Gene of the month: DDIT3.

DNA damage-inducible transcript 3 (DDIT3) gene, mapped to the human chromosome 12q13.3, encodes a protein that belongs to the CCAAT/enhancer-binding protein family of transcription factors. DDIT3 is involved in the proliferative control that responds to endoplasmic reticulum stress in normal conditions, dimerising other transcription factors with basic leucine zipper (bZIP) structural motifs. DDIT3 plays a significant role during cell differentiation, especially adipogenesis, arresting the maturation of adipoblasts. In disease, FUS/EWSR1::DDIT3 fusion is the pathogenic event that drives the development of myxoid liposarcoma. The amplification of DDIT3 in other adipocytic neoplasms mediates the presence of adipoblast-like elements. Another fusion, GLI1::DDIT3, has rarely been documented in other tumours. This paper reviews the structure and function of DDIT3, its role in disease-particularly cancer-and its use and pitfalls in diagnostic testing, including immunohistochemistry as a tissue-based marker.

Primary Orbital Myxoid Liposarcoma.

Although liposarcoma is the most prevalent soft tissue sarcoma in adults, head and neck liposarcomas are rare and account for less than 5% of all liposarcomas. The primary orbital location is even more exceptional, with fewer than 100 cases documented in the medical literature. Given the scarcity of cases of orbital liposarcoma and the limited familiarity of physicians and pathologists with this pathology, there is an increased risk of non-diagnosis or misdiagnosis, which may lead to inappropriate patient management. To address these challenges, we present a case of primary orbital myxoid liposarcoma and subsequently discuss the primary findings of this case based on the evidence documented in the medical literature. This comprehensive text is designed to serve as a valuable resource for healthcare professionals and pathologists, with the goal of promoting both clinical suspicion and accurate diagnosis and treatment of this rare condition in future cases.

Distribution and Rate of Myxoid Liposarcoma Spine Metastases: Impact on Surveillance Imaging.

BACKGROUND: Myxoid liposarcoma (LPS) has a unique tendency to spread to extrapulmonary sites, including osseous sites such as the spine, and adjacent sites such as the paraspinous tissue. No clear consensus exists to guide the approach to imaging in these patients. OBJECTIVE: The aim of this study was to investigate the rate and distribution of spine metastases in patients with myxoid LPS and detection modality. METHODS: Records of all patients with myxoid LPS evaluated at our sarcoma center were retrospectively reviewed. Disease patterns and imaging modality utilization were analyzed. RESULTS: Between 2000 and 2020, 164 patients with myxoid LPS were identified. The majority (n = 148, 90%) presented with localized disease, with half (n = 82, 50%) of all patients developing metastases or recurrence during their disease course. With a median follow-up of 69.2 months, spine/paraspinous metastases developed in 38 patients (23%), of whom 35 (92%) already had synchronous, non-spine metastases. Spine disease was only visible on magnetic resonance imaging (MRI), as opposed to other imaging modalities, for over one-quarter of patients with spine metastases (n = 10). For patients with metastatic disease, spine metastases were associated with worse median overall survival (2.1 vs. 8.7 years, p < 0.001). CONCLUSION: Spine metastases occurred in nearly one-quarter of patients with myxoid LPS and represented an advanced disease state, as they primarily presented in the setting of synchronous, non-spine metastases, and were associated with worse overall survival. Routine surveillance with spine MRI in patients with localized disease likely provides no benefit but may be considered in those with known metastatic disease.

The Conundrum of Dedifferentiation in a Liposarcoma at a Peculiar Location: A Case Report and Literature Review.

Dedifferentiated liposarcoma of the deep soft tissue of the lower extremities is an infrequent finding. Myxoid liposarcoma is considered the most common soft tissue neoplasia arising in this anatomic region. Divergent differentiation usually occurs within well-differentiated liposarcoma and is exceedingly rare in a myxoid liposarcoma. We report a 32-year-old man who developed a dedifferentiated liposarcoma of the thigh on the background of a pre-existing myxoid liposarcoma. The gross examination of the surgical specimen showed a 11/7/2 cm tumour mass with solid tan-grey areas and focal myxoid degeneration. The microscopic examination revealed a malignant lipogenic proliferation, containing round cells with hyperchromatic nuclei and atypical lipoblasts, confined to the basophilic stroma with a myxoid aspect. Abrupt transition towards a hypercellular, non-lipogenic area consisting of highly pleomorphic spindle cells with atypical mitotic figures was also noted. Immunohistochemical staining was performed. Tumour cells in the lipogenic area were intensely positive for S100 and p16, and CD34 staining highlighted an arborizing capillary network. The dedifferentiated tumour areas showed positive MDM2 and CDK4 staining within neoplastic cells, with the Ki 67 proliferation marker expressed in approximately 10% of the cells. Wild-type TP53 protein expression pattern was documented. Thus, the diagnosis of a dedifferentiated liposarcoma was established. This paper aims to provide further knowledge about liposarcomas with divergent differentiation at peculiar locations, emphasizing the importance of histopathologic examination and immunohistochemical analysis for establishing the diagnosis and assessing the therapeutic response and prognosis of this condition.

A rare case of primary giant myxoid liposarcoma of the pericardium.

Primary pericardial neoplasms account for 6.7-12.8% of all primary tumors arising in the cardiac region. Pericardial tumors are most likely to be metastatic and are an extension of the primary tumors from the surrounding structures. Sarcomas of the pericardium are rare. Myxoid liposarcoma (ML) represents about 5% of all the soft-tissue sarcomas in adults. They are usually located in the deep soft tissues of the extremities. There have been less than 20 cases of pericardial liposarcomas reported on PubMed since 1973. Here, we present a rare case of primary giant pericardial myxoid liposarcoma (ML) in a 46-year-old female diagnosed on frozen section and later was confirmed histopathologically.

Myxoid Liposarcoma: How to Stage and Follow.

OPINION STATEMENT: Myxoid liposarcoma (MLPS) is a rare soft tissue sarcoma, with propensity to metastasize to locations such as soft tissue and bone. Thus, whole-body MRI should be a consideration as part of staging for patients with a new diagnosis of MLPS since PET and CT may not identify extrapulmonary disease. Surveillance imaging should be tailored, with consideration of more frequent and longer duration of monitoring for large tumors or tumors with round cell component. This review focuses on studies evaluating imaging in MLPS as well as recent publications on survival and prognostic tools in MLPS.

Myxoid Liposarcomas: Systemic Treatment Options.

OPINION STATEMENT: Myxoid/round-cell liposarcoma (MRCL) account for 30% of liposarcomas and are the most chemo-sensitive subtype of liposarcoma. The 5-year local relapse and distant metastasis rates are 10% and 20%, respectively. In the advanced setting, the first-line median progression-free survival and overall survival is 9 and 30 months, respectively. The overall response rate (ORR) by RECIST with anthracycline-based chemotherapy is around 40% and with trabectedin is 20%, although response is higher when captured by CHOI criteria. Anthracycline-based combination chemotherapy regimens remain the standard of care first-line treatment option. However, trabectedin is also effective and may be considered in the first-line setting when anthracyclines cannot be prescribed. Beyond chemotherapy, new therapeutic classes are being developed, including autologous adoptive modified T cell receptor cellular therapies which have shown promising results thus far. These new therapies utilize the immunogenic potential of cancer testis antigens, NY-ESO-1 and MAGE-A4, which are expressed in the vast majority of MRCL. Early phase trials have shown encouraging results with up to 40% ORR and a median progression-free survival up to 8.7 months. Other innovative strategies are being developed, tailored to the molecular biology of MRCL. This review summarizes current evidence for the use of standard chemotherapy and the new biomarker-selected treatments under development.

Comprehensive genomic profiling of a unique liposarcoma arising in a patient with Li-Fraumeni syndrome and the novel detection of c-myc amplification: a case report.

BACKGROUND: Germline TP53 mutations have been frequently reported in patients with Li-Fraumeni syndrome (LFS), resulting in a predisposition to various malignancies. Mutations other than germline TP53 mutations can also cause LFS-associated malignancies, but their details remain unclear. We describe a novel c-myc amplification in a unique liposarcoma in a patient with LFS. CASE PRESENTATION: A female patient with LFS developed breast cancer twice at the age of thirty; both were invasive ductal carcinomas harboring HER2 amplifications. Computed tomography revealed an anterior mediastinal mass, which was surgically resected. Histological analysis revealed three different lesions corresponding to myxoid liposarcoma-, pleomorphic liposarcoma-, and well-differentiated liposarcoma-like lesions. Fluorescence in-situ hybridization (FISH) analysis did not detect MDM2 amplification, Rb1 deletion, break apart signals of EWS, FUS, DDIT3, or c-myc, or c-myc-IGH fusion signals, but it did detect more c-myc signals. Further FISH analysis and comprehensive genomic profiling revealed c-myc amplification. We considered two differential diagnoses, dedifferentiated liposarcoma lacking MDM2 amplification and myxoid pleomorphic liposarcoma (MPLPS), and determined that this case is most likely MPLPS. However, definite diagnosis could not be made because a clear-cut differentiation of the case from liposarcomas was not possible. CONCLUSIONS: A previous study demonstrated that c-myc amplification could not be detected in various liposarcomas, but the present unique liposarcoma showed c-myc amplification, so the c-myc amplification may indicate that the present liposarcoma is an LFS-related tumor. The present case further clarifies the pathological features of MPLPS and LFS-related liposarcomas by broadening their histopathological and genetic diversities.

Myxoid pleomorphic liposarcoma in the teres minor muscle: A case report.

RATIONALE: Myxoid pleomorphic liposarcoma (MPL) is a rare aggressive adipocytic tumor that mainly presents in children and adolescents. It is most frequently observed in the mediastinum and rarely in the head and neck, perineal region, or back. Herein, we report the first published case of MPL of the teres minor muscle. PATIENT CONCERNS: A 24-years-old woman presented with a painless palpable mass in her right shoulder. DIAGNOSES: Magnetic resonance imaging identified a 9.0 × 7.0 × 4.0 cm mass suspected to be a sarcoma in the teres minor muscle. Positron emission tomography/computed tomography revealed no evidence of distant metastasis. Histopathological examination revealed the mass to be an MPL, which was assigned a histologic grade of 3 according to the French Federation of Cancer Centers Sarcoma Group system. No tumor cells were observed along the resected margins. INTERVENTIONS: Under general anesthesia, the right teres minor muscle containing the mass was excised en bloc and frozen biopsy confirmed that the tumor cells did not invade the surrounding tissues. OUTCOMES: The patient underwent radiotherapy and was followed up for 6 months without complications. LESSONS: Although MPL in the teres minor muscle is rare, it should be considered in the differential diagnosis in patients with a mass in the teres minor muscle due to its poor prognosis.

Myxoid Liposarcoma of the Vulva: A Rare Malignancy Mimicking Benign Vulvar Mass.

BACKGROUND Liposarcoma of the vulva is an exceptionally rare malignant tumor. Clinically, vulvar liposarcoma often mimics benign lesions, thus misdiagnosis is common. Herein, we present a case of myxoid liposarcoma of the vulva. To the best of our knowledge, this is the first case report of vulvar liposarcoma from Indonesia. CASE REPORT We present a case of a 39-year-old woman with left vulvar mass of 6 years duration that progressively increased in size. The patient reported having pressure and discomfort, especially during movement, but reported no pain. Lipoma was initially suspected. Surgical excision was performed and histopathological examination revealed a well-differentiated myxoid liposarcoma. The base and excised margins of the tumor were free of malignant cells. Post-operative course was uneventful and she was discharged in a satisfactory condition. The patient had been under regular follow-up and is currently symptom- and recurrence-free. We also review other cases of vulvar liposarcoma to further comprehend characteristics of this rare malignant tumor. CONCLUSIONS Liposarcoma of the vulva occurs very rarely, but clinicians and pathologists should always consider it as a differential diagnosis when presented with vulvar mass. Biopsy of a vulvar mass is crucial. Surgical excision remains the mainstay of treatment. Adjuvant radiotherapy may be considered in certain cases. Comprehensive follow-up for recurrences or metastasis is recommended throughout life.

[Myxiod pleomorphic liposarcoma: a clinicopathological and molecular genetic analysis of six cases].

Objective: To investigate the clinicopathologic and molecular genetic characteristics of myxoid pleomorphic liposarcoma (MPLPS). Methods: Six cases of MPLPS diagnosed and consulted in Fujian Provincial Hospital from 2015 to 2021 were collected for histomorphological observation, immunohistochemistry, and fluorescence in situ hybridization (FISH) detection of DDIT3 (CHOP) gene translocation and MDM2/CDK4 gene amplification. Results: There were four males and two females, aged 26-74 years (mean 53.8 years). The tumor size was 3.8-16.0 cm (mean 11.8 cm). All six cases had similar histopathologic features, showing overlapping histologic morphology of myxoid liposarcoma and pleomorphic liposarcoma. Four cases (4/6) were positive for S-100 protein, and the Ki-67 index was 50%-95%. All cases (6/6) were negative for DDIT3 (CHOP) translocation and MDM2/CDK4 amplification by FISH. TP53 (p.R248w) germline mutation was found in one case. Conclusions: MPLPS is a rare subtype of liposarcoma, characterized by overlapping morphology of myxoid liposarcoma and pleomorphic liposarcoma. Genetically, a few of them have TP53 gene germline mutations, but they lack of DDIT3 (CHOP) translocation or MDM2/CDK4 amplification.

Well-Differentiated Liposarcoma of the Hypopharynx Exhibiting Myxoid Liposarcoma-like Morphology with MDM2 and DDIT3 Co-Amplification.

Well-differentiated liposarcoma (WDL) is one of the most common soft tissue sarcomas in adults. It has a predilection for middle-aged males and arises in deep-seated locations such as retroperitoneum, mediastinum, and spermatic cord. Its occurrence in young individuals at the hypopharyngeal region is an exceedingly rare event. Myxoid liposarcoma (ML)-like changes can seldom occur in some cases of WDL, which makes the diagnosis of WDL more challenging. Amplification of DDIT3 gene in a subset of cases of WDL has shown to be associated with such unique morphology. Herein, we present a case of a 36-year-old gentleman who presented with difficulty in breathing and swallowing for 3 months duration. CT scan of the neck revealed a lesion along the posterior wall of the hypopharynx measuring 3.5 cm. Histopathologic examination revealed a tumor composed of lobules of oval to spindle cells in a prominent myxoid stroma with delicate chicken-wire vasculature. In the vicinity, there were lobules composed of variably sized adipocytes separated by thick fibrous septa that contains atypical hyperchromatic spindle cells. By immunohistochemistry, the tumor cells in both components were immunoreactive for CDK4, but negative for MDM2. Fluorescence in-situ hybridization (FISH) confirmed the presence of MDM2 gene amplification. There was no evidence of FUS-DDIT3 gene rearrangement, however, DDIT3 gene was also amplified. The diagnosis of well-differentiated liposarcoma with prominent myxoid stroma was rendered. This is the first documentation of WDL with ML-like morphology harboring co-amplification of MDM2 and DDIT3 in the hypopharynx.

Expression of CTAG1B clone EPR13780 versus DDIT3 gene rearrangement distinguishes myxoid liposarcoma from its mimics with detection of novel DDIT3 gene copy number variations.

Myxoid liposarcoma (MLPS) has different patterns that are often difficult to distinguish from other soft tissue lesions. MLPS is characterized by a reciprocal translocation involving the DNA Damage Inducible Transcript 3 gene (DDIT3) that can be detected using fluorescent in situ hybridization (FISH). Recently, the marker for cancer testis antigen 1b (CTAG1B) was found to be expressed in MLPS. The aim of the present study was to assess the potential use immunohistochemistry (IHC) for CTAG1B expression and DDIT3 rearrangement to diagnose MLPS and distinguish it from similar lesions. Out of 29 cases including MLPS and its mimics, CTAG1B was expressed in 92.86% of cases of MLPS and 20% of its mimics. DDIT3 rearrangement was 100% sensitive and 92.86% specific in distinguishing MLPS from its mimics. The DDIT3 rearrangement was found to be more sensitive but less specific than cytoplasmic expression of CTAG1B marker. DDIT3 polysomy and amplification were detected in some cases. Therefore, both CTAG1B expression and FISH for DDIT3 gene can be used to distinguish MLPS from similar tumors. The use of both immunohistochemistry for CTAG1B in addition to DDIT3 gene rearrangement detection by FISH was more specific than using either of them alone. However, the DDIT3 gene rearrangement alone was the most sensitive test for distinguishing MLPS from its mimics.

Advances in the classification of round cell sarcomas.

Round cell sarcomas represent a diagnostic challenge for pathologists, owing to the poorly differentiated features of these high-grade tumours. The diagnosis of round cell sarcoma requires large immunohistochemical panels and molecular testing in many cases. This spectrum of malignancies is largely dominated by Ewing sarcomas (ESs), which represent the most common family of these tumours. Nonetheless, new families have been delineated in the past few years, with the addition of two additional families in the 2020 World Health Organization classification of bone and soft tissue tumours, namely sarcomas with CIC rearrangements and sarcomas with BCOR alterations. EWSR1, one of the genes involved in the driver fusion of ESs, is also implicated in the translocation of many other tumours with heterogeneous lineages and variable levels of aggressiveness. Round cell sarcomas associated with fusions inwhichEWSR1is partnered with genes encoding transcription factors distinct from those of the 'Ewing family' represent a heterogeneous group of rare tumours that require further study to determine whether their fusions may or not define a specific subgroup. They include mainly sarcomas with NFATc2 rearrangements and sarcomas with PATZ1 rearrangements. At this point, PATZ1 fusions seem to be associated with tumours of high clinical and morphological heterogeneity. Molecular studies have also helped in the identification of more consistent biomarkers that give tremendous help to pathologists in triaging, if not diagnosing, these tumours in practice. This review compiles the latest accumulated evidence regarding round cell sarcomas, and discusses the areas that are still under investigation.

The utility of fluorescence in situ hybridization (FISH) in determining DNA damage-inducible transcript 3 (DDIT3) amplification in dedifferentiated liposarcomas - an important diagnostic pitfall.

BACKGROUND AND OBJECTIVE: Dedifferentiated liposarcoma (DDLPS) is characterized by non-lipogenic sarcoma fields coexisting with adipocyte-rich well-differentiated areas. Amplification of the 12q13-15 region includes the MDM2 and DDIT3 genes. MDM2 amplification is considered a genetic hallmark of DDLPS, while DDIT3 is typically rearranged in myxoid liposarcoma. Recent studies showed that DDIT3 amplification is associated with myxoid liposarcoma-like (LPS-like) morphology in DDLPS. Our study aimed to evaluate the status of MDM2 and DDIT3 by FISH in DDLPS and correlate it with MLPS-like features. MATERIAL AND METHODS: Six patients with MLPS-like morphology DDLPS were investigated pathologically, immunohistochemically, and genetically. The control groups of patients with classical DDLPS morphology and well-differentiated liposarcoma (WDLPS) were established and molecularly assessed as well. Fluorescence in situ hybridization (FISH) used in routine diagnostics was performed to determine the status of MDM2 and DDIT3 genes. RESULTS: The patient's mean age was 64 (range from 43 to 85 years) with a 5:4 male to female ratio. Tumors were localized retroperitoneally (15) and extra-retroperitoneally (3). All cases demonstrated amplification of the 12q15 region containing MDM2 gene and co-amplification of the 5' DDIT3 FISH Probe representing DDIT3 telomeric tag. However, we did not find the relation of myxoid LPS-like morphology with DDIT3 amplification as previously reported. CONCLUSIONS: The biopsy material from DDLPS with myxoid areas can be misclassified as myxoid liposarcoma. Indeed, according to the histological image, DDIT3 status may be evaluated first. In these cases, we show that the DDIT3 telomeric tag amplification assessed by FISH, is a common, nonspecific feature, which is also found in classical DDLPS and WDLPS. Therefore, we believe that co-amplification of DDIT3 and MDM2 may be considered a spectrum of the 12q13-15 region amplification due to the specification of FISH methodology.

Nuclear expression of DDIT3 distinguishes high-grade myxoid liposarcoma from other round cell sarcomas.

Myxoid liposarcoma (MLPS) is a malignant adipocytic neoplasm with predilection for the extremities. MLPS is genetically defined by a t(12;16) translocation leading to FUS-DDIT3 (95%) or more rarely t(12;22) leading to EWSR1-DDIT3. Low-grade MLPS is characterized by bland spindle cells within a myxoid matrix containing delicate "chicken-wire" vasculature, whereas high-grade ("round cell") MLPS may be indistinguishable from other round cell sarcomas. In many cases, cytogenetic or molecular genetic techniques are applied to confirm the diagnosis. A recent study documented the utility of DDIT3 immunohistochemistry (IHC) in the differential diagnosis of adipocytic and myxoid soft tissue tumors. The purpose of this study was to evaluate DDIT3 IHC as a surrogate for molecular testing in high-grade MLPS. IHC was performed using a mouse monoclonal antibody directed against the N-terminus of DDIT3 on whole tissue sections from 50 high-grade MLPS cases and 319 histologic mimics used as controls (170 on whole tissue sections and 149 on a tissue microarray). Histologic mimics included Ewing sarcoma, CIC-rearranged sarcoma, sarcomas with BCOR genetic alterations, poorly differentiated synovial sarcoma, alveolar and embryonal rhabdomyosarcomas, mesenchymal chondrosarcoma, desmoplastic small round cell tumor, and neuroblastoma. Nuclear staining in >5% of cells was considered positive. By IHC, 48 (96%) high-grade MLPS showed strong diffuse nuclear staining for DDIT3. Of the controls, 2% of cases were positive, with no more than 25% nuclear staining. An additional 19% of control cases displayed less than 5% nuclear staining. Overall, DDIT3 IHC showed 96% sensitivity and 98% specificity for high-grade MLPS; strong, diffuse staining is also 96% sensitive but is 100% specific. IHC using an antibody directed against the N-terminus of DDIT3 is highly sensitive and specific for high-grade MLPS among histologic mimics and could replace molecular genetic testing in many cases, although limited labeling may be seen in a range of other tumor types.