Case of the Month: Thigh

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2014, case 02, and is an extrarenal malignant rhabdoid tumor.

The clinicopathologic findings in this patient’s case support a diagnosis of extrarenal malignant rhabdoid tumor (EMRT). EMRT is a rare malignant soft tissue neoplasm primarily affecting infants and young children. Extrarenal tumors are most commonly encountered as axial and paravertebral lesions and within the extremities. The tumor is more common in males than females. Rhabdoid tumors are most commonly encountered in the kidney and central nervous system. EMRT are also associated with coexisting primitive neuroectodermal tumors of the central nervous system. Gross pathologic findings of the tumor typically include a soft, fleshy tan to tan-white tumor with invasive, nonencapsulated appearance. Histologic features of these tumors include epithelioid cells with eccentric, hyperchromatic nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm with round, perinuclear hyaline intracytoplasmic PAS positive inclusions. Electron microscopic study documents that intracytoplasmic hyaline inclusions include aggregates of intermediate filaments consisting of both keratins and vimentin. Immunohistochemically, tumor cells stain for epithelial membrane antigen (EMA), cytokeratin, and vimentin, but are negative for INI-1, a protein which is critical for proper DNA maintenance. Lack of staining for INI-1 is not specific for EMRT, as epithelioid sarcomas may also be negative for INI-1. EMRT has also been reported to express CD99, S100 protein, synaptophysin, smooth muscle actin, and muscle specific actin. Myogenin and MyoD1 are negative in these tumors. EMRT usually contain deletion or mutation of the INI-1 gene located on chromosome 22q. Synonyms for the INI-1 gene include hSNF5, SMARCB1, and BAF47. It is important to note that a variety of tumors contain rhabdoid cells including synovial sarcoma, rhabdomyosarcoma, paraganglioma, malignant melanoma, epithelioid sarcoma, neuroblastoma, some adenocarcinomas (renal cell, adrenocortical), desmoplastic small round cell tumor, and leiomyosarcoma, among others; therefore, it is necessary to rule out these tumors prior to rendering a diagnosis of primary EMRT. Essentially no effective treatments are available for this tumor type, thus the prognosis is generally very poor. Fewer than 50% of patients survive to 5 years regardless of the therapy employed.

The classical and proximal types of epithelioid sarcoma are also diagnostic considerations since this tumor contains epithelioid cells with hyaline inclusions giving tumor cells a rhabdoid appearance. The classical form of epithelioid sarcoma is usually encountered in the upper extremity including fingers, hands, and lower arm and present as one or more ulcerated cutaneous nodules, while the proximal type epithelioid sarcoma occurs primarily in the pelvis, perineum, and genital tract. Many consider proximal type epithelioid sarcoma to be a variant of EMRT. Unlike patients diagnosed with EMRT, epithelioid sarcoma occurs most commonly in adolescents and young adults. While epithelioid sarcomas sometimes contain rhabdoid cells, there is a spectrum of histologic features encountered. Some tumors contain bland-appearing epithelioid cells growing in sheets or nodules containing central necrosis, while some tumors show a spindled morphology. Epithelioid sarcomas may also contain pseudovascular changes and, more rarely, metaplastic bone. Epithelioid sarcomas contain an immunoprofile overlapping with EMRT. Both types of tumor are immunoreactive for low- and high-molecular weight cytokeratins and vimentin. Up to 90% of epithelioid sarcomas also show loss for INI-1. Unlike EMRT, epithelioid sarcomas express CD34 in up to 50% of cases. The prognosis for epithelioid sarcomas is similar to EMRT.

Embryonal rhabdomyosarcoma containing rhabdoid cellular features may also be considered in the differential diagnosis in this patient given the patient's age and histology of the tumor. Embryonal rhabdomyosarcoma is the most commonly encountered soft tissue sarcoma and the most commonly encountered type of rhabdomyosarcoma in children, primarily occurring in children less than 16 years of age. The most commonly affected anatomic sites include the genitourinary system and the head and neck region. Proximal extremity involvement by this tumor, as seen in this patient, would not typically fit with a diagnosis of embryonal rhabdomyosarcoma. The histologic features of embryonal rhabdomyosarcoma are variable. The conventional variant of the tumor demonstrates sheets of tumor cells ranging from spindle-shaped cells to classical rhabdomyoblasts containing round nuclei and eccentric eosinophilic cytoplasm. Unlike EMRT, no consistently encountered molecular abnormalities have been described to date. Immunohistochemistry is most helpful in discriminating between EMRT and embryonal rhabdomyosarcoma. Unlike EMRT, embryonal rhabdomyosarcoma is typically negative for cytokeratin and is usually positive for INI-1 by immunohistochemistry. In addition, rhabdomyosarcoma is characterized by immunoreactivity for desmin, myogenin, and MyoD1.

Given the patient's age and location of the tumor, alveolar rhabdomyosarcoma may also be a diagnostic consideration. Alveolar rhabdomyosarcoma is rare and most frequently involves the deep soft tissues of the extremities, so this entity would certainly be considered in a young child presenting with an extremity mass. This tumor most commonly affects children and young adults, primarily between the ages of 2 and 20 years. Histologic features of alveolar rhabdomyosarcoma includes a small round, blue cell tumor with variable degrees of rhabdomyoblastic differentiation, but these tumors are also usually characterized by nests of tumor separated by fibrovascular septa and scattered multinucleated giant cells. EMRT is most likely confused with the solid variant of alveolar rhabdomyosarcoma, a subtype which is characterized by sheets of round, dyscohesive cells with variable rhabdomyoblastic differentiation. Immunohistochemistry, cytogenetic and molecular pathology are useful in distinguishing between EMRT and alveolar rhabdomyosarcoma. Immunohistochemical features of alveolar rhabdomyosarcoma are similar to embryonal rhabdomyosarcoma and include staining for desmin, myogenin, and MyoD1 with no loss of INI-1 staining and absence of cytokeratin immunoreactivity.

The translocation t(2;13)(q35;q14) leads to the juxtaposition of the PAX3 gene located on chromosome 2 with the FOXO1 (FKHR) gene located on chromosome 13. In a subset of alveolar rhabdomyosarcomas the variant translocation t(1;13)(p36;q14) leads to the juxtaposition of the PAX7 gene located on chromosome 1 with the FOXO1 gene located on chromosome 13. The solid variant of alveolar rhabdomyosarcoma may not show PAX-FOXO1 fusion products. Like EMRT, essentially no effective therapy is available. The prognosis for alveolar rhabdomyosarcoma is typically worse than embryonal rhabdomyosarcoma.

Nonsarcomatous tumors may also be considered given the clinicopathologic features of this case. Anaplastic large cell lymphoma (ALCL), a T cell lymphoma, may sometimes be confused with a poorly differentiated epithelioid cell tumor and rhabdomyosarcoma. This type of lymphoma is typically characterized by cells with eccentric horseshoe or kidney-bean shaped nuclei, cells classically referred to as hallmark cells. A prominent perinuclear eosinophilia is also typical of hallmark cells, features which may be confused with the cytoplasmic eosinophilia of rhabdoid tumors. The tumor also contains other hints of the diagnosis including a variable admixture of lymphocytes, histiocytes, and neutrophils. These tumors can be separated into two main categories: ALK positive and ALK negative. ALK positive ALCL is most commonly encountered in the pediatric population and may involve lymph nodes and extranodal sites including bone, skin, and gastrointestinal tract. Immunohistochemistry can help differentiate between ALCL and a soft tissue tumor like EMRT or rhabdomyosarcoma. ALCL is typically positive for CD30, one or more T-cell antigens, EMA, galectin-3, and ALK. In addition, ALCL carries the t(2;5).

1. Which of the following immunohistochemical markers is negative in extrarenal malignant rhabdoid tumor?
   
   1. Cam 5.2
   2. Epithelial membrane antigen
   3. INI-1
   4. Pan-cytokertain
   5. Vimentin
2. Which of the following immunostains is useful in distinguishing extrarenal malignant rhabdoid tumor from classical epithelioid sarcoma?
   
   1. INI-1 immunostaining characteristics
   2. Keratin immunoreactivity
   3. MyoD1 immunoreactivity
   4. Negative CD34 immunoreactivity
   5. Synaptophysin immunoreacitivity
3. Which of the following cytogenetic abnormalities do extrarenal malignant rhabdoid tumors classically demonstrate?
   
   1. Deletion of chromosome 17p
   2. Deletion of chromosome 22q
   3. t(1;13)
   4. t(2;13)
   5. t(X;18)

1. Folpe AL, Inwards CY. Bone and Soft Tissue Pathology. Philadelphia, PA: Elsevier; 2010.
2. Machado I, Noguera R, Santonja N, et al. Immunohistochemical study as a tool in the differential diagnosis of pediatric malignant rhabdoid tumor. Appl Immunohistochem Mol Morphol. 2010;18(2):150-158.
3. Weiss SW, Goldblum JR. Soft Tissue Tumors. Philadelphia, PA: Elsevier; 2008.

2014
Noel A. Brownlee, MD, PhD FCAP
Surgical Pathology Committee
Bon Secours Saint Francis Health System
Greenville, SC

1. INI-1 (c). 
2. Negative CD34 immunoreactivity (d). 
3. Deletion of chromosome 22q (b).