Experts recommend genetic testing of all sarcomas

Molecular genetic testing should be mandatory during the diagnosis of sarcoma, even when patients have been diagnosed histologically by an expert pathologist, according to the researchers of a prospective observational study.

“An increasing number of specific genetic aberrations including chromosomal translocations, gene amplification, and mutation have been identified in various types of sarcoma,” Antoine Italiano, MD, PhD, investigator in the sarcoma and early phase trial units at Bergonie Cancer Institute in Bordeaux, France, and colleagues wrote. “These findings allowed sarcomas to be divided into two main groups: those with defined diagnostic molecular events and those with variable complex genetic changes.”

Despite these findings, the diagnosis of sarcomas is often challenging due to their rarity and heterogeneity. Thus, they are often misdiagnosed.

Italiano and colleagues surmised that the implementation of molecular assays may curb sarcoma misdiagnosis.

The multicenter, observational GENSARC study included 384 patients receiving treatment at 32 centers of the French Sarcoma Group/Reference Network in Pathology of Sarcomas. All patients underwent biopsy or surgical resection, with review by at least one expert pathologist.

The analysis included six cohorts based on the suspicion of sarcoma subtypes:

dermatofibrosarcoma protuberans (cohort 1; n = 50; median age, 48 years; 46% male);

dedifferentiated liposarcoma (cohort 2; n = 30; median age, 74 years; 50% male);

Ewing's sarcoma family of tumors (cohort 3; n = 112; median age, 25 years; 63% male);

synovial sarcoma (cohort 4; n = 97; median age, 47 years; 40% male);

alveolar rhabdomyosarcoma (cohort 5; n = 46; median age, 14 years; 54% male); and

myxoid or round cell liposarcoma (cohort 6; n = 49; median age, 48 years; 57% male).

Pathologists made a primary diagnosis for each patient, followed by two differential diagnoses based exclusively on histological characteristics. They classified these diagnoses as certain, probable or possible.

To determine the molecular classification, the researchers used fluorescence in-situ hybridization on paraffin-embedded samples for cohort 1, as well as comparative genomic hybridization and quantitative polymerase chain reaction (PCR) for cohort 2 and reverse transcriptase PCR for cohorts 3 through 6 on frozen and paraffin-embedded samples.

Patients received final diagnoses based on these molecular results.

Forty-three percent (n = 166) of initial diagnoses received a classification of “certain,” with 34% (n = 129) classified as probable and 23% (n = 89) classified as possible.

Fifty-three patients had their initial diagnoses modified due to molecular genetics, including:

eight patients (16%) in cohort 1;

seven patients (23%) in cohort 2;

13 patients (12%) in cohort 3;

16 patients (16%) in cohort 4;

seven patients (15%) in cohort 5; and

two patients (4%) in cohort 6.

In 45 cases, these modifications affected the primary management or prognosis assessment.

“Based on the present results, the steering committee of the GENSARC study has recommended systematic performance of a molecular test for any suspicion of a mesenchymal tumor type known for harboring a molecular abnormality,” Italiano and colleagues wrote. “In 2014, this recommendation was followed in about 80% of cases owing to a national network of molecular platforms recognized by the French National Cancer Institute.”

These findings may lead to the use of molecular genetic profiling for the treatment and diagnosis of soft tissue sarcomas, R. Lor Randall, MD, FACS, director of sarcoma services at University of Utah’s Huntsman Cancer Institute and Primary Children’s Medical Center, and Matthew G. Cable, MD, visiting instructor of orthopedic surgery at Huntsman Cancer Institute, wrote in an accompanying editorial.

“Genotyping has shown that most soft tissue sarcomas have cytogenetic abnormalities that are either exclusive or plethoric, with no middle ground,” Randall and Cable wrote. “For plethoric sarcomas, it is still unknown whether molecular testing will help to find unique differences in soft tissue sarcomas for diagnoses, or converge on common oncogenic pathways for possible treatment.

“The brain might eventually supersede the microscope and the expert human eye — but not yet,” Randall and Cable continued. “Before we can treat soft tissue sarcoma appropriately, we have to at least identify it correctly, and molecular genetic testing will play an integral role alongside histopathology moving forward to maximize our fidelity.” – by Cameron Kelsall

Disclosure: The researchers report no relevant financial disclosures. Randall reports honoraria from Biomet, as well as institutional research funding from the Musculoskeletal Transplant Foundation. Cable reports no relevant financial disclosures.