Habitat escalated adaptive therapy (HEAT): a phase 2 trial utilizing radiomic habitat-directed and genomic-adjusted radiation dose (GARD) optimization for high-grade soft tissue sarcoma.

BACKGROUND: Soft tissue sarcomas (STS), have significant inter- and intra-tumoral heterogeneity, with poor response to standard neoadjuvant radiotherapy (RT). Achieving a favorable pathologic response (FPR ≥ 95%) from RT is associated with improved patient outcome. Genomic adjusted radiation dose (GARD), a radiation-specific metric that quantifies the expected RT treatment effect as a function of tumor dose and genomics, proposed that STS is significantly underdosed. STS have significant radiomic heterogeneity, where radiomic habitats can delineate regions of intra-tumoral hypoxia and radioresistance. We designed a novel clinical trial, Habitat Escalated Adaptive Therapy (HEAT), utilizing radiomic habitats to identify areas of radioresistance within the tumor and targeting them with GARD-optimized doses, to improve FPR in high-grade STS. METHODS: Phase 2 non-randomized single-arm clinical trial includes non-metastatic, resectable high-grade STS patients. Pre-treatment multiparametric MRIs (mpMRI) delineate three distinct intra-tumoral habitats based on apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) sequences. GARD estimates that simultaneous integrated boost (SIB) doses of 70 and 60 Gy in 25 fractions to the highest and intermediate radioresistant habitats, while the remaining volume receives standard 50 Gy, would lead to a > 3 fold FPR increase to 24%. Pre-treatment CT guided biopsies of each habitat along with clip placement will be performed for pathologic evaluation, future genomic studies, and response assessment. An mpMRI taken between weeks two and three of treatment will be used for biological plan adaptation to account for tumor response, in addition to an mpMRI after the completion of radiotherapy in addition to pathologic response, toxicity, radiomic response, disease control, and survival will be evaluated as secondary endpoints. Furthermore, liquid biopsy will be performed with mpMRI for future ancillary studies. DISCUSSION: This is the first clinical trial to test a novel genomic-based RT dose optimization (GARD) and to utilize radiomic habitats to identify and target radioresistance regions, as a strategy to improve the outcome of RT-treated STS patients. Its success could usher in a new phase in radiation oncology, integrating genomic and radiomic insights into clinical practice and trial designs, and may reveal new radiomic and genomic biomarkers, refining personalized treatment strategies for STS. TRIAL REGISTRATION: NCT05301283. TRIAL STATUS: The trial started recruitment on March 17, 2022.

Clinical, pathological, and genomic features of EWSR1-PATZ1 fusion sarcoma.

Molecular diagnostics of sarcoma subtypes commonly involve the identification of characteristic oncogenic fusions. EWSR1-PATZ1 is a rare fusion partnering in sarcoma, with few cases reported in the literature. In the current study, a series of 11 cases of EWSR1-PATZ1 fusion positive malignancies are described. EWSR1-PATZ1-related sarcomas occur across a wide age range and have a strong predilection for chest wall primary site. Secondary driver mutations in cell-cycle genes, and in particular CDKN2A (71%), are common in EWSR1-PATZ1 sarcomas in this series. In a subset of cases, an extended clinical and histopathological review was performed, as was confirmation and characterization of the fusion breakpoint revealing a novel intronic pseudoexon sequence insertion. Unified by a shared gene fusion, EWSR1-PATZ1 sarcomas otherwise appear to exhibit divergent morphology, a polyphenotypic immunoprofile, and variable clinical behavior posing challenges for precise classification.

Response to Checkpoint Inhibitor Therapy in Advanced Classic Kaposi Sarcoma: A Case Report and Immunogenomic Study.

Kaposi sarcoma (KS) is an uncommon angioproliferative malignancy that is associated with human herpesvirus 8. Although there has been recent enthusiasm for evaluating immune checkpoint inhibition as a therapeutic option for viral-associated tumors, the clinical utility in this disease is currently unknown. We report a case of advanced classic KS refractory to multiple lines of chemotherapy that experienced a partial response to anti-PD-1 therapy. Comprehensive molecular profiling was performed on a diagnostic tumor biopsy sample. Molecular profiling data from 8 additional male patients with KS were reviewed and compared with those of the index case. The genomic profile of the index case was notable for higher-than-typical somatic mutational burden, including pathogenic mutation in multiple well-described cancer genes, such as TP53, CDKN2A, NOTCH1, and KRAS Our case suggests that further clinical study of checkpoint inhibitor therapy in classic KS is warranted, and provides a hypothesis for future immunogenomic biomarker analysis in this disease.

Knockdown of CSE1L Gene in Colorectal Cancer Reduces Tumorigenesis in Vitro.

Human cellular apoptosis susceptibility (chromosomal segregation 1-like, CSE1L) gene plays a role in nuclear-to-cytoplasm transport and chromosome segregation during mitosis, cellular proliferation, and apoptosis. CSE1L is involved in colon carcinogenesis. CSE1L gene expression was assessed with three data sets using Affymetrix U133 + gene chips on normal human colonic mucosa (NR), adenomas (ADs), and colorectal carcinoma (CRC). CSE1L protein expression in CRC, AD, and NR from the same patients was measured by immunohistochemistry using a tissue microarray. We evaluated CSE1L expression in CRC cells (HCT116, SW480, and HT29) and its biological functions. CSE1L mRNA was significantly increased in all AD and CRC compared with NR (P < 0.001 and P = 0.02, respectivly). We observed a change in CSE1L staining intensity and cellular localization by immunohistochemistry. CSE1L was significantly increased during the transition from AD to CRC when compared with NR in a CRC tissue microarray (P = 0.01 and P < 0.001). HCT116, SW480, and HT29 cells also expressed CSE1L protein. CSE1L knockdown by shRNA inhibited protein, resulting in decreased cell proliferation, reduced colony formation in soft agar, and induction of apoptosis. CSE1L protein is expressed early and across all stages of CRC development. shRNA knockdown of CSE1L was associated with inhibition of tumorigenesis in CRC cells. CSE1L may represent a potential target for treatment of CRC.

Myoepithelial carcinoma with RB1 mutation: remarkable chemosensitivity to carcinoma of unknown origin therapy.

BACKGROUND: Myoepithelial carcinoma of soft tissue is a rare, malignant neoplasm that is morphologically and immunophenotypically similar to its counterpart in salivary gland. It demonstrates myoepithelial differentiation, possessing both epithelial and myogenic characteristics. Thought to be chemotherapy insensitive, the optimal treatment regimen of this tumor has yet to be established and only a select few cases in the literature discuss treatment efficacy in detail. CASE PRESENTATION: Here we present a case of a young adult with metastatic myoepithelial carcinoma with an initial excellent response to systemic therapy utilizing carboplatin and paclitaxel with continued complete response after 3 years. The patient also underwent complete surgical excision and received adjuvant radiation to the primary site of disease. Exome sequencing revealed an inactivating mutation in RB1 which we believe to be the first such mutation to be reported in this cancer type. CONCLUSIONS: Given increasing evidence suggesting RB1 loss is associated with responsiveness to conventional chemotherapies, particularly platinum-based regimens, we hypothesize that this genetic feature predisposed chemosensitivity in our patient's tumor.

Practical Issues for Retroperitoneal Sarcoma.

BACKGROUND: Retroperitoneal sarcoma is rare. Using initial specimens on biopsy, a definitive diagnosis of histological subtypes is ideal but not always achievable. METHODS: A retrospective institutional review was performed for all cases of adult retroperitoneal sarcoma from 1996 to 2015. A review of the literature was also performed related to the distribution of retroperitoneal sarcoma subtypes. A meta-analysis was performed. RESULTS: Liposarcoma is the most common subtype (45%), followed by leiomyosarcoma (21%), not otherwise specified (8%), and undifferentiated pleomorphic sarcoma (6%) by literature review. Data from Moffitt Cancer Center demonstrate the same general distribution for subtypes of retroperitoneal sarcoma. A pathology-based algorithm for the diagnosis of retroperitoneal sarcoma is illustrated, and common pitfalls in the pathology of retroperitoneal sarcoma are discussed. CONCLUSIONS: An informative diagnosis of retroperitoneal sarcoma via specimens on biopsy is achievable and meaningful to guide effective therapy. A practical and multidisciplinary algorithm focused on the histopathology is helpful for the management of retroperitoneal sarcoma.

Molecular Pathology of Soft-Tissue Neoplasms and Its Role in Clinical Practice.

BACKGROUND: Soft-tissue neoplasms embody a histologically diverse group of mesenchymal tumors. Oftentimes the histopathological diagnosis of soft-tissue tumors is challenging due to overlapping pathological features. METHODS: We reviewed the current and most importantly known recurrent or tumor-specific genetic abnormalities involving soft-tissue tumors, focusing on how they are useful in working up differential diagnoses and the relevance of potentially targeted therapies. RESULTS: Molecular diagnostic tools have shown great advantage as an aid in the differentiation between different soft-tissue tumor entities, providing a potential avenue in the identification of novel therapeutic targets. Gastrointestinal stromal tumor is a well-known example of a soft-tissue tumor with a successful, molecularly driven treatment with response rates of more than 80% in stable disease and partial remission. Classifying soft-tissue neoplasms by their molecular genetic pathology has been considered as molecular testing becomes more integrated into various diagnostic and prognostic algorithms. CONCLUSIONS: Molecular pathology provides a unique opportunity for pathologists to play a crucial role in the multidisciplinary care of patients with sarcoma. These opportunities include but are not limited to the appropriate triage of tissue for molecular testing and the integration of molecular testing results, with histological and immunohistochemical findings providing actionable information for the diagnosis, prognosis, and choice of therapeutic modality.

Pathology Residents' Perceptions and Attitudes Toward Breast Pathology: A National Survey.

CONTEXT.­: Breast pathology (BP) is considered to be subject to interobserver variability among pathologists, emphasizing the need for adequate training. However, specifics of BP residency training have not been elucidated. OBJECTIVE.­: To assess the characteristics of BP residency training in the United States. DESIGN.­: A Qualtrics-managed online survey was emailed to program directors of all US pathology residency programs, requesting them to forward the survey link to their pathology residents. RESULTS.­: One hundred seventeen residents' survey responses were evaluable. Most responses (92; 79%) came from residents in university hospital-based programs. Thirty-five respondents (30%) had a dedicated BP rotation in their program. Most respondents believed that BP was an important part of training (96 of 100; 96%) and pathology practice (95 of 100; 95%). Seventy-one respondents believed that their BP training was adequate overall (71 of 100; 71%). Forty-one percent of respondents indicated that they would not like BP to be a significant part of their future practice. The main reasons given were that they had a different preferred area of interest, that they lacked interest in BP, or that breast cases were time-consuming to sign out. CONCLUSIONS.­: Our results show that in the United States, most programs do not offer a dedicated BP rotation, but breast cases are signed out by subspecialized or experienced breast pathologists. In addition, most respondents believed that they received adequate training and would be competent to independently sign out BP in the future. Additional studies addressing new-in-practice pathologists' proficiency in BP will further help elucidate the quality of BP training in the United States.

Science, Medicine, and Cytology: an educational program of the Diversity, Equity, and Inclusion Committee of the American Society of Cytopathology.

INTRODUCTION: As our field of pathology continues to grow, our trainee numbers are on the decline. To combat this trend, the ASC Diversity, Equity, and Inclusion Committee established the Science, Medicine, and Cytology SumMer Certificate program to improve exposure to pathology/cytopathology with a focus on diversity, equity, and inclusion. Herein, we report our findings of the first 2 years of the program. MATERIALS AND METHODS: An online course was developed targeting students who are underrepresented in medicine at the high school and college level. It consisted of several didactic sessions, presenting the common procedures involving cytopathologists and cytologists. Interviews with cytopathologists were also included. Participants were surveyed for demographic information and provided course evaluations. RESULTS: In the first year of the program (2021), 34 participants completed the program, which increased to 103 in 2022. In both years there was a diversity in participant demographic backgrounds; however, only a minority of participants self-identified as being underrepresented in medicine. A vast majority (>85%) of participants in both years were high school or college students. In 2021, 100% of participants stated that the program format was effective and 94% thought the content was appropriate for their level of education; in 2022 the results were similar. In 2021, 66% considered health care as a potential career; this value increased in 2022 to 83%. In 2021 and 2022, 31% and 38%, respectively, considered cytology as a career. CONCLUSIONS: Evaluations were excellent, generating interest in cytopathology. Barriers in reaching underrepresented minorities exist and additional work is needed. Expansion to a wider audience may increase outreach.

Ethnicity and age disparities in Ewing sarcoma outcome.

This institutional retrospective review studied Ewing sarcomas from 1987-2011. Among 135 patients, 127 (19 Hispanic and 108 white/non-Hispanic) were analyzed (excluding small sample sized groups) finding 15% Hispanic, 85% non-Hispanic, 27% <18 years, 21% >40 years and 1-272 months follow-up (median 41). Age was significantly associated with overall survival (OS) (p = 0.01), whereby <18 years had a higher probability of 5-year survival (OS 61%) than >40 years (OS 37.6%). Ethnicity was marginally statistically significant (OS, p = 0.065); whereby median survival was clinically significant (white non-Hispanic 63 months and Hispanic 23 months). Hispanic ethnicity and older age are independent poor prognostic factors.

A Case of Hepatic Malignant Solitary Fibrous Tumor: A Case Report and Review of the Literature.

A 73-year-old man with a history of atrial myxoma and basal cell carcinoma presented with unexplained fever. Contrast-enhanced CT abdomen showed a large left hepatic lobe mass with early enhancement and delayed venous washout, concerning for hepatocellular carcinoma. Fine needle aspiration showed numerous spindle cells with malignant nuclear features, suggestive of malignant spindle cell neoplasm. The patient underwent left hepatectomy. The surgical specimen showed a well-circumscribe solid mass (14.6 × 13.0 × 10.0 cm) with necrosis. Histopathological examination revealed a proliferation of spindle tumor cells with characteristic staghorn-shaped blood vessels, frequent mitoses, and necrosis. The tumor cells showed strong and diffuse expression of CD34 and STAT6, confirming the diagnosis of malignant solitary fibrous tumor. Solitary fibrous tumor is a rare fibroblastic tumor characterized by a staghorn vasculature and NAB2-STAT6 gene rearrangement. Solitary fibrous tumor of the liver is a rare occurrence. Although most solitary fibrous tumors behave in a benign fashion, solitary fibrous tumors might act aggressively. This case is unique in that it demonstrates an excellent correlation between radiologic, macroscopic, and microscopic features which can contribute to the improvement of radiologic and pathologic diagnostic accuracy.

p21 Protein Outperforms Clinico-pathological Criteria in Predicting Liver Metastases in Pancreatic Endocrine Tumors.

BACKGROUND/AIM: P21 is a cyclin-dependent kinase inhibitor regulating the cell cycle as a tumor suppressor. Using a p21 immunohistochemistry (IHC) assay, we compared tumor p21 levels with conventional clinico-pathological criteria in primary pancreatic endocrine tumor subsets with and without liver metastases. MATERIALS AND METHODS: Sections from tissue microarray (TMA) including 13 archival metastatic primary and 18 non-metastatic primary pancreatic endocrine carcinomas/tumors (MP-PECAs/NMP-PETs) were stained with a monoclonal anti-p21WAFI,CIP primary antibody. Tumor p21 IHCs were scored as the sum of intensity (0-3) and proportion scores (0-5) (Total Allred score: 0-8), and as p21% labelling index in the tumor. ROC curve analysis was used for most optimal p21 score cut-off (4 or >) and Fisher's exact test was used to compare the association among tumor p21 scores, conventional prognostic criteria, and liver metastases. RESULTS: For PET/PECA patients, mean ages were 55.6 years (27-73) and 49.3 years (28-71), M/F ratios were 7/11 and 7/6. Mean p21 labelling index (%) for MP- PECAs was 24% (range=3-63%) vs. 9% for NMP-PETs (range=1-25%) (p=0.022). The mean p21 index in MP-PECAs was significantly higher (24%) as compared to PIs (7%) (p=0.0047). Using a p21 Allred score of ≥4, high p21 IHC score had strong association with the presence of liver metastases (p-value <0.001). High tumor p21 IHC score had a 93% sensitivity, 68% specificity, 78% predictive accuracy, 66% positive, and 94% negative predictive values. CONCLUSION: In patients with primary PETs, p21 IHC is superior to conventional criteria in predicting presence or absence of liver metastases.

Assessing ROSE for adequacy of EBUS-TBNA compared with a direct-to-cell block approach as a response to the COVID-19 pandemic.

INTRODUCTION: Rapid on-site evaluation (ROSE) has been used during the endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) procedure as standard practice. Because of the COVID-19 (coronavirus disease 2019) pandemic, our institute had had to discontinue ROSE and adopt a direct-to-cell block approach. In the present study, we aimed to determine whether this change has had significant effects on the cytopathology quality. MATERIALS AND METHODS: A total of 1903 EBUS-TBNA cases from 734 patients were collected (1097 cases with ROSE for 452 patients; 806 cases without ROSE but with direct-to-cell block for 282 patients). The clinical and cytology data were analyzed using SAS, version 9.4, software to render calculated standardized residuals and a fitted multivariate generalized linear model. RESULTS: On average, a biopsy from a patient with ROSE was 0.936 (=exp -0.066) times less likely to be reported as satisfactory compared with a biopsy from a patient without ROSE, although the difference was not statistically significant (P = 0.785). The inadequacy rate of EBUS-TBNA was 6.4% higher on average for cases with ROSE compared with a direct-to-cell block approach. However, this difference was also not statistically significant. The proportions of biopsies reported as diagnostic for malignancy and other were significantly different between the ROSE and no-ROSE groups with a standardized residual of 1.80 (P = 0.036) and -2.27 (P = 0.012), respectively. CONCLUSIONS: Discontinuing ROSE and using a direct-to-cell block approach had no negative effects on cytopathology quality. This practice can be considered acceptable during the COVID-19 pandemic when social distancing and the shortage of staff and supplies have resulted in challenges to delivering quality care to cancer patients whose treatment cannot be postponed.

A Case of Retroperitoneal Synovial Sarcoma in Pregnancy Treated with Antepartum Doxorubicin plus Ifosfamide Chemotherapy.

We report a case of a 25-year-old pregnant woman diagnosed with a large, unresectable retroperitoneal synovial sarcoma. Successful neoadjuvant treatment with doxorubicin plus ifosfamide prepartum and continuing postpartum resulted in significant disease response allowing for later tumor resection. Following the first prepartum chemotherapy cycle, a decreased amniotic fluid index was noted, representing a potential complication of chemotherapy. Induction of labor was performed at 33 weeks gestation with excellent outcome in the newborn. This case highlights the complex medical decision-making process in the setting of cancer diagnosed during pregnancy, balancing oncologic and obstetric concerns, and to our knowledge is only the second reported case of synovial sarcoma treated with neoadjuvant cytotoxic chemotherapy in the antepartum period.

Results of treating primary pulmonary sarcomas and pulmonary carcinosarcomas.

OBJECTIVE: Primary pulmonary sarcomas (PPS) and pulmonary carcinosarcomas (PCS) are rare aggressive lung malignancies. We reviewed our 21-year experience with the surgical and nonsurgical treatment of both tumors, comparing their clinical, histopathologic, and treatment results. METHODS: All patients with PPS or PCS who underwent surgical and nonsurgical treatment between 1998 and 2019 at our cancer center were retrospectively reviewed. Multivariable Cox proportional hazards model was constructed. RESULTS: In total, 100 patients were analyzed: 45 with PPS and 55 with PCS. Among patients with PPS, 31 of 45 (69%) underwent surgery with 1 (3%) operative mortality. For patients with PCS, 29 of 55 (53%) underwent surgery with no operative mortality. Patients with PPS were younger than PCS (P < .01). Fewer patients were smokers among PPS (58%) versus PCS (93%) (P < .01). For resected PPS, mean tumor size was 8.2 ± 4.1 cm (range 2.2-18.0) compared with 10.1 ± 5.0 cm (range 3.9-17.0) for unresected PPS. Tumor size for resected PCS was 6.2 ± 2.6 cm (range 2.0-10.5) versus 6.8 ± 3.5 cm (range 1.2-13.5) for unresected PCS. Of resected patients, 5 of 31 (16%) with PPS and 9 of 29 (31%) with PCS were node positive. Overall survival estimates were as follows: for PPS, median survival and 5-year overall survival for resected versus unresected cases were 39.6 months/28.7% versus 4.9 months/7.8%. For PCS, survival estimates were 23.6 months/31.0% versus 14.9 months/28.2%, respectively. In multivariable analyses (N = 100), age, smoking history, histology, and surgery were risk factors of survival. CONCLUSIONS: At initial evaluation, PPS and PCS presented with large-sized tumors and usually were not stage I. Surgery had a positive impact on survival among patients with PPS. Whenever feasible, surgical resection, even in locally advanced disease, may yield long-term survival in these aggressive lung tumors, although the level of evidence is low.

ACGME Milestones 2.0: why and what's new for cytopathology?

BACKGROUND: Primary stakeholders in the Accreditation Council for Graduate Medical Education (ACGME) Milestones Project are: ACGME, Residency Programs, Residents, Fellowship Programs, Fellows, and Certification Boards. The intent of the Milestones is to describe the educational and professional developmental trajectory of a trainee from the first stages of their postgraduate education through the completion of their clinical training. The Milestones 2.0 project includes changes made based on experience with Milestones 1.0. METHODS: The ACGME solicited volunteers to participate in the development of subspecialty Milestones 2.0. The workgroup was charged with reviewing/making any additions to the four "Harmonized Milestones", developing subspecialty specific milestones for the Patient Care and Medical Knowledge competencies, and creating a supplemental guide. The Milestones were finalized following review of input from an open comment period. RESULTS: The Cytopathology Milestones 2.0 will go into effect July 2021. They include additional subcompetencies in the 4 harmonized competency areas and cytopathology-specific edits to the patient care and medical knowledge subcompetencies. Although the number of subcompetencies has increased from 18 to 21, within each subcompetency, the number of milestone trajectories has decreased. Additionally, within each subcompetency, the wording has been streamlined. A supplemental guide was created and Milestones 1.0 were compared to 2.0; however, curriculum mapping has been left to programs to develop. CONCLUSIONS: The ultimate goal of the Cytopathology Milestones 2.0 is to provide better real-time documentation of the progress of cytopathology fellows. The expected outcome is to produce highly competent cytopathologists, improving the care they provide, regardless of the program at which they trained.

Intraosseous lipoma of the clavicle with extraosseous extension.

Intraosseous lipomas are rare primary benign bone tumors which present with highly nonspecific radiographic features that may lead to equivocal diagnoses. Advanced imaging studies such as MRI with and without contrast and, in some selected cases, tissue sample analyses are required in the diagnostic pathway. Here we describe the second case in the literature of an intraosseous lipoma of the clavicle and the first with extraosseous extension. Subsequent to histologic confirmation the lesion was monitored with clinical and radiologic evaluation.

Intrapelvic melanocytic schwannoma resection with computer-assisted navigation.

Melanocytic schwannoma is a rare nerve tumor characterized by melanin-producing neoplastic Schwann cells. Wide surgical resection is the management of choice for this tumor; however, anatomical location and proximity to nerve roots can make locating this tumor and the surgical resection challenging. Here we describe the case of 49-year-old male with a melanocytic schwannoma in the presacral area adjacent to the second sacral nerve root that was managed by wide resection aided by computer-assisted navigation due to the difficulty in identifying its location intraoperatively. The utilization of computer-assisted navigation improves accuracy and precision through the creation of a virtual continuous tridimensional map, particularly useful when oftentimes tumor margins may seem equivocal and further resection would compromise the patient's functionality. The value of computer-assisted navigation for soft tissue tumor resections in orthopedic oncology is still in its infancy, though, in certain scenarios it may advance the technique for some soft tissue resections.

Sclerosing epithelioid fibrosarcoma: cytologic characterization with histologic, immunohistologic, molecular, and clinical correlation of 8 cases.

INTRODUCTION: Sclerosing epithelioid fibrosarcoma (SEF) is an uncommon malignant fibroblastic neoplasm. The diagnosis is typically made on core needle biopsy or resection specimens. Cytomorphologic characterization of SEF has been limited to rare case reports in the literature. The goal of this study was to review a series of cases of SEF and to determine the feasibility of cytologic diagnosis of this rare tumor. MATERIAL AND METHODS: Eight SEF cases from 2009 to 2019 were identified in a retrospective review of 3 participating institutions. Cytomorphologic and corresponding histologic, immunophenotypic, molecular, and clinical data were examined and described. RESULTS: Patients were of median age 41 years old at diagnosis with a median follow-up of 35.5 months. These tumors, with a median greatest dimension of 13.4 cm, were located in the lower extremities, abdomen, retroperitoneum, head, groin, sacrum, and lung. The tumor cells ranged from small round, medium-sized ovoid/short spindle, to epithelioid/plasmacytoid cells. A sclerotic, fibrous to myxoid stroma was seen. Most samples revealed low-grade cytology. Two cases showed tumor necrosis. Only 3 cases with cell block/positive MUC4 immunostain were diagnostic. Corresponding molecular testing for EWSR1 gene rearrangement and/or EWSR1-CREB3L1 fusion were positive in 5 of 8 cases on biopsy or surgical samples. An additional case was positive for FUS-CREB3L2 fusion. CONCLUSIONS: Diagnosis of SEF based solely upon cytologic features remains challenging. Epithelioid or plasmacytoid morphology mimics common malignancies. A supportive clinical history, MUC4 immunohistochemistry, and characteristic molecular result should be used to aid the diagnosis.