Cyril Fisher

Tumours of soft tissues – update on IHC and molecular morphology

Soft tissue tumours are classified according to their line of differentiation, which can be expressed in varying degree. Some tumours show morphological features of differentiation towards a specific mesenchymal tissue, but many appear only as pleomorphic, small round cell, spindled or epithelioid cell tumours and ancillary diagnostic techniques are required to elucidate their nature. These increasingly include molecular diagnostic techniques, while new antibodies continue to be developed for diagnostic immunohistochemistry including those derived from molecular investigations. These include SOX10, CAMTA-1, MUC4, NKX2.2, STAT6, BCOR & CCNB3, ETV4, and ERG. However, these and others such as INI1, over time become less specific and need to be used within selected panels related to specific diagnostic problems.

A growing number of malignant, intermediate and benign soft tissue tumours are now known to have consistent genetic abnormalities, including translocations (detectable by FISH) resulting in fusion genes (with products detectable by PCR), or mutations, amplifications and deletions of specific genes or chromosomal segments. These findings are applied for diagnosis, predicting behaviour, and identifying potential therapeutic targets. They have helped to identify new clinico-pathologic entities and informed the classification of small round cell tumours, fibro-myofibroblastic neoplasms and myoepithelial tumours, as well as defining molecular subgroups and widening the range of treatment options as for example with liposarcoma. However, similar genetic changes can be found in remarkably diverse tumour types so that, as with immunohistochemistry, lack of specificity of molecular changes is a frequent phenomenon. Examples of this include YWHAE-NUTM2A/B in endometrial stromal sarcoma and clear cell renal sarcoma; ETV6-NTRK3, found in congenital fibrosarcoma, mesoblastic nephroma, mammary analogue secretory carcinoma of salivary gland, and others; and subsets of the large group of tumours with EWSR1 gene rearrangement such as those with EWSR1-CREB1 or EWSR1-ATF1 fusions. Thus, soft tissue diagnosis now requires careful integration of clinicoradiological, morphological, immunohistologic and molecular genetic and cytogenetic information.

Advanced molecular techniques are also becoming more widely applied in soft tissue tumour pathology. Expression profiling can lead to development of new antibodies and define prognostic gene signatures, and next generation sequencing can identify large numbers of molecular events, some of which might prove valuable for diagnosis and for targeted therapy. The pathologist needs to assess the molecular findings within the overall features of the case, and to be aware of the limitations of these findings.

CV

Professor Cyril Fisher, MA MD DSc FRCPath, is Professor of Tumour Pathology and Consultant Histopathologist at the Royal Marsden Hospital and Institute of Cancer Research (University of London), UK. Professor Fisher graduated in medicine from Oxford University and trained in pathology at University College Hospital Medical School, London. He has held academic appointments in both USA and UK. His principal diagnostic and research interest is in soft tissue tumour pathology, including the application and evaluation of new diagnostic techniques, and close collaborations with scientists and clinicians. He deals with about 3000 specimens of soft tissue tumours and related conditions each year, and has been involved in discovery of several sarcoma translocations and in characterization of many new tumour entities. Professor Fisher is Past-President of the International Society of Bone and Soft Tissue Pathology, has given some 250 invited lectures in 23 countries, is Editor-in-Chief of International Journal of Surgical Pathology, an editor of Sarcoma and a member of several other international editorial boards including American Journal of Surgical Pathology. He has authored or co-authored over 500 scientific publications, is lead or sole author of three new textbooks on diagnosis of soft tissue tumours published in the last 6 years (one now in 2nd edition), and has contributed chapters to 19 other books.

Selected Publications

  1. Fisher C, Montgomery E, Thway K. Biopsy Interpretation of Soft Tissue Tumors Lippincott Williams & Wilkins, Philadelphia, 2nd Edn 2015

  2. Noujaim J, Jones RL, Swansbury J, Gonzalez D, Benson C, Judson I, Fisher C, Thway K. The spectrum of EWSR1-rearranged neoplasms at a tertiary sarcoma centre; assessing 772 tumour specimens and the value of current ancillary molecular diagnostic modalities. Br J Cancer 2017 in press

  3. Thway K, Wren D, Lee J, Thompson L, Fisher C, Gonzalez D. Evaluation of the optimal provision of formalin-fixed, paraffin-embedded material for reverse transcription-PCR in soft-tissue tumour diagnosis. J Clin Pathol. 2017;70:20-24.

  4. Fisher C. The diversity of soft tissue tumours with EWSR1 rearrangement. A review Histopathology 2014;64:134-150.

  5. Thway K, Flora R, Shah C, Olmos D, Fisher C. Diagnostic utility of p16, CDK4 and MDM2 as an immunohistochemical panel in distinguishing well differentiated and dedifferentiated liposarcomas from other adipocytic tumors. Am J Surg Pathol 2012; 36: 462-469.

  6. Thway K, Fisher C Tumors with EWSR1-CREB1 and EWSR1-ATF1 fusions: the current status (Special Article)  Am J Surg Pathol 2012 Jul;36(7):e1-e11

  7. Fisher C Immunohistochemistry in diagnosis of soft tissue tumours. Histopathology 2011;58:1001-1012.