The neoplasms described in this chapter are a heterogeneous group of tumors, with uncertain histogenesis and no known normal tissue counterpart. Each is characterized by its own distinctive clinical and pathologic features. All are translocation-associated.
As discussed in Chapter 4 , chromosomal aberrations have been found in virtually all tumor types, some of which are primary and clearly central to the pathogenesis of a given tumor. In contrast, others are secondary, probably occurring later in tumor development and progression. Approximately 20% of soft tissue sarcomas are characterized by a specific balanced translocation resulting in the creation of a fusion gene. The ability to detect these translocations by molecular methods such as fluorescence in situ hybridization (FISH), reverse transcriptase–polymerase chain reaction (RT–PCR), and next-generation sequencing is increasingly critical to the diagnosis and management of patients with these diseases.
Ewing Sarcoma
Ewing sarcoma (ES) is defined as a small round cell sarcoma with gene fusions involving one member of the FET family of genes (usually EWSR1 ) and a member of the ETS family of transcription factors. Ewing sarcoma was first described by Stout in his 1918 report of a 42-year-old man with an ulnar nerve tumor composed of rosette-forming undifferentiated round cells. Three years later, Ewing reported a round cell neoplasm in the radius of a 14-year-old girl, calling it a “diffuse endothelioma of bone,” and proposed an endothelial derivation. Over the following decades, there was much debate regarding the histogenesis of this neoplasm. It was not until 1975 that Angervall and Enzinger described the first ES arising in soft tissue ( extraskeletal Ewing sarcoma ). Subsequent reports confirmed the clinical and pathologic features of this tumor.
Also, in 1975, Seemayer et al. described peripheral primitive neuroectodermal tumors (PNETs) arising in the soft tissues that were unrelated to structures of the peripheral or sympathetic nervous system; subsequently, Jaffe et al. reported identical tumors in bone. In 1979, Askin et al. described the “malignant small cell tumor of the thoracopulmonary region” (Askin tumor) as having histologic features similar to those of PNET but with a unique clinicopathologic profile. With the advent of immunohistochemical, cytogenetic, and molecular genetic techniques, it is now clear that these tumors represent ends of a morphologic spectrum and are all part of what has been referred to as the “Ewing family of tumors.” , Identification of a common cytogenetic abnormality, t(11;22)(q24;q12), in ES and PNET clearly supports these neoplasms being histogenetically related. Since these early reports, numerous additional studies have found this translocation or variants involving 22q12, the site of the Ewing sarcoma ( EWSR1 ) gene, in almost all tumors in this family. , This chapter refers to these tumors simply as “Ewing sarcoma” (ES); the term PNET is now considered archaic.
Clinical Features
Most patients with ES are adolescents or young adults, the majority younger than 30 years. There is a slight male predilection, and the disease is rare in non-Caucasians. There is no evidence of familial predisposition or an association with environmental factors. Although some patients treated for ES develop secondary neoplasms, such as radiation-associated osteosarcoma or therapy-related acute myeloid leukemia, ES rarely occurs as a second neoplasm after therapy for another tumor.
ES may arise at virtually any anatomic site but usually occurs in the deep soft tissues of the extremities, most often the upper thigh and buttock, followed by the upper arm and shoulder. Tumors that are intimately attached to a major nerve may give rise to signs and symptoms related to diminished neurologic function. Less frequently, the tumor arises in the paravertebral soft tissues or the chest wall, often in close association with the vertebrae or the ribs. Well-characterized examples of ES, often with molecular confirmation, have been reported in virtually every anatomic site.
In general, ES presents as a rapidly growing, deeply located mass measuring 5–10 cm in greatest diameter. Superficially located cases occur but are uncommon. The tumor is painful in about one-third of cases. If peripheral nerves or the spinal cord is involved, there may be progressive sensory or motor disturbances. As with other round-cell sarcomas, the preoperative duration of symptoms is usually less than 1 year. Unlike neuroblastoma, catecholamine levels are within normal limits. Computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) are a routine part of the evaluation to determine anatomic relationships, the presence of distant disease, and the extent of therapeutic response to (neo)adjuvant therapy.
Gross and Microscopic Findings
The gross appearance of the tumor varies. In general, it is multilobulated, soft, and friable, rarely exceeding 10 cm in its greatest diameter. The cut surface has a gray-yellow or gray-tan appearance, often with large areas of necrosis, cyst formation, or hemorrhage. Despite the extensive necrosis, calcification is rare ( Fig. 34.1 ).
Gross photograph of Ewing sarcoma with a fleshy tan cut surface.
There is a spectrum of histologic change in the Ewing family of tumors; in the older literature, criteria distinguishing ES, so-called atypical ES (large cell variant), and PNET varied. In a large clinicopathologic study of this family of tumors, based on morphologic criteria alone, Llombart-Bosch et al. classified 280 cases as conventional ES, 53 as PNET, and 80 as atypical ES. Because these lesions comprise a spectrum of histogenetically related tumors, the precise criteria for designating a tumor as an extraskeletal ES, atypical ES, or PNET are less critical. Therefore, cases across the spectrum can simply be labeled “Ewing sarcoma”. The morphologic spectrum of this family of tumors is now known to include adamantinoma-like cases, keratin-positive tumors, and rare desmin-positive cases. , , , As discussed later, cases with classic morphologic features can be accurately diagnosed using light microscopy with ancillary immunohistochemistry (IHC). However, given the broad morphologic spectrum, genetic confirmation is essential for the diagnosis of unusual morphologic variants, as well as in select circumstances (e.g., unusual immunophenotype, entry into clinical trial).
The histologic features of classic ES include a solidly packed, lobular pattern of strikingly uniform round cells ( Figs. 34.2 to 34.12 ). The individual cells have a round or ovoid nucleus with a distinct nuclear membrane, fine powdery chromatin, and one or two inapparent or small nucleoli. Multinucleated giant cells are not seen. The cytoplasm is poorly defined, scanty, pale staining, and, in many cases, irregularly vacuolated as a result of intracellular deposits of glycogen ( Figs. 34.5 and 34.6 ). Intracellular glycogen is present in most cases, but the amount varies from tumor to tumor and sometimes in different portions of the same neoplasm. Glycogen droplets may compress and indent the nucleus ( Fig. 34.6 ). The number of mitotic figures varies, and, in many cases, the paucity of mitotic figures contrasts with the immature appearance of the neoplastic cells.
A, Low-power view of extraskeletal Ewing sarcoma characterized by lobular round cell pattern of striking uniformity. B, Typical low-power view of the monotonous appearance of this tumor.
Extraskeletal Ewing sarcoma composed of sheets of relatively uniform round cells.
A-B, Primitive cells in Ewing sarcoma with finely stippled chromatin pattern.
Ewing sarcoma with clear cytoplasm secondary to glycogen deposits.
A-B, Cytoplasmic vacuoles secondary to deposition of intracellular glycogen often indent the nuclei in Ewing sarcoma.
Hemorrhagic zone in extraskeletal Ewing sarcoma resembling a vascular neoplasm.
Alveolar pattern in Ewing sarcoma caused by degeneration.
Necrosis and crushed cells in Ewing sarcoma.
Zonal necrosis in Ewing sarcoma.
A-B, Ewing sarcoma composed of sheets of larger cells, so-called large cell or atypical Ewing sarcoma.
High-power view of large cell Ewing sarcoma.
Although the tumor is richly vascular, the thin-walled vessels are compressed and obscured by the closely packed tumor cells; this rich vascularity is often discernible only in areas of degeneration and necrosis. On occasion, ES may show a pseudovascular or pseudoalveolar pattern caused by small, fluid-filled pools or blood lakes amid the solidly arranged tumor cells ( Figs. 34.7 and 34.8 ). This feature occasionally is misinterpreted as evidence of angiosarcoma or alveolar rhabdomyosarcoma by those unfamiliar with this secondary change. The association of distinct vascular structures with degenerated or necrotic ghost cells is a common, striking feature ( filigree pattern ) ( Figs. 34.9 and 34.10 ). Approximately 75% show these classic morphologic features. A minority of cases display moderate nuclear enlargement, irregular nuclear contours, and frequently prominent nucleoli, corresponding to the atypical or large cell variant of ES ( Figs. 34.11 and 34.12 ).
The so-called adamantinoma-like ES, originally described by Bridge et al., is a rare tumor, and it is controversial whether it is a variant of ES or a separate entity. A recent methylation study by Fritchie et al. clearly demonstrated that these tumors form a distinct methylation cluster, segregating from ES. This supports the view that these tumors should be considered a distinct entity, although, at this point, adamantinoma-like tumors are treated identically to more conventional Ewing sarcoma.
Adamantinoma-like tumors have accounted for up to 5% of cases in some consultation-based series of ES, but are much less common in routine practice. These tumors show a distinctly nested, epithelioid growth pattern with striking stromal desmoplasia ( Fig. 34.13 A-C). The nests of tumor cells may display prominent peripheral nuclear palisading and contain large polygonal cells with irregularly contoured, hyperchromatic nuclei, prominent nucleoli, and moderate amounts of cytoplasm ( Fig. 34.13B ). , Rarely, squamous pearls may be seen ( Fig. 34.13D ). Immunophenotypically, in addition to expressing markers of conventional ES (e.g., CD99, NKX2.2) ( Fig. 34.14A and B ), adamantinoma-like ES typically show strong, uniform expression of keratins, including high-molecular-weight (HMW) keratins, as well as the basal cell/squamous cell-associated marker p40. Adamantinoma-like tumors most often harbor the EWSR1::FLI1 gene fusion but can also harbor FUS rearrangements. , ,
A, Nested growth pattern with surrounding desmoplasia in adamantinoma-like Ewing sarcoma. B, Higher-power view.
C, Prominent peripheral palisading and surrounding desmoplasia. D, Adamantinoma-like Ewing sarcoma with squamous pearls.
Courtesy Dr. Justin Bishop, University of Texas-Southwestern, Dallas, TX.
Despite unusual morphologic features, adamantinoma-like Ewing sarcoma typically show diffuse, and nuclear expression for NKX2.2 ( A ) and membranous expression for CD99 ( B ).
These unusual tumors are typically diffusely positive with pan-keratin antibodies (shown), and may express basal cell markers, such as high-molecular-weight keratins, p63 and p40 ( C ).
Approximately 15% of tumors form rosettes, which are similar to those seen in neuroblastomas and contain a central solid core of neurofibrillary material ( Homer Wright rosette ) ( Figs. 34.15 and 34.16 ). Rarely, the rosettes resemble those of retinoblastoma and contain a central lumen or vesicle ( Flexner-Wintersteiner rosette ). Rare cases of ES with extensive neural differentiation, including neuropil and ganglion cells resembling ganglioneuroblastoma, have been described. Some tumors are composed of cords or trabeculae of small round cells. These areas resemble a carcinoid tumor or a small cell undifferentiated carcinoma. However, histogenetically, they are properly compared to primitive neuroepithelium. Exceptionally, ES may show evidence of cartilaginous or osseous differentiation.
A-B, Ewing sarcoma with distinctive lobular architecture and numerous Homer Wright rosettes apparent at low magnification.
A-B, Ewing sarcoma with Homer Wright rosettes.
Immunohistochemical Findings
For many years, the diagnosis of ES was essentially an immunohistochemical diagnosis of exclusion. Beginning in the early 1990s, however, numerous studies confirmed the utility of the product of the MIC2 gene (CD99) in recognizing this group of tumors, confirming the high sensitivity of this marker for ES ( Fig. 34.17A ). The MIC2 gene is a pseudoautosomal gene located on the short arms of the sex chromosomes; its product is a membranous glycoprotein (CD99) that can be detected on IHC using a variety of antibodies, including 12E7, HBA71, and O13. Although initially believed to be highly specific for ES, it is now well recognized that most other round cell tumors in the differential diagnosis occasionally show membranous immunoreactivity for CD99 ( Table 34.1 ). These include lymphomas (particularly T-lymphoblastic lymphoma and precursor B-lymphoblastic lymphoma ), Merkel cell carcinoma, small cell carcinoma, rhabdomyosarcoma, small cell osteosarcoma, desmoplastic small round cell tumor, mesenchymal chondrosarcoma, and CIC -rearranged sarcomas. Notably, childhood neuroblastomas do not express CD99. Given the high sensitivity but poor specificity of CD99, it is best considered a “screening marker” for ES and should always be used as part of a panel of immunostains. CD99 expression in ES is typically diffuse and membranous; patchy (or absent) CD99 expression in a “Ewing-like” round cell sarcoma should always raise concern for a CIC- or BCOR -rearranged tumor (see later).
A , Strong and membranous CD99 immunoreactivity in Ewing sarcoma. B , Diffuse nuclear NKX2.2 immunoreactivity in Ewing sarcoma.
Table 34.1
Immunohistochemical Analysis of Round Cell Tumors
| CD99 | TdT | Myogenin | Desmin | NKX2.2 | ETV4 | WT1 | BCOR | DUX4 | |
|---|---|---|---|---|---|---|---|---|---|
| Ewing sarcoma | + | − | − | − | + | Rare (focal) | − | − | − |
| ARMS | 15% | − | + | + | − | − | − | − | − |
| Lymphoblastic lymphoma | >90% | + | − | − | − | − | − | − | − |
| DSRCT | 20% | − | − | + (dotlike) | 20% | 20% | + | − | − |
| CIC -rearranged sarcoma | 85% (patchy) | − | − | − | 5% | + | + | − | + |
| BCOR -rearranged sarcoma | 40% (patchy) | − | − | − | − | − | − | + | − |
ARMS, Alveolar rhabdomyosarcoma; DSRCT, desmoplastic small round cell tumor.
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