Abstract Perivascular epithelioid cell tumors, or PEComas, are mesenchymal neoplasms composed of histologically and immunohistochemically distinctive epithelioid or spindle cells, which are ...immunoreactive for both smooth muscle and melanocytic markers. The cells in PEComas are typically arranged around blood vessels and appear to form the vessel wall, often infiltrating the smooth muscle of small- to medium-sized vessels. Periluminal cells are usually epithelioid and the more peripheral cells are spindle shaped. The cells have small, round to oval nuclei, sometimes with focal nuclear atypia, and clear to eosinophilic cytoplasm, and no counterpart normal cell has been identified. The PEComa “family” now includes angiomyolipoma, pulmonary clear cell “sugar” tumor and lymphangioleiomyomatosis, primary extrapulmonary sugar tumor, clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres, abdominopelvic sarcoma of perivascular epithelioid cells, and other tumors with similar features at various sites that are simply termed PEComa . Some PEComas occur in patients with tuberous sclerosis complex and share the genetic abnormalities. There is a behavioral spectrum from benign to frankly malignant, and histologic criteria have been proposed for assessing malignant potential. The differential diagnosis can include carcinomas, smooth muscle tumors, other clear cell neoplasms, and adipocytic tumors. PEComas constitute a genetically diverse group that includes neoplasms harboring TFE3 gene rearrangements and those with TSC2 mutations, indicating alternative tumorigenic pathways. Recent advances in therapy of malignant PEComas relate to increased knowledge of specific genetic changes and their effects on metabolic pathways that are susceptible to specific interventions. We review PEComas, emphasizing the diagnostic spectrum and recent immunohistochemical and genetic findings.
Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of intermediate biologic potential and uncertain differentiation, most often arising in the superficial extremities of children ...and young adults. While it has characteristic histologic features of nodular distributions of ovoid and spindle cells with blood-filled cystic cavities and a surrounding dense lymphoplasmacytic infiltrate, there is a significant morphologic spectrum, which coupled with its rarity and lack of specific immunoprofile can make diagnosis challenging. Angiomatoid fibrous histiocytoma is associated with 3 characteristic gene fusions, EWSR1-CREB1 and EWSR1-ATF1, which are also described in other neoplasms, and rarely FUS-ATF1. Angiomatoid fibrous histiocytoma is now recognized at an increasing number of sites and is known to display a variety of unusual histologic features.
To review the current status of AFH, discussing putative etiology, histopathology with variant morphology and differential diagnosis, and current genetics, including overlap with other tumors harboring EWSR1-CREB1 and EWSR1-ATF1 fusions.
Review of published literature, including case series, case reports, and review articles, in online medical databases.
The occurrence of AFH at several unusual anatomic sites and its spectrum of morphologic patterns can result in significant diagnostic difficulty, and correct diagnosis is particularly important because of its small risk of metastasis and death. This highlights the importance of diagnostic recognition, ancillary molecular genetic confirmation, and close clinical follow-up of patients with AFH. Further insight into the genetic and epigenetic changes arising secondary to the characteristic gene fusions of AFH will be integral to understanding its tumorigenic mechanisms.
Abstract Synovial sarcoma (SS) is a malignant mesenchymal neoplasm with variable epithelial differentiation, with a propensity to occur in young adults and which can arise at almost any site. It is ...generally viewed and treated as a high-grade sarcoma. As one of the first sarcomas to be defined by the presence of a specific chromosomal translocation leading to the production of the SS18-SSX fusion oncogene, it is perhaps the archetypal “translocation-associated sarcoma,” and its translocation remains unique to this tumor type. Synovial sarcoma has a variety of morphologic patterns, but its chief forms are the classic biphasic pattern, of glandular or solid epithelial structures with monomorphic spindle cells and the monophasic pattern, of fascicles of spindle cells with only immunohistochemical or ultrastructural evidence of epithelial differentiation. However, there is significant morphologic heterogeneity and overlap with a variety of other neoplasms, which can cause diagnostic challenge, particularly as the immunoprofile is varied, SS18-SSX is not detected in 100% of SSs, and they may occur at unusual sites. Correct diagnosis is clinically important, due to the relative chemosensitivity of SS in relation to other sarcomas, for prognostication and because of the potential for treatment with specific targeted therapies in the near future. We review SS, with emphasis on the diagnostic spectrum, recent immunohistochemical and genetic findings, and the differential diagnosis.
Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLGT) is a rare malignant neoplasm that occurs in the wall of the small bowel, stomach, or large bowel, predominantly in young adults. ...It is an aggressive neoplasm that frequently presents with metastatic disease and has a high mortality rate. Histologically, it is usually composed of medium-sized primitive ovoid or epithelioid cells with pale or clear cytoplasm that are arranged in sheets or in papillary or alveolar architectures. Clear cell sarcoma-like tumor of the gastrointestinal tract is positive for S100 protein, invariably negative for melanocyte-specific markers and is often also positive for neuroendocrine markers. The etiology of CCSLGT is unknown, but many studies have shown associations with EWSR1-CREB1 gene fusions and, less frequently, with EWSR1-ATF1 fusions. Here, we discuss the current status of CCSLGT, including histologic, immunophenotypic, and molecular findings.
Well-differentiated liposarcoma (WDL)/atypical lipomatous tumor and dedifferentiated liposarcoma (DDL) together comprise the largest subgroup of liposarcomas, and constitute a histologic and ...behavioral spectrum of one disease. WDL and DDL typically occur in middle-aged to older adults, particularly within the retroperitoneum or extremities. WDL closely resembles mature adipose tissue, but typically shows fibrous septation with variable nuclear atypia and enlargement. WDL does not metastasize, but can dedifferentiate to DDL, which is associated with more aggressive clinical behavior, with a greater propensity for local recurrence and the capacity for metastasis. Although distant metastasis is rarer in DDL compared with other pleomorphic sarcomas, behavior is related to location, with a significantly worse outcome in retroperitoneal tumors. DDL typically has the appearance of undifferentiated pleomorphic or spindle cell sarcoma, and is usually a non-lipogenic sarcoma that is adjacent to WDL, occurs as a recurrence of WDL or which can arise de novo. WDL and DDL share similar background genetic aberrations; both are associated with high-level amplifications in the chromosomal 12q13-15 region, which includes the CDK4 and MDM2 cell cycle oncogenes. In addition, DDL harbor further genetic changes, particularly 6q23 and 1p32 coamplifications. While surgical excision remains the treatment mainstay with limited medical options for patients with aggressive recurrent disease or metastases, novel targeted therapies towards the gene products of chromosome 12 are being evaluated. This review summarizes the pathology of WDL and DDL, discussing morphology, immunohistochemistry, genetics and the differential diagnosis.
Although traditional morphological evaluation remains the cornerstone for the diagnosis of soft tissue tumors, ancillary diagnostic modalities such as immunohistochemistry and molecular genetic ...analysis are of ever-increasing importance in this field. New insights into the molecular pathogenesis of soft tissue tumors, often obtained from high-throughput sequencing technologies, has enabled significant progress in the characterization and biologic stratification of mesenchymal neoplasms, expanding the spectrum of immunohistochemical tests (often aimed towards recently discovered genetic events) and molecular genetic assays (most often fluorescence in situ hybridization and reverse transcription-polymerase chain reaction). This review discusses selected novel molecular and immunohistochemical assays with diagnostic applicability in mesenchymal neoplasms, with emphasis on diagnosis, refinement of tumor classification, and treatment stratification.
Adipocytic tumors are the most common type of soft tissue neoplasms. Distinguishing atypical lipomatous tumor-well-differentiated liposarcoma (WDL) from benign adipocytic neoplasms and ...dedifferentiated liposarcoma (DDL) from pleomorphic or myxoid liposarcoma (LPS) can be difficult. WDL and DDL characteristically harbor amplifications of the MDM2 and CDK4 cell cycle oncogenes with protein overexpression and can also overexpress the cell cycle regulator p16. We assessed the utility of immunohistochemistry for CDK4, MDM2, and p16 in the routine histopathologic diagnosis of WDL/DDL from other adipocytic tumors. Immunohistochemistry for the trio of markers was performed on 216 adipocytic neoplasms (31 WDLs, 57 DDLs, 11 myxoid LPS, 2 pleomorphic LPS, 91 lipomas (including intramuscular, fibro, angio, and ossifying subtypes), 18 spindle/pleomorphic lipomas, and 6 hibernomas. Sixty-eight percent of WDLs and 72% of DDLs expressed all 3 antigens, whereas 100% of WDLs and 93% of DDLs expressed at least 2 antigens. The sensitivity and specificity of the trio for detecting WDLs/DDLs were 71% and 98%, respectively. The sensitivity and specificity of CDK4 for detecting WDLs/DDLs were 86% and 89%, those of MDM2 were 86% and 74%, and those of p16 were 93% and 92%, respectively. The immunohistochemical trio of CDK4, MDM2, and p16 is a useful ancillary diagnostic tool that provides strong support in distinguishing WDLs and DDLs from other adipocytic neoplasms and is potentially more sensitive than previously assessed combinations of CDK4 and MDM2. p16 was the most sensitive and specific marker for detecting WDL/DDL, and the combination of CDK4 and p16 is of more discriminatory value than the combination of either with MDM2, the least sensitive and specific of the 3 markers.
Abstract 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. DFSP is characterized by a specific translocation t(17;22)(q22;q13) leading to 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, while radiotherapy may be used for margin-positive disease where re-excision is not possible, or for inoperable disease. DFSP 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.
Soft-tissue sarcoma (STS) is a rare and heterogeneous group of tumours that comprise approximately 1% of all adult cancers, and encompass over 50 different subtypes. These tumours exhibit a wide ...range of differing behaviours and underlying molecular pathologies, and can arise anywhere in the body. Surgical resection is critical to the management of locoregional disease. In the locally advanced or metastatic disease settings, systemic therapy has an important role in the multidisciplinary management of sarcoma. Cytotoxic therapy that usually consists of doxorubicin and ifosfamide has been the mainstay of treatment for many years. However recent advances in molecular pathogenesis, the development of novel targeted therapies, changes in clinical trial design and increased international collaboration have led to the development of histology-driven therapy. Furthermore, genomic profiling has highlighted that some STS are driven by translocation, mutation or amplification and others have more complex and chaotic karyotypes. In this Review, we aim to describe the current gold standard treatment for specific STS subtypes as well as outline future promising therapies in the pipeline.
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