To sustain the role of expert in cutaneous medicine, dermatologists and dermatopathologists must embrace the molecular advances in medicine, according to Dr. Pedram Gerami.
"For the vast majority of dermatologists and dermatopathologists trained in traditional clinical medicine, the sheer volume of newly identified gene mutations, chromosomal aberrations, and related molecular tests, even within a focused area of specialization, is truly overwhelming. As in many aspects of life, such rapid and transformative changes may be met with welcome or resistance," wrote Dr. Gerami, who was a guest editor of the December issue of Seminars in Cutaneous Medicine and Surgery, which focused on molecular medicine.
Pedram Gerami
Rather than giving in to the common fear that new technological advancements may replace years of clinical training, it is important to recognize that these advances are meant to supplement – not replace – the clinical expertise of dermatologists and dermatopathologists (Sem. Cut. Med. Surg. 2012;31:203).
"The greatest threat to our practice is not the technologic advancement but rather loss of certain aspects of our practice to other specialties [that] better embrace the molecular revolution," he said, adding that active leadership with respect to integrating molecular medicine into the specialty will have a protective effect.
The first step is gaining a deeper understanding of these rapidly emerging advances. Among them are:
Diagnosis of Cutaneous Soft-Tissue Tumors
The identification of genetic abnormalities that characterize soft-tissue tumors has led to the development of diagnostic molecular testing, according to Dr. Alison L. Cheah and Dr. Steven D. Billings, both of the department of anatomic pathology at the Cleveland Clinic.
"Specific genetic signatures characterize a growing number of soft-tissue tumors that affect the skin. Molecular testing on FFPE [formalin-fixed paraffin-embedded tissue] complements histology and immunohistochemistry in the diagnosis of these tumors, especially in challenging cases with atypical morphology, nonspecific immunophenotype, and/or limited sampling," they wrote.
Molecular diagnostics also has implications for more accurate classification and prognostication of poorly understood entities (Sem. Cut. Med. Surg. 2012;31:221-33). "The identification of these disease-defining genetic signatures is the basis for the development of targeted therapies," they wrote.
Take dermatofibrosarcoma protuberans (DFSP), for example. "In practice, molecular testing in DFSP has utility both as a diagnostic aid in challenging cases and to guide therapy," they explained.
While most cases are easily diagnosed based on histopathologic features, significant diagnostic challenges can arise in certain cases, such as in CD34-negative tumors that are superficially sampled, or in tumors with varying histology or an unusual presentation.
For guiding treatment, molecular testing can be helpful for confirmation of COL1A1-PDGF-beta, which is vital if treatment with imatinib mesylate is being considered, because tumors lacking the fusion gene do not respond to this drug, they noted. Imatinib mesylate recently received Food and Drug Administration approval for the treatment of unresectable metastatic or recurrent DFSP.
Real-time polymerase chain reaction (RT-PCR) is the most studied test for detecting COL1A1-PDGF-beta and has a reported sensitivity between 74% and 96%. Though not as well studied, fluorescence in situ hybridization (FISH) assays also show promise.
"FISH assays using both PDGF-beta break-apart and COL1A1-PDGF-beta dual-color dual-fusion probe techniques have also been used," they wrote, noting that some reports show a greater sensitivity of FISH than RT-PCR for DFSP.
Molecular assays can also be helpful in confirming the diagnosis of angiomatoid fibrous histiocytoma (AFH).
In a study of 17 cases, FISH assays with dual-color break-apart probes had a sensitivity of 76% for identifying EWSR1 and FUS gene rearrangements, regardless of the translocation partner, they noted. FISH results should be interpreted with caution, though, because a negative result does not rule out the diagnosis of AFH, as rearrangements that are not detectable with the particular FISH probes used, or translocations with different chromosomes altogether, could explain a negative FISH result.
"Of note, EWSR1 rearrangements occur in several other soft tissue sarcomas, including Ewing sarcoma family of tumors, desmoplastic small round-cell tumors, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and a subset of myoepithelial tumors," they noted, adding that correlation with the histologic and immunohistochemical findings remains paramount.
RT-PCR is also a sensitive and specific assay for AFH, but its practical utility is limited by the multiple primers to account for the various fusion transcripts described in AFH.
Another area in which molecular testing plays an important role – albeit complementary– is in the diagnosis of low-grade fibromyxoid sarcoma (LGFMS), they reported. On the basis of RT-PCR results, for example, a significant number of cases previously diagnosed as LGMFS had to be reclassified.
RT-PCR assays performed on FFPE tissues had a sensitivity of 81%-88%, and FISH testing for FUS gene rearrangement is less sensitive at about 70%, but is nonetheless a good alternative to PCR, particularly in paraffin blocks with poor quality RNA.