Contributed by Louis Samson, MD and Eduardo Zambrano, MDFINAL DIAGNOSIS
Sarcoma with BCOR genetic alterations, morphologically consistent with a Primitive Myxoid Mesenchymal Tumor of Infancy (PMMTI).
DISCUSSION
Sarcomas with BCOR genetic alterations are uncommon and affect mainly soft tissues and bones. Their epidemiology and clinical presentation vary according to their underlying genetic alterations. Sarcomas with BCOR internal tandem duplication (ITD) usually occur within the first year of life and can be seen congenitally. Their clinical presentation is protean, with a soft tissue mass formation of varying size [1]. They are mostly seen in the soft tissues of the trunk, retroperitoneum, and head and neck. BCOR-fusion sarcomas (most common is BCOR-CCNB3, but also BCOR-MAML3, ZC3H7B-BCOR, and others [2]) affect older children and young adults (90% before 20 years of age) and show a striking male predilection (M:F ratio 4.5:1) [3]. They arise slightly more frequently in the bones, and are seen mainly in the pelvis, lower extremities, head and neck, lungs, and kidneys. They usually manifest clinically as local pain or swelling [1]. Small round cell sarcomas with YWHAE-NUTM2B fusion are also considered part of the BCOR family tumors as they are associated with BCOR upregulation and share morphologic features with other subgroups [1]. They affect predominantly the viscera like the kidneys and uterus [1, 4].
Since the identification of BCOR as an oncogenic gene, several entities have been shown to harbor BCOR rearrangement. Notable examples are clear cell sarcomas of the kidney [1], a subset of high-grade endometrial stromal sarcomas [4], and high-grade neuroepithelial tumor of the central nervous system with BCOR ITD [5]. Additional research is needed in order to determine if those entities should be considered as part of the BCOR-rearranged sarcoma family.
Histologically, sarcomas with BCOR genetic alterations have a wide morphological spectrum, showing undifferentiated primitive round cells, elongated to short spindle cells, or an admixture of both [1, 2, 6]. Architecturally, these tumors can form sheets of varying cellularity embedded in a myxoid to sclerotic stroma. Short intersecting fascicles may also be appreciated in spindle cell-rich lesions. They most often show a rich vascular network of small arciform capillaries, sometimes reminiscent of chicken-wire [1, 2]. The neoplastic cells typically display ill-defined eosinophilic cytoplasm but may also show cytoplasmic vacuoles or have a rhabdoid morphology [1, 2, 6]. Monotonous, mildly atypical, round to irregular nuclei with inconspicuous nucleoli are typically seen. Soft tissue tumors forming variably cellular sheets of primitive round cells set in a myxoid stroma, with a delicate capillary meshwork are classic examples of BCOR-ITD related sarcomas. When seen in the soft tissues of an infant, they are referred to as PMMTI [7]. It is important to note, nonetheless, that significant morphological overlap exists between all molecular subtypes of BCOR-rearranged sarcomas, and that definitive diagnosis requires an integration of the clinical, histological, and molecular features [2, 3, 6].
Immunophenotypically, all subtypes of sarcomas with BCOR rearrangements express BCL1, SATB2, and TLE1 [1, 8, 9]. BCOR immunohistochemical stain is strongly positive in 92.9 to 100% of cases but is not entirely specific, and must show diffuse and strong nuclear staining to be considered as such [1, 6, 8, 9]. BCL6 and CD99 may also be expressed [1, 6].
The differential diagnosis of sarcomas with BCOR genetic alterations is broad owing to its non-specific clinical presentation and highly variable morphology. They are currently classified as being a type of undifferentiated small round cell sarcomas of bone and soft tissue by the new WHO Classification of Pediatric Tumors and the latest WHO Classification of Soft Tissue and Bone Tumors [1, 10]. Based on morphology alone, a differential diagnosis incorporating the much more common Ewing sarcoma is paramount. CIC-rearranged sarcomas, round cell sarcomas with EWSR1 or FUS and non-ETS family genes (namely EWSR1-NFATC2 and EWSR1-PATZ1), desmoplastic small round cell tumor, and mesenchymal chondrosarcoma must also be considered [2, 6]. Infantile fibrosarcoma and synovial sarcoma also enters the differential diagnosis of spindle cell rich BCOR-rearranged sarcomas [1, 2, 7].
Precise molecular subclassification of BCOR-rearranged sarcomas might have prognostic significance. Sarcomas with BCOR-CCNB3 show 5-year survival rates of 72-80%, whereas sarcomas with BCOR ITD show a significantly worse prognosis, with a 5-year survival rate of 34% [1]. Metastatic disease is not uncommon, especially in BCOR-fusion sarcomas, and the most common sites are the lungs, bones, soft tissues, and visceral locations [1].
Pathogenesis and molecular diagnosis
Sarcomas with BCOR genetic alterations are a group of tumors characterized by translocations or mutations resulting in BCOR gene activation [1, 2, 3, 6, 9]. BCOR or Bcl6 CO-Repressor is a gene situated on chromosome X at the Xp11.4 locus. As its name implies, it is implicated in the BCL6-mediated transcriptional repression and acts as an epigenetic regulator [11]. Although its function in a normal state has been elucidated, much is still to learn about its contribution to oncogenesis. Nonetheless, BCOR ITD and BCOR fusion sarcomas display similar gene expression profiles, with overexpression of BCOR and genes of the homeobox family [1, 3, 11]. Molecular mechanisms around BCOR activation and its downstream pathways are currently not well understood. Interestingly, sarcomas with YWHAE-NUTM2B fusion are also associated with BCOR upregulation, but the underlying mechanism is not fully understood [1, 6].
Multiple molecular assays can be used to detect BCOR genetic alterations. Targeted Sanger sequencing and fragment length analysis can detect BCOR ITD, but not BCOR-fusions. Fusions can be detected using FISH either with break apart or dual fusion assays [1, 3, 6]. Dual fusion FISH assay has shown better sensitivity than break apart FISH assay as BCOR-CCNB3 fusion involves an intrachromosomal rearrangement [6]. RNA-based sequencing (RNA seq) and NGS both have the advantage of detecting fusions and ITD in a single assay with high sensitivity [6].
MULTIPLE CHOICE QUESTIONS
1. Which molecularly defined subtype of sarcomas with BCOR genetic alterations is most likely to present as a lytic bone lesion?
2. True or false. FISH analysis can be used to detect BCOR ITD?
3. Which combination of histologic features is most suggestive of a BCOR-rearranged sarcoma?
4. What entity(ies) must be considered in the differential diagnosis of sarcomas with BCOR genetic alterations?
5. What is the most common fusion occurring in a BCOR-rearranged sarcoma?
REFERENCES
Contributed by Louis Samson, MD and Eduardo Zambrano, MD
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