High sensitivity of FISH analysis in detecting homozygous SMARCB1 deletions in poorly differentiated chordoma: a clinicopathologic and molecular study of nine cases

Abstract

Poorly differentiated chordomas (PDCs) represent a rare subset of notochordal neoplasms, affecting primarily children and associated with an aggressive outcome. In contrast to conventional chordomas, PDC show solid growth and increased cellularity, cytologic atypia, and mitotic activity. Recent studies have shown that PDCs are characterized by recurrent deletions encompassing the SMARCB1 locus, resulting in consistent loss of nuclear SMARCB1 expression. Thus PDC joined the expanding family of SMARCB1-deficient tumors characterized by various SMARCB1 structural abnormalities, ranging from large homozygous deletions to small intragenic mutations. In the present study, we investigate the SMARCB1 abnormalities in a group of nine well-characterized PDCs and to establish the sensitivity of the FISH method in detecting these changes in the clinical setting. We further assessed the pathologic features and clinical behavior of this cohort managed at our referral center over a 20-year period. The mean age at diagnosis was 10 years-of-age. All except one case occurred in the cranial region. All demonstrated strong nuclear expression of brachyury and loss of SMARCB1 expression. FISH identified homozygous SMARCB1 deletions in all except one case; additionally two cases revealed a heterozygous EWSR1 locus co-deletion. Clinical follow-up information was available in five patients. Two patients presented with distant metastases at initial diagnosis. Two of the three remaining patients with primary disease failed both locally and distantly after multimodality therapy. We conclude that PDCs are highly aggressive tumors and the dominant mechanism of loss of SMARCB1 expression is through large, homozygous SMARCB1 deletions that can be readily detected by FISH.

Molecular characteristics of poorly differentiated chordoma

“…6,8,10,12 This may be true even when there is morphologic over- SMARCB1 is a chromatin remodeling member of the SWI/SNF complex that has been known to be lost in a number of sarcomas, including malignant rhabdoid tumor, epithelioid sarcoma, epithelioid malignant peripheral nerve sheath tumor, and myoepithelial carcinoma. This finding correlates well with immunohistochemical loss of expression of SMARCB1, and prior FISH or MLPA analysis which shows homozygous SMARCB1 deletion in a majority of cases.…”

“…This finding correlates well with immunohistochemical loss of expression of SMARCB1, and prior FISH or MLPA analysis which shows homozygous SMARCB1 deletion in a majority of cases. 6,8,10,12 This may be true even when there is morphologic over- expression by immunohistochemistry and SMARCB1 point mutations. 11 As a result, given the limited number of cases tested in this study, the possibility of other mechanisms of loss of SMARCB1 expression cannot be entirely excluded.…”

Poorly differentiated chordoma: review of 53 cases

“…Although they usually lack the physaliphorous cells (42/53, 79%) and an extracellular myxoid or chondroid matrix mimicking hyaline cartilage, tumors with INI1 loss and morphology resembling classical chordoma have been also reported . Cellular morphology and tissue pattern may vary as Owosho et al described in their cases as epithelioid, rhabdoid, spindled architecture in nests, acini, or solid form . Some cases were reported to show active to chronic inflammatory infiltrate (Fig.…”

“…Homozygous or heterozygous SMARCB1 deletions which can be shown by fluorescent in situ hybridization (FISH) or multiplex ligation‐dependent probe amplification (MLPA) seem to be the main mechanism. Owosho et al performed fluorescence in situ hybridization (FISH) directed at chromosome 22q11–12 region, which showed that all cases demonstrated homozygous SMARCB1 deletions except one. They also claimed that FISH is more sensitive than MLPA in the detection of INI1 losses.…”

“…Inclusion criteria in this review included involvement of axial skeleton (vertebra and clivus, which are common locations for classical chordoma), INI1 loss (either with the aid of immunohistochemistry or various molecular techniques), and immunohistochemical brachyury expression. According to these qualifications, we came up with 53 cases reported up to March 2018, from different institutions (2)(3)(4)(5)(8)(9)(10)(11)(12)(13)(14)(15). The clinical, imaging, histopathological features, and immunohistochemical and molecular findings of those 53 cases were given in Table 1 and summarized in Table 2.…”