Histiocytoma Research Articles

Using pan-sarcoma multiomic analysis for identifying sarcoma subtypes with immunogenic potential.

11551 Background: Immune checkpoint inhibitors (ICI) have limited efficacy for most sarcomas. Yet, responses are seen in particular sarcoma subtypes, highlighting the need for better predictive biomarkers. The T cell inflamed score (TIS), a gene expression signature reflective of an active tumor immune microenvironment, is associated with ICI response in multiple solid tumors. We evaluated the TIS across a large database of sarcomas to identify which histologic subtypes may benefit from ICI. Methods: Next generation sequencing of DNA (592 gene or whole exome)/RNA (whole transcriptome) was performed for 3605 sarcoma patient samples, representing 45 histologic subtypes (Caris Life Sciences, Phoenix, AZ). TIS (18 gene weighted coefficient composite value; Cristescu 2018) was calculated and the Microenvironment Cell Populations-counter tool (Becht 2016) was used to quantify immune cell populations. Results were compared to melanoma (n = 1255), a representative immunogenic tumor type. High TIS was defined as a score within the upper quartile of melanoma TIS (> 5.5). Percentage with high TIS are reported with 95% CI. Results: Median TIS was highest in inflammatory myofibroblastic tumor (IMT), epithelioid sarcoma (EPIS), myxofibrosarcoma (MFS), well differentiated liposarcoma, and solitary fibrous tumor (SFT). These did not differ significantly from melanoma (p > 0.06). Median TIS was lowest in embryonal rhabdomyosarcoma, desmoid tumor (DES), synovial sarcoma (SYNS), and Ewing sarcoma (ES). Histologic subtypes where > 10% of samples had a high TIS included IMT (29.9% ± 21.7%), MFS (23.3% ± 12.6%), pleomorphic sarcoma (PLSARC) (21.9% ± 5.8%), cutaneous angiosarcoma (ANGS) (18.4% ± 13.9%), spindle cell sarcoma (17.5% ± 7.6%), liposarcoma (LPS) (17% ± 10.7%), EPIS (15.4% ± 19.6%), visceral ANGS (13.2% ± 10.7%), pleomorphic LPS (13.6% ± 14.3%), fibrosarcoma (12.5% ± 13.2%), leiomyosarcoma (11.6%± 3.4%), malignant peripheral nerve sheath tumor (MPNST) (10.2% ± 7.7%), and perivascular epithelioid cell tumor (PEComa) (10% ± 10.7%). The relative abundance of immune and stromal cell populations was highly variable across sarcoma subtypes, yet a strong positive correlation between TIS and immune cell populations was observed for most subtypes (e.g. T cells, Spearman R range: 0.56 [P = 0.08] - 0.96 [P < 0.0001]). A notable exception was SFT, which had a relatively high median TIS but low abundance of CD8+ T cells and B cells. Conclusions: We found high median TIS and/or significant proportions of samples with a high TIS in sarcoma subtypes with previously demonstrated responsiveness to ICI, including MFS, PLSARC, LPS, and ANGS, while unresponsive tumor types such as RMS, DES, SYNS, and ES had low TIS. We further identified subtypes with high TIS but limited prior clinical data supporting ICI use, such as IMT, EPIS, MPNST, SFT, and PEComa. Our results warrant prospective exploration of TIS as a predictive biomarker for ICI use in sarcoma.

Myxofibrosarcoma of the abdominal wall : A case report and literature review.

IntroductionMyxofibrosarcoma (MFS) is a subtype of soft tissue sarcoma characterized by diffuse infiltration patterns. Myxofibrosarcoma arises often in extremities. Its occurrence in the abdominal wall is extremely rare.Herein, we present here a case of high-grade MFS of the abdominal wall discovered in a 58-year-old woman complaining of an abdominal mass.Presentation of caseThis report illustrates the case of a female who presented a mass in the right lower quadrant of the abdomen. Abdominal computed tomography (CT) scan revealed a well-circumcised, heterogeneous soft tissue mass. We performed a wide margin excision of the mass. Histology concluded in myxofibrosarcoma of the abdominal wall. Adjuvant radiotherapy was performed.Clinical discussionWe reported successful surgical treatment for myxofibrosarcoma of the abdominal wall. To our knowledge, this is the second report in English literature.MFS is a subtype of soft tissue sarcoma with a locally infiltrative behavior.To ensure the best curative treatment, It is important to excise the tumor with wide margins.Knowing that MFS has a propensity for local recurrence (16 to 57 %), adjuvant radiotherapy has emerged as an efficient treatment for improving local control.The role of chemotherapy is controversial and has not shown effects on survival.ConclusionMyxofibrosarcoma is a connective tissue neoplasm. Its occurrence in the abdominal wall is extremely rare.Surgical treatment with large negative margins is the cornerstone of the treatment. Adjuvant radiotherapy is essential in preventing local recurrences.

Myxofibrosarcoma of neck: A rare case

Myxofibrosarcoma (MFS) is commonly seen among elderly patients, usually sixth to eighth decade of life. Most of these tumours arise in the extremities (lower limbs > upper limbs) and are less commonly seen on the Trunk, Head and Neck, Retroperitoneum and Pelvic areas. The World Health Organization (WHO) defines MFS as the malignant fibroblastic neoplasm characterized by cellular pleomorphism, variably prominent myxoid stroma, and prominent elongated, thin-walled stromal blood vessels. Head Neck MFS is rare site of occurrence with 19 cases reported worldwide till date, described subsites being Maxillary sinus, Infra Temporal fossa, Pterygopalatine fossa, or Parotid gland. The Surgical wide local excision is the main modality of treatment for Non metastatic stage followed by Adjuvant Radiotheraphy.We are presenting a young adult male, presenting with Asymptomatic progressive neck mass, predominantly in posterior triangle distorting upper Aerodigestive tract anatomy. The Diagnosis of MFS done with MRI imaging of neck, Trucut biopsy and CECT scan thorax. With the anticipation of difficult intubation, Broncoscopic directed intubation is planned and done. The surgical wide resection amounted in excision of Sternomastoid, IJV, SAN and part of posterior triangle bed muscles for getting margin free status. The Histopathology showed spindle cells with Myxoid stroma, areas of necrosis with circumferential free margins, along with IHC showed positive for vimentin and CD34 with diagnosis as High Grade Myxofibrosarcoma. Post op patient was adviced Adjuvant Radiotheraphy.

The landscape of genetic aberrations in myxofibrosarcoma.

Myxofibrosarcoma (MFS) is a rare subtype of sarcoma, whose genetic basis is poorly understood. We analyzed 69 MFS cases using whole-genome (WGS), whole-exome (WES) and/or targeted-sequencing (TS). Newly sequenced genomic data were combined with additional deposited 116 MFS samples. WGS identified a high number of structural variations (SVs) per tumor most frequently affecting the TP53 and RB1 loci, 40% of tumors showed a BRCAness-associated mutation signature, and evidence of chromothripsis was found in all cases. Most frequently mutated/copy number altered genes affected known disease drivers such as TP53 (56.2%), CDKN2A/B (29.7%), RB1 (27.0%), ATRX (19.5%) and HDLBP (18.9%). Several previously unappreciated genetic aberrations including MUC17, FLG and ZNF780A were identified in more than 20% of patients. Longitudinal analysis of paired diagnosis and relapse time points revealed a 1.2-fold mutation number increase accompanied with substantial changes in clonal composition over time. Our study highlights the genetic complexity underlying sarcomagenesis of MFS.

Clinicopathological Assessment of Cancer/Testis Antigens NY-ESO-1 and MAGE-A4 in Highly Aggressive Soft Tissue Sarcomas.

We aimed to investigate the clinical significance of the expression of NY-ESO-1 and MAGE-A4 in soft tissue sarcoma (STS). Immunostaining for NY-ESO-1, MAGE-A4, and Ki67 was performed using pathological specimens harvested from 10 undifferentiated pleomorphic sarcoma (UPS), nine myxofibrosarcoma (MFS), and three malignant peripheral nerve sheath tumor (MPNST) patients treated at our hospital. We examined the correlation of NY-ESO-1 and MAGE-A4 expression levels with tumor size, histological grade, and SUVmax values. Positive cell rates of various markers were also compared between patients in remission and those who were not in remission. The rates of cases positive for NY-ESO, MAGE-A4, and Ki67 were 50%, 63.6%, and 90.9%, respectively. The average rates of cells positive for NY-ESO, MAGE-A4, and Ki67 in all STS types were 18.2%, 39.4%, and 16.8%, respectively. A positive correlation was observed between rates of cells positive for NY-ESO-1 and MAGE-A4 and between NY-ESO-1 and MAGE-A4 expression levels and clinical features. There was no significant difference in the positive cell rate of NY-ESO-1 or MAGE-A4 between remission and non-remission cases. Our results suggest that NY-ESO-1 and MAGE-A4 expression may be useful for the diagnosis and prognostication of UPS, MFS, and MPNST.

Overall Survival of Patients with Myxofibrosarcomas: An Epidemiological Study.

Simple SummaryMyxofibrosarcoma (MFS) is a rare soft tissue sarcoma type with high local recurrence and amputation rates. Robust epidemiological data on overall survival of patients with MFS and prognostic factors are lacking due to the rareness of the disease. In this study, we therefore report prognostic factors and real-life outcomes of the largest myxofibrosarcoma cohort to date including 908 patients. Five-year overall survival was 68%. Multivariate analyses revealed known prognostic factors for OS, such as age, tumour size, and histological grade with the addition of sex. In a more detailed subcohort of 177 patients, 39% developed a local recurrence and 28% distant metastases. The survival outcomes and recurrence rates found in this study emphasize the need to improve treatment strategies.Myxofibrosarcoma (MFS) is a rare mesenchymal soft tissue sarcoma type, with a high local recurrence (LR) rate. Robust epidemiological data on MFS are lacking. We, therefore, aimed to identify prognostic factors and describe real-life outcomes of a large cohort of 908 MFS patients obtained from the nationwide database of the Netherlands Cancer Registry and diagnosed between 2002 and 2019. Median Overall survival (OS) was 155 (range 0.1–215) months, with a five-year OS of 67.7%. No improvement of OS was found over time. Multivariable Cox regression survival analysis demonstrated known prognostic factors for OS, such as older age, tumour size, and histological grade with the addition of sex. Surgery at sarcoma expertise centres, instead of general hospitals, was associated with better OS outcomes. In a subcohort of 177 patients, 39% developed LR with a median time to recurrence of 20 months. From LR on, the median OS was 64.0 months (CI 95% 38.5–89.5). In 28%, distant metastases were diagnosed with a median OS of 34.3 months (CI 95% 28.8–39.8) after diagnosis of the primary tumour. In this largest nationwide cohort so far, survival outcomes and recurrence rates for MFS patients did not improve over time, emphasizing the need to improve treatment strategies and suggesting a role for sarcoma expertise centres.

Treatment strategies and outcomes of primary Myxofibrosarcomas in a large patients cohort

Backgroundthis study analysed primary myxofibrosarcoma (MFS) to investigate patient outcomes focusing on histopathologic margins and perioperative treatments. Patients and methodsdata from consecutive patients affected by primary and localized MFS of the extremities or trunk wall who underwent surgery (2002–2017) were analysed. Local recurrence (LR), amputation rate, incidence of distant metastasis (DM), and overall survival (OS) were studied. ResultsOf 293 included patients, 52 (17%) patients received perioperative treatments and 54 (18%) had positive microscopic histopathologic margins (R1). Median follow-up was 80 months (IQR, 49–109). 5-yr CCI of LR was 0.12 (SE: 0.02). Status of histopathologic margins (P < 0.001), tumour malignancy grade (P = 0.018) and size (P = 0023) were independent prognostic factor for LR. Nine amputations (amputation rate: 3%) were performed (N = 1 for primary tumour; N = 8 for LR). Larger tumour size (P = 0.015) and higher grade (P = 0.025) were independent prognostic factor for DM. 5-year OS was 0.84 (95%CI 0.79–0.88). Patient age (P = 0.008), tumour size (P = 0.013) and malignancy grade (P = 0.018) were independently associated to OS. In the subgroup of patients who had a re-excision for a primary MFS (N = 116, 40%), the presence of residual disease was not associated with LR, DM, or OS. Conclusionin this study 5-year LR, DM and OS were 12%, 17%, and 84%, respectively. One in six patients had a positive surgical margin, which was a prognostic factor for LR, while DM and OS were predicted by tumour grade and size. Findings from this large patient cohort may set benchmarks for investigating new treatment options for MFS.

Establishment and Characterization of NCC-MFS5-C1: A Novel Patient-Derived Cell Line of Myxofibrosarcoma.

Myxofibrosarcoma (MFS) is a highly aggressive malignancy with complex karyotypes and a postoperative recurrence tendency, owing to its strong invasiveness. Although systemic chemotherapy is considered in patients with unresectable MFS, the efficacy of conventional chemotherapy is hitherto unclear. Recently, drug screening analysis using a large number of tumor cell lines has been attempted to discover novel therapeutic candidate drugs for common cancers. However, the number of MFS cell lines is extremely small because of its low incidence—this hinders the conduction of screening studies and slows down the development of therapeutic drugs. To overcome this problem, we established a novel MFS cell line, NCC-MFS5-C1, which was shown to harbor typical MFS genetic abnormalities and thus had useful properties for in vitro studies. We conducted the largest integrated screening analysis of 210 drugs using NCC-MFS5-C1 cells along with four MFS cell lines, which we previously reported. Bortezomib (a proteasome inhibitor) and romidepsin (a histone deacetylase inhibitor) showed stronger antitumor effects than the standard drug, doxorubicin. Therefore, the NCC-MFS5-C1 cell line can potentially contribute to elucidating MFS pathogenesis and developing a novel MFS treatment.

Myxofibrosarcoma landscape: diagnostic pitfalls, clinical management and future perspectives.

Myxofibrosarcoma (MFS) is a common entity of adult soft tissue sarcomas (STS) characterized by a predilection of the extremities and a high local recurrence rate. Originally classified as a myxoid variant of malignant fibrous histiocytoma, this musculoskeletal tumor has been recognized since 2002 as a distinct histotype showing a spectrum of malignant fibroblastic lesions with myxoid stroma, pleomorphism and curvilinear vessels. Currently, the molecular pathogenesis of MFS is still poorly understood and its genomic profile exhibits a complex karyotype with a number of aberrations including amplifications, deletions and loss of function. The diagnosis is challenging due to the unavailability of specific immunohistochemical markers and is based on the analysis of cytomorphologic features. The mainstay of treatment for localized disease is represented by surgical resection, with (neo)-adjuvant radio- and chemotherapy. In the metastatic setting, chemotherapy represents the backbone of treatments, however its role is still controversial and the outcome is very poor. Recent advent of genomic profiling, targeted therapies and larger enrollment of patients in translational and clinical studies, have improved the understanding of biological behavior and clinical outcome of such a disease. This review will provide an overview of current diagnostic pitfalls and clinical management of MFS. Finally, a look at future directions will be discussed.

Assessment of the effectiveness of the use of tumoroids for personalized drug therapies for solid tumors

The approach to the management of cancerous neoplasms, which aims to define the effective curative strategies in each patient, defines the requirement for the elaboration and use of modelling systems that replicate the structures and the biology of human solitary tumors. Three-dimensional cultures of spheroids/tumoroids, which are multi-cell aggregates of malignized cells, can create the intercellular connections of interest, gradients of the nutrients and oxygen, and cell polarity, all of which are absent in the conventional two-dimensional single-layer system. The present work is dedicated to a comparison study of in vitro viability and invasiveness of solid tumor cells of patients under the effect of chemopreparations and their combinations in view of evaluating the efficacy of the 3D-cell modelling system in the translational personalized medicine context. Cell cultures of patients who were treated at the N.N. Petrov National Medicine Research Center of oncology were used as a basis for the development of 3D-cell models. N.N. Petrov NMRC in 2015-2021. Tumor tissue pieces were acquired intraoperatively: 1 - leiomyosarcoma (LMS), 1 - rhabdomyosarcoma (RMS), 1 - synovial sarcoma (SS), 2 - myxofibrosarcoma (MFS), 2 - osteogenic sarcoma (OS), 1 - skin melanoma (MC), 1 - breast cancer (BC) (n=9). Our individual comparison of the effectiveness of in vitro chemotherapeutic agents against tumor cells of various origins cultivated in 2D and 3D model systems with real clinically relevant cases confirmed that the monolayer culture as the test system was less adequate for selecting and personalizing the treatment of malignant tumor patients: the 3D cell system proved itself in 77.7% of cases, and the monolayer culture - in 44.4% of cases. The combination of doxorubicin/iforsfamide and paclitaxel significantly suppressed the motility in the matrigel of spheroid cells, but did not affect tumor cell viability, which was seen in all but OS #921 and MK #929 cases. The cultivation of tumor cells in form of spheroids/tumoroids allows to utilize them as more adequate pre-clinical model as individual predictive test-system, enabling the personalized selection of therapy.

Epithelioid Variant of High-Grade Myxofibrosarcoma in the False Vocal Fold: A Case Report

Myxofibrosarcoma (MFS) is a histologic subtype of malignant fibrous histiocytoma (MFH), with a predominant myxoid component. MFS is characterized by locally aggressive behavior and a high rate of local recurrence, however, with a good prognosis. Head and neck MFS accounts for 3% of all cases of MFS. To date, only two cases of laryngeal MFS have been reported. Owing to the rarity of MFS, the clinical characteristics and optimal treatment options remain controversial. Surgical resection with a clear margin is considered the treatment of choice. Compared to traditional MFS tumors, epithelioid variants have worse prognosis. Other factors associated with a poor prognosis of MFS tumors include inadequate surgical margins, large tumor size, old age, and high-grade tumors. Herein, we report a case of high-grade epithelioid variant MFS located in the false vocal fold, requiring total laryngectomy to obtain an adequate surgical margin. To our knowledge, this is the first case report of epithelioid variant of high-grade MFS presenting in the larynx.

Oncological Outcomes in Patients with Appendicular Myxofibrosarcomas: A Retrospective Study.

Background Myxofibrosarcoma (MFS) is notorious for its infiltrative growth pattern, making wide excisions difficult to achieve. Our objective was to assess the impact of surgical margins and other factors that affected rates of local recurrence (LR), distant metastasis (DM), and overall survival (OS) of individuals undergoing resection for MFS. Methods We retrospectively reviewed the medical records of 209 patients with appendicular soft tissue sarcomas between January 2012 and June 2018. Of these, 29 patients (14%) were diagnosed with myxofibrosarcoma. These patients underwent a total of 33 resections. The pathological analyses were conducted by an experienced musculoskeletal (MSK) pathologist. Demographics data, operative details, adjuvant therapy, and oncological outcomes were assessed. Results Of the 29 patients (33 resections), the overall LR rate was 24% (7/29) and the 2-year LR rate was 17% (5/29). Factors associated with negative oncological outcomes were as follows: tumor size ≤10 cm (2-year local recurrence-free rates (LRFRs), 65%; 95% CI, 44–86%; p=0.02) and positive surgical margins grouped with surgical margins ≤0.1 cm (hazard ratio (HR), 11.74; 95% CI, 1.41–97.74; p=0.02). Chemotherapy and radiotherapy together increased the 2-year LRFR (LRFR, 100%; 95% CI, 100%, p=0.001). Two-year DM and OS rates were 15% and 79%, respectively. Female gender was a predictor of distant metastasis. Local recurrence had a negative impact on overall survival. Intraoperative analysis of resection margin accuracy was 75% (12/16) when non-MSK pathologists were involved but 100% accurate (12/12) when analyzed by an MSK pathologist. Conclusion Myxofibrosarcomas showed high LR rates after treatment. Close margins (≤0.1 cm) should be considered as a risk factor for LR, and LR is associated with negative overall survival. Neoadjuvant therapy in terms of combined chemotherapy and radiation therapy associates with decreased LR rates. If intraoperative assessment of margins is to be done, it should be performed by an experienced MSK pathologist.

Activity of PD-1 Inhibitor Combined With Anti-Angiogenic Therapy in Advanced Sarcoma: A Single-Center Retrospective Analysis.

Background: Immune checkpoint inhibitors (ICIs) are employed to treat various cancers, including soft tissue sarcomas (STSs), and less than 20% of patients benefit from this treatment. Vascular endothelial growth factor (VEGF) promotes the immunosuppressive tumor microenvironment and contributes to ICI-resistant therapy. Anti-VEGF receptor tyrosine-kinase inhibitors (TKIs) combined with ICIs have shown antitumor activity in patients with alveolar soft-part sarcoma (ASPS). However, they have not been extensively studied to treat other STS subtypes, such as leiomyosarcoma (LMS), dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), and angiosarcoma (AS). Methods: In this retrospective study, we collected data from 61 patients who were diagnosed with advanced STS based on imaging and histology, including LMS, DDLPS, and UPS. Among them, 41 patients were treated with ICIs combined with TKIs and 20 patients received ICI therapy. The endpoints of progression-free survival (PFS) and overall response rate (ORR) were analyzed in the two groups, and the overall response [partial response (PR), stable disease (SD), and progressive disease (PD)] of each patient was determined using RECIST 1.1 evaluation criteria. Results: In total, 61 STS patients had the following subtypes: LMS (n = 20), DDLPS (n = 17), UPS (n = 8), ASPS (n = 7), MFS (n = 7), and AS (n = 2). The median PFS (mPFS) was significantly prolonged after ICI treatment in combination with TKIs (11.74 months, 95% CI 4.41–14.00) compared to ICI treatment alone (6.81 months, 95% CI 5.43–NA) (HR 0.5464, p = 0.043). The 12-month PFS rates of patients who received ICI–TKI treatment were increased from 20.26% (95% CI 0.08–0.53) to 42.90% (95% CI 0.27–0.68). In the combination therapy group, 12 patients (30%) achieved PR, 25 patients (62.5%) achieved SD, and 3 patients (7.5%) achieved PD for 3 months or longer. In the non-TKI-combination group, 2 patients (9.5%) achieved PR, 14 patients (66.7%) achieved SD, and 5 patients (23.8%) achieved PD within 3 months. The ORRs in the two groups were 30.0% (ICI–TKI combination) and 9.5% (ICI only), respectively. A notable ORR was observed in the ICI–TKI combination group, especially for subtypes ASPS (66.7%), MFS (42.9%), and UPS (33.3%). The PD-L1 expression (n = 33) and tumor mutation burden (TMB, n = 27) were determined for each patient. However, our results showed no significant difference in PFS or response rates between the two groups. Conclusion: This study suggests that ICI–TKI treatment has antitumor activity in patients with STS, particularly the ASPS and MFS subtypes. Moreover, effective biomarkers to predict clinical outcomes are urgently needed after combination therapy in the STS subtypes.

Assessment of H3K27me3 immunohistochemistry and combination of NF1 and p16 deletions by fluorescence in situ hybridization in the differential diagnosis of malignant peripheral nerve sheath tumor and its histological mimics

BackgroundA definitive diagnosis of malignant peripheral nerve sheath tumor (MPNST) is challenging, especially in cases without neurofibromatosis 1 (NF1), because MPNST lacks specific markers on immunohistochemistry (IHC).MethodsWe performed IHC for histone 3 trimethylated on lysine 27 (H3K27me3) and evaluated the percentage of cells with H3K27me3 loss using measured values at 10% intervals, categorized as complete loss (100% of tumor cells lost staining), partial loss (10% to 90% of tumor cells lost staining), and intact (no tumor cells lost staining). We conducted fluorescence in situ hybridization (FISH) for NF1 and p16 deletions comparing 55 MPNSTs and 35 non-MPNSTs, consisting of 9 synovial sarcomas (SSs), 8 leiomyosarcomas (LMSs), 10 myxofibrosarcomas (MFSs), and 8 undifferentiated pleomorphic sarcomas (UPSs). We assessed the percentage of cells with homozygous and heterozygous deletions and defined “deletion” if the percentage of either the NF1 or p16 deletion signals was greater than 50% of tumor cells.ResultsAmong the 55 MPNSTs, 23 (42%) showed complete H3K27me3 loss and 32 (58%) exhibited partial loss or intact. One each of the 9 SSs (11%), 8 LMSs (12%), and 8 UPSs (12%) showed complete H3K27me3 loss and many non-MPNSTs exhibited intact or partial H3K27me3 loss. Among the 55 MPNSTs, 33 (60%) and 44 (80%) showed NF1 or p16 deletion, respectively. Co-deletion of NF1 and p16 was observed in 29 (53%) MPNSTs. Among the 23 MPNTSs showing H3K27me3 complete loss, 18 (78%) and 20 (87%) exhibited NF1 or p16 deletion, respectively. Among the 32 MPNSTs with H3K27me3 partial loss or intact, 15 (47%) and 24 (75%) exhibited NF1 or p16 deletion, respectively. The frequency of NF1 and/or p16 deletion tended to be lower in non-MPNSTs than in MPNSTs. Approximately 90% of MPNSTs included cases with H3K27me3 complete loss and cases showing H3K27me3 partial loss or intact with NF1 and/or p16 deletion. Approximately 50% of MPNSTs showed co-deletion of NF1 and p16 regardless of H3K27me3 loss.ConclusionsFISH for NF1 and p16 deletions, frequently observed in high-grade MPNSTs, might be a useful ancillary diagnostic tool for differentiating MPNST from other mimicking spindle cell and pleomorphic sarcomas.

Analysis of prognostic factors in 171 patients with myxofibrosarcoma of the trunk and extremities: a cohort study.

BackgroundMyxofibrosarcoma (MFS) of the trunk and extremities has unique clinical features. However, it is not clear which indicators are the influencing factors of recurrence, metastasis, and survival of trunk and limb MFS. The aim of the present study was to analyze clinical features and prognosis of trunk and limb MFS.MethodsThe data of 171 patients with MFS of the trunk and extremities and a median follow-up period of 67 months from January 1999 to July 2018 were retrospectively analyzed. Risk factors for survival, recurrence and metastasis following resection of MFS of trunk and extremities were analyzed. The Kaplan-Meier method (log-rank test) was used for the univariate analysis and a Cox regression model was used for the multivariate analysis.ResultsThe median age of the patients was 53 years; there were 111 males and 60 females. A total of 132 cases had French Federation of Cancer Centers grade 1, 24 cases had grade 2, and 15 cases had grade 3 MFS. The 3-year recurrence, 3-year metastasis, and 5-year survival rates were 29.2%, 19.3%, and 93.6%, respectively. Kaplan-Meier survival analysis showed that the surgical margin (χ2=22.228, P<0.001) and tumor size (χ2=6.697, P=0.010) were associated with recurrence. The surgical margin (χ2=12.353, P<0.001) and CD44 expression (χ2=5.227, P=0.022) were associated with metastasis. The multivariate analysis showed that the surgical margin [hazard ratio (HR) =3.635, 95% confidence interval (CI): 1.883–7.016, P<0.001] and tumor size (HR =1.889, 95% CI: 1.039–3.435, P=0.037) were risk factors for local recurrence. In addition, the surgical margin (HR =4.475, 95% CI: 1.918–10.438, P=0.001) and presence of CD44 (HR =3.406, 95% CI: 1.462–8.405, P=0.005) were risk factors for distant metastasis.ConclusionsA negative surgical margin can be reduced effectively the rate of recurrence and metastasis in patients with MFS of the trunk and limbs. In addition, CD44 may be used to assess the metastatic risk of patients with MFS.

Prognostic value of CD34 expression status in patients with myxofibrosarcomas and undifferentiated pleomorphic sarcomas

It is controversial whether patients with myxofibrosarcomas (MFSs) have better prognoses than those with undifferentiated pleomorphic sarcomas (UPSs). No useful prognostic factors have been established to date. We therefore aimed to evaluate the prognostic value of CD34 expression status in 192 patients with MFSs and UPSs. Using the log-rank test, we showed that patients with MFSs had a significantly better overall survival than did those with UPSs when defining the former as having a > 10% myxoid component (p = 0.03), but not when defining it as having a > 50% myxoid component (p = 0.1). Under the definition of MFSs as > 10% myxoid component, the log-rank test revealed that the diagnosis of the UPS and the CD34 loss (p < 0.001) were significant adverse predictors of overall survival. As per the Cox model, the CD34 loss remained an independent prognostic factor (hazard ratio = 3.327; 95% confidence interval 1.334–8.295), while the diagnosis of the UPS was a nonsignificant confounding factor (hazard ratio = 1.084; 95% confidence interval 0.679–1.727). In conclusion, CD34 expression status is a useful prognostic factor in patients with MFS and UPS, and it should be incorporated into grading systems that are used to predict outcomes.

Impact of histological subtype on radiological and pathological response after neoadjuvant radiotherapy in soft tissue sarcoma

BackgroundEvaluation of response to neoadjuvant radiotherapy (NART) does not consider soft tissue sarcoma (STS) heterogeneity. We aimed to investigate radiological and pathological response of 4 major histotypes. MethodsExtremity or trunk STS patients who received 50 Gy NART between 2009 and 2020 were retrospectively included. Relative variation in tumor size (RVTS) and pathological response were reported in the overall population and in undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), myxoid liposarcoma (MLS) and synovial sarcoma (SS) patients to identify response modalities of each histotype. ResultsAmong the 121 included patients, 49, 19, 13 and 11 presented UPS, MFS, MLS and SS. Median RVTS were 0% (IQR -18-+18), +8% (IQR 0-+24), −12% (IQR -20–3) and −11% (IQR -15–9), respectively (p = 0.001). Median viable cells were 10%, 60%, 20% and 70% (p = 0.007). In overall population, pathological complete response and median necrosis were 27.7% and 10% without significant correlation to histotype (p = 0.18 and 0.06). Nineteen (38.8%) UPS specimens presented cysts that were emptied during the sampling process and distorted the microscopic response evaluation. Infiltrative growth pattern was observed in 28% and 38.9% UPS and MFS patients. Five (38.5%) MLS presented mature adipocytes without proven prognostic value. Cysts were observed in 36% of SS specimens. In the absence of initial tumor limits, the great viable cellularity of SS may be overestimated by their nodular aspect. ConclusionAfter NART, we highlighted disparate response of UPS, frequent progression of MFS, and confirmed MLS and SS radiosensitivity. Response must be interpreted with caution and consider the histotype-specific patterns.

Characterization of PD-1/PD-L1 immune checkpoint expression in soft tissue sarcomas.

Inhibitors of the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint system are used for treating various malignancies. However, evidence on their use in soft tissue sarcomas (STS) is limited. This study aimed to retrospectively investigate the relationship between the expression of PD-1/PD-L1 and related antigens in STS, and their association with clinical characteristics. Immunostaining for CD4, CD8, PD-1, PD-L1, IL-2, and IFN-γ was performed using pathological specimens harvested at the time of biopsy from 10 patients with undifferentiated pleomorphic sarcoma (UPS), nine with myxofibrosarcoma (MFS), and three with malignant peripheral nerve sheath tumor (MPNST) who were treated at our hospital. Subsequently, the positive immunostaining cell rates were calculated. We also examined the correlation between each immune positive cell rate and age, tissue grade, size, and maximum standardized uptake (SUV-max) values. The 3-year event-free survival (EFS) and overall survival (OS) rates were compared between the positive and negative groups (positive rate >10%; negative <10%) for various immune stains. The positive rates were also compared between the presence and absence of events groups. There was positive staining for the immune checkpoint molecules in every STS type except for PD-1 in MPNST. CD4, CD8, and PD-1 stained lymphocytes in close proximity to the tumor in adjacent tissue sections. A positive correlation was observed between the positive cell rates of each immune component including inflammatory cytokines such as IL-2 and IFN-γ. Additionally, the clinical features positively correlated with the positive PD-1/PD-L1 expression rates. No significant differences in the 3-EFS and OS rates were observed between the PD-1/PD-L1 positive and negative groups. Our results suggest that an inducible immune checkpoint mechanism may be involved in UPS, MFS, and MPNST.

Abstract CT239: ENVASARC: A Pivotal Trial of Envafolimab, and Envafolimab in Combination with Ipilimumab, in Patients with Advanced or Metastatic Undifferentiated Pleomorphic Sarcoma or Myxofibrosarcoma who have Progressed on Prior Chemotherapy

Abstract Background: Metastatic undifferentiated pleomorphic sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to front line chemotherapy can approach 20%, in the 2nd line setting and beyond, efficacy remains limited. Pazopanib, the only approved treatment in the refractory setting has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered rapidly by subcutaneous (SQ) injection that is being studied in two additional pivotal trials: MSI-H cancer and biliary tract cancer. The activity of envafolimab is similar to other PD-1 antibodies administered intra-venously. Envafolimab demonstrated a 32% ORR in MSI-H colorectal cancer that failed three approved chemotherapeutics, similar to the ORR of 28% and 33%, with nivolumab and pembrolizumab, respectively. The rationale for the ENVASARC trial is based on the previously reported efficacy of checkpoint inhibition in UPS/MFS. Single agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at ~25 U.S. centers) open-label, randomized, non-comparative, parallel cohort study of treatment with envafolimab 300 mg every 3 weeks by SQ injection (cohort A; n=80) or envafolimab 300 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks intra-venously for four doses (cohort B; n=80) in patients with locally advanced, unresectable or metastatic UPS/MFS who have progressed on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed of the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response (DOR), PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy (neoadjuvant and adjuvant therapy excluded), ECOG ≤ 1. Citation Format: Sandra D'Angelo, Steven Robinson, Joelle Lam, Bonne Adams, James Freddo, Charles P. Theuer, Robert Maki. ENVASARC: A Pivotal Trial of Envafolimab, and Envafolimab in Combination with Ipilimumab, in Patients with Advanced or Metastatic Undifferentiated Pleomorphic Sarcoma or Myxofibrosarcoma who have Progressed on Prior Chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT239.

Comprehensive Genomic Profiling (CGP) Informs Molecular Diagnosis, Prognosis, and Therapeutic Decision-Making for Patients with Angioimmunoblastic T-Cell Lymphoma (AITL)

Background: AITL, under the 2016 WHO umbrella classification of nodal peripheral T cell lymphomas (PTCL) with a T follicular helper (TFH) phenotype, accounts for ~20% of all PTCL cases. Genomic analysis has revealed recurrent somatic mutations, such as RhoA G17V, that are hallmarks of AITL. Overlapping genomics have been observed in other PTCL subgroups, such as PTCL not otherwise specified (PTCL-NOS). We and others have reported frequent co-occurrence of RhoA G17V with mutations in the epigenetic regulators TET2 and IDH2R172 in AITL (Morley Blood 2015). Since treatment for the disease remains unsatisfactory, efforts are underway to assess the clinical utility of genomic information to guide therapy. The current study aimed to comprehensively assess the genomic landscape of AITL further, including identification of diagnostically and therapeutically relevant alterations.Methods: We explored the FoundationCORE™ database (Foundation Medicine Inc, Cambridge, MA) for cases assigned as AITL or harboring RhoA G17V positivity irrespective of disease ontology. This led to the inclusion of 42 cases: confirmed AITL (concordant diagnoses by internal and external pathologists, 29), suspected AITL (discordant diagnoses, 9), lymph node lymphoma NOS (PTCL, 1), or other neoplasm [pleomorphic myxofibrosarcoma (MFS), 1; marginal zone lymphoma (MZL), 1; cutaneous T-cell lymphoma (CTCL), 1]. Median cohort age was 65.5 years, 65 years for the AITL-specific subset; range for both, 34-88y. Pathology reports indicated Epstein-Barr virus positivity in 16/38 of AITL cases and prior autologous stem cell transplant in 4/38. DNA and RNA were extracted from formalin-fixed paraffin embedded samples or peripheral blood, and CGP performed using the CLIA-certified, NYS-approved, CAP-accredited FoundationOne® Heme assay (He Blood 2016).Results: RhoAG17V was seen in 57% (24/42) of cases in the cohort, including 53% (20/38) of AITL samples and in 1 case each of MFS, MZL, CTCL, and PTCL. Confirmed AITL harbored RhoAG17V in 52% (15/29), and suspected AITL in 56% (5/9), of samples. TET2 mutations (m TET2) were found in 89% of AITLs (26/29, confirmed; 8/9, suspected), and in 1/1 PTCL; as reported previously, m TET2 was not identified in the MFS, MZL, or CTCL. IDH2 mutations (m IDH2), all occurring at R172, were seen in 16% (6/38) of AITL cases, with all 6 co-occurring with RhoAG17V plus m TET2 . DNMT3A mutations (m DNMT3A) were seen in 32% (12/38) of AITLs (9/29, confirmed; 3/9, suspected) and in the single PTCL. RhoAG17V co-occurred with m TET2 (but notm DNMT3A orm IDH2) in 26% (10/38), m TET2 plus m DNMT3A in 7.9% (3/38), and m TET2, mDNMT3A, plus m IDH2 in 7.9% (3/38) of cases; all RhoAG17V cases(20/20) co-occurred with m TET2 . TP53 mutation was seen in 21% (8/38) of AITL cases. Other recurrent somatic mutations included BRCA1 or BRCA2 in 7.9% (3/38), CTNNB1 in 7.9% (3/38), and KRAS, ATM or STAT3 in 2.6% (1/38), of AITL samples. Assessment of tumor mutational burden (TMB), a biomarker for checkpoint inhibitor efficacy in solid tumors, revealed low TMB (<6 mutations/Mb) in 8/10 AITL cases and intermediate TMB (TMB-Intermediate, 6-19 mutations/Mb) in 2/10.Conclusion: This study utilized CGP to explore alterations of diagnostic and therapeutic potential in AITL. Confirming prior studies, in a significant proportion of AITL cases RhoAG17V co-occurred with m TET2 and m IDH2 ; all AITL cases positive for RhoAG17V had concurrent m TET2. We also found RhoAG17V, but not m TET2 or m IDH2, in solitary cases of MZL, MCL, and CTCL.Taken together, co-occurrence of RhoAG17V and m TET2 may provide greater specificity for AITL diagnosis than RhoAG17V alone. We also detected putative actionable targets in AITL. While predictors of response to hypomethylating agents (e.g. m TET2, m IDH2) were seen in most cases, a subset were found to have mutations in BRCA1/2 (3 pts), KRAS (1 pt), CTNNB1 (3 pts), or STAT3 (1 pt). These findings suggest alternative therapeutic opportunities in AITL (e.g. inhibitors of PARP, MEK, mTOR, and STAT3). We further report that mutational burden in AITL is generally low; however, a subset of cases (2/10) were TMB-Intermediate. Although the predictive power of TMB in lymphoma is unclear, in some solid tumors TMB-Intermediate status predicts response to immune checkpoint inhibition. In total, our findings highlight the utility of CGP to identify alterations that may influence the clinical management of AITL. DisclosuresMorley:Foundation Medicine: Employment, Other: Stock. He:Foundation Medicine, Inc: Employment, Other: Stock. Bailey:Foundation Medicine: Employment, Other: stock. Nahas:Foundation Medicine inc: Employment, Other: stockholder. Heilmann:Foundation Medicine, Inc: Employment, Other: Stockholder. Chudnovsky:Foundation Medicine, Inc: Employment, Other: Stockholder. Fabrizio:Foundation Medicine, Inc: Employment, Other: Stockholder. Ali:Foundation Medicine, Inc: Employment, Other: Stock. Lipson:Foundation Medicine: Employment, Other: stock. Stephens:Foundation Medicine Inc.: Employment, Equity Ownership. Ross:Foundation Medicine Inc: Employment, Other: stockholder. Miller:Foundation Medicine: Employment, Other: Stock. Severson:Foundation Medicine: Employment, Other: Stock. Vergilio:Foundation Medicine: Employment, Other: Stock. Erlich:Foundation Medicine: Employment, Other: stock. Mughal:Foundation Medicine, Inc: Employment, Other: Stock.