Jonathan Noujaim

The Current Status of Solitary Fibrous Tumor Diagnostic Features, Variants, and Genetics

Solitary fibrous tumor (SFT) is a fibroblastic mesenchymal tumor originally described in the pleura but now shown at almost every anatomic site. Histopathologically, SFT is characteristically a circumscribed neoplasm composed of variably cellular and patternless distributions of bland spindle and ovoid cells within prominent collagenous stroma and shows diffuse expression of CD34, but it has a broad spectrum of both morphology and of biologic behavior. Many different names (particularly hemangiopericytoma) were previously used in the course of our understanding of this neoplasm but are now subsumed under the term “SFT,” and the putative cell of origin was debated. However, it is now recognized that SFT is a translocation-associated neoplasm, consistently associated with NAB2-STAT6 gene fusions arising from recurrent intrachromosomal rearrangements on chromosome 12q, and this translocation is a likely major contributor to its pathogenesis. While most SFT with classical morphologic features behave in an indolent manner and those with overtly malignant histologic features tend to be aggressive neoplasms that behave as high-grade sarcomas, the behavior of SFT is unpredictable, and it is important to be aware of the propensity for aggressive behavior in a minority of histologically classical SFT and to ensure adequate clinical follow-up. Surgical excision remains the treatment gold standard; while radiotherapy and conventional chemotherapeutic agents have only shown limited efficacy, further understanding of the molecular events underlying tumorigenesis may allow the development of novel targeted treatments. We review SFT, discussing the morphologic spectrum and variants, including malignant and dedifferentiated subtypes, clinicopathological aspects, recent molecular genetic findings, and the differential diagnosis.

Dedifferentiated Liposarcoma: Updates on Morphology, Genetics, and Therapeutic Strategies

Well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DDL) form the largest subgroup of liposarcomas, and represent a morphologic and behavioral spectrum of 1 disease entity, which arises typically in middle to late adult life, most frequently within the retroperitoneum or extremities. DDL is defined as nonlipogenic sarcoma that is juxtaposed to WDL, occurs as a recurrence of WDL or which can arise de novo, and typically has the appearance of undifferentiated pleomorphic or spindle cell sarcoma. DDL have a propensity for local recurrence, whereas distant metastasis is rarer, and behavior is related to anatomic site, with retroperitoneal neoplasms showing a significantly worse prognosis. Surgical resection remains the mainstay of treatment, and medical options for patients with aggressive recurrent or metastatic disease are limited. DDL share similar genetic abnormalities to WDL, with high-level amplifications of chromosome 12q14-15, including the MDM2 and CDK4 cell cycle oncogenes, and DDL harbor additional genetic changes, particularly coamplifications of 6q23 and 1p32. Novel therapies targeted at the gene products of chromosome 12 are being tested in clinical trials. We review the pathology and genetics of DDL, discussing morphologic patterns, immunohistochemical and genetic findings, the differential diagnosis, and future therapeutic strategies.

Dermatofibrosarcoma protuberans: pathology, genetics, and potential therapeutic strategies

Dermatofibrosarcoma protuberans (DFSP), the most common dermal sarcoma, is a malignant fibroblastic tumor most frequently arising in middle-aged adults. It is typically a low-grade sarcoma that grows slowly but has a high rate of local recurrence with low metastatic potential. Dermatofibrosarcoma protuberans is characterized by a specific translocation t(17;22)(q22;q13) leading to the formation of COL1A1-PDGFB fusion transcripts. Histologically, DFSP has characteristic morphology, of storiform islands of bland spindle cells, and immunohistochemically, it shows diffuse expression of CD34. However, the morphology and immunoprofile can overlap with a variety of other soft tissue neoplasms. The preferred management of localized disease is wide surgical resection or Mohs micrographic surgery, whereas radiotherapy may be used for margin-positive disease where reexcision is not possible, or for inoperable disease. Dermatofibrosarcoma protuberans is generally regarded as refractory to conventional chemotherapy. Treatment options for systemic disease have been previously limited, but the PDGFβR, KIT, and ABL inhibitor imatinib is now an option for effective systemic therapy. Continued insight into the tumorigenic molecular changes generated by the fusion oncogene may lead to further specific targeted treatments. We review DFSP, discussing the morphologic spectrum and variants, immunohistochemistry, molecular genetic findings, potential targeted treatments, and the differential diagnosis.

Histology-Driven Therapy: The Importance of Diagnostic Accuracy in Guiding Systemic Therapy of Soft Tissue Tumors.

Soft tissue tumors (STTs) are rare mesenchymal neoplasms accounting for less than 1% of adult cancers. More than 50 different subtypes of STTs have been identified, with this number expected to grow as our understanding of the complex genetic landscape of these diseases improves. As the classification of soft tissue neoplasms continues to diversify, so does the approach to therapy. Accurate histopathologic diagnosis, utilizing the appropriate ancillary immunohistochemical and molecular diagnostic platforms, underpins the oncologic management of soft tissue sarcomas. As increasing numbers of reproducible genetic abnormalities in soft tissue neoplasms are defined, molecular genetic and molecular cytogenetic investigations have become a standard part of the ancillary diagnostic repertoire. However, other soft tissue neoplasms lack reproducible genetic abnormalities, and for these, traditional histology and immunohistochemistry remain the cornerstones for diagnosis. Here, we give an overview of histology-driven therapy in STTs, highlighting the critical role of accurate surgical pathology in guiding the systemic treatment of patients with these neoplasms, and the importance of close collaboration between the surgical pathologist and the oncologist. We also summarize what is considered standard practice in nonhistology- and histology-driven therapy.

Epithelioid Sarcoma: Diagnostic Features and Genetics

Epithelioid sarcoma (ES) is a rare, aggressive soft-tissue neoplasm of uncertain differentiation, characterized by nodular aggregates of epithelioid cells, which are immunoreactive to cytokeratins (CKs) and epithelial membrane antigen, and often for CD34. It has a propensity for multifocal disease at presentation, local recurrence, and regional metastasis. These are aggressive neoplasms with particularly poor prognosis after regional or distant metastatic disease, for which surgical resection is still the mainstay of treatment, and options for patients with metastatic disease remain undefined. There are 2 distinct variants: classic ES, which typically presents as a subcutaneous or deep dermal mass in the distal extremities of young adults and comprises nodular distributions of relatively uniform epithelioid cells with central necrosis, and the proximal variant, which has a predilection for proximal limbs and limb girdles and the midline of the trunk, which is composed of sheets of larger, more atypical cells with variable rhabdoid morphology. Both classic and proximal-type ESs are associated with the loss of SMARCB1/INI1 protein expression, but appear otherwise molecularly relatively heterogeneous. We review classic and proximal-type ES, discussing morphology, immunohistochemical and genetic findings, the differential diagnosis, and the future potential for targeted therapies.

Phosphoproteomics in translational research: a sarcoma perspective

Phosphoproteomics has been extensively used as a preclinical research tool to characterize the phosphorylated components of the cancer proteome. Advances in the field have yielded insights into new drug targets, mechanisms of disease progression and drug resistance, and biomarker discovery. However, application of this technology to clinical research has been challenging because of practical issues relating to specimen integrity and tumour heterogeneity. Beyond these limitations, phosphoproteomics has the potential to play a pivotal role in translational studies and contribute to advances in different tumour groups, including rare disease sites like sarcoma. In this review, we propose that deploying phosphoproteomic technologies in translational research may facilitate the identification of better defined predictive biomarkers for patient stratification, inform drug selection in umbrella trials and identify new combinations to overcome drug resistance. We provide an overview of current phosphoproteomic technologies, such as affinity-based assays and mass spectrometry-based approaches, and discuss their advantages and limitations. We use sarcoma as an example to illustrate the current challenges in evaluating targeted kinase therapies in clinical trials. We then highlight useful lessons from preclinical studies in sarcoma biology to demonstrate how phosphoproteomics may address some of these challenges. Finally, we conclude by offering a perspective and list the key measures required to translate and benchmark a largely preclinical technology into a useful tool for translational research.

The spectrum of EWSR1-rearranged neoplasms at a tertiary sarcoma centre; assessing 772 tumour specimens and the value of current ancillary molecular diagnostic modalities

Background:EWSR1 rearrangements were first identified in Ewing sarcoma, but the spectrum of EWSR1-rearranged neoplasms now includes many soft tissue tumour subtypes including desmoplastic small round cell tumour (DSRCT), myxoid liposarcoma (MLPS), extraskeletal myxoid chondrosarcoma (EMC), angiomatoid fibrous histiocytoma (AFH), clear cell sarcoma (CCS) and myoepithelial neoplasms. We analysed the spectrum of EWSR1-rearranged soft tissue neoplasms at our tertiary sarcoma centre, by assessing ancillary molecular diagnostic modalities identifying EWSR1-rearranged tumours and reviewing the results in light of our current knowledge of these and other Ewing sarcoma-like neoplasms.Methods:We retrospectively analysed all specimens tested for EWSR1 rearrangements by fluorescence in situ hybridisation (FISH) and/or reverse transcription–PCR (RT–PCR) over a 7-year period.Results:There was a total of 772 specimens. FISH was performed more often than RT–PCR (n=753, 97.5% vs n=445, 57.6%). In total, 210 (27.9%) specimens were FISH-positive for EWSR1 rearrangement compared to 111 (14.4%) that showed EWSR1 fusion transcripts with RT–PCR. Failure rates for FISH and RT–PCR were 2.5% and 18.0%. Of 109 round cell tumours with pathology consistent with Ewing sarcoma, 15 (13.8 %) cases were FISH-positive without an identifiable EWSR1 fusion transcript, 4 (3.7%) were FISH-negative but RT–PCR positive and 4 (3.7%) were negative for both. FISH positivity for DSRCT, MLPS, EMC, AFH and CCS was 86.3%, 4.3%, 58.5%, 60.0% and 87.9%, respectively. A positive FISH result led to diagnostic change in 40 (19.0%) EWSR1-rearranged cases. 13 FISH-positive cases remained unclassifiable.Conclusions:FISH is more sensitive for identifying EWSR1 rearrangements than RT–PCR. However, there can be significant morphologic and immunohistochemical overlap between groups of EWSR1-rearranged neoplasms, with important prognostic and therapeutic implications. FISH and RT–PCR should be used as complementary modalities in diagnosing EWSR1-rearranged neoplasms, but as tumour groups harbouring EWSR1 rearrangements are increasingly characterised and because given translocations involving EWSR1 and its partner genes are not always specific for tumour types, it is critical that these are evaluated by specialist soft tissue surgical pathologists noting the morphologic and immunohistochemical context. As RT–PCR using commercial primers is limited to only the most prevalent EWSR1 fusion transcripts, the incorporation of high-throughput sequencing technologies into the standard diagnostic repertoire to assess for multiple molecular abnormalities of soft tissue tumours in parallel (including detection of newly characterised Ewing sarcoma-like tumours) might be the most effective and efficient means of ancillary diagnosis in future.

Desmoplastic Small Round Cell Tumor: Pathology, Genetics, and Potential Therapeutic Strategies

Desmoplastic small round cell tumor (DSRCT) is an aggressive small round cell neoplasm which predominantly occurs intra-abdominally in adolescents and young adults with a male predominance, and which is characterized by a recurrent t(11;22)(p13;q12) translocation leading to formation of the EWSR1-WT1 fusion gene, which generates a chimeric protein with transcriptional regulatory activity. Histologically, DSRCT has a characteristic morphology, of islands of monotonous small cells within prominent sparsely cellular fibroblastic stroma, and immunohistochemically it shows polyphenotypic multidirectional differentiation, with expression of epithelial, muscle, and neural markers. However, DSRCT can arise more rarely in other sites and exhibit a spectrum of both histologic features and immunoprofile, which may confuse diagnosis with other small round cell neoplasms. Correct diagnosis is important to ensure correct treatment and prognostication; DSRCT are almost universally fatal neoplasms with patients usually succumbing to disease within the first 2 years of diagnosis. While combination treatment strategies can confer a survival benefit, the overall prognosis remains poor. Further insight into the tumorigenic molecular changes generated by the fusion oncogene may lead to the generation of specific targeted therapies. We review DSRCT, discussing morphology and immunohistochemistry, molecular genetic findings, potential targeted treatments, and the differential diagnosis.

Dermatofibrosarcoma protuberans: from translocation to targeted therapy.

Dermatofibrosarcoma protuberans (DFSP), the most common dermal sarcoma, is a low-grade, slow growing fibroblastic malignant neoplasm that most frequently affects middle aged adults and is characterized by a high local recurrence rate and a low propensity for metastasis. Wide surgical resection or Mohs micrographic surgery (MMS) are the preferred approaches for localized disease, while radiation therapy is warranted for inoperable disease or for cases with positive margins where re-excision is not possible. DFSP is generally regarded as refractory to conventional chemotherapy. Treatment options for systemic disease were limited until the discovery of a unique translocation, t(17;22)(q22;q13) (COL1A1;PDGFB) found in a majority of cases. In recent years, imatinib, a PDGFβR, ABL and KIT inhibitor, has revolutionized systemic therapy in DFSP. In this review, we summarize the epidemiological, clinical, histological and genetic characteristics of DFSP and update the readers on its current management.

Successful Ifosfamide Rechallenge in Soft-Tissue Sarcoma

Objectives: Treatment options for metastatic soft-tissue sarcomas are limited. The aim of this study was to investigate the clinical activity of ifosfamide rechallenge in synovial sarcoma (SS), liposarcoma (LPS), leiomyosarcoma (LMS), and high-grade sarcomas not otherwise specified. Methods: A retrospective search of the Royal Marsden Sarcoma Unit Database was performed to identify patients initially treated with ifosfamide (as single agent or in combination) and who were subsequently rechallenged with single-agent ifosfamide. Baseline demographics and response assessment were retrospectively obtained. Results: Sixty-seven patients were identified and the median age at diagnosis was 41 years (range, 18 to 71 y). There were 29 cases of SS, 17 of LPS, 12 of LMS, and 9 of sarcomas not otherwise specified. First-line ifosfamide-containing therapy was given to 14 patients as adjuvant therapy (adjuvant group) and 53 patients as palliative therapy (palliative group). Clinical activity (partial response or stable disease) with single-agent ifosfamide rechallenge was documented in 50.0% of patients in the adjuvant group (7 in the second line) and 34.0% of patients in the palliative group (15 in the second line, 1 in third line, and 2 in the fourth line). The median progression-free survival in patients with documented clinical activity was 11.5 months (95% CI, 8.8-12.3) and 6.9 months (95% CI, 5.1-9.0), respectively, in the adjuvant and palliative group. Ifosfamide rechallenge was mostly active in SS patients (49.3%, 14 out of 29 patients with partial remission or stable disease). Conclusions: Ifosfamide rechallenge has clinical activity in soft-tissue sarcoma and can be considered a viable option in treating metastatic disease.