Ewing Sarcoma/Primitive Neuroectodermal Tumor (Pnet)



Ewing Sarcoma/Primitive Neuroectodermal Tumor (Pnet)


G. Petur Nielsen, MD

Andrew E. Rosenberg, MD










Ewing sarcoma is shown arising in the metadiaphysis of the humerus manifests as a fleshy mass centered in the medullary cavity, breaking through the cortex and forming a circumferential soft tissue mass.






Radiograph of a Ewing sarcoma shows a highly aggressive and ill-defined destructive mass in the proximal humerus. The mass has broken through the cortex and extended into the adjacent soft tissues.


TERMINOLOGY


Abbreviations



  • Ewing sarcoma (EWS)


  • Primitive neuroectodermal tumor (PNET)


Synonyms



  • Peripheral neuroepithelioma


  • Askin tumor


Definitions



  • Round cell sarcoma showing variable degree of neuroectodermal differentiation



    • Undifferentiated tumors have been diagnosed as Ewing sarcoma


    • Tumors demonstrating neuroectodermal differentiation by light microscopy, immunohistochemistry, or electron microscopy have traditionally been labeled PNET


ETIOLOGY/PATHOGENESIS


Neoplasm



  • Evidence suggests stem cell origin


CLINICAL ISSUES


Epidemiology



  • Incidence



    • Accounts for 6-10% of primary malignant bone tumors



      • Follows osteosarcoma and chondrosarcoma in frequency in adults, and osteosarcoma in children and adolescents


  • Age



    • Most patients between 10 and 15 years of age


    • Approximately 80% are younger than 20 years


  • Gender



    • Boys affected more frequently than girls (1.3-1.4:1)


  • Ethnicity



    • Striking predilection for whites (3/1,000,000); Africans, Asians, and Native Americans rarely affected (0.2/1,000,000)


Site



  • Can arise in any portion of skeleton



    • Usually develops in diaphysis or metadiaphysis of long tubular bones and flat bones of pelvis


  • Approximately 22% of cases arise in femur followed by ilium, tibia, humerus, fibula, and ribs



    • Tumors that originate in chest wall have been called Askin tumor


Presentation



  • Painful enlarging mass


  • Affected site is frequently tender, warm, and swollen


  • Some patients have systemic findings that mimic infection: Fever, elevated sedimentation rate, anemia, and leukocytosis


  • Pathologic fracture is an uncommon complication


Treatment



  • Usually treated with a combination of chemotherapy and surgery


  • Chemotherapy is usually given preoperatively, which allows for pathologic assessment of subsequent surgical specimen for effectiveness of drug regimen


  • Chemotherapy-induced necrosis ≥ 90% is considered a good response


  • Therapy-related cytologic changes of tumor cells are uncommon



    • Changes include ganglion cell differentiation, marked enlargement, hyperchromasia, pleomorphism, and presence of rhabdoid-like cells


  • Radiotherapy is reserved for tumors located in surgically inaccessible sites, for surgical beds in which tumors have been excised with inadequate margins, and for palliation



Prognosis



  • Effective chemotherapy has improved prognosis from 5-15% to 75% 5-year survival



    • At least 50% are long-term cures


  • Important factors influencing prognosis include stage of disease at time of diagnosis and site of tumor


  • Other important factors



    • Type of translocation, percentage of chemotherapyrelated tumor necrosis, presence of chimeric transcripts in cells from peripheral blood or bone marrow after treatment, and development of local recurrence


IMAGE FINDINGS


Radiographic Findings



  • Destructive and lytic


  • Poorly defined margins



    • Can lead to significant underestimation of the intraosseous extent on plain radiography, a feature that can be clarified by MR


  • Permeation of cortex usually results in concentric soft tissue mass that can be very large


  • Extraosseous tumor frequently erodes outer cortex producing “saucerization” of bone


  • Displaced periosteum deposits layers of reactive bone in onion skin-like or sunburst-like fashion


  • Tumor diminishes in size, sometimes completely, after therapy


MR Findings



  • Helpful in mapping intra- and extraosseous extent of tumor and relationship of mass to important anatomic structures


  • Low signal intensity on T1-weighted images


  • High signal intensity on T2-weighted images


  • May be useful in assessing post-chemotherapy tumor viability


CT Findings



  • Large, destructive intraosseous mass with extension into soft tissues


Bone Scan



  • Tumor has avid uptake of radionuclides


MACROSCOPIC FEATURES


General Features



  • Tan-white, fish flesh-like in appearance; usually transgresses cortex and periosteum, producing soft tissue mass



    • Soft tissue borders may be deceptively well circumscribed by pseudocapsule


  • Frequently contains areas of hemorrhage and necrosis


  • Thin layers of reactive bone underpin raised periosteum


  • Underlying osseous structure is eroded and destroyed


  • Intramedullary margins of tumor poorly defined


MICROSCOPIC PATHOLOGY


Histologic Features



  • Tumor cells are 1-2x size of lymphocytes with scant cytoplasm


  • Tumor cells grow in sheets or irregular islands delineated by dense fibrous tissue


  • Architectural features suggestive of neural differentiation traditionally include organoid growth pattern within which Homer Wright rosettes may be present


  • Cells have oval nuclei with finely distributed chromatin and inconspicuous nucleoli, as well as scant eosinophilic or clear cytoplasm


  • Cell nuclei in tumors with obvious neural differentiation are frequently slightly elongated and darkly staining


  • Occasionally, tumor cells are larger and have irregular nuclear contours and prominent nucleoli




    • Neoplasms with this morphology previously designated as atypical or large cell variant of Ewing sarcoma


  • Islands of tumor cells may show palisading and cording, known as adamantinoma-like variant


  • Mitoses may be infrequent or numerous


  • Necrosis may be extensive


  • Stroma is scant, lymphoid infiltrate absent, and supportive vascular tree is inconspicuous


  • Special histochemical stains (PAS) demonstrate glycogen in up to 75% of tumors


Ultrastructural Features



  • Primitive in appearance


  • Contain few organelles and may have abundant cytoplasmic glycogen



    • Small number of mitochondria, poorly developed Golgi complexes, free ribosomes, and inconspicuous rough endoplasmic reticulum present


  • Neural differentiation suggested by interdigitating cytoplasmic cell processes connected by primitive junctions, scattered microtubules, and neurosecretory granules


  • Definite tonofibrils and well-developed basal lamina can be identified in some keratin-positive tumors


ANCILLARY TESTS


Immunohistochemistry



  • Cells express vimentin, CD99 (90%), and FLI-1 (90%)



    • CD99 is also expressed by many other malignant small round cell tumors, including lymphoblastic lymphoma, small cell osteosarcoma, mesenchymal chondrosarcoma, and small cell carcinoma



      • Small cell osteosarcoma and mesenchymal chondrosarcoma are negative for FLI1


    • Negative staining for CD99 stain should raise possibility that tumor may not be EWS/PNET


    • Tumors with neuroectodermal differentiation express 1 or more neural markers including NSE, CD57, or S100


  • Neurofilament and keratin positivity is seen in approximately 20% of cases


Molecular Pathology



  • Approximately 85% harbor t(11;22)(q24;q12)


  • 5-10% have t(21;22)(q22;q12)


  • < 1% of tumors show EWS fusion with ETV1 (7p22), E1AF (17q12) or FEV (2q33)


  • Fusion genes generated from translocations play vital role in molecular genesis of neoplasms


  • Translocation results in chimeric proteins that function as aberrant transcription factors governing biological behavior


  • Some EWS negative tumors have been shown to harbor FUS/ERG fusion – t(16;21)



    • If the tumor is also FUS/ERG fusion negative, then possibility of CIC/DUX4 fusion should be considered


DIFFERENTIAL DIAGNOSIS


Malignant Lymphoma



  • Cells in large cell lymphoma are frequently larger than those of EWS/PNET



    • Cells in large cell lymphoma also have more cytoplasm, and their nuclei may be irregular, cleaved, and hyperlobated


  • Lymphoblastic lymphoma is composed of uniform round cells and, as with most lymphomas, frequently contains admixed benign infiltrating lymphocytes



    • Can express CD99 but are FLI-1 negative and TdT positive


  • Lymphomas express lymphoid antigens; ultrastructurally, cells have marginated chromatin, lack intercellular junctions, and do not contain glycogen


  • Chromosomal translocations associated with malignant lymphoma do not include those identified in Ewing sarcoma/PNET


Neuroblastoma



  • Metastatic undifferentiated neuroblastoma can be difficult to distinguish from EWS/PNET on strict histologic grounds



    • Neuroblastoma negative for CD99 and FLI-1; N-MYC is amplified


  • Helpful findings in poorly differentiated neuroblastoma are presence of neuropils and evidence of ganglion cell differentiation


  • Neuroblastoma has loss of chromosome 1p and does not have a translocation involving chromosome 22


Small Cell Osteosarcoma



  • If matrix is prominent, EWS/PNET is easily distinguished from small cell osteosarcoma



    • EWS may contain reactive woven bone that can cause confusion with osteosarcoma; look for osteoblastic rimming


Mesenchymal Chondrosarcoma



  • Contains areas of chondroid differentiation admixed with malignant small round cell component


  • Tumor has nodular architecture and prominent vascular tree that frequently has hemangiopericytomalike pattern, which is usually not present in EWS/PNET


DIAGNOSTIC CHECKLIST


Pathologic Interpretation Pearls



  • Sheets of malignant small round cells: Think EWS/PNET



SELECTED REFERENCES

1. Machado I et al: Molecular diagnosis of Ewing sarcoma family of tumors: a comparative analysis of 560 cases with FISH and RT-PCR. Diagn Mol Pathol. 18(4):189-99, 2009

2. Shing DC et al: FUS/ERG gene fusions in Ewing’s tumors. Cancer Res. 63(15):4568-76, 2003






Image Gallery




Imaging Features






(Left) Radiograph of EWS shows a large saucerization defect along the femoral shaft image causing thinning of the cortex. This results from the tumor permeating the cortex, forming an extraosseous soft tissue mass. A Codman triangle is seen proximally image. (Right) T1-weighted, contrast-enhanced coronal MR with fat saturation shows a Ewing sarcoma arising in the diaphysis of the femur and extending into adjacent soft tissues image, causing saucerization of the medial femoral shaft image.






(Left) Radiograph shows Ewing sarcoma arising in the diaphysis of the femur, producing a slight increase in density within the medullary cavity. The tumor has extended into adjacent soft tissues, causing secondary subtle saucerization defect image. (Right) MR shows Ewing sarcoma arising in the shaft of the mid diaphysis of the femur, forming a large, hyperintense mass in the adjacent lateral soft tissues image. The intramedullary component is barely visible in this image.






(Left) X-ray of a Ewing sarcoma arising in the proximal humerus shows a lucent lesion with areas of endosteal resorption and periosteal new bone formation image along the medial and lateral cortices. (Right) Coronal T2-weighted MR of a Ewing sarcoma shows hyperintense signal replacing the marrow in the proximal humeral shaft with permeation of tumor through an irregular thinned cortex. The linear dark signal perpendicular to the cortex image represents sunburst periosteal new bone.

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Jul 6, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Ewing Sarcoma/Primitive Neuroectodermal Tumor (Pnet)
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