College of American Pathologists
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2008 —August Case of the Month

Updated August 20, 2008


CAP Foundation August 2008 Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A seven-year-old boy presented with a painless paratesticular mass. A partial excisional biopsy was performed. Several fragments of tissue were submitted for histological examination.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2005, Case 09 and is an embryonal rhabdomyosarcoma (NOS).

Criteria for Diagnosis and Comments:
Fragments of tumor tissue comprising a malignant small blue cell tumor with areas of necrosis are evident. The bulk of the tumor is composed of undifferentiated round to oval cells arranged in nondescript sheets, with occasional areas demonstrating nests. The cells are tightly packed with little intercellular stroma.

In most sections of this case, differentiating cells containing abundant eosinophilic fibrillar cytoplasm pushing the round nucleus aside are noted. These cells represent round rhabdomyoblastic differentiation and are characteristic of embryonal rhabdomyosarcoma. In some sections, tumor cells have a clear or vacuolated cytoplasm representing abundant glycogen accumulation. However, abundant glycogen is also a feature of peripheral primitive neuroectodermal tumor (PPNET)/Ewing sarcoma and should therefore not be used as a diagnostic distinguishing feature between these two neoplasms. In a few sections, minor foci of anaplasia comprising lobated hyperchromatic nuclei are noted, but insufficient to classify the tumor as anaplastic. Support for the diagnosis of rhabdomyosarcoma is obtained from myogenin (myf4) and myoD1 immunopositivity in the nuclei (these markers are specific for skeletal muscle differentiation). Desmin and pan-actin (HHF35) are also expressed in the cytoplasm, but are not specific.

Embryonal rhabdomyosarcoma is a malignant small blue cell tumor with a predilection for pediatric patients (first two decades of life), being the most common malignant soft tissue tumor in this age group. Overall, the most common site of embryonal rhabdomyosarcoma is the head and neck (especially orbit and parameninges), followed by the genitourinary tract and deep soft tissue of the extremities, pelvis and retroperitoneum. Four histologic subtypes of embryonal rhabdomyosarcoma are recognized: embryonal (NOS), botryoid, spindle cell, and anaplastic. It is important to subtype these tumors as they carry different prognoses and require different therapies. Hence, it is an expectation to specify the subtype in the diagnosis line of the surgical pathology report. Surgery and multi-drug chemotherapy (+/- irradiation) have resulted in an improvement in patient survival over the last couple of decades.

Tumors in patients following chemotherapy or radiation may show evidence of skeletal muscle differentiation comprising bland, well-differentiated mature skeletal muscle cells. There is no role for further therapy in this context, as the fully differentiated cells apparently lose their ability to divide, proliferate, and metastasize. However, the presence of undifferentiated cells (even focal) is an indication for further therapy. Hence, thorough sampling is mandatory.

Desmoplastic small round cell tumor is composed of small round cells with a prominent stromal desmoplasia. Although frequently presenting in the abdominal cavity, these tumors may have rare presentations in a paratesticular location. Whilst the histogenesis of these tumors is uncertain, a consistent and distinctive complex pattern of simultaneous polyphenotypic differentiation is both characteristic and diagnostic in the morphological setting. The majority of cases are immunoreactive for epithelial (cytokeratin, EMA), muscular (desmin, vimentin) and neural (NSE) differentiation. In addition, nuclear expression of WT1 is usually demonstrated, and CD99 is positive in up to 28% of cases. The presence of t(11;22)(p13;q12) translocation is a consistent cytogenetic feature.

Tumors of the peripheral primitive neuroectodermal tumor/Ewing sarcoma (PPNET/EWS) group are malignant neoplasms comprising cells that vary from uniform small round nuclei with glycogen-rich cytoplasm and non-descript growth pattern to larger cells with more irregular nuclei, Homer-Wright rosettes and pseudorosettes. PPNET/EWS has a predilection for bone and soft tissue of the lower extremities and thorax but can develop in any bone or soft tissue site. In some areas the finding of eosinophilic or amphophilic cytoplasm may suggest the possibility of skeletal muscle differentiation. However, the tumor cells of PPNET/EWS express the MIC2 gene recognized by CD99 in nearly 100 percent of cases in a diffuse membranous staining pattern. Whilst the tumor cells of rhabdomyosarcoma uniformly express desmin and muscle-specific actin, CD99 is negative or only weakly and focally positive in under 10 percent of tumors. Typically PPNET/EWS demonstrates the unique translocation t(11;22)(q24;q12) in 80-90 percent of cases and the translocation t(21;22)(q22;q12) in the majority of the remaining cases.

Although unlikely in the paratesticular location, neuroblastoma enters the differential diagnosis of a malignant small round blue cell tumor. Comprising mostly neuroblasts, these tumors are subdivided into undifferentiated, poorly differentiated and differentiating forms depending on the percentage of cells showing ganglionic differentiation. The most primitive neuroblastomas are composed of sheets of small round cells that are divided into small lobules by delicate fibrovascular stroma. The tumor cells are mostly devoid of cytoplasm and have round to polygonal deeply staining nuclei similar to lymphocytes. With progressive differentiation, the neuroblasts acquire attenuated cytoplasmic processes (neurites) to form Homer-Wright rosettes. Significantly, the absence of muscle markers and MIC2 gene product is useful to rule out rhabdomyosarcoma and PPNET/EWS, respectively.

Lymphoblastic lymphoma enters the differential diagnosis as a malignant childhood small round blue cell tumor that may present with gonadal involvement. Precursor T-lymphoblastic lymphoma comprises about 85 percent of lymphoblastic lymphomas. Typically composed of small to medium sized blast cells with scant cytoplasm, the lymphoblasts are TdT positive, CD7 positive and cytoplasmic CD3 positive. Importantly, lymphoblastic lymphoma may also express CD99, a potential pitfall with PPNET/EWS.

Finally, when confronted with a “small blue cell tumor”, a small fragment of fresh tissue should be routinely snap frozen for potential molecular analysis, since characteristic translocations and fusion genes have been identified in many soft tissue neoplasms and may serve as a critical diagnostic tool in arriving at the correct diagnosis.

Supplementary Questions For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. Which tumor is characterized by a unique polyphenotypic immunohistochemical profile with epithelial (cytokeratin, EMA), muscular (desmin, vimentin) and neural (NSE) differentiation? A.  Desmoplastic small round cell tumor
B.  Embryonal rhabdomyosarcoma
C.  Lymphoblastic lymphoma
D.  Neuroblastoma
E.  Peripheral primitive neuroectodermal tumor/Ewing sarcoma
2. Which neoplasm is typically and uniformly CD99 (MIC2 gene product) negative? A.  Desmoplastic small round cell tumor
B.  Embryonal rhabdomyosarcoma
C.  Lymphoblastic lymphoma
D.  Neuroblastoma
E.  Peripheral primitive neuroectodermal tumor/Ewing sarcoma
3. Which is the most common malignant soft tissue tumor in the first two decades of life? A.  Desmoplastic small round cell tumor
B.  Embryonal rhabdomyosarcoma
C.  Lymphoblastic lymphoma
D.  Neuroblastoma
E.  Peripheral primitive neuroectodermal tumor/Ewing sarcoma


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  2. Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds): World Health Organization Classification of Tumours:Pathology and Genetics of Tumors of Haematopoietic and Lymphoid Tissues. IARC: Lyon; 2001.
  3. Kempson RL, Fletcher CDM, Evans HL, Hendrickson MR, Sibley RK. Atlas of Tumor Pathology: Tumors of the Soft Tissues. AFIP Fascicle 30. AFIP, Washington; 2001.
  4. Weiss SW, Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors, 4th Edition. Mosby, St. Louis; 2001.