Dedifferentiated Component Research Articles

The Diverse Aspects of Uterine Serous Cancer: An NCI workshop on the status of and opportunities for advancement of research.

The marked increase in incidence and mortality in endometrial cancer over the last two decades is driven in part by rising rates of higher grade, more aggressive endometrial cancers with mutations in TP53, uterine serous cancers and their dedifferentiated component, uterine carcinosarcomas (collectively USC). USC rates have been increasing among all racial and ethnic groups, with higher rates of this aggressive uterine cancer in Black women. The National Cancer Institute (NCI) hosted a workshop in June 2023 to examine the diverse aspects of USC across epidemiology, biology, and molecular genetics, and to advance knowledge from basic to preclinical and translational efforts. Key stakeholders came together including basic scientists, clinical investigators, and patient advocates to identify critical research gaps that, when addressed, would facilitate more comprehensive and rapid progress in understanding and ultimately treating USC across all patients. NCI released a supplemental funding opportunity (NOT-CA-24-044) in Spring 2024 to facilitate rapid translation of these recommendations.

Identification of the First Case of Dedifferentiated Liposarcoma in Amphibians: Insights from Maculopaa medogensis

Dedifferentiated liposarcoma (DDLPS) is a rare and aggressive type of cancer primarily reported in humans, with no documented cases in animals. In this study, we present the first case of DDLPS in a wild amphibian species, Maculopaa medogensis. The tumor was discovered during a routine examination and diagnosed through a combination of advanced diagnostic methods, including micro-CT imaging, gross anatomical inspection, histological analysis, and immunohistochemistry. The tumor exhibited both well-differentiated and dedifferentiated components, characteristic of DDLPS, with evidence of tissue invasion and multiple metastases. Immunohistochemical analysis revealed the strong positive expression of markers such as S100A4, CDK4, MDM2, and CD34, while Leptin expression was negative, further confirming the diagnosis. This is the first reported case of DDLPS in a non-human species, expanding our understanding of cancer in wildlife and underscoring the significance of amphibians as environmental indicators. These findings provide valuable insights for veterinary medicine and wildlife conservation, particularly regarding the role of environmental stressors in cancer development. This study highlights the need for comprehensive diagnostic approaches in wildlife pathology.

Cellular origin and clonal evolution of human dedifferentiated liposarcoma

Dedifferentiated liposarcoma (DDLPS) is the most frequent high-grade soft tissue sarcoma subtype. It is characterized by a component of undifferentiated tumor cells coexisting with a component of well-differentiated adipocytic tumor cells. Both dedifferentiated (DD) and well-differentiated (WD) components exhibit MDM2 amplification, however their cellular origin remains elusive. Using single-cell RNA sequencing, DNA sequencing, in situ multiplex immunofluorescence and functional assays in paired WD and DD components from primary DDLPS tumors, we characterize the cellular heterogeneity of DDLPS tumor and micro-environment. We identify a population of tumor adipocyte stem cells (ASC) showing striking similarities with adipocyte stromal progenitors found in white adipose tissue. We show that tumor ASC harbor the ancestral genomic alterations of WD and DD components, suggesting that both derive from these progenitors following clonal evolution. Last, we show that DD tumor cells keep important biological properties of ASC including pluripotency and that their adipogenic properties are inhibited by a TGF-β-high immunosuppressive tumor micro-environment.

Molecular characteristics of dedifferentiated liposarcoma with broad rhabdomyosarcomatous differentiation.

e23530 Background: Dedifferentiated liposarcoma (DDLPS) with broad rhabdomyosarcomatous differentiation has a worse prognosis compared with other types of DDLPS. Therefore, it is of importance to recognize its molecular characteristics in order to investigate individualized treatment strategies. Methods: We conduct next-generation sequencing (NGS) including DNA and RNA sequencing analysis in 5 DDLPS patients with broad rhabdomyosarcomatous differentiation and perform comparative analysis between well-differentiated and dedifferentiated components from the patients. Results: In the ten samples, several somatic copy-number variations (CNVs) including the gain of 12q are considered as frequent molecular alterations. IGFN1, FGFR4, BLM, RICTOR, RUNX1 and TOP1 mutation is the high-frequency single-nucleotide variations (SNVs). Novel BEST3/CD63/LGR5/CENPL-MDM2 and ERBB3-TAFA2 fusion genes are identified in this subtype of tumor. The comparative analysis between well-differentiated and dedifferentiated components recognized two categories of molecular variations: shared variations, such as FGFR4 and BLM mutation, ERBB3-TAFA2 fusion, and MYC amplification that are associated with tumorigenesis, and dedifferentiated-specific variations including GRIN2A, FOXP1 and TP53 mutation, CERS4-PTPRB and TRIO-TERT fusion, and ESR1 amplification, which are related with malignant progression. After surgery, the patient received adjuvant therapy. The mean follow-up of the patients was 30 months, and the mean recurrence-free survival (RFS) was 9.6 months. Conclusions: This NGS analysis disclosed the possible progression mechanisms and therapeutic targets in DDLPS with broad rhabdomyosarcomatous differentiation and provided insights contributing to the refinement of management in this tumor. [Table: see text]

A case of dedifferentiated liposarcoma discovered due to an intrascrotal calcified ossification.

Dedifferentiated liposarcoma is a rare cancer with a poor prognosis. A 52-year-old man presented with a chief complaint of a mass in his left scrotum. He came with suspected testicular tumor, but all the measured tumor markers were negative. Imaging test showed approximately 2cm diameter mass accompanied by calcification with some substantial components between the testis and epididymis. Left high testicular resection was performed. The tumor had no continuity between the testis and epididymis, and the spermatic cord transection was negative. Pathological findings showed well differentiated fatty component and a dedifferentiated component around the trabecular bone-like tissue. We observed dedifferentiated dysmorphic cells mixed with fatty droplets of unequal size. Immunostaining led to the diagnosis of dedifferentiated liposarcoma. No additional postoperative therapy was performed. The possibility of dedifferentiated liposarcoma should be kept in mind even if mass is confined to the scrotum and consisted of calcification. In the case of an intrascrotal calcified mass with malignant perspective, radical surgery is highly recommended.

Low-grade central osteosarcoma with extraosseous dedifferentiation: a rare case.

Low-grade central osteosarcoma (LGCOS), which arises from the intramedullary cavity of the metaphysis of long bones, occasionally exhibits extraosseous spread. Approximately 10-30% of patients with LGCOS exhibit dedifferentiation, but it is rare to experience a primary tumor with a dedifferentiated component. A 38-year-old female patient presented with right knee pain for two months. Imaging studies revealed a bone mass with extraosseous involvement. Wide resection was performed, and pathologic examination led to the diagnosis of LGCOS with a dedifferentiated extraosseous lesion. A single defect in the bone cortex constituted the boundary between the low- and high-grade components. The extraosseous high-grade component included more tumor cells with p53 overexpression and more murine double minute 2 (MDM2) copies compared with the low-grade component. These genetic mutations and copy number alterations can be associated with malignant transformation of LGCOS.

Abstract PR006: ARID1A/B mutations retarget mSWI/SNF chromatin remodeler activity and define a spectrum of dedifferentiation in endometrial carcinoma

Abstract Dedifferentiated/undifferentiated endometrial carcinoma (DEC/UEC) is a highly aggressive histologic subtype of uterine cancer with a higher incidence among non-Hispanic Black women. Recent exome-wide sequencing studies have revealed frequent and often concomitant mutations in the ARID1A and ARID1B genes in over 50% of DEC/UEC cases and 30% of all endometrial carcinomas. The mSWI/SNF family of chromatin remodelers are critical regulators of cell type-specific chromatin accessibility and gene expression, existing in three distinct forms: canonical BAF (cBAF), Poly bromodomain-associated BAF (PBAF), and non-canonical BAF (ncBAF). The paralog subunits, ARID1A and ARID1B, specifically nucleate the assembly of cBAF complexes. However, the precise role ARID1A/ARID1B mutations (cBAF loss) play in the development of dedifferentiated endometrial carcinoma remains unclear. In this study, we define an expression signature associated with endometrial “dedifferentiation” by profiling the well-differentiated and dedifferentiated components of cBAF loss DEC cases through laser capture microdissection followed by RNA sequencing. Introduction of ARID1A or ARID1B in cBAF loss DEC cell lines demonstrated the restoration of cBAF assembly, confirmed by glycerol gradient and IP mass spectrometry. Upon the expression of ARID1A or ARID1B, we observed widespread chromatin occupancy and DNA accessibility at distinct paralog-specific sites, along with common sites associated with epithelial lineage differentiation, estrogen receptor, and PI3K/AKT pathway signaling. These findings align with the differentiation signature, defined in DEC cases demonstrating downregulation of genes associated with Myc targets, cell cycle checkpoint pathways, and DNA repair, suggesting these pathways represent potential therapeutic avenues for targeting DEC/UEC. Collectively, these data establish that well-differentiated endometrial carcinoma and DEC/UEC with mSWI/SNF mutations represent a spectrum of cBAF loss, defining the unique roles of ARID1A and ARID1B in endometrial carcinoma development. Furthermore, these findings imply that cBAF loss drives the widespread changes in DEC morphology, gene expression, and clinical behavior, enhancing our understanding of the etiology and therapeutic options for these cancers. Citation Format: Jessica D. St. Laurent, Grace Xu, Kasey Cervantas, Ajinkya Patil, Akshay Sankar, Shary Chen, David Kolin, Yemin Wang, David G. Huntsman, Cigall Kadoch. ARID1A/B mutations retarget mSWI/SNF chromatin remodeler activity and define a spectrum of dedifferentiation in endometrial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr PR006.

Orbital Liposarcoma Progression From a Well-Differentiated to a Dedifferentiated Type in a Young Patient.

A young male patient presented with unilateral proptosis of the left eye. Laboratory tests and an initial computed tomography scan of the orbit were compatible with euthyroid orbitopathy. He subsequently underwent decompression surgery for unfavorable cosmesis and corneal exposure symptoms with good results, but returned 1 year later for recurrence of proptosis. There was a superomedial fatty density extraconal mass on computed tomography scan. A biopsy done a year later confirmed the diagnosis of well-differentiated liposarcoma from the previously noted mass and a dedifferentiated component in the newly appeared mass in the intraconal space. Orbital exenteration with radial forearm free flap was performed followed by orbital radiotherapy. No disease recurrence or metastasis was seen on follow-ups for 7 years since undergoing treatment.

Partially Dedifferentiated Primitive Malignant Melanoma with Pseudo-Angiomatous Features: A Case Report with Review of the Literature.

Malignant melanoma (MM) is traditionally known as the "great mime" of human pathology, as it is potentially capable of imitating the most disparate neoplasms. It is known that in addition to the more classic histotypes of MM, there are also rare forms, including angiomatoid MM. Similarly, it has been amply demonstrated in the literature that MM is capable of dedifferentiating, losing melanocytic lineage markers, constituting a diagnostic challenge for the pathologist. Although 5 cases of primary angiomatoid MM have been described in the literature, to the best of our knowledge, no cases of dedifferentiated melanoma with pseudo-angiomatoid aspects have ever been described. In this paper, we present a very rare case of partially dedifferentiated MM in which the most dedifferentiated component lost melanocytic lineage immunohistochemical markers and assumed a pseudo-angiomatous morphology. Given the rarity of the case, we carried out a literature review of similar cases described, trying to draw new future perspectives not only about this particular variant of MM but also about the widest field of dedifferentiation/undifferentiation of MM.

Loss of H3K27 trimethylation in a distinct group of de-differentiated chordoma of the skull base.

De-differentiated chordoma is defined as a high-grade sarcoma lacking notochordal differentiation, which arises in association with conventional chordoma. The mechanism underlying de-differentiation remains unclear. We immunohistochemically investigated trimethylation at lysine 27 of histone 3 (H3K27me3) in nine de-differentiated chordomas. The tumours occurred at the skull base (n=5) or the sacrum (n=4) in four men and five women with a median age of 50 years. De-differentiation occurred de novo in four cases and at recurrence/metastasis in five cases. Five tumours retained H3K27me3, whereas four showed complete loss of H3K27me3 only in the de-differentiated component, while the conventional chordoma component retained H3K27me3. All the H3K27me3-negative tumours showed co-loss of dimethylation at H3K27 (H3K27me2), consistent with inactivation of polycomb repressive complex 2. Two genetically analysed H3K27me3-negative tumours harboured EED homozygous deletions. All four H3K27me3-negative de-differentiated chordomas affected the skull base of young or middle-aged women. Unlike dense proliferation of highly pleomorphic spindle or epithelioid cells in the H3K27me3-positive de-differentiated chordomas, all H3K27me3-negative tumours displayed swirling fascicles of relatively uniform spindle cells with alternating cellularity and perivascular accentuation, resembling malignant peripheral nerve sheath tumour (MPNST). Rhabdomyoblastic differentiation was present in one H3K27me3-negative tumour. We identified a novel group of de-differentiated chordomas in the skull base that lost H3K27me3/me2 only in the de-differentiated component, which was associated with EED homozygous deletion and MPNST-like histology. Our data suggest a distinct 'polycomb-type' de-differentiation pathway in chordoma, similar to a recently described de-differentiated chondrosarcoma with H3K27me3 loss.

Dedifferentiated chondrosarcoma with minimal or small dedifferentiated component

AbstractDedifferentiated chondrosarcoma (DDCS) is an aggressive bone sarcoma characterized by low-intermediate grade cartilage component with abrupt transition to a high-grade non-chondrosarcomatous component. Generally, the dedifferentiated (DD) component is large. However, rare cases have minimal (<1 cm) or small (1–2 cm) areas of DD. We describe the clinicopathologic features of such tumors and evaluate the prognostic significance of this finding compared to cases with large DD (>2 cm). Available slides were re-reviewed for assessment of histologic features. The medical record was reviewed for imaging studies and clinical characteristics. Thirty-five cases were included. Six patients had minimal DD, four had small DD and 25 had large DD. None of the minimal DD showed definitive imaging evidence of DD. Two minimal DD (33%) locally recurred and 2 (33%) developed distant metastases. None of the small DD cases showed definitive imaging evidence of DD. None of the small DD locally recurred and at least 1 (25%) developed distant metastases. There was no significant difference in age, gender, pelvic site, tumor size >8 cm, tumor necrosis or undifferentiated pleomorphic sarcoma-like morphology between minimal or small DD compared to large DD, though osteosarcomatous differentiation was significantly more common in large DD. There was no significant difference in overall survival between minimal or small DD compared to large DD (p = 0.81 and p = 0.17, respectively), or in progression-free survival (p = 0.47 and 0.29, respectively), or metastasis-free survival (p = 0.06 and 0.62, respectively). DDCS with minimal or small DD show similar demographic distribution, anatomic localization and histologic features to large DD. DD in these cases is unlikely to be detected on imaging. Furthermore, at least a subset of these tumors is extremely aggressive despite the limited extent of DD. This highlights the need for thorough gross and histologic examination and sampling.

A transcriptomic analysis of retroperitoneal well differentiated liposarcoma (WDLPS) and well differentiated (WD) and dedifferentiated (DD) components of dedifferentiated liposarcoma (DDLPS).

e23520 Background: Retroperitoneal DDLPS is an aggressive tumor characterized by a WD component, morphologically similar to a WDLPS, and a DD component that drives patient prognosis. We aimed at unraveling whether WDLPS and DDLPS are distinct entities or entail a progressive evolution from WDLPS to DDLPS through a transcriptomic analysis. Methods: A transcriptomic analysis was performed in a retrospective series of 107 patients with primary retroperitoneal WDLPS (N = 68, 63.5%) or DDLPS (N = 39, 36.5%) who underwent surgery (2011-15). Paired DD, WD, and normal fat (NF) components were sampled in DDLPS, while paired WD and NF components were sampled in WDLPS. RNA-Seq data were normalized according to the trimmed mean of M-value (TMM) algorithm and differential expression was evaluated with the voom method implemented into the edgeR package. Enrichment in hallmark gene sets from Molecular Signatures Database (MSigDB) was evaluated with gene sets enrichment analysis (GSEA), by using t-statistic as measure of ranking. A false discovery rate (FDR) adjusted p-value &lt; 0.05 was considered for statistical significance. Results: Differential expression analysis revealed marked transcriptional changes within paired components of DDLPS (DD, WD, NF) and WDLPS (WD, NF). Changes of WD and NF components between WDLPS and DDLPS were not statistically significant. Gene sets were analyzed to evaluate the ensemble and overcome the FDR correction applied to single genes. Hallmarks deregulated in WD component of DDLPS compared to WDLPS were detected also in their paired DD component. Among them, G2M checkpoint and mitotic spindle were up-regulated, while adipogenesis, fatty acid metabolism, cholesterol homeostasis, oxidative phosphorylation, and peroxisome were down-regulated. These differences persisted also when NF components were compared with their paired WD component of DDLPS and WDLPS. G2M checkpoint and mitotic spindle gene sets did not differ between NF of DDLPS and NF of WDLPS, suggesting these two hallmarks as tumor-specific. Conversely, expression of adipogenesis, fatty acid metabolism, and oxidative phosphorylation was up-regulated together with other gene sets related to metabolism in NF of DDLPS. Tumor inflammation and interferon response were up-regulated in WD components compared to their paired NF components. Also, interferon response was down-regulated in WD component of DDLPS compared to WDLPS, and inflammation was down-regulated in DD component compared to both WD components. Conclusions: Transcriptomic changes that distinguished WDLPS and WD component of DDLPS increased progressively also in the paired DD component of DDLPS, supporting the hypothesis of a progression from WDLPS to DDLPS in some liposarcomas. Changes observed in NF may suggest a paracrine effect sustaining tumor dedifferentiation.

Telomere as a Therapeutic Target in Dedifferentiated Liposarcoma.

Simple SummaryDDLPS is a non-lipogenic tumor with aggressive clinical behavior. DDLPS patients have limited therapeutic options, especially those with retroperitoneal tumors, and their outcome remains largely unsatisfactory, highlighting the need for novel treatment strategies. Gene expression analysis carried out in clinical samples from primary retroperitoneal DDLPS indicated that these tumors highly express genes involved in telomere maintenance, the cellular process that guarantees immortality to tumor cells. In this study, we evaluated the effect of RHPS4, a molecule able to alter telomere by binding to telomeric structures called G-quadruplexes, in patient-derived DDLPS cell lines. Exposure to RHPS4 induced DNA damage and decreased cell proliferation and migration, thus suggesting telomere as a novel target and G-quadruplex binders as innovative therapeutic agents in DDLPS.Background: Well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS) accounts for ~60% of retroperitoneal sarcomas. WDLPS and DDLPS divergently evolve from a common precursor and are both marked by the amplification of the 12q13–q15 region, leading to the abnormal expression of MDM2, CDK4, and HMGA2 genes. DDLPS is a non-lipogenic disease associated with aggressive clinical behavior. Patients have limited therapeutic options, especially for advanced disease, and their outcome remains largely unsatisfactory. This evidence underlines the need for identifying and validating DDLPS-specific actionable targets to design novel biology-driven therapies. Methods: Following gene expression profiling of DDLPS clinical specimens, we observed the up-regulation of “telomere maintenance” (TMM) pathways in paired DD and WD components of DDLPS. Considering the relevance of TMM for LPS onset and progression, the activity of a telomeric G-quadruplex binder (RHPS4) was assessed in DDLPS patient-derived cell lines. Results: Equitoxic concentrations of RHPS4 in DDLPS cells altered telomeric c-circle levels, induced DNA damage, and resulted in the accumulation of γ-H2AX-stained micronuclei. This evidence was paralleled by an RHPS4-mediated reduction of in vitro cell migration and induction of apoptosis/autophagy. Conclusions: Our findings support telomere as an intriguing therapeutic target in DDLPS and suggest G-quadruplex binders as innovative therapeutic agents.

Primary de-differentiated, trans-differentiated and undifferentiated melanomas: overview of the clinicopathological, immunohistochemical and molecular spectrum.

Primary cutaneous and mucosal melanoma shows a wide histological spectrum. The correct diagnosis depends upon the demonstration of melanocytic differentiation by recognition of an associated in-situ component or immunohistochemical evidence of a melanocytic phenotype using conventional melanocytic markers, such as S-100, SOX10, Melan-A and HMB-45. Exceptionally, melanomas lose their melanocytic phenotype, at least focally, and show differentiation towards other lineages. Review of the literature shows that de- and trans-differentiation in melanoma is rare but probably under-recognised and under-reported. These often large and frequently ulcerated tumours affect adults and show a wide anatomical distribution, including mucosal sites, although there is a predilection for sun-damaged skin of the head and neck. Histologically, the tumours are biphasic and contain a pre-existing conventional melanoma. The de-differentiated component closely resembles atypical fibroxanthoma, both morphologically and immunohistochemically. Trans-differentiated melanoma may show rhabdomyosarcomatous or spindle cell carcinomatous features. Undifferentiated melanomas are similar tumours in which the conventional melanoma component is absent. Their diagnosis depends entirely upon the clinical context and identification of a classical melanoma driver gene mutation, i.e. BRAF V600E. The diagnosis of these rare and unusual tumours is challenging, and requires thorough tumour sampling and recognition of the background of a pre-existing but often focal conventional melanoma together with molecular analysis.

Dedifferentiation within well-differentiated liposarcoma of the extremity or trunk: Implications for clinical management.

In extremity or trunk liposarcoma, the implications of a dedifferentiated (DD) component within a well-differentiated (WD) tumor are unclear. We evaluated outcomes after surgery and identified potential predictors of survival in these patients compared to those with an entirely WD tumor. Retrospective data were collected for patients who underwent complete resection from 2009 to 2019. Cumulative incidences of local recurrence (LR) and distant metastasis (DM) were calculated, and overall survival (OS) was estimated. Associations between OS and clinicopathologic variables were evaluated by univariable models. A total of 210 patients with MDM2-verified tumors were studied, including 58 (27.6%) with DD. In primary disease, LR occurred only in DD and worse OS was observed versus WD (p < 0.001). In recurrent disease, the LR incidences were similar between WD and DD (p = 0.559); however, worse OS persisted in DD (p = 0.004). The incidence of DM was extremely low (3.8%) and limited to DD. Higher grade (p < 0.001) and DD size (p = 0.043), but not overall tumor size were associated with worse OS. In extremity or trunk liposarcoma, the presence of DD leads to significantly worse outcomes in both primary and recurrence diseases. Further study is needed to determine if these patients benefit from adjunct therapies (e.g., radiation).

Retroperitoneal Dedifferentiated Liposarcoma.

We aimed to test the hypothesis that in retroperitoneal dedifferentiated liposarcoma (DDLS) the presence of the dedifferentiated (DD) component at the resection margin is associated with adverse outcome. We retrospectively searched the archive for primary resections of retroperitoneal DDLS performed at our institution between 1990 and 2017. Slides were rereviewed for diagnosis, Fédération Nationale des Centres de Lutte Contre le Cancer grade, myogenic differentiation, and the presence of the well-differentiated (WD) or DD component at the resection margin. The medical records were reviewed for patient age, sex, tumor size, tumor focality, adjuvant/neoadjuvant therapy, local recurrence, distant metastases, local recurrence-free survival (LRFS), overall survival (OS), and follow-up duration. The presence of the DD component at the resection margin was associated with worse LRFS compared with cases without the DD component at the margin (P = .002). However, OS was not significantly affected (P = .11). LRFS is significantly shorter in cases with the DD component at the margin compared with cases without DD tumor at the margin, while there is no association with OS. We recommend reporting the presence or absence of DD tumor at the margin in retroperitoneal DDLS, as it adds meaningful prognostic information.

Myogenic dedifferentiation is associated with poor outcomes in retroperitoneal dedifferentiated liposarcomas.

Sarcomas are a heterogenous group of malignant tumors with origin or mesenchymal differentiation, they comprise 1–2% of all solid tumors. Retroperitoneum is the second most frequent site affected. Prognosis is worse compared to the limbs, with a 5y OS of 36–58%, and 50–60% patients will relapse. Dedifferentiated liposarcomas (ddLPS) are more aggressive, it is known that presence of a de-differentiated component increases the probability of distant recurrence and lowers OS. There is little information about the specific impact of each type of de-differentiation. To determine if the presence of myogenic differentiation markers in DDLPS is an adverse prognostic factor. A retrospective, observational, analytic cohort study was performed. Cases identified from the electronic clinical files from the National Cancer Institute in Mexico City, we included cases from January 1st 2005 to December 31st 2016. We correlated the presence of expression of myogenic markers (Smooth muscle actin, Calponin, H-caldesmon, Desmin and Myogenin) in the dedifferentiated component of DDLPS with overall survival and surgical outcomes. One hundred and forty-three cases were analyzed. Eighty-two were liposarcomas, and 38 had a dedifferentiated component. Of these 38 cases, 21(55.3%) were males and, 17(44.7%) were females. Median age was 54.1(27–79) years, median tumor size was 28 cm (13–56). Most patients had locally advanced disease: 32(84.2%) were in stage IIIB. 2.6% had metastatic disease and 5(13.2%) had stage Ib at diagnosis. Myogenic marker expression was found in 18.4% of cases; these patients had a worse median survival than cases with no myogenic expression: 18 months (95% CI 15.4–20.5) vs 32 months (95% CI 21.8–42.1) p = 0.01, we also found a relation with higher postoperative morbidity in these cases (p = 0.045). The presence of myogenic differentiation markers might be associated with a worse prognosis, in our series it corelated with worse OS, however it is not a common event. Relation with surgical morbidity is to be analyzed in further studies.

Targeted Next-Generation Sequencing Identifies Molecular and Genetic Events in Dedifferentiated Chondrosarcoma.

Dedifferentiated chondrosarcoma is a rare adult bone tumor with a dismal prognosis and is composed of a conventional chondrosarcoma juxtaposed to high-grade nonchondrogenic sarcoma. Dedifferentiated chondrosarcomas may represent tumor progression from a differentiated to a primitive histotype. To determine the genetic and molecular events that drive progression from a conventional chondrosarcoma to high grade nonchondrogenic sarcoma. We analyzed the genomic landscape of paired conventional and dedifferentiated components of 11 dedifferentiated chondrosarcoma using targeted next-generation DNA sequencing with immunohistochemical validation. Clinical, radiographic, and pathologic features of tumors were reviewed. Capture-based DNA sequencing targeting the coding regions of 479 cancer genes and select introns was performed. The tumors arose in the femur (n = 4; 36%), scapula (n = 3; 27%), pelvis (n = 3; 27%), and humerus (n = 1; 9%) of 7 men (64%) and 4 women (36%; median age, 61 years). DNA was adequate for sequencing from all 11 dedifferentiated components (100%) and 9 paired conventional chondrosarcoma components (82%). All tumors (100%) harbored either IDH1 p.R132 or IDH2 p.R172S hotspot mutations. Seven tumors (64%) displayed COL2A1 alterations. TERT promoter mutations were present in 5 of 9 pairs (56%) and 2 (22%) additional unpaired dedifferentiated components. IDH1/2, COL2A1, and TERT mutations were identical in both components of the paired samples. Pathogenic missense or truncating mutations in TP53 and large-scale copy number alterations were more common in dedifferentiated components than in those of matched conventional components. The results support IDH1/2, COL2A1, and TERT promoter mutations being common in dedifferentiated chondrosarcoma and as likely early events in progression, whereas inactivating mutation of TP53 and high-level copy number alterations may be later events in the dedifferentiated phenotype.

What Are the Results of Resection of Localized Dedifferentiated Liposarcomas in the Extremities?

Dedifferentiated liposarcoma (DDLPS) is a rare malignancy that transitions from an atypical lipomatous tumor to a sarcoma with a variable morphologic appearance. The behavior of this tumor in the retroperitoneum is aggressive, but the behavior of DDLPS in the extremities is less well-defined because it is rare. Few reports have assessed the imaging features and clinical outcomes of primary DDLPS in the extremities. In patients with primary DDLPS of the extremity, we asked the following questions: (1) How frequently do additional primary malignancies occur in patients with DDLPS? (2) What is the rate of overall survival, metastases, and local recurrence in DDLPS? (3) What factors are associated with metastasis-free survival and local recurrence in DDLPS? We defined DDLPS as a biphasic neoplasm that transitions from an atypical lipomatous tumor (ALT) to a sarcoma of variable morphologic appearance and histologic grades. We retrospectively evaluated the medical records of patients with DDLPS of the extremities who underwent surgery in our institution between 2003 and 2017. During that time, 16 patients were treated for this diagnosis; one was excluded from this study because the patient did not have an MRI, leaving 15 patients (nine men, six women; their median [range] age was 67 years [42 to 87]) for evaluation. All had a minimum of 2 years follow-up (median [range] 54 months [25 to 136]); 14 of 15 have been seen in the last 5 years (one patient, who was doing well at the time, was lost after 9 years of follow-up). In 11 patients, MRI demonstrated two components: an ALT component with high intensity on both T1-weighed and T2-weighted sequences and a dedifferentiated component low-to-intermediate intensity on T1-weighed and heterogeneous hyperintensity on T2-weighted sequence. Nine patients were evaluated using 2-deoxy-2-18F-fluoro-D-glucose positron emission tomography (FDG-PET) combined with CT (PET/CT). PET/CT showed a biphasic pattern with a close relationship to MRI findings. The dedifferentiated component presented with high FDG uptake (median [range] maximum standardized uptake value 5.1 [1.9 to 22.6]), while the atypical lipomatous tumor component showed almost no FDG uptake. In all patients, immunohistochemical studies of p16 and cyclin-dependent kinase-4 (CDK4) were investigated. Positive staining for both p16 and CDK4 were seen in 13 of 15 patients.We retrospectively evaluated the electronic medical records of all patients in our institution for the presence of additional primary malignancies, local recurrence-free survival, metastasis-free survival, and overall survival. The survival rate was estimated using the Kaplan-Meier method. The Wilcoxon exact test was used to determine the prognostic importance of the following survival variables: age, sex, maximum tumor size, radiotherapy, and surgical margin. Seven additional primary malignancies developed in five of 15 patients (two lung cancers, two sarcomas, one renal cell cancer, one uterine cancer, and one non-Hodgkin lymphoma). The 3- and 5-year metastasis-free survival rates were 86% (95% CI 0.67 to 1.00) and 75% (95% CI 0.49 to 1.00), respectively. With the numbers available, we found no factors associated with metastasis-free survival. The 3- and 5-year overall survival rates were 100% (95% CI 1.00 to 1.00) and 88% (95% CI 0.65 to 1.00), respectively. Three of 15 patients had local recurrence. The 3- and 5-year local recurrence-free survival rates were 86% (95% CI 0.67 to 1.00) and 75% (95% CI 0.49 to 1.00), respectively. Large (> 15 cm) tumors were more likely to have a local recurrence (p = 0.04). In this small series, we found that the extremities are a favorable site for DDLPS compared with the retroperitoneum, although we did not directly compare the two sites. This rare tumor has a relatively high likelihood of being associated with other malignancies. We believe patients should be assessed and monitored carefully for this possibility. In the future, larger studies are needed to better define predictors of local recurrence, although the tumor's size may be associated with a greater propensity for local recurrence. Level II, prognostic study.

Correlation between percutaneous biopsy and final histopathology for retroperitoneal sarcoma: a single-centre study.

Retroperitoneal sarcomas are rare soft tissue tumours accounting for 10-15% of soft tissue sarcomas. Patient prognosis and treatment recommendations (including extent of surgery and neoadjuvant strategies) are determined by the pre-operative histopathological subtype and grade obtained from biopsy and thus it is important to understand the accuracy of biopsy in retroperitoneal masses. This study presents a case series of primary retroperitoneal sarcomas managed at Peter MacCallum Cancer Centre (PMCC) between 2008 and 2019. Statistical analyses were performed to determine correlation between histopathology from percutaneous biopsy and surgical excision. A total of 117 patients who underwent percutaneous core biopsy and surgical excision of retroperitoneal sarcoma were included. Diagnostic accuracy varied with histopathological diagnosis, but overall precise concordance between biopsy and final histopathology was seen in 61% (κ = 0.57). Biopsy was most sensitive for identifying well-differentiated liposarcoma (WDLPS) (sensitivity 85%, 95% CI 0.06-0.96) and leiomyosarcoma (sensitivity 81%, 95% CI 0.54-0.96) and was least sensitive for identifying de-differentiated liposarcoma (DDLPS) (sensitivity 40%, 95% CI 0.25-0.56). Overall agreement between biopsy and final histopathology increased with use of PET/CT scan pre-biopsy and with use of fluorescence in situ hybridisation testing on biopsy, however, neither test improved recognition of de-differentiated components within WD/DDLPS on core biopsy. Pre-operative biopsy is important for clinical decision making in the treatment of retroperitoneal sarcoma. A significant portion of patients with a WDLPS will have a de-differentiated component identified at the time of resection that was not identified on initial biopsy.