Myxoid pleomorphic liposarcoma (MPLPS), a rare, aggressive liposarcoma subtype, is thought to occur chiefly in adolescents with a mediastinal predilection. MPLPS lack DDIT3 rearrangements or MDM2 amplification; a small number have recently been shown to harbor widespread copy-neutral loss of heterozygosity (cnLOH). We studied a large series of MPLPS and compared them to other sarcomas, particularly other LPS. Available slides/blocks for cases coded as "MPLPS" were retrieved (2008-2026). We also searched our single nucleotide polymorphism (SNP) assay records for tumors demonstrating 1) high cnLOH frequency (>30%), and 2) "liposarcoma" or "pleomorphic sarcoma" diagnosis. Non-mesenchymal tumors were excluded. Twenty-four MPLPS cases were identified, occurring in 10 females (42%) and 14 males (58%), ranging from 5-85 years of age (median 46 years). Involved anatomical locations included the mediastinum/thorax (n=12), trunk (n=3), head and neck (n=3), various intra-abdominal sites (n=3), retroperitoneum/pelvis (n=2) and extremities (n=1). Two patients had clinical features of Li-Fraumeni syndrome or a germline TP53 mutation. All tumors displayed characteristic features of MPLPS, including areas resembling conventional myxoid liposarcoma and hypercellular, pleomorphic liposarcoma-like foci. SNP testing (n=22) demonstrated cnLOH of >50% in 19 cases (86%), often with pseudohyperdiploidy. One tumor showed cnLOH of 38%; two otherwise typical tumors did not have widespread cnLOH. Other recurrent alterations included gains of chromosomes 1/1q, 6- 8, and 18-21 and loss of chromosome 14. Specific losses/gains involving the RB1 and TP53 loci were seen in 12 and 2 cases, respectively. Clinical follow-up (n=22; median 16 months; range 1-75 months) showed 9 patients dead of disease (median survival 12 months), 6 patients alive with disease, and 6 patients alive without disease. Local recurrences and distant metastases were seen in 6 and 8 patients, respectively. We conclude that the age range and anatomical distribution of MPLPS are considerably wider than has been previously appreciated, including tumors arising in the elderly and various non-mediastinal locations. Although most MPLPS harbor widespread cnLOH, rare otherwise-typical tumors do not. MPLPS are aggressive sarcomas with poor prognosis.

Even for experts, the diagnosis of soft tissue tumors remains challenging, owing to their rarity, striking diversity, and sometimes subtle morphological differences. Over the past decade, however, significant advances have been made in our collective understanding of the molecular genetic pathogenesis of these rare lesions, especially with the discovery that many are characterized by the presence of characteristic gene fusions, which can be exploited for diagnostic purposes. This review article focuses on four fusion-driven soft tissue tumors which illustrate different aspects of our evolving understanding of these tumors: (1) NUTM1-rearranged sarcoma, a prototypical example of a novel, clinically significant entity defined almost entirely by molecular genetics; (2) SRF-rearranged myoid neoplasm, an entity whose recognition greatly clarifies our understanding of pediatric "leiomyosarcomas;" (3) superficial FET-ETS neurocristic tumor, a very recently described, clinically benign entity sharing identical fusion events with often-lethal Ewing sarcoma; and (4) an evolving family of glomoid/myoid neoplasms harboring EWSR1::WT1 fusions, but clearly differing from desmoplastic small round cell tumor. These examples illustrate the complexity of fusion-driven soft tissue tumors and the importance of integrating molecular genetic testing with other clinicopathological data, rather than viewing it in isolation.

Despite advances in molecular genetics that have helped elucidate the pathogenesis of many soft tissue neoplasms, subsets of fibromyxoid tumors remain difficult to subclassify because of their nonspecific morphologic and immunohistochemical features, and lack of discrete molecular alterations. We report 7 cases of a distinctive fibromyxoid soft tissue neoplasm characterized at the cytogenomic level by massive loss of heterozygosity, resulting in a near-haploid or pseudohyperdiploid cytogenome. The tumors occurred in superficial and deep soft tissue locations (mesentery, mediastinum, thigh, pelvis, leg, orbit, and head) of 5 males and 2 females (median age, 45 years). They ranged in size from 2.6 to 14 cm (median, 5 cm) and were composed of small, bland spindled cells in a variably vascularized, fibromyxoid stroma with abundant wiry collagen. Mitotic activity was low, and necrosis was absent in all but 1 case, which demonstrated foci of infarct-type necrosis. One tumor showed infiltrative growth into surrounding tissue while all others were circumscribed and noninfiltrative. Immunohistochemistry demonstrated CD34 (5/5) and desmin (3/5) expression; S100 protein, SOX10, MUC4, and GLUT1 were negative, among others. All tumors demonstrated massive loss of heterozygosity with copy number gain and retained heterozygosity of selected chromosomes, including chromosomes 8 and 19, evaluated with OncoScan single-nucleotide polymorphism array. Biallelic inactivation of NF1 was seen in 2 cases, including 1 in a patient with neurofibromatosis type 1. Three patients showed possible evidence of stable locally recurrent/residual disease following incomplete resection while all other patients were free of disease (median follow-up, 17 months). The tumors presented in this study are essentially identical to those of a very recently reported series of 5 cases, strongly suggesting that these collectively represent a novel entity, which we propose terming distinctive near-haploid fibromyxoid neoplasm.

PATZ1-rearranged sarcomas are diagnostically challenging due to their rather non-specific morphology and immunophenotype. These tumors are characterized by bland, round-to-spindled cells within a fibromyxoid matrix with variable microcysts, fibrous septa, hyalinized vessels, and cellular whorls. PATZ1-rearranged sarcomas are often positive for neural, skeletal muscle, and epithelial markers. Identification of these tumors is further complicated by the cryptic nature of the characteristic EWSR1::PATZ1 fusion, which generally makes fluorescence in situ hybridization analysis unreliable if rearrangement is not detected. As a result, costly and time-intensive molecular assays are often currently necessary for definitive diagnosis. The purpose of this study was to assess immunohistochemistry (IHC) for PATZ1 as a surrogate for detecting the gene fusion. In total, 533 tumors from whole-tissue sections and tissue microarrays were evaluated, including 14 PATZ1-rearranged sarcomas as well as other benign and malignant mesenchymal neoplasms. IHC for PATZ1 was positive in 12/14 (86%) PATZ1-rearranged sarcomas. Of the remaining tumor types, 495 (95%) were negative for PATZ1. Notably, PATZ1 expression was observed in a subset of other tumor types, including myoepithelial carcinoma (2/4; 50%), myoepithelioma (2/15; 13%), rhabdomyosarcoma (RMS) (13/99; 13%), desmoplastic small round cell tumor (1/10; 10%), dermatofibrosarcoma protuberans (1/10; 10%), myxoid liposarcoma (1/16; 6%), schwannoma (1/22; 5%), and malignant peripheral nerve sheath tumor (3/70; 4%). The 13 RMS cases that were positive were classified as embryonal (n = 7), alveolar (n = 5), and RMS, not otherwise specified (n = 1). In conclusion, PATZ1 IHC is moderately sensitive and specific for PATZ1-rearranged sarcomas, and it may be a helpful diagnostic marker for this challenging tumor. Although most tumors with morphologic overlap with PATZ1-rearranged sarcomas are negative for PATZ1 by IHC, expression in a subset of myoepithelial tumors and RMS represents a potential diagnostic pitfall.

Bone and soft tissue sarcomas harboring EWSR1::NFATC2 and FUS::NFATC2 fusions (NFATC2-rearranged sarcomas) are a recently defined entity with a morphologic spectrum and clinical behavior that are not fully elucidated. We studied 32 such sarcomas that occurred in 21 male and 11 female patients. The EWSR1::NFATC2 fusion was found in tumors of 25 patients (17 men and 8 women; median age, 40 years; range, 14-78 years), 16 of which arose in soft tissue, while 8 originated in the bone. Morphologically, they showed relatively consistent morphologic features yet variable degrees of cytologic atypia, mitotic rates, and necrosis. Follow-up (19 patients; median, 22 months; range, 1-70 months) demonstrated local recurrence in 3 patients, while distant metastases occurred in 6 patients. Two patients died of disease, 4 were alive with disease, and 13 were alive without evidence of disease. In contrast, the FUS::NFATC2 fusion was exclusively seen in osseous tumors, which occurred in 7 patients (4 men and 3 women; median age, 32 years; range, 4-62 years). Further, FUS::NFATC2 tumors showed significant morphologic heterogeneity. Follow-up (6 patients; median, 18 months; range, 13-60 months) demonstrated local recurrence in 2 patients and lung metastases in 2 patients. At the last follow-up, 3 patients were alive with disease, while 3 patients were alive without evidence of disease. Using a 2-tiered grading scheme based on cytologic atypia, mitotic rate, and necrosis, patients with low-grade tumors experienced significantly fewer adverse events than those with high-grade tumors (P = .026); however, estimated metastasis-free survival was not statistically significant due to our limited sample size. Overall, our study expands on the morphologic spectrum of NFATC2-rearranged sarcomas and highlights the clinicopathologic, molecular, and genetic differences between the EWSR1- and FUS-rearranged tumors. Although additional long-term follow-up data are required, our study further suggests that a subset of these sarcomas have a protracted clinical course, while high-grade morphologic features such as atypia, mitotic activity, and necrosis may correlate with worse behavior.

Background: Localized soft tissue sarcoma (STS) is primarily treated with surgical resection with or without radiotherapy (RT), while the role of chemotherapy (CT) as a radiosensitizer remains unclear. We report our single-institution experience with combined chemoradiotherapy (CCRT) in treating localized STS. Methods: We conducted a retrospective analysis of patients with localized STS treated at Mayo Clinic with mitomycin, cisplatin, and doxorubicin (MitoAP) concurrently with RT between 1/1/85 and 12/12/19. Results: We identified 179 patients (median age 58 years; median tumor size 9.5 cm), with 83.8% of tumors located in the extremities or trunk. Among them, 77.1% received perioperative CT in addition to CCRT, with 95% of those treated in the neoadjuvant setting. Median RT dose was 50 Gray. The 5-year disease-specific survival (DSS) was 77.9% (95% confidence interval, CI: 70.8-83.4%). The addition of perioperative CT to CCRT was associated with improved DSS compared with CCRT alone (p = 0.01, Hazard Ratio, HR: 0.48, 95% CI: 0.27-0.85). Median post-CCRT tumor viability was 30% and did not differ by CT use (p = 0.39), but varied significantly by histology (p < 0.001). Conclusions: Our institutional protocol utilizing two cycles of MitoAP with RT was well tolerated. DSS in our cohort was similar to historical data using perioperative RT alone, suggesting no clear benefit from CCRT. However, the majority of patients in our cohort were classified as high risk, which may have attenuated a potential survival benefit in the absence of appropriate comparative controls. Furthermore, additional perioperative CT to CCRT was associated with improved DSS and differential histology-specific responses in tumor viability, suggesting that a more aggressive neoadjuvant and perioperative approach may be beneficial in selected patients.

The ever-increasing availability and affordability of molecular genetic testing has revolutionized our understanding of the pathogenesis and proper classification of soft tissue tumors but has also brought new challenges. As is known, many soft tissue tumors harbor gene fusion events, and while it was initially thought that individual entities would be defined by single, specific fusions, it quickly became clear that some entities could be caused by several different fusion events (e.g., EWSR1::FLI1, EWSR1::ERG, EWSR1:FEV and others in Ewing sarcoma). More recently, it has become apparent that these fusion events themselves are "promiscuous", appearing in more than one discrete entity (e.g., EWSR1::CREB1 in clear cell sarcoma, angiomatoid fibrous histiocytoma and others). This review article will briefly discuss the best known examples of genetic promiscuity, the EWSR1/FUS::ATF1/CREB1 and ETV6::NTRK3 fusions, and more comprehensively cover recently discovered and less well-known examples of genetic promiscuity, including EWSR1::WT1, MALAT1::GLI1, YAP1::TFE3 and fusions involving members of the FET and ETS gene families.

This article discusses very rare rhabdomyosarcomas of bone, in particular, those harboring FET::TFCP2 (EWSR1 or FUS::TFCP2) or MEIS1::NCOA2 fusions. The diagnosis of these tumors may be challenging, owing to their rarity, and requires integrations of clinical, radiologic, morphologic, immunohistochemical, and molecular genetic data. The differential diagnosis of osseous rhabdomyosarcomas is also discussed.

Eccrine spiradenomas are benign sweat gland neoplasms that rarely undergo malignant transformation. Carcinosarcoma arising from an eccrine spiradenoma is exceptionally rare. A 41-year-old male presented with a rapidly growing neck/shoulder mass, progressive numbness, spasticity, and weakness. Further workup additionally revealed an epidural mass with spinal cord compression. Both masses were excised and predominantly showed morphologic features of high-grade osteosarcoma, with overtly malignant spindled cells producing lace-like osteoid. However, a single section from the upper back mass contained a roughly 2 mm focus of conventional eccrine spiradenoma, with an adjacent small focus having features of a poorly differentiated non-small cell carcinoma. The final diagnosis was that of a high-grade carcinosarcoma with heterologous osteosarcomatous differentiation, arising from a pre-existing eccrine spiradenoma, with metastasis to the T4-5 epidural region. The patient experienced rapid regrowth of the spinal mass and underwent radiotherapy but had unresectable metastatic disease at 2 months follow-up. We describe what is to our knowledge only the 21st example of carcinosarcoma arising from eccrine spiradenoma, mimicking metastatic osteosarcoma. Awareness of this very rare entity, careful sampling, close microscopic examination, and, in selected cases, ancillary immunohistochemistry are the keys to making this challenging diagnosis.

Ossifying fibromyxoid tumor (OFMT) is a rare mesenchymal neoplasm harboring variable malignant potential and showing an immunophenotype classically described as co-expression of desmin and S100. Since its original description, considerable effort has been employed to fully characterize the immunophenotype of OFMT. Prompted by a consultation case of a histologically classic OFMT in which desmin expression was accompanied by expression of the skeletal muscle-specific nuclear regulatory protein MyoD1, we examined the frequency of MyoD1 and myogenin expression in a series of forty four cases of OFMT. Of the 44 cases, MyoD1 expression was present in 23 (52 %) cases, while none were myogenin-positive. MyoD1 expression was found in 20/31 (65 %) desmin-positive tumors, whereas desmin expression was present in 20/23 (87 %) MyoD1-positive tumors. A subset of five cases were stained for PAX7, and a single case of malignant OFMT showed weak expression. To our knowledge, this is the first formal study of rhabdomyoblastic marker expression in OFMT.

Background: Myxofibrosarcomas are notoriously highly infiltrative soft-tissue sarcomas, making negative surgical margins difficult to obtain. Recently, vacuum-assisted closure (VAC) is used to delay wound closure until a negative margin has been achieved; however, this can delay care and increase costs. Our institution has historically performed single-stage resections with intraoperative frozen margin analysis and reconstruction in these patients. The purpose of this study is to report the outcomes of this technique. Methods: We reviewed 112 patients (62 males, mean age 70 ± 14 years) with superficial myxofibrosarcoma. Eighty-eight patients received preoperative radiation. All patients underwent surgical resection with intraoperative frozen margin analysis, and the planned reconstruction was performed in a single anesthetic. Results: The 10-year local recurrence-free survival was 90%; positive intraoperative frozen section (HR 7.44, p = 0.004) and final permanent margins (HR 8.53, p = 0.007) were associated with local recurrence. Intraoperative margins were negative in 103 (92%) of patients, 1 of which was positive on final permanent section. There were nine cases of microscopically positive margins, of which seven underwent immediate re-excision to a negative margin. The accuracy of frozen margin assessment for myxofibrosarcoma was between 92.92 and 98.23%. All patients underwent reconstruction at the time of resection, with 19% needing an additional procedure, most commonly due to a wound complication (12%). Conclusions: Multidisciplinary single-stage excision with intraoperative frozen margin assessment and soft-tissue reconstruction yields low rates of local recurrence in patients with superficial myxofibrosarcoma.

RATIONALE AND OBJECTIVES:To examine MRI characteristics of malignant tenosynovial giant cell tumors (TSGCTs) and elucidate features to differentiate benign and malignant TSGCTs. MATERIALS AND METHODS:With IRB approval, the medical record was retrospectively reviewed from 2004-2024 for cases of pathologically-proven benign and malignant TSGCTs evaluated by MRI. RESULTS:12 malignant TSGCTs (5F/7M, mean age 48.7 +/- 17.6 years) and 23 benign TSGCTs (13F/10M, mean age 43.7 +/- 18.7 years) were identified. There was no significant difference in age (p=0.45), gender (p=0.63), MRI signal characteristics (T1 signal p=0.57, T2 signal p=0.46, T2 signal heterogeneity p>0.99, presence of low T2 signal p>0.99), type of enhancement (presence of enhancement p=0.21, degree of enhancement p=0.12, heterogenous vs. homogenous enhancement p=0.21, presence of non-enhancing areas p=0.11), blooming artifact (p=0.065), or presence of perilesional edema (p=0.16) between benign and malignant TSGCTs. Four MRI features were more commonly associated with malignant TSGCTs: extra-articular location (p=0.009), irregular margins (p=0.0014), perilesional vessels (p=0.0014), and larger average maximal dimension (8.6 +/- 8.4 cm malignant vs. 2.8 +/- 2.2 cm benign, p=0.036). CONCLUSION:Although there are overlapping MRI characteristics between benign and malignant TSGCTs, malignant TSGCTs are more likely to exhibit larger size, extra-articular location, irregular margins and prominent perilesional vessels compared to their benign counterparts. Some malignant TSGCTs may not be associated with a synovial-lined structure on imaging.

Poorly differentiated chordoma (PDC) is an aggressive subtype of chordoma characterized by SMARCB1 (INI1) loss and a dismal prognosis. It typically involves the axial skeleton, most commonly the skull base and the cervical spine. To our knowledge, only 5 cases of extraaxial PDC (EAPDC) have been reported, and the natural history of these tumors is not fully understood. We studied 6 cases of EAPDC, with the goal of better understanding these exceptionally rare tumors. The tumors occurred in 4 women and 2 men, ranging from 37 to 68 years of age (median, 57.5 years) and involved or originated in the left knee joint (3 cases), right knee joint (2 cases), and right wrist (1 case). Grossly, all were solid and lobulated, with areas of necrosis. Histologically, the tumors were identical to axial PDC, with sheets and lobules of overtly malignant-appearing epithelioid-to-rhabdoid cells with prominent nucleoli. Mitotic activity and necrosis were present. By immunohistochemistry, all cases expressed keratins and brachyury and were SMARCB1 deficient. Molecular genetic analysis identified SMARCB1 loss-of-function alterations in 4 of the tested cases, including mutations (2 cases) and copy number loss (2 cases). DNA methylation profiling of 4 cases of EAPDC showed clustering with axial PDC. Clinical follow-up (6 patients; median, 11.5 months; range, 1-26 months) showed 4 patients to have received transfemoral amputation and 1 extraarticular resection. None received neoadjuvant radiotherapy; 1 received neoadjuvant chemotherapy and 1 adjuvant chemotherapy/ immunotherapy. Local recurrences were seen in 2 patients at 7 and 8 months; 3 patients developed metastases 7-11 months after surgery. Two patients were alive with metastatic disease (at 7 and 13 months), 1 died of disease (20 months), and 3 were disease free (1-26 months). We conclude that EAPDC are aggressive malignancies with an unusual predilection for the knee joint and unknown pathogenesis. (c) 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

An amplicon-based targeted next-generation sequencing (NGS) assay for the detection of gene fusions in sarcomas was developed, validated, and implemented. This assay can detect fusions in targeted regions of 138 genes and BCOR internal tandem duplications. This study reviews our experience with testing on the first 652 patients analyzed. Gene fusions were detected in 238 (36.5%) of 652 cases, including 83 distinct fusions in the 238 fusion-positive cases, 10 of which had not been previously described. Among the 238 fusion-positive cases, the results assisted in establishing a diagnosis for 137 (58%) cases, confirmed a suspected diagnosis in 66 (28%) cases, changed a suspected diagnosis in 25 (10%) cases, and were novel fusions with unknown clinical significance in 10 (4%) cases. Twenty-six cases had gene fusions (ALK, ROS1, NTRK1, NTRK3, and COL1A1::PDGFB) for which there are targetable therapies. BCOR internal tandem duplications were identified in 6 (1.2%) of 485 patients. Among the 138 genes in the panel, 66 were involved in one or more fusions, and 72 were not involved in any fusions. There was little overlap between the genes involved as 5'-partners (31 different genes) and 3'-partners (37 different genes). This study shows the clinical utility of a next-generation sequencing gene fusion detection assay for the diagnosis and treatment of sarcomas.

Matrix-producing tumors of the sinonasal region are diagnostically challenging, with a large number of similar-appearing neoplasms having different prognoses, treatment strategies, and genetic syndrome associations. Osteochondromyxoma (OCM) is a very rare tumor known to be associated with Carney complex. Since its initial description in 2001, fewer than 20 cases have been reported, with the sinonasal tract being an apparently favored site. Herein we describe 6 new cases of sinonasal OCM. OCM cases with available slides were retrieved from the surgical pathology files of the authors’ practices. The tumors arose in 4 boys and 2 girls, ranging from 4 to 17 years (mean, 9.5 years). All presented with nasal obstruction and a mass. Radiologically the tumors presented as indolent-appearing, heterogeneous, calcified, expansile masses. Histologically the tumors all consisted of bland, normochromatic spindled to stellate cells in a myxoid to collagenized stroma, with variable amounts of cartilage and bone formation. Mitotic activity was very low and necrosis was absent. All demonstrated complete loss of PRKAR1A expression by immunohistochemistry. Of these 6 cases, 3 had been originally diagnosed as nasal chondromesenchymal hamartomas, and one as osteosarcoma. Treatment and follow up information were available for 5 patients: all were treated with surgery, with one also receiving chemotherapy after an initial osteosarcoma diagnosis. At the time of last clinical follow-up, all 5 patients were alive, one with residual disease. No patient was known to have other stigmata of Carney complex. Although rare, OCM preferentially occurs in the sinonasal tract, and therefore may be encountered by head and neck pathologists. Given their predilection for young patients and overlapping morphologic features, OCM are easily misdiagnosed as other matrix-forming sinonasal tumors, especially nasal chondromesenchymal hamartoma. Immunohistochemical demonstration of PRKAR1A loss is valuable for confirming an OCM diagnosis, which should prompt clinical investigation for the possibility of Carney complex.

Soft tissue tumors with smooth muscle differentiation are rare in pediatric patients. Despite often showing morphologic features sufficient for classification as "leiomyosarcoma" in adults (eg, high cellularity and mitotic activity), clinical follow-up has shown only indolent behavior. The pathological features of recently reported SRF-rearranged "cellular myofibromas/myopericytomas," typically occurring in children, overlap with those of true smooth muscle tumors. We studied a large series of pediatric tumors with morphologic and immunohistochemical evidence of smooth muscle differentiation, with the goals of better understanding their natural history and molecular genetic features. Seventy-eight tumors were identified in 45 males and 33 females, with a median age of 10 years. Clinical follow-up (50 patients; median, 45.5 months) disclosed local recurrence in 7 patients (15%). No metastases or deaths because of disease occurred. Group 1 (73/78) tumors consisted of cellular fascicles of mildly to at most moderately atypical, bland, ovoid to spindled cells with distinctly eosinophilic cytoplasm, appreciable mitotic activity (median, 5/50 high-power fields), and no necrosis. Group 2 tumors (5/78) showed greater cellularity, significant nuclear pleomorphism, and brisk mitotic activity (median, 59/50 high-power fields). Subsets of group 1 tumors harbored SRF rearrangements (16/47), and all group 2 tumors showed TP53 biallelic inactivation ( 5/5). SRF fusion partners included CITED1, NCOA2, C3orf62, RELA, ARGFXP1, ARNTI2, ICA1L, and unknown (n 1/4 1). We conclude that the prognosis for pediatric tumors with smooth muscle differentiation that fall into group 1 is excellent. SRF rearrangements are present in a significant minority of tumors, typically showing features of smooth muscle rather than myopericy tic differentiation. A smaller subset with more worrisome morphologic features harbor biallelic inactivation of TP53. To emphasize their unique features, we propose the term "pediatric-type myoid neoplasms of somatic soft tissue" rather than simply "leiomyoma" or "leiomyosarcoma" for group 1 tumors, and the designation of leiomyosarcoma in children should be limited to group 2 tumors. (c) 2025 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Angiomatoid fibrous histiocytoma (AFH) is a rare mesenchymal neoplasm of borderline malignancy (locally recurring, rarely metastasizing), most often involving the limbs, trunk, and head/neck. Rarely, AFH may involve unusual locations. Herein, we characterize the clinicopathologic features of 26 AFH of the distal extremities, including acral sites. The tumors occurred in 19 females and 7 males ranging in age from 12 to 76 years (median, 23 years). Tumors involved the upper (n = 19) and lower (n = 6) distal extremity; one affected an unspecified digital site. Twenty-two cases occurred in acral locations (hands and feet). Subsets of cases showed the following morphologic features: multinodular architecture (26/26), lymphoid cuffs (23/26), prominent stromal myxoid change (11/25), angiomatoid features (9/26), and cytologic pleomorphism (8/26). The average mitotic count was 1/10 HPF; 3 cases showed brisk mitotic activity (> 10 mitoses/10 HPF). Immunohistochemistry revealed variable expression of desmin (16/25), EMA (14/21) and ALK (5/8). Molecular testing revealed EWSR1 rearrangements in 17/18 cases (94%). Among 12 tumors with known fusion partners, the fusions partner was CREB1 in 6 cases (50%), CREM in 4 tumors (33%), ATF1 in one tumor (8%) and PBX3 (8%) in another tumor. Prominent myxoid features were noted in 75% CREM versus 33% of CREB1 versus 0% of ATF1-fused tumors. AFH occurring in distal extremity/acral locations have a predilection for females, upper extremity locations, frequent unusual (solid, non-angiomatoid and myxoid) morphology and higher frequency of CREM over ATF1 fusions. Awareness of the morphologic spectrum of these rare neoplasms is essential for correct classification.

BACKGROUND:We retrospectively assessed volumetric response of myxoid liposarcoma (MLPS) with preoperative radiotherapy (RT) and sought to identify disease and treatment characteristics associated with response. PATIENTS AND METHODS:We identified all patients with a histologic diagnosis of MLPS who received preoperative RT from 2013 to 2021 at our institution. We used cone beam computed tomography (CBCT) to assess changes in tumor volume and greatest dimension during treatment. Tumors were contoured on CBCT images prior to treatment and at the end of each week of RT. Percentage change in tumor volume and greatest dimension were calculated based on pre-treatment and final week contours. Patients with tumors incompletely visualized on CBCT were excluded from volume analysis but included on greatest dimension analysis. Magnetic resonance imaging (MRI) was used to evaluate pre- and post-RT radiographic features. Surgical pathology was reviewed to record pathologic characteristics. RESULTS:Twenty patients met inclusion criteria. Most tumors (18/20) were low grade. The most frequent dose/fractionation scheme was 50 Gy in 25 fractions (16/20), with 3 patients receiving 36 Gy in 18 fractions. Median pre-RT volume and greatest dimension were 120 cc (interquartile range [IQR]: 56-399) and 11.2 cm (IQR: 8.4-14.1), respectively. Median percentage change in volume and greatest dimension were -37% (IQR: -57 to -29) and -10% (IQR: -20 to -7). All evaluable tumors decreased in volume during RT. Between pre- and post-RT MRI, most patients had a decrease in intratumoral (16/20) and peritumoral edema (11/20). Sixteen patients exhibited extensive pathologic response. There were no significant associations between radiographic and pathologic features and volumetric change. Local failure at 3 years was 9% (95% confidence interval: 1-59). CONCLUSIONS:We report significant decreases in MLPS tumor size during preoperative RT. There may be a role for adaptive RT planning to reduce target volumes and minimize RT-associated morbidity.