Study characterizes metastatic giant cell tumor of orbital soft tissue

A new case report describes a metastatic giant cell tumor of orbital soft tissue that is associated with PALB2 variant.

Findings

The authors describe a 34-year-old patient with an aggressive giant cell tumor of the soft tissue of the orbit/adnexa and a history of nodular sclerosing-type stage IIE Hodgkin lymphoma. The patient previously underwent chemotherapy and radiation. The tumor initially involved the upper lid and lacrimal gland. It recurred locally, extended intracranially despite multiple resections and adjuvant treatments, and finally metastasized. Exome sequencing of the tumor tissue revealed a splicing mutation in the tumor suppressor gene, PALB2 (c.2515-1G>A).

It has been suggested that giant cell tumors of the soft tissue are genetically and phenotypically different from their bone counterparts. The vast majority of giant cell tumors of the bone (>90%) have a driver mutation in the H3F3A gene that is not detected in the soft tissue counterpart. The genetic alterations in the soft tissue counterpart are not well defined. The PALB2 variant identified in this study is classified as likely pathogenic in ClinVar. Somatic mutations of PALB2 have been reported in multiple different cancers (ranging from 0-6.2%). Homozygous germline PALB2 mutations are a rare cause of Fanconi anemia. Germline variants also increase the risk for breast, pancreatic and possibly other cancers.

Limitations

This is a single case report and it is unclear whether this PALB2 mutation identified on the exome sequencing of tumor tissue is germline or somatic. Allele frequency of the variant was not listed. If the variant is somatic, it could have implications for the genetics of these rare tumors. If the variant is germline, further assessment of copy number variation leading to bi-allelic inactivation of PALB2 (two-hits) in the tumor is necessary to properly assess any potential association of the germline mutation with this rare tumor. The paper does not report any family history of cancer.

Clinical significance

This is the first report of PALB2 in giant cell tumor of the soft tissue of the orbit/adnexa. Little is known about the molecular genetics of this tumor and assessment of driver mutations of PALB2 in other soft tissue giant cell tumors is warranted. In similar cases with actionable variants detected through tumor-only testing, germline variants should be ruled-out. Germline PALB2 variants could have implications for the management of the patient and family members.