and other sarcomas with foci of rhabdoid differentiation. Electron microscopy shows the presence of intracytoplasmic whorls of intermediate filament.5 These filaments are paranuclear and are generally about 10 nm in size. Also, the cytoplasm may contain free ribosomes, a few mitochondria, a dilated rough endoplasmic reticulum, and lipid droplets.
The histogenetic origin of this designation remains obscure. A variety of antigens, including epithelial, mesenchymal, and even neural markers, have been detected in these neoplasms. Positivity for vimentin and/or cytokeratin or other epithelial markers, such as CAM 5.2, has been detected by immunohistochemical staining. Fanburg-Smith et al6 showed marked variability in the immunohistochemical expression of soft tissue rhabdoid tumors. Ninety-four percent of the cases were positive for vimentin, 59% were positive for pan-cytokeratin, and 76% stained with vimentin and epithelial markers simultaneously.6 Parham et al7 observed marked polyphenotypia with immunoreactivity to a wide array of antibodies against epithelial, glial, neural, and myogenic markers. They concluded that MERTs represent a heterogeneous group of neoplasms and suggested “poorly differentiated neoplasm with rhabdoid features” as an alternative term for these lesions. This polyantigenic expression also suggests that MERTs develop from pleuripotent cells capable of differentiating along different lines.
Cytogenetic analysis, fluorescent in situ hybridization, and loss of heterozygosity inquiries have shown that MERTs frequently contain translocations and/or deletions at chromosome segment 22q11.2.8 MERTs arising in the central nervous system have consistently shown monosomy 22 by fluorescent in situ hybridization studies. Schofield et al9 have described a loss of heterozygosity on 22q in a majority of renal rhabdoid tumors and have proposed the presence of a tumor-suppressor gene at this locus. This locus was found to contain the hSNF5/INI1 gene.10 This gene is thought to regulate the transcription of various human genes; however, the precise molecular pathways involved in the tumorigenesis of this lesion are still unknown. Some case studies have shown other cytogenetic aberrations, such as inv(11)(p13p15) and trisomy 7, in MERTs.
In summary, the existence of MERTs as discrete pathologic entities has been contentious in spite of frequent reports cited in the literature. The question remains as to whether this neoplasm represents a distinct clinicopathologic entity or a phenotype representing a final pathway shared by several high-grade malignancies. Despite variations at the cellular level, the “rhabdoid” morphology is consistently linked with aggressive biologic behavior and a poor clinical outcome.