Poorly differentiated neoplasms of unknown primary site: diagnostic usefulness of a molecular cancer classifier assay

Definition of the lineage of poorly differentiated neoplasms (PDNs) presenting as cancer of unknown primary site (CUP) is important since many of these tumors are treatment-sensitive. Gene expression profiling and a molecular cancer classifier assay (MCCA) may provide a new method of diagnosis when standard pathologic evaluation and immunohistochemical (IHC) staining is unsuccessful.

Thirty of 751 CUP patients (4%) seen from 2000-2012 had PDNs without a definitive lineage diagnosed by histology or IHC (median 18 stains, range 9-46). Biopsies from these 30 patients had MCCA (92-gene reverse transcriptase-polymerase chain reaction mRNA) performed. Additional IHC, gene sequencing, fluorescent in situ hybridization for specific genetic alterations, and repeat biopsies were performed to support MCCA diagnoses, and clinical features correlated. Seven patients had MCCA performed initially and received site-specific therapy.

Lineage diagnoses were made by MCCA in 25 of 30 (83 %) patients, including ten carcinomas (three germ cell, two neuroendocrine, five others), eight sarcomas [three peritoneal mesotheliomas, one primitive neuroectodermal tumor (PNET), four others], five melanomas, and two lymphomas. Additional IHC and genetic testing [BRAF, i(12)p] supported the MCCA diagnoses in 11 of 16 tumors. All seven patients (two germ cell, two neuroendocrine, two mesothelioma, one lymphoma) responded to site-specific therapy based on the MCCA diagnosis, and remain alive (five progression-free) from 25+ to 72+ months.

The MCCA provided a specific lineage diagnosis and tissue of origin in most patients with PDNs unclassifiable by standard pathologic evaluation. Earlier use of MCCA will expedite diagnosis and direct appropriate first-line therapy, which is potentially curative for several of these tumor types.