From morphological to molecular diagnosis of soft tissue tumors

Our plain-English summary of From morphological to molecular diagnosis of soft tissue tumors, by M. Miettinen (Advances in Experimental Medicine and Biology, 2006).

The study

• Author: M. Miettinen
• Journal: Advances in Experimental Medicine and Biology
• Published: 2006;587:99-113
• Type of article: Review
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Cytogenetic discoveries of balanced translocations in soft tissue tumors have opened the way to molecular genetic definition of these translocations as gene fusions from the late 1980s. Many sarcomas are known to have such fusions, and the demonstration of the fusion transcripts in tumor tissue is of great value in specific diagnosis of synovial sarcoma (SYT-SSX), Ewing sarcoma (EWS-Fli1), clear cell sarcoma (EWS-ATF1), myxoid liposarcoma (FUS-CHOP), and other sarcomas. These translocations are believed to be disease-specific and pathogenetic forces, despite occasional observations to the contrary. Demonstration of SYT-SSX and EWS-ATF1 fusion assists in the diagnosis of synovial and clear cell sarcomas in unusual locations, such as the gastrointestinal tract, where these tumors occur with low frequency. Demonstration of sarcoma translocations and their fusion by different assays is well established; use of in situ hybridization is limited by availability of specific probes. In two exceptional instances, the same translocation and gene fusion occurs in two unrelated diseases: ETV6-NTRK fusion in infantile fibrosarcoma and secretory carcinoma of the breast, and ALK-TPM3 fusion in inflammatory myofibroblastic tumor and large cell anaplastic lymphoma. Thus, the target cell of the genetic change is an important factor to define the resulting disease. Activating mutations in two related receptor tyrosine kinases (RTKs), KIT, and platelet-derived growth factor receptor alpha (PDGFRA) is central to the pathogenesis of gastrointestinal stromal tumors (GISTs), and countering the mutational activation by specific tyrosine kinase inhibitors, such as Imatinib mesylate, is now standard treatment for metastatic GISTs. KIT exon 11 mutations (in frame deletions, point mutations, and duplications) occur in GISTs of all locations, whereas a characteristic exon 9 insertion-duplication AY502-503 is nearly specific for intestinal vs gastric tumors. In contrast, PDGFRA mutations are nearly specific for gastric GISTs, especially those with epithelioid morphology. Mutation type influences therapy responsiveness, but fortunately very few GISTs carry primarily Imatinib-resistant mutations. Secondary drug resistance acquired during Imatinib treatment based on new, Imatinib-resistant mutations is a major problem limiting treatment success. Loss of NF2 tumor suppressor gene in a biallelic fashion is believed to be central in the pathogenesis of neurofibromatosis 2 (NF2) associated and sporadic schwannomas and meningiomas. The mechanism includes nonsense or missense mutation in NF2 gene, and loss of the other NF2 allele as a part of losses in chromosome 22q. Schwannoma types may differ in their pathogenesis: gastrointestinal schwannomas lack NF2 changes suggesting a different pathogenesis. Intraneural and sclerosing perineuriomas display similar NF2 gene alterations as seen in meningioma, indicating a similar pathogenesis and molecular homology. Specific viral sequences of human herpesvirus 8 (HHV8) are diagnostic markers for Kaposi sarcoma (KS), and are absent in angiosarcoma. Despite discovery on simian virus SV40 sequences in mesothelioma as a possible pathogenetic factor, recent studies suggest that the presence of these sequences may be artifactual and based on common presence of some SV40 sequences as PCR contaminants.

In plain English

This book chapter was a review, not a new study. The author described how molecular tests can help diagnose soft tissue tumors. It covered gene fusions in sarcomas, KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs), NF2 gene changes in nerve sheath tumors, and viral sequences in tumors. The chapter did not discuss asbestos. Mesothelioma or mesothelial cells came up in three places. First, the author noted that synovial sarcoma often shows calretinin and keratin 5, as mesothelioma does, but not WT1. Second, the author raised the possibility that desmoplastic small round cell tumor could be related to mesothelial cells and their tumors. Third, on simian virus 40 (SV40), the chapter noted that other investigators had reported SV40 sequences in malignant mesothelioma. It added that a recent report found SV40 sequences to be common laboratory contaminants. It also cited a lack of increased mesothelioma risk in patients who received an SV40-contaminated adenovirus vaccine. The author concluded that recent studies suggest SV40 findings in mesothelioma may be artifacts of PCR contamination.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: narrative review (book chapter)
• Who was studied: No study population. The chapter reviewed published research and the author's group's experience with soft tissue tumors (sarcomas, GISTs, schwannomas, perineuriomas, Kaposi sarcoma, mesothelioma).
• Exposure: No asbestos exposure was discussed. The chapter covered molecular changes in tumors and viral sequences: human herpesvirus 8 in Kaposi sarcoma and SV40 in mesothelioma.
• Main results:
  • The author noted that synovial sarcoma epithelia often express calretinin and keratin 5, similar to mesothelioma, but not WT1.
  • The author raised the possibility that desmoplastic small round cell tumor, which typically occurs in the serous cavities, could be related to mesothelial cells and their tumors.
  • The chapter cited a report finding SV40 sequences as common laboratory contaminants. That report raised the question whether SV40 findings in mesothelioma had been overestimated.
  • The chapter cited a lack of increased mesothelioma risk in patients who received an SV40-contaminated adenovirus vaccine as a reason the role of SV40 has been questioned.
  • The author noted that PCR-based detection of sarcoma gene fusions can give false positive results from cross contamination of DNA or cDNA templates.
  • The chapter stated that approximately 60 to 65 percent of GISTs have KIT mutations and 15 percent have PDGFRA mutations, and that the two do not occur together.
  • The chapter stated that gastrointestinal schwannomas have neither losses of the NF2 allele nor NF2 mutations.
• The authors' conclusion: The author concluded that recent studies suggest SV40 sequences found in mesothelioma may be artifactual, reflecting common presence of SV40 sequences as PCR contaminants.

Topics

Medical terms in this study, explained in our Lexicon: Translocation, Sarcoma, Synovial Sarcoma, NTRK Fusion, Carcinoma, Platelet-Derived Growth Factor (PDGF), Tyrosine Kinase Inhibitor, Epithelioid.

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